MXPA00011490A - Peptide antiangiogenic drugs - Google Patents
Peptide antiangiogenic drugsInfo
- Publication number
- MXPA00011490A MXPA00011490A MXPA/A/2000/011490A MXPA00011490A MXPA00011490A MX PA00011490 A MXPA00011490 A MX PA00011490A MX PA00011490 A MXPA00011490 A MX PA00011490A MX PA00011490 A MXPA00011490 A MX PA00011490A
- Authority
- MX
- Mexico
- Prior art keywords
- lle
- val
- arg
- sar
- gly
- Prior art date
Links
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- MAKUBRYLFHZREJ-JWBQXVCJSA-M sodium;(2S,3S,4R,5R,6R)-3-[(2S,3R,5S,6R)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylate Chemical compound [Na+].CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@H](O)[C@H]1O MAKUBRYLFHZREJ-JWBQXVCJSA-M 0.000 description 1
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- HQXXUNOALAIGFF-DGZWAERASA-L zinc;(2R,3S,4R,5R,6R)-5-amino-2-(aminomethyl)-6-[(1R,2R,3S,4R,6S)-4,6-diamino-2-[(2S,3R,4S,5R)-4-[(2R,3R,4R,5S,6S)-3-amino-6-(aminomethyl)-4,5-dihydroxyoxan-2-yl]oxy-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-3-hydroxycyclohexyl]oxyoxane-3,4-diol;N-[(2S)- Chemical compound [Zn+2].OS(O)(=O)=O.OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@@H]1[C@@H](CO)O[C@@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)N)[C@@H]1O.N1C(=O)[C@H](CCN)NC(=O)[C@@H](NC(=O)[C@H](CCN)NC(=O)[C@H](C(C)O)NC(=O)[C@H](CCN)NC(=O)CCCCC(C)C)CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1CC1=CC=CC=C1.S1C([C@@H](N)C(C)CC)=NCC1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC([O-])=O)C(=O)N[C@@H](C(C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H](C(C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2NC=NC=2)C(=O)N[C@H](CC([O-])=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 HQXXUNOALAIGFF-DGZWAERASA-L 0.000 description 1
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Abstract
Peptides having the formula:A0-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10 wherein A0 is selected from hydrogen or an acyl group;A10 is a hydroxyl group or an amino acid amide;and A1, A2, A3, A4, A5, A6, A7, A8 and A9 are amino acyl residues as defined herein.
Description
ANTIANGALOGENIC DRUGS OF P EPTI DO
Technical Field The invention relates to novel compounds having activity useful for treating conditions that arise or are exacerbated by angiogenesis, to pharmaceutical compositions comprising these compounds, to a method for treating using said compounds, and to a method for inhibiting angiogenesis.
BACKGROUND OF THE INVENTION Angiogenesis is the fundamental process through which new blood vessels are formed and is essential for a variety of normal body activities (such as reproduction, development and wound repair). Although the process is not completely understood, it is believed to involve a complex interaction of molecules that both stimulate and inhibit the growth of endothelial cells, the main cells of the capillary blood spleens. Under normal conditions, it is. The molecules appear to keep the microvascularization in a state of sufficiency (that is, one without capillary growth) for prolonged periods, which can last as long as weeks, or in some cases decades. However, when necessary (such as during wound repair), these same cells may undergo rapid proliferation and change over a period of five days. (Folkman, J. and Shing, Y., The Journal of Bio loe ica I
«MÍZ-Z ZA .., * ^. .,. .-. H, ^. ^ ...... and ...
Chemistry, 267 (16): 1 0931-10934, and Folkman, J. And Kiagsbrun, M., Science, 235: 442-447 (1988)). Although angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as "angiogenic diseases") are triggered by persistent unregulated angiogenesis. In other words, unregulated angiogenesis can either cause a particular disease directly or exacerbate an existing pathological condition. For example, ocular neovascularization has been implicated as the most common case of blindness. In certain existing conditions such as arthritis, newly formed capillary blood vessels invade the junctions and destroy the cartilage. In diabetes, new capillaries are formed in the retina and invade the vitreous body, bleed and cause blindness. The growth and metastasis of solid tumors are also dependent on angiogenesis (Folkman, J., Cancer Research, 46: 467-473 (1986), Folkman, J., Journal of the National Cancer Institute, 82: 4-6 (1989) It has been shown, for example, that tumors that grow more than 2 mm must obtain their own blood supply and do this by inducing the growth of new capillary blood vessels, once these new blood vessels are drunk. the tumor, provide a means for tumor cells to enter the circulation and metastasize to distant sites, such as liver, lung or bone (Weidner,., and others, The New England Journal of Medicine, 324 (1 ): 1-8 (1991) Although various angiogenesis inhibitors are currently under development for use in the treatment of angiogenic diseases (Gasparini, G. and Harris, AL, J Clin Oncol 13 (3): 7 (55-782, (1995)), there are disadvantages associated with several of es'.o s For example, suramin is a potent inhibitor of angiogenesis, but it causes (at doses required to achieve anti-tumor activity) severe toxicity in humans. Other compounds such as retinoids, interferons and antiestrogens are safe for human use, but have only a weak antigenic effect.
SUMMARY OF THE INVENTION In one aspect, the present invention provides a compound of the formula:
Ao-A ^ Az-Aa-A ^ As-Ae-A ^ Aβ-Aí ATo (I) (SEQ ID NO: 1)
or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, wherein: A0 is hydrogen or an acyl group selected from: (1) R- (CH2) n-C (O); wherein n is an integer from 0 to 8 and R is selected from hydroxyl; methyl; N-acetylamino; methoxy, carboxyl; cyclohexyl optionally containing one or two double bonds and optionally substituted with 1 to 3 hydroxyl groups; and a ring
- ^ jgjg ^ S? ^ aromatic or non-aromatic 5- or 6-membered optionally containing one or two heterogeneous atoms selected from nitrogen, oxygen and sulfur, wherein the ring is optionally substituted with a selected portion of alkyl, alkoxy, and halogen; and (2) R1-CH2CH2- (OCH2CH2O) p-CH2-C (O) -; wherein R1 is selected from hydrogen, alkyl, N-acetylamino, and p is an integer from 1 to 8; AT is an aminoacyl residue selected from: (1) alanyl, (2) asparaginyl, (3) citrulil, (4) glutaminyl, 15 (5) glutamyl, (6) N-ethylglycyl, (7) methionyl, (8) ) N-methylalanyl, (9) prolyl, 20 (10) pyro-glutamyl, (11) sarcosyl, (12) seryl, (13) threonyl, (14) -HN- (CH2) qC (O) -, wherein q is 1 to 8, and 25 (15) -HN-CH2CH2- (OCH2CH2?) r -CH2-C (O) -, where r is
"p M '" üf-T 1 to 8; A2 is a residue of amino acyl selected from: (1) alanyl, (2) asparaginyl, (3) aspartyl, (4) glutaminyl, (5) glutamyl, (6) leucyl, (7) methionyl, (8) phenylalanyl, (9) prolyl, (10) seryl, (11) -HN- (CH2) qC (O), wherein q is 1 to 8, and (12) -HN-CH2CH2- (OCH2CH2O) r -CH2-C ( O) -, where r is 1 to 8; A3 is an amino acyl selected from: (1) alanyl; (2) asparaginyl, (3) citrullyl, (4) cyclohexylalanyl, (5) cyclohexylglycyl, (6) glutaminyl, (7) glutamyl, (8) glycyl, (9) isoleucyl, (10) leucyl, (11) methionyl, (12) norvalyl, (13) phenylalanyl, (14) seryl, (15) t-butylglycyl, (16) threonyl, (17) vallyl, (18) penicillaminyl, and (19) cystyl; A is an amino acyl residue of the L or D configuration selected from: (1) allo-isoleucyl, (2) glycyl, (3) isoleucyl, (4) prolyl, (5) dehydroleucyl, (6) D-alanyl, ( 7) D-3- (naphth-1-yl) alanyl, (8) D-3- (naphth-2-yl) alanyl, (9) D (3-pyridyl) -alanyl, (10) D-2- aminobutyryl, (11) D-allo-isoleucyl, (12) D-allo-threonyl, (13) D-allylglycyl, (14) D-asparaginyl, (15) D-aspartyl, (16) D-benzotienilalanilo, (17 ) D-3- (4,4-biphenyl) alanyl, (18) D-chlorophenylalanyl, (19) D-3- (3-trifluoromethylphenyl) alanyl,
(20) D-3- (3-cyanophenyl) alanyl, (21) D-3- (3,4-difluorof in yl) alanyl,
(22) D-citrullyl, (23) D-cicIohexilalanilo, (24) D-cicIohexilglicilo, (25) D-cystyl, (26) D-cistil (Sf-butyl), (27) D-glutaminyl, (28) D-glutamyl, (29) D-histidyl, (30) D-homoisoleucyl, (31) D-homophenylalanyl, (32) D-homoseryl, (33) D-isoleucyl, (34) D-leucyl, (35) D -lisil (N-epsilon-nicotilino),
(36) D-lysyl, (37) D-methionyl, (38) D-neopentyl glycyl,
- - - "* * * • ^ jttHH ^ ^^ agKM ^ (39) D-norleucyl, (40) D-norvalyl, (41) D-ornithyl, (42) D-penicillaminyl, (43) D-penicillaminyl ( acetamidomethyl), (44) D-penicillaminyl (S-benzyl), (45) D-phenylalanyl, (46) D-3- (4-aminophenyl) alanyl, (47) D-3- (4-methylphenyl) alanyl, 10 (48) D-3- (4-nitrophenyl) alanyl, (49) D-3- (3,4-dimethoxyphenyl) alanyl, (50) D-3- (3, 4, 5-trif luorofenil) alani lo, (51) D-prolyl, (52) D-seryl, 15 (53) D-seryl (O-benzyl), (54) Df-butyglycyl, (55) D-thienylalanyl, (56) D-threonyl, (57) D-threonyl (O-benzyl), 20 (58) D-triptyl, (59) D-tyrosyl (O-benzyl), (60) D-tyrosyl (O-ethyl), (61) D-tyrosyl , and (62) D-vally; A5 is an amino acyl residue of the L or D configuration
&- selected from: (1) alanyl, (2) (3-pyridinyl) alanyl, (3) 3- (naphth-1-yl) alanyl, (4) 3- (naphth-2-yl) alanyl, ( 5) allo-threonyl, (6) allylglycyl, (7) glutaminyl, (8) glycyl, (9) histidyl, (10) homoseryl, (11) isoleucyl, (12) lysyl (N-epsilon-acetyl), (13 ) methionyl, (14) norvalyl, (15) octylglycyl, (16) ornithyl, (17) 3- (4-hydroxyphenylphenyl) alanyl,
(18) prolyl, (19) seryl, (20) threonyl, (21) triptyl, (22) tyrosyl, (23) D-allo-threonyl, (24) D-homoseryl, (25) D-seryl, (26) ) D-threonyl, (27) penicillaminyl, and (28) cystyl: A6 is an amino acyl residue of the L or D configuration of the selected configuration of: (1) alanyl, (2) 3- (naphth-1-yl) ) alanyl, (3) 3- (naphth-2-yl) alanyl, (4) (3-pyridyl) alanyl, (5) 2-aminobutyryl, (6) allyl glycyl, (7) arginyl, (8) asparaginyl, (9) aspartyl, (10) citrulil, (11) cyclohexylalanyl, (12) glutaminyl, (13) glutamyl, (14) glycyl, (15) histidyl, (16) homoalanyl , (17) homoleucyl, (18) homoseryl, (19) isoleucyl, (20) leucyl, (21) lysyl (N-epsilon-acetyl), (22) lysyl (N-epsilon-isopropyl), (23) methionyl ( sulfone), (24) methionyl (sulfoxide), (25) methionyl, (26) norleucyl, (27) norvalyl, (28) octylglycyl, (29) phenylalanyl, (30) 3- (4-carboxyamidaphenyl) alanyl,
(31) propalglycyl, (32) seryl, (33) threonyl, (34) triptyl, (35) tyrosyl, (36) valium, (37) D-3- (naphth-1-yl) alanyl, (38) D -3- (naphth-2-yl) alanyl, (39) D-glutaminyl, (40) D-homoseryl, (41) D-leucyl, (42) D-norvalyl, (43) D-seryl, (44) penicillaminyl, and (45) cystyl; A7 is an amino acyl residue of the L or D configuration selected from: (I) alanyl, (2) allylglycyl, (3) aspartyl, (4) citrulil, (5) cyclohexylglycyl, (6) glutamyl, (7) glycyl, (8) homoseryl, (9) isoleucyl, (10) allo-isoleucyl, (II) leucyl, (12) lysyl (N-epsilon-acetyl), (13) methionyl, (14) 3- (naft-1) -yl) alanyl, (15) 3- (naphth-2-yl) alanyl, (16) norvalyl, (17) phenylalanyl, (18) prolyl, (19) seryl, (20) f-butylglycyl, (21) triptyl , (22) tyrosyl, (23) vallyl, (24) D-alo-isoleucyl, (25) D-isoleucyl, (26) penicillaminyl, and (27) cystyl; A8 is an amino acyl residue selected from: (1) 2-amino-4 - [(2-amino) -pyrimidinyl] butanoyl, (2) alanyl (3-guanidino), (3) alanyl [3-pyrrolidinyl (2 -N-amidino)], 10 (4) alanyl [4-piperidinyl (N-amidino)], (5) arginyl, (6) arginyl (NGNG'diethyl), (7) citrulil, (8) 3- (cyclohexyl ) alanyl (4-N-isopropyl), 15 (9) glycyl [4-piperidinyl (N-amidino)], (10) histidyl, (11) homoarginyl, (12) lysyl, (13) lysyl (N-epsilon- isopropyl), 20 (14) lysyl (N-epsilon-nicotinyl), (15) norargyllyl, (16) ornithyl (N-delta-isopropyl), (17) ornithyl (N-delta-nicotinyl), (18) ornithyl [ N-delta- (2-imidazolinyl)], 25 (19) [4-amino (N-isopropyl) methyl) phenyl] alanyl,
ßtáa áu ^ í (20) 3- (4-guanidinophenyl) alanyl, and (21) 3- (4-amino-N-isopropylphenyl) alanyl; A9 is an amino acyl residue of the L or D configuration selected from: (1) 2-amino-butyryl, (2) 2-amino-isobutyryl, (3) homoprolyl, (4) hydroxyprolyl, (5) isoleucyl, ( 6) leucyl, (7) phenylalanyl, (8) prolyl, (9) seryl, (10) f-butylglycyl, (11) 1, 2,3,4-tetrahydroisoquinoline-3-carbonyl, (12) threonyl, (13) ) vally, (14) D-alanyl, and (15) D-propyl; and A10 is a hydroxyl group or an amino acid amide and is selected from: (1) azaglycylamide, (2) D-alanylamide, (3) D-alanylethylamide, (4) glycylamide, (5) g lici lethyl amide, (6) ) sarcosylamide, (7) serylamide, (8) D-serylamide, (9) a group represented by the formula:
-NH- (CH2) S-CHR3; and (9) a group represented by the formula -NH-R4; wherein: s is an integer selected from 0 to 8, R2 is selected from hydrogen, alkyl and a cycloalkyl ring of from 5 to 6 members; R3 is selected from hydrogen, hydroxy, alkyl, phenyl, alkoxy, and a 5- to 6-membered ring optionally containing one to two heterogeneous atoms selected from oxygen, nitrogen and sulfur, provided that s is not 0 when R3 is hydro < i or alkoxy; and R4 is selected from hydrogen and hydroxy. In another aspect, the present invention provides a composition for treating a patient in need of anti-angiogenesis therapy, comprising a peptide defined above in combination with a pharmaceutically acceptable carrier. Another object of the present invention provides a method for treating a patient with the need for anti-angiogenesis therapy comprising administering to the patient a therapeutically effective amount of a peptide as defined above. Another aspect of the present invention provides a composition for the treatment of a disease selected from cancer, arthritis, psoriasis, eye angiogenesis associated with infection or surgical intervention, macular degeneration and diabetic retinopathy, comprising a peptide as defined above in combination with a pharmaceutically acceptable vehicle. In still another aspect, the present invention provides a method for isolating a receptor from an endothelial cell, which comprises binding a peptide as defined above, to the receptor to form a peptide receptor complex isolating the peptide receptor complex, and purify the receiver.
Detailed Description of the Invention Definition of Terms The term "alkyl", as used herein, refers to a monovalent group derived from a straight or branched chain saturated hydrocarbon through the removal of a hydrogen atom. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tertbutyl, pentyl, hexyl, and the like. Preferred alkyl groups for the invention are alkyl groups of 1 to 6 carbon atoms having 1 to 6 carbon atoms. Alkyl groups of 1 3 carbon atoms (Cn-Ca alkyl) are very preferred for the invention. The term "nicotinyl," as used herein, refers to the acyl group derived from nicotinic acid, ie, pyridine-3-carboxylic acid. The term "2-Me-nicotinyl" or "2-methylnicotinyl" refers to a nicotinyl portion substituted with a methyl group with the carbon adjacent to the nitrogen uptake. The term "shikimil" as used herein, refers to the acyl residue derived from shikimic acid or [3R- (3a, 4a, 5ß) -3,4,5-trihydroxy] -1-cyclohexen-1-carboxylic acid . A group
"Dihydroshikimil" denotes the fully saturated analogue of shikimic acid. The term "succinyl", as used herein, refers to the residue derived from succinic acid or (1,4-dioxobutyl) -1-carboxylic acid. The term "N-acetylamino", as used herein, refers to a substituted amino (-NH2) moiety on the nitrogen atom with an acetyl group (CH3C (O) -). The term "carbonyl", as used herein, refers to the group -C (O) -. The term "carboxy" or "carboxyl", as used herein, refers to the group -C (O) OH. The term "alkoxy," as used herein, refers to an alkyl group as defined above, attached to a molecular moiety of origin through an ether linkage. Illustrative alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like. The term "aromatic ring", as used herein, refers to an unsaturated cyclic hydrocarbon associated with a p-electron linkage system. One to two carbon atoms of the hydrocarbon ring can be substituted with a heterogeneous atom selected from nitrogen, oxygen or sulfur. Illustrative 5 or 6 member aromatic rings, include, but are not limited to, benzyl, pyridyl, furyl, tetrahydrofuryl, thienyl, and pyrrolyl. An aromatic ring, including rings substituted with a heterogeneous atom, may be optionally substituted on one or more carbon atoms with substituents selected from alkyl, alkoxy, carboxy, and halogen, for example, tolyl, bromobenzyl, r-butylbenzyl, nicotinyl, 2-methylnicotinyl, 2-furoic acid, and the like. The term "non-aromatic ring", as used herein, refers to a saturated or unsaturated cyclic hydrocarbon ring, which may be optionally substituted with one or more heterogeneous atoms selected from nitrogen, oxygen or sulfur. The illustrative non-aromatic rings are cyclohethylene. ilo, tetrahydropyranyl, pyrrolidinyl, and piperidinyl. The term "N-protecting group," as used in the present, refers to an easily removable group, which is known in the art to protect an amino group against undesirable reaction during synthetic procedures and which may be selectively removable. The use of N-protecting groups is well known in the art to protect groups against undesirable reactions during a synthetic procedure and many protecting groups are known, cf., for example, T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2a. Edition, John Wiley & Sons, New York (1991). Examples of N-protecting groups include, but are not limited to, acyl groups including acetyl, trifluoroacetyl, acyl isothiocyanate, aminocaproyl, benzoyl, and the like, and acyloxy groups, including f-butyloxycarbonyl (Boc) and carbobenzyloxy (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), and the like. As used herein, the terms "Leu", "Sar", "Gln", "Gly", "Val", "Me", "Thr", "Nva", "Arg", "Asn", " pyroGlu "," Ser "," Ala "," Homoala "," Cha "," Pro "," Phe "," Trp "," 1-Nal "," 2-Nal "," Azagly "and" NIe " refer to leucine, sarcosine (N-methylglycine), glutamine, glycine, valine, isoleucine, threonine, norvaline, arginine, asparagine, pyroglutamic acid, serine, alanine, homoalanine, cyclohexylalanine, proline, phenylalanine, tryptophan, 1-naphthylalan? na, 2-naphthylalanine, azaglycine and norleucine, respectively, in their L-, D- or DL forms. Unless otherwise indicated by a prefix "D", for example, D-Ala or D-lle (also D-lle), the stereochemistry of the α-carbon of the amino acids and aminoacyl residues in peptides described in this specification and the annexed claims is the natural configuration or "L". The "R" and "S" designations of Cahn-Ingold-Prelog are used to specify the stereochemistry of
Mt? ÉkÉßMHÜri chiral centers in certain of the acyl substituents in the N-terminus of the peptides of this invention. The designation "R, S" represents that it indicates a racemic mixture of the two enantiomeric forms. This nomenclature cites that described by R.S. Cahn, and others, Angew. Chem. Int. De. Engl., 5, 385-415 (1966). For the most part, the names in naturally occurring or unnatural aminoacyl residues used here follow the naming conventions suggested by IUPAC Commission on the Nomenclature of Organic Chemistry and IUPAC-IUB Commission on Biochemical Nomenclature, as set out in " Nomenclature of a-Amino Acids (Recomendations, 1974) "Biochemistry, 14 (2), (1975). To the extent that the names and abbreviations of amino acids and aminoacyl residues used in this specification and appended claims differ from those suggestions, they will become clearer to the reader. Some useful abbreviations for describing the invention are defined later in the following Table 1.
Table 1
If they are not found in the previous Table, the nomenclature and abbreviations can also be clarified by referring to Calbiochem-Novabiochem Corp. 1999 Catalog and Peptide Synthesis Handbook or Chem-lmpex International, Inc. Tools for Peptide & Solid Phase Synthesis 1998-1999 Catalog. The term "pharmaceutically acceptable salt", as used herein, refers to salts that are, within the scope of medical judgment, suitable for use in contact with tissues; of humans and lower animals without toxicity, irritation, undue allergic response, and the like, and are in agreement with a reasonable benefit / risk ratio. The salts
Pharmaceutically acceptable are well known in the art. For example, S.M.Berge, et al. Describe pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66: -19. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include salts of acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate ,. cyclopentanpropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glycoheptanoate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurisulfate, malate, maleate, malonate, methanesulfonate, 2- naphthanesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearite, succinate, sulfate, tartrate, thiocyanate, toluenesulfon to, undecanoate, valerate, and Similar. Representative alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations, including, but not limited to, ammonium, tetramethylammonium , tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
The term "ester pharmaceutically acceptable" refers to esters that hydrolyze in vivo and include those that are easily broken in the human body to leave the parent compound or a salt thereof. Suitable ester include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, wherein each alkyl or alkenyl portion advantageously have no more than 6 carbon atoms Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates The term "pharmaceutically acceptable solvate" represents an aggregate comprising one or more solute molecules, such as a compound of the formula (I), with one or more solvent molecules. The term "pharmaceutically acceptable prodrugs" as used herein, refers to those prodrugs of the compounds of the present invention, which are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, according to a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to produce the parent compound of the above formula, for example, through hydrolysis in the blood. A broad discussion is provided by T. Higuchi and V. Estella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C.S. Symposium Series and by Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both incorporated herein by reference. The term "receptor", as used herein, refers to a chemical group or molecule on the cell surface or inside the cell that has an affinity for a specific chemical group, molecule or virus. The isolation of receptors relevant to the angiogenic activity of the peptide of the invention can provide useful diagnostic tools. In one embodiment, the present invention relates to compounds of the structure:
Ao-A1-A2-A3-A -A5-A6-A7-A8-A9-A1o (I)
wherein A0-A1-A2-A3-A -A5-A6-A7-A8-A9 and A10 are as defined above. The N-terminus of a nonapeptide represented by can be represented by an amino acyl group represented by A 0. The I group A? 0 represents a suitable group to modify the C term of the compound. In the present embodiment, A4 is an amino acyl residue having a D configuration selected from D-alo-isoleucyl, D-allylglycyl, D-3- (3-cyanophenyl) alanyl, D-cystyl, D-isoleucyl, D-leucyl , D-penicillaminyl, D-phenylalanyl, D-3- (3,4,5-trifluorophenyl) alanyl, and D-3- (4-aminophenyl) alanyl; A5 is an amino acyl residue selected from octylglycyl, glycyl, penicillaminyl, seryl, threonyl, and tyrosyl; and A6 is an amino acyl residue of glutaminyl, leucyl, norvalyl and seryl. In another embodiment of the invention, the compounds have the structure (I) as defined above, wherein A is sarcosyl, A2 is glycyl, A3 is valyl, A7 is isoleucyl, A8 is arginyl, and A9 is propyl. The compounds of the present embodiment can be prepared through the structure:
A0-Sar-Gli-Val-A4-A5-A6-lle-Arg-Pro-A10 (II) (SEQ ID NO: 2)
wherein A0 is hydrogen or an acyl group by modifying the N-terminus. Suitable groups for A0 can be represented by the formula R- (CH) n-C (O) -; wherein n is an integer from 0 to 8 and R is selected from hydroxyl; methyl; N-acetylamino; methoxyl; carboxyl; cyclohexyl optionally containing one or two double bonds and optionally substituted with one or two hydroxyl groups; and an aromatic or non-aromatic 5- or 6-membered ring optionally containing 1 or 2 heterogeneous atoms selected from nitrogen, oxygen and sulfur, wherein the ring is optionally substituted with a selected portion of alkyl, alkoxy and halogen; or R1-CH2CH2- (OCH2CH2?) p-CH2-C (O); where R1 is selected from
^ íi? Hydrogen, alkyl, and N-acetylamino, and p is an integer of 1 to 8. A4 is an aminoacyl residue of the L or D configuration selected from allo-isoleucyl, dehydroleucyl, glycyl, isoleucyl, prolyl, D- alanyl, D-3- (naphth-1-yl) alanyl, D-3- (naphth-2-yl) alanyl, D-? 3-pyridyl) -alpha nyl, D-2-aminobutyryl, D-alo-isoleucyl , D-allo-threonyl, D-aliglycyl, D-asparaginyl, D-aspartyl, D-benzothienylalanyl, D-3- (4,4-biphenyl) alanyl, D-chlorophenylalanyl, D-3- (3-trifluoromethylphenyl) alanyl , D-3- (3-cyanophenyl) alanyl, D-3- (3,4-difluorophenyl) alanyl, D-citrulyl, D-cyclohexylalanyl, D-cyclohexylglycyl, D-cystyl, D-cystyl (Sy-butyl), D-glutaminyl, D-histidyl, D-homoisoleucyl, D-homophenylalanyl, D-homoseryl, D-isoleucyl, D-leucyl, D-lysyl (N-epsilon-nicotinyl), D-lysyl, D-methionyl, D-neopentyl glycyl , D-norleucyl, D-norvalyl, D-ornityl, D-penicillaminyl, D-penicillaminyl (acetamidomethyl), D-penicillalaminyl (S-benzyl), D-phenylalanyl, D-3- (4-aminophenyl) alanyl, D-3- (4-methylphen il) -alanyl, D-3- (4-nitrophenyl) alanyl, D-3- (3,4-dimethoxyphenyl) alanyl, D-3- (3,4,5-trifluorophenyl) alanyl, D-prolyl, D- seryl, D-seryl (O-benzyl), D-butylglycium, D-thienylalanyl, D-threonyl, D-threonyl (O-benzyl), D-triptyl, D-tyrosyl (O-benzyl), D-tyrosyl (O ethyl), D-tyrosyl, and D-valyl. A5 is an aminoacyl residue of the L or D configuration selected from alanyl, (3-pyridyl) -alanyl, 3- (naphth-1-yl) alanyl, 3- (naphth-2-yl) alanyl, allo-threonyl, allyl glycyl , glutaminyl, glycyl, histidyl, homoseryl, isoleucyl, lysyl (N-epsilon-acetyl), methionyl, norvalyl, licit octylg, ornityl, 3- (4-hydroxymethylphenyl) alanyl, prolyl, seryl, threonyl, triptyl, tyrosyl, D- allo-threonyl, D-homoseryl, D-seryl, D-threonyl, penicillaminyl, and cystyl. A6 is an aminoacyl residue of the L or D configuration selected from alanyl, 3- (naphth-1-yl) alanyl, 3- (naphth-2-yl) alanyl, (3-pyridyl) alanyl, 2-aminobutyryl, Tg I i ci lo, arginyl, asparaginyl, aspartyl, citrulyl, cyclohexylalanyl, glutaminyl, glutamyl, glycyl, histidyl, homoalanyl, homoleucyl, hemoseryl, isoleucyl, leucyl, lysyl (N-epsilon-acetyl), lysyl (N-epsilon-isopropyl), methi oni I (sulfone), methionyl (sulfoxide), methionyl, norleucyl, norvarlyl, licit octylg, phenylalanyl, 3- (4-carboxyamidophenyl) alanyl , propargylglycyl, septal, threonyl, triptyl, tyrosyl, vallyl, D-3 (naphth-1-yl) alanyl, D-3- (naphth-2-yl) alanyl, D-glutaminyl, D-homoseryl, D-leucyl, D-norvalyl, D-seryl, penicillaminyl, and cystyl. A10 is a hydroxyl group or an amino acid amide selected from azaglycylamide, D-alanylamide, D-alanylethylamide, glycylamide, glycylethylamide, sarcosylamide, serylamide, D-serylamide, or A10 is a group represented by the formula:
NH- (CH2) s-CHR '
or a group represented by the formula -NH-R4, wherein s is an integer selected from 0 to 8; R2 is selected from hydrogen, alkyl, and a cycloalkyl ring of 5 to 6 members; R3 selected from hydrogen, hydroxy, alkyl, phenyl, alkoxy, and a 5- to 6-membered ring optionally containing from 1 to 2 heterogeneous atoms selected from oxygen, nitrogen and sulfur, provided that S is not zero when R3 is hydroxy or alkoxy; R4 is selected from hydrogen and hydroxy. Preferred compounds of the invention have the structure (II) as defined above, wherein A4 is an aminoacyl residue having a D configuration selected from D-alanyl, D-3- (naphth-1-yl) alanyl, D -3- (naphth-2-yl) alanyl, D- (3-pyridyl) -alanyl, D-2-aminobutyryl, D-alo-isoleucyl, D-allo-threonyl, D-allylglycyl, D-asparaginyl, D- aspartyl, D-chlorophenylalanyl, D-3- (3-trifluoromethylphenyl) alanyl, D-3- (3-cyanophenyl) alanyl, D-3- (3,4-difluorophenyl) alanyl, D-cyclohexylalanyl, D-cyclohexylglycyl, D -cystyl, D-glutaminyl, D-glutamyl, D-histidyl, D-homoisoleucyl, D-homophenylalanyl, D-homoseryl, D-isoleucyl, D-leucyl, D-lysyl (N-epsilon-nicotinyl), D-methionyl, D-neopentyl glycyl, D-norleucyl, D-norvalyl, D-penicilaminyl, D-penicillaminyl (acetamidomethyl). D-penicillaminyl (S-benzyl), D-phenylalanyl, D-3- (4-aminophenyl) alanyl, D-3- (4-methylphenyl) alanyl, D-3- (4-nitrophenyl) alanyl, D-3- (3,4-dimethoxyphenyl) alanyl, D-3- (3,4,5-trifluorophenyl) alanyl, D-prolyl, D-seryl, D-seryl (O-benzyl). D-f-butyl Ig I, D-thienylalanyl, D-threonyl, D-threonyl (O-benzyl), D-tyrosyl (O-ethyl), D-tyrosyl, D-valyl, and D-cystyl. Other preferred compounds of the present invention have the structure of formula (II), wherein A5 is selected from glycyl, licit octylg, penicilaminyl, seryl, threonyl, and tyrosyl. Other additional preferred compounds of the present
The invention has the structure represented by formula (II), wherein A6 is selected from glutaminyl, leucyl, norvarlyl and seryl. The most preferred amino acid residues to replace the position represented by A4 are amino acids of the D configuration selected from D-alo-isoleucyl, D-allylglycyl, D-3- (3-cyanophenyl) alanyl, D-cystyl, D-isoleucyl, D-leucyl, D-penicilaminyl, D-phenylalanyl, D-3- (3,4,5-trifluorophenyl) alanyl, and D-3- (4-aminophenyl) alanyl. Preferred groups A0 for modifying the N-terminus of the compounds within the scope of the invention are selected from acetyl, butyryl, caproyl, (4-N-acetylamino) butyryl, N-acetyl-beta-alanyl, (6-N-acetylamino ) caproyl, chloronicotinyl, cyclohexylacetyl, furoyl, gamma-aminobutyryl, 2-methoxyacetyl, methylcarinyl, nicotinyl, (8-N-acetylamino) -3,6-dioxooctanoyl, phenylacetyl, propionyl, shikimil, succinyl, and tetrahydrofuroyl. Preferred groups A10 for modifying the C-terminus of the invention are selected from D-alanylamide, azagiicilamide, serylamide, ethylamide, hydroxylamide, isopropylamide, propylamide, 2- (cyclohexyl) ethylamide, 2- (1-pyrrolidine) ethylamide, 1- ( cyclohexyl) ethylamide, 2- (methoxy) ethylamide, 2- (hydroxy) ethylamide), 2- (2-pyricin) ethylamide, (2-pyridine) methylamide, 2- (3-pyridine) ethylamide, 2- (2- ( 1-methyl) pyrrolidine) ethylamide, 2- (N-morpholin) ethylamide, and cyclopropyl-methylamide. Compounds contemplated within the scope of the present invention include, but are not limited to:
N-Ac-Sar-GI y-Val-D-lle-Thr-Nva-lle-Arg-ProNHCHzCHa, piroGlu-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac- Sar-G ly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH3, N-Ac-Sar-G ly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2 (CH3) 2, N-Ac-Sar-G ly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH2- (1-pyrrolidyra) N-Ac-Sar-G ly-Val-D-lle-Thr-Nva-lle -Arg-ProNHeti I piperidine, N-Ac-Sar-G ly-Val-D-lle-Thr-Nva-lle-Arg-ProNHmethylcyclopropyl, N-Ac-Sar-G ly-Val-D-lle-Thr-Nva -lle-Arg-ProNH (ethyl-1- (R) -cyclohexyl), N-Ac-Sar-G ly-Val-D-lle-Thr-Nva-lle-Arg-ProNH2, N-Ac-Sar-G ly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH2? CH3, N-Ac-Sar-G ly-Val-D-lle-Thr-N a-lle-Arg-ProÑHCH2CH2ciclohexyl, N-Ac-Sar-G ly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2 (CH3) 2, N-Ac-Sar-G ly-Val-D-alolle-Thr-Nva-lle -Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-lle-Thr-Nva-lle-Arg -ProNHCH2CH3, (SEQ ID NO: 3) N-Ac-Sar-G ly-Val-Gly-Thr-Nva-lle-Arg-ProNHCH2CH3, (SEQ ID NO: 4) N-Ac-Sar-G ly-Val -D-Val-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D-Ala-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val -D-Met-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D-Nle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val -D-Phe-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D-Tyr-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val -D-4,4'-Biphenylala-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D-Cha-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar -G ly-Val-D-Chg-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-4-CIPhe-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac- Sar-Gly-Val-D-Hphe-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-Dehdroleu-Thr-Nva-lle-Arg-ProNHCH2CH3, (SEQ ID NO: 6 ) N-Ac-Sar-Gly-Val-D-3-CF3Phe-Th r-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-pentaFPhe-Thr-N a-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-3,4 -diCIPhe-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-3-CIPhe-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D -2-Thienylala-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-3-CNPhe-Thr Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- D-lle-Thr-DN a-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D -lle-Thr-Cha-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Gly-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle -Thr-Ala-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Val-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr -Abu-lle-Arg-ProNHCH2CH3 N-Ac-Sar-Gly-Val-D-lle-Thr-Alilgly-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Octilgly- lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Met-lle-Arg-ProNHCHzCHs, N-Cyclohexyl-acetyl-Sar-Gly-Val-D-lle-Thr-Nva-lle- Arg-ProNHCH2CH: i, N- (2-Me-Nicotinyl) -Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Gly-V al-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, NN icotinyl-Sar-Gly-Val-D-lle-Thr-N va-I le-Arg-ProNHCH2CH3, N-Propionyl-Sar-Gly-Val -D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3,
M ^ BdMHlMIB? Rili N- (Meo) acetyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N- (Shikimil) -Sar-Gly-Val-D-lle-Thr- Nva-lle-Arg-ProNHCH2CH3, N- (2-Furoyl) -Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Butyryl-Sar-Gly-Val-D-lle Thr-Nva-lle-Arg-ProNHCH2CH3, N (2-THFcarbonyl) -Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 N- [CH3CONH- (CH2) 2-O- (CH2 ) 2-O-CH2-C (O)] - Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 N [6-N-acetyl- (CH2); C (O)] - Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg- ProNHCH2CH3, N-Hexanoyl-Sar, -Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N- [4- N-Acetylaminobutyryl] -Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, H-Sar-Gly-Val-D-lle-Thr-N a-lle-Arg-ProNHCH2CH3, N- Ac-Sar-Gly-Asn-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N- [CH3C (O) NH- (CH2) 2-O- (CH2) 2-O-CH2-C (O )] - Gly-Val-D-lle-Thr-Nva-Me-ArgProNHCH2CH3, N-Ac-Pro-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Gly-Gly -Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Ala-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-NEtGly-Gly-Val -D-lle-Thr-Nva-lle-Arg-ProNHC H2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Ser-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-D-AlaNH2 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-D -ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-AbuNHCH2CH3, N-Ac-Sar-Gly-Val- • D-lle-Thr-Nva-ile-Arg- Phe-NHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Tic-NHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle -Arg-Hyp-NHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Aib-NHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr- Nva-lle-Arg-D-Ala-NHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pip-NHCH2CH3, N-Ac-Sar-Gly-Val-D- Tyr (Et) -Thr Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Cys (tBu) -Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val -D-Cys-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Tyr (Bzl) -Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly- Val-D-Ser (Bzl) -Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-1-Nal-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly -Val -D-tButilgly-Thr-Nva-lle-Arg-Pro NHCH2CH3, N-Ac-Sar-Gly-Val-D-Orn-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Thr (Bzl) -Thr-N a-lle Arg-ProNHCH2CH3l N-Ac-Sar-Gly-Val-D-2Nal-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Phe (4-Me) -Thr-Nva- lle-Arg-ProNHCH2CH3,
N-Ac-Sar-Gly-Val-D-Phe- (3,4-diMeO) -Thr-Nva-lle-Arg-ProNHCH2CH3,
N-Ac-Sar-Gly-Val-D-Phe (3,4,5-triF) -Thr-Nva-lle-Arg-ProNHCH2CH: t,
N-Ac-Sar-Gly-Val-D- (4-NO2) Phe-Thr-Nva-lle-Arg-ProNHCH2CH3,
N-Ac-Sar-Gly-Val-D-Pen-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Pen (Acm) -Thr-Nva-lle-Arg-ProNHCH2CH3 , N-Ac-Sar-Gly-Val-D-Abu-Thr-Nva-tle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Phe (4-NH2) -Thr-Nva-lle- Arg-ProNHCH2CH3,
N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ala-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Met-Arg-ProNHCH2CH3, N- Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Phe-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Tyr-Arg-ProN HCH2CH3, N-Ac -Sar-Gly-Val- D-Leu-Thr-Nva-Nva-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- -D-Leu-Thr-Nva-Asp-Arg-ProNHCH2CH3, N-Ac- Sar-Gly-Val- -D-Leu-Thr-Nva-Gly-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- -D-Leu-Thr-Nva-Lys (Ac) -Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val- -D-Leu-Thr-Nva-Leu-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- -D-Leu-Thr-Nva-2Nal-Arg-ProN HCH2CH3, N-Ac-Sar-Gly-Val- -D-Leu-Thr-Nva-1 Nal-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- -D-Leu-Thr-Nva-Allygly-Arg-ProNHCH2CH3 , N-Ac-Sar-Gly-Val- -D-Leu-Thr-Nva-Cit-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- -D-Leu-Ala-Nva-lle-Arg-ProNHCH2CH3 , N-Ac-Sar-Gly-Val- -D-Leu-Pro-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- -D-Leu-Trp-Nva-l le-Arg- ProNHCH2CH3, N-Ac-Sar-Gly-Val- -D-Leu-Tyr-Nva-l le-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- -D-Leu-Nva-Nva-l le- Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val - -D-Leu-Gly-Nva-l le-Arg-ProN HCH2CH3, N-Ac-Sar-Gly-Val- -D-Leu-Lys (Ac) -Nva-l le-Arg-ProN HCH2CH3, N- Ac-Sar-Gly-Val- -D-Leu-2Nal-Nva-l le-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- -D-Leu-1 Nal-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Leu-Octylgly-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Leu-Gln-Nva-lle-Arg-ProNHCH2CH3, N- Ac-Sar-Gly-Val-D-Leu-Met-Nva-l Le-Arg-Pro N HCH2CH3, N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-l Le-Arg-ProN HCH2CH3 ,
nt * mt ai *? --------- mm-- ^^ ^^ - ^^ ----- and - m ^^^ -. 38 N -Ac-Sar-Gly-Val-D-Leu-Allygly-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-Leu-lle-Nva-lle-Arg-ProNHCH2CH3, N Ac-Sar-Gly-Val-D-Leu-D-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-lle-lle-Arg-ProNHCH2CH3, 5 N -Ac-Sar-Gly-Val-D-lle-Thr-Nle-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-lle-Thr-Cit-lle-Arg-ProNHCH2CH3, N- Ac-Sar-Gly-Val-D-lle-Thr-Met (? 2) -lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-lle-Thr-Arg-l le-Arg-ProNHCH2CH3 , N -Ac-Sar-Gly-Val-D-lle-Thr-Tyr-lle-Arg-ProNHCH2CH3, 10 N -Ac-Sar-Gly-Val-D-lle-Thr-Glu-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-lle-Thr-Lys (Ac) -lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-lle-Thr-Propargylgly-lle-Arg-ProNHCH2CH3 ,
N -Ac-Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-Leu-Thr-Gln-lle-Arg-ProNHCH2CH3, 15 N -Ac-Bala-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Phenylacetyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCHzCHs,
N -Ac-Sar-Gly-Val-D-lle-Thr-N a-lle-Arg-Pro-Azagly-NH2, N -Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg -Sar-NHCHzCHa, N -Ac-Sar-Gly-Val-D-lle-Thr-N a-lle-Arg-Pro-SerNH2, 20 N -Succinyl-Sar-Gly-Val-D-Leu-Thr-Nva -lle-Arg-ProNHCHzCHs,
N -Ac-Sar-Ala-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Leu-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N- Ac-Sar-Phe-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Glu-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, 25 N -Ac -Sar-Pro-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Asn-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Sar -Asp-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Asn-Gly-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Gln-Gly -Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Ser-Gly-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Cit-Gly-Val -D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Glu-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH-CH3, N -Ac-Gaba-Gly-Val -D-lle-Thr-Nva-tle-Arg-ProNHCHzCHa, N -Ac-Bullet-Gly-Val-D-le-Thr-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Gln-Gly-Val-D -ile-Thr-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Gly-D-lle-Thr-Nva-lle-Arg-ProNHCHzCHa, N -Ac-Sar-Gly-Glu-D-lle -Thr-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2)
N -Succinyl-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3,
N -Succinyl-Sar-Gly-Val-D-Leu-Thr-Gln-lle-Arg-ProNHCH2CH3,
N -Succinyl-Sar-Gly-Val-D-Leu-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2,
N -Ac-Sar-Gly-Val-D-Leu-Thr-Asp-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-lle-Thr-Asp-lle-Arg-ProNHCH2CH3, N- Ac-Sar-Gly-Val-D-lle-Thr-Asn-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Met (O) -lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Val-D-Leu-Thr-Asn-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-Thr-Thr-Nva-lle-Arg-ProNHCH2CH3, N- Ac-Sar-Gly-Val-D-Ser-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Hser-Thr-Nva-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Val-D-Gln-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Asn-Thr-Nva-lle-Arg-ProNHCH2CH3, N- Ac-Sar-Gly-Val-D-Cit-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Hcy-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac- Sar-Gly-Val-D-Hle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Neopentylgly-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar- Gly-Val-D-lle-Thr-Phe (4-CONH2) -lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-His-ProNHCH2CH3, N-Ac -Sar-Gly-Val-D-lle-Thr-Nva-lle-Lys (lsp) -ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Lys (N? C) -ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Om (Nic) -ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle- Om (lsp) -ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Phe (4-Nlsp) -ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle Thr-Nva-lle-Cha (4-Nlsp) -ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Harg-ProNHCHzCHa, N-Ac-Sar-Gly-Val-D -lle-Thr-Nva-lle-Norarg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Cit-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle -Thr-Nva-lle-Lys-P RNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Phe (4-CH2OH) -Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle -Phe (4-guanidino) -ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle -Thr- Nva-lle-A minopyrimidinylbutanoyl-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr -Nva-lle-Phe (4-CH2NHIsp) -ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Gly [4-P? P (N-am? D? No) ] -ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Ala [4-P? P (N-am? D? No)] -
MKMÉiÉttlIill ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Ala- (3-guanidino) -ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva -lle-Ala (3-pyrrolidinilamidino) -ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Om (2-imidazo) -ProNHCH2CH3, N-Succinyl-Sar-Gly-Val -D-alolle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Gly-Val-D -lle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, N-Succinyl-Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Gly-Val -D-Alolle-Thr-Glntlle-Arg-Pro-D-AlaNH2,
N-Succinyl-Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2, N-Succinyl-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg- ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-Pro-D-AlaNH2, N-Ac-Sar-Gly-Val-D-alolle-Thr- Nva-lle-Arg-ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, N-Ac-Sar-Gly-Val- D-lle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, N-Ac- Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-SarNHz, N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-Pro-SarNH2, N-Ac-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro- SarNH2, N-Ac-Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-SarNH2, N-Ac-Sar-Gly-Val-D-alolle-Thr-Ser-lle-Arg- Pro-D-AlaNH2, N-Ac-Sar-Gly-Val-D-alolle-Thr-Ser-lle-Arg-ProNHCH2 (CH3) z, N-Ac-Sar-Gly-Val-D-alolle-Thr- Ser-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Orn (Ac) -lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr -Gln-lie-Arg-Pro-AzaglyNH2, N-Ac-Sar-Gly-Val-D-Alolle-Thr-Nva-lle-Arg-Pro-Az aglyNHz, N-Ac-Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-AzaglyNH2, N- (2-THFcarbonyl) -Sar-Gly-Val-D-alolle-Thr-Nva- lle-Arg- ProNHCH2CH3, N- (2-THFcarbonyl) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, N- (2-THFcarbonyl) -Sar-Gly-Val-D- alolle-Thr-Gln-lle-Arg-ProNHCH2 CH3 N- (2-THFcarbonyl) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, N- (2-THFcarbonil ) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, N- (2-THFcarbonyl) -Sar-Gly-Val-D-alolle-Thr-Gln-lle- Arg-ProNHCH2 (CH3) 2, N- (6-Ac-Aca) -Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCH2CH3, N- (6-Ac-Aca) -Sar- Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, N- (6-Ac-Aca) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2CH3, N- (6-Ac-Aca) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, N- (6-Ac-Aca) -Sar-Gly-Val-D- alolle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, N- (6-Ac-Aca) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2, N- (4-Ac-Gaba) -Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCH2CH3, N- (4-Ac-Gaba) -Sar-Gly-Val-D-lle- Thr-Gln-lle-Arg-ProNHCH2CH3, N- (4-Ac-Gaba) -Sar-Gly- Val-D-alolyl-Thr-Gln-lle-Arg-ProNHCH2CH3, N- (4-Ac-Gaba) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, N- (4-Ac-Gaba) -Sar-Gly-Val-D-alolle-Thr-GlnJle-Arg-Pro-D-AlaNH: ,, N- (4-Ac-Gaba) -Sar-Gly-Val- D-alolyl-Thr-Gln-l le-Arg-ProNHCH2 (CH3) 2 N- (2-Furoyl) -Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCH2CH3, N- (2 -Furoil) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, N- (2-Furoyl) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg- ProNHCH2CH3, N- (2-Furoyl) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, N- (2-Furoyl) -Sar-Gly-Val-D- alolle-Thr-Gln-lle-Arg-Pro-D-AlaNH2,
N- (2-Furoyl) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2, N- (Shikimil) -Sar-Gly-Val-D-alolle-Thr- Nva-lle-Arg-ProNHCH2CH3, N- (Shikimil) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, N- (Shikimil) -Sar-Gly-Val-D-alolle- Thr-Gln-lle-Arg-ProNHCH2CH3, N- (Shikimil) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, N- (Shikimil) -Sar-Gly- Val-D-alolle-Thr-Gln-lle-Arg-Pro-D-AlaN H2, N- (Shikimil) -Sar-Gly-Val-D-alolle-Thr-Gln-l le-Arg-ProN HCH2 (CH3 ):!, N- (2-Me-Nicotinyl) -Sar-Gly-Val-D-alolle-Thr-Nva-l le-Arg- ProN HCH2CH3, N- (2-Me-Nicotinyl) -Sar-Gly- Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3,
N- (2-Me-Nicotinyl) -Sar-Gly-Val-D-alolle-Thr-Gln-l le-Arg-ProNHCH2
CH3 N- (2-Me-N icotinyl) -Sar-Gly-Val-D-lle-Thr-Gln-l le-Arg-Pro-D-AlaN H:!, N- (2-Me-Nicotinyl) - Sar-Gly-Val-D-Alolle-Thr-Gln-lle-Arg-Pro-D-Alal? M H2
N- (2-Me-N icotinyl) -Sar-Gly-Val-D-alol le-Thr-Gln-l le-Arg- ProNHCH2 (CH3) 2, N-Ac-Sar-G ly-Val-D- alolle-Thr-Leu-l le-Arg-Pro-D-Ala N H2, N-Ac-Sar-Gly-Val-Dl le-Thr-Leu-l le-Arg-ProN HCH2 (C H3) 2, N -Ac-Sar-G ly-Val-D-alol le-Thr-Leu-l le-Arg-ProN? CH2CH3,
? Hfü Jn ^ n ^ n ^ N- -Ac-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-Pro-D-AlaNH2, N- -Succinyl-Sar-Gly-Val-D- lle-Thr-Leu-lle-Arg-Pro-D-AlaNH2, N -Succinyl-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-ProNHCH2 (CH3) 2,
N -Succinyl-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-ProNHCH2CH3, N -Succinyl-Sar-Gly-Val-D-alolle-Thr-Leu-lle-Arg-ProNHCH2CH3,
N -Succinyl-Sar-Gly-Val-D-alolle-Thr-Leu-lle-Arg-Pro-D-AlaNH2,
N -Succinyl-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-Pro-AzaglyNH2, N -Ac-Sar-Gly-Val-D-Alolle-Thr-Nva-lle-Arg-ProNHethyl- (l-pyrrolidine),
N -Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNH (ethyl-l-cyclohexyl),
N -Ac-Sar-Gly-Val-D-ll e-Thr-GIn-ll e-Arg-ProNHethyl- (1-pyrrolidine),
N -Ac-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNH (ethyl-l-cyclohexyl),
N -Succinyl-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNH (ethyl-l-cyclohexyl)
N -Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCH2CH2OCH3,
N -Ac-Sar-Gly-Val-D-lle-Thr-GIn-lle-Arg-ProNHCHzCHOCHs, N -Ac-Sar-Gly-Val-D-lle-Thr-Ser-lle-Arg-ProNHCH2CH2OCH3, N- Ac-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-ProNHCH2CH2OCH3, N -Succinyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH2OCH3,
N -Succinyl-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH2OCH3,
N -Succinyl-Sar-Gly-Val-D-allolle-Thr-Gln-lle-Arg-ProNHCH2CH2? CH3,
N -Ac-Sar-Gly-Val-D-lle-Ser-Nva-lle-Arg-ProNHCH2CH2OCH3, N -Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2CH2OCH3, N- Ac-Sar-Gly-Val-D-alolle-Thr-Aligly-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Aligly-lle-Arg-ProNHCH2 (CH3) 2, N -Ac-Sar-Gly-Val-D-lle-Thr-Aligly-lle-Arg-Pro-D-AlaNH2, N -Ac-Sar-Gly-Val-D-alolle-Thr-Aligly-lle-Arg- Pro-D-AlaNH2,
.-go.
N- -Succinyl-Sar-Gly-Val-D-lle-Thr-Al? Gly-lle-Arg-Pro-D-AlaNH2,
N- -Ac-Sar-Gly-Val-D-lle-Ser-Aligly-lle-Arg-Pro-ProNHCHzCHa,
N- -Ac-Sar-Gly-Val-D-Leu-Ser-Aligly-lle-Arg-Pro-ProNHCH2CH3,
N- -Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-SarNH2, N -Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHOH , N- -Ac-Sar-Gly-Val-D-lle-Ser-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-alolle-Ser-Nva-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Val-D-Leu-Hser-Nva-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-GIn-D-lle-Thr-Nva-lle-Arg-ProNHCHsCHa, N -Ac-Sar-Gly-Nva-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-lle-D-lle-Thr-Nva-lle-Arg-ProNHCHaCH3, N -Ac-Sar-Gly-Phe-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Leu-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Ser-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3,
N -Ac-Thr-Gly-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Val-D-alolle-Thr-Ala-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Val-D-lle-Thr-Ala-lle-Arg-ProNHCH2 (CH3) 2,
N -Ac-Sar-Gly-Val-D-lle-Thr-Ala-lle-Arg-Pro-D-AlaNH2, N -Ac-Sar-Gly-Val-D-alolle-Thr-Ala-lle-Arg- Pro-D-AlaNH2,
N -Succinyl-Sar-Gly-Val-D-lle-Thr-Ala-lle-Arg-Pro-D-AlaNH2,
N -Ac-Sar-Gly-Val-D-lle-Ser-Ala-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-Leu-Ser-Ala-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Val-D-alolle-Thr-Val-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Val-D-lle-Thr-Val-lle-Arg-ProNHCH2 (CH3) 2,
N -Ac-Sar-Gly-Val-D-lle-Thr-Val-ll e-Arg-Pro-D-AlaNH2, "- - t ^^ tt ^ ¿¿^ ^ íí ^ l ^^^ N- • Ac-Sar-Gly-Val-D-alol le-Thr-Val-l le-Arg-Pro-D-AlaN H2,
N- -Succinyl-Sar-Gly-Val-D-l le-Thr-Val-lle-Arg-Pro-D-AlaNH2,
N- -Ac-Sar-Gly-Val-Dl le-Ser-Val-lle-Arg-ProN HCH2CH3, N -Ac-Sar-Gly-Val-D-Leu-Ser-Val-lle-Arg-ProN HCH2CH3, N -Ac-Sar-Gly-Val-D-alol le-Thr-D-Nva-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Val-D-l le-Thr-D-Nva-l le-Arg-ProNHCH2 (CH3) 2,
N -Ac-Sar-Gly-Val-D-lle-Thr-D-Nva-lle-Arg-Pro-D-AlaNHz,
N -Ac-Sar-Gly-Val-D-alol le-Thr-D-Nva-lle-Arg-Pro-D-AlaNHz,
N -Succinyl-Sar-Gly-Val-D-lle-Thr-D-Nva-lle-Arg-Pro-D-AlaNH2,
N -Ac-Sar-Gly-Val-D-l le-Ser-D-Nva-l le-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Val-D-Leu-Ser-D-Nva-l le-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Val-D-l le-Ser-Gln-l le-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-Pro-D-AlaNH2,
N -Ac-Sar-Gly-Val-Dl le-Ser-Nva-lle-Arg-Pro-D-AlaN Hz, N -Succinyl-Sar-Gly-Val-D-Leu-Ser-Nva-l le-Arg -ProNHCH2CH3,
N -Succinyl-Sar-Gly-Val-D-lle-Ser-Nva-lle-Arg-ProNHCH2CH3,
N -Succinyl-Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2CH3,
N -Succinyl-Sar-Gly-Val-D-lle-Ser-Gin-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Val-D-lle-Ser-Ser-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-Leu-Ser-Ser-l le-Arg-ProN HCH2CH3,
N -Ac-Sar-Gly-Val-D-Leu-Ser-Nva-l le-Arg-ProNHCH2 (CH3) 2,
N -Ac-Sar-Gly-Val-D-l le-Ser-N va-l le-Arg-ProN HCH2 (CH3) 2,
N -Ac-Sar-Gly-Val-D-Leu-Ser-Leu-l le-Arg-ProN HCH2CH3,
N -Ac-Sar-Gly-Val-Dl le-Ser-Leu-l le-Arg-ProN HCH2CH3, N-Ac-Sar-Gly-Val-D-alolle-Ser-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-alolle-Ser-Gln-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Gly-Val-D-alolle-Ser-Nva-lle-Arg-ProNHCH2CH3, N-Ac -Sar-Gly-Val-D-alolle-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Val-D-alolle-Ser-Nva-lle-Arg-Pro-D -AlaNH2, N-Ac-Sar-Gly-Val-D-alolle-Ser-Leu-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-alolle-Ser-Ser-lle-Arg-ProNHCH2CH3 , N-Ac-Sar-Gly-Val-D-lle-Gly-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-alolle-Gly-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-Leu-Gly-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Gly-Gln-lle-Arg-ProNHCH2CH3, N-Ac -Sar-Gly-Val-D-Alolle-Gly-GIn-lle-Arg-ProNHCHzCHa, N-Ac-Sar-Gly-Val-D-lle-Tyr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar -Gly-Val-D-alolle-Tyr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Leu-Tyr-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly -Val-D-lle-Tyr-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-alolle-Tyr-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Va lD-Ser-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Thr-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D- Gln-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Asn-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Arg- Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-3-Pal-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Glu- Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Asp-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-His-Thr- Nva-lle-Arg-ProN HCH2CH3, N-Ac-Sar-Gly-Val-D-Hser-Thr-Nva-l le-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-aloThr-Thr- Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-Dl le-Thr-Nva-D-lle-Arg-ProN HCH2CH3, N-Ac-Sar-Gly-Val-D-Ser-Thr- Gln-lle-Arg-ProN HCH2CH3, N-Ac-Sar-Gly-Val-D-Thr-Thr-Gln-l le-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-aloThr-Thr- Gln-lle-Arg-ProN HCH2CH3, N-Ac-Sar-Gly-Val-D-Ser-Ser-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Thr-Ser-Nva -lle-Arg-ProN HCH2CH3, N-Ac-Sar-Gly-Val-D-aloThr-Ser-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-aloThr-Ser-Gln- l le-Arg-ProN HCH2CH3, N-Ac-Sar-Gly-Val-D-Thr-Ser-Gln-lle-Arg-ProNHCH2CH3, N- (6-Ac-Aca) -Sar-Gly-Val-D-Leu-Ser-Gin-lle- Arg-ProN HCH2 (CH3) 2, N- (6-Ac-Aca) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2, N- (4-Ac- Gaba) -Sar-Gly-Val-D-Leu-Ser-Gln-l le-Arg-ProN HCH2 (CH3) 2, N- (4-Ac-Gaba) -Sar-Gly-Val-D-Leu-Ser -Nva-lle-Arg-ProNHCH2 (CH3) 2, N- (2-Furoyl) -Sar-Gly-Val-D-Leu-Ser-Gln-l le-Arg-ProNHCH2 (CH3) 2, N- (2 -Furoil) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProN HCH2 (CH3) 2, N- (Shikimil) -Sar-Gly-Val-D-Leu-Ser-Gln-l le-Arg-ProNHCH2 (CH3) 2, N- (Shikimil) -Sar-Gly-Val-D-Leu-Ser-Nva-l le-Arg-ProN HCH2 (CH3) 2, N- (Shikimil) -Sar- Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2 (CH3) 2, N- (Shikimil) -Sar-Gly-Val-D-Leu-Ser-Nva-l le-Arg-ProN HCH2 ( CH3) 2, N- (2-Me-nicotinyl) -Sar-Gly-Val-D-Leu-Ser-Gln-l le-Arg- N- (2-Me-nicotinyl) -Sar-Gly-Val-D -Leu-Ser-a-lle-Arg- ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProN Hethyl-1 - (R) -cyclohexyl, N-Ac-Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHethyl-1 - (R) -cyclohexyl, N-Ac-Sar-Gly-Val-D-lle-Thr-Ser- lle-Arg -ProNHethyl-1 - (R) -cyclohexyl, 5 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-l le-Arg-ProNHethyl-1 - (R) -cyclohexyl, N-Ac-Sar -Gly-Val-D-Leu-Ser-Ser-l le-Arg-ProNHethyl-1 - (R) -cyclohexyl, N-Ac-Sar-Gly-Val-Dl le-Thr-Nva-l le-Arg- ProN Hethyl-1 - (S) -cyclohexyl, N-Ac-Sar-Gly-Val-D-Pen-Ser-Nva-l le-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Pen Gly-Nva-lle-Arg-ProNHCH2CH3, 10 N-Ac-Sar-Gly-Val-D-Pen-Thr-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Pen-Ser -Nva-lle-Arg-ProNHCH2 (CH3) 2, N-Succinyl-Sar-Gly-Val-D-Pen-Ser-Nva-lle-Arg-ProN HCH2CH3, N-Ac-Sar-Gly-Val-D-Pen-Ser- to le-Arg-Pro-D-AlaNH2, N-Ac-Sar-Gly-Val-D-Pen-Ser-Gln-l le-Arg -ProN HCH2CH3, 15 N-Ac-Sar-Gly-Val-D-Pen-Gly-Gln-l le-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Pen-Ser-Ser-lle- Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Pen-Thr-Ser-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Pen-Thr-Leu-lle-Arg- ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Pen-Ser-Leu-l le-Arg-ProNHCH2CH3, 20 N-Succinyl-Sar-Gly-Val-D-Pen-Ser-Ser-lle-Arg- ProN HCHzCHa, N-Succinyl-Sar-Gly-Val-D-Pen-Ser-Leu-lle-Arg-ProN HCH2CH3, N-Succinyl-Sar-Gly-Val-D-Pen-Thr-Gln-l le-Arg -ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Val-D-Cys-Thr-Nva-lle-Arg- ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Cys-Ser-Nva-lle -Arg-ProNHCH2CH3, 25 N-Ac-Sar-Gly-Val-D-Cys-Gly-Nva-l le-Arg-ProNHCH2CH3,
MtM ?? UW N- -Ac-Sar-Gly-Val- D-Cys-Thr-Gln-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-Cys-Ser-Nva-lle-Arg -ProNHCH2 (CH3) 2,
N -Succinyl-Sar-Gly-Val-D-Cys-Ser-Nva-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Val-D-Cys-Ser-Nva-lle-Arg-Pro-D-AlaNH2, N -Ac-Sar-Gly-Val-D-Cys-Ser-Gln-lle-Arg- ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-Cys-Gly-Gln-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-Cys-Ser-Ser-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-Cys-Thr-Ser-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-Cys-Thr-Leu-lle-Arg-ProNHCH2CH3, N- Ac-Sar-Gly-Val-D-Cys-Ser-Leu-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Gly-Val-D-Cys-Ser-Ser-lle-Arg-ProNHCH2CH3,
N -Succinyl-Sar-Gly-Val-D-Cys-Ser-Leu-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Pen-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Cys-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N- Ac-Sar-Gly-Pen-D-alolle-Thr-Nva-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Pen-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Pen-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Pen-D-lle-Ser-Nva-lle-Arg-ProNHCH2CH3, N- Ac-Sar-Gly-Pen-D-lle-Thr-Nva-lle-Arg-ProNHCH2 (CH3) 2,
N -Ac-Sar-Gly-Pen-D-lle-Thr-Nva-lle-Arg-Pro-D-AlaNH2. N -Succinyl-Gly-Pen-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3,
N -Succinyl-Sar-Gly-Pen-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3,
N -Succinyl-Sar-Gly-Pen-D-lle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2,
N -Ac-Sar-Gly-Val-D-Leu-Pen-Nva-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Val-D-lle-Pen-Nva-lle-Arg-ProNHCH2CH3,
'g ^^ g ^ tó ^^^^^^^^^^^^^^^^^^^^ N-Ac-Sar-Gly-Val-D-alolle-Pen-N á- lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Pen-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Pen-Ser-lle- Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Pen-Leu-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Pen-Nva-lle-Arg- ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Val-D-lle-Pen-Nva-lle-Arg-Pro-D-AlaNHz, N-Succinyl-Sar-Gly-Val-D-lle-Pen- Nva-tle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Gly-Val-D-lle-Pen-Gln-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Gly-Val-D-lle-Pen-Gln- lle-Arg-ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Val-D-lle-Thr-Pen-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-alolle-Thr- Pen-lle-Arg-ProNHCH2CH3, N-Ac-Sar-GI y-Val-D-Leu-Thr-Pen-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Pen -lle-Arg-Pro-D-AlaNH2, N-Succinyl-Sar-Gly-Val-D-lle-Thr-Pen-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr -Pen-lle-Arg-ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Val-D-Leu-Ser-Pen-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Leu -Gly-Pen-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Gly-Val-D-Leu-Ser-Pen -lle-Arg-ProNHCH2CH3l N-Ac-Sar-Gly-Val-D-Phe (3,4,5-triF) -Thr-Gln-lle-Arg-ProNHCH2CH; t, N-Ac-Sar-Gly-Val -D-Phe (3,4,5-triF) -Ser-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Phe (3,4,5-tr¡F) -Gly -Nva-lle-Arg-ProNHCH2CH3l N-Ac-Sar-Gly-Val-D-Phe (3,4,5-triF) -Ser-Leu-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val -D-Phe (3,4,5-triF) -Ser-Nva-lle-Arg-Pro-D-AlaNH2, N-Succ? Nyl-Sar-Gly-Val-D-Phe (3,4,5- tr? F) -Thr-Gln-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Gly-Val-D-Phe (3,4,5-triF) -Ser-Gln-lle-Arg- ProNHCH2CH3, N- Succinyl-Sar-Gly-Val-D-Phe (3,4,5-triF) -Thr-Gin-lle-Arg- ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Val-D-Phe (3 , 4,5-triF) -Ser-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Phe (3,4,5-triF) -Ser-Ser-lle-Arg-ProNHCH2CH3 . N-Ac-Sar-Ala-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCHzCHs, N-Ac-Sar-Ala-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3, N- Ac-Sar-Ala-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Ala-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2CH3, N-Ac- Sar-Ala-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Ala-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar- Ala-Val-D-lle-Thr-Gln-Nva-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Ala-Val-D-lle-Thr-Gln-Nva-lle-Arg-ProNHCH2 (CH3) 2, N-Succinyl-Sar-Ala-Val-D-lle-Thr-Gln-Nva-lle-Arg-Pro-D-AlaNH2,
N- (3-Ac-Bullet)) - Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCH2CH3,
N- (, 3-Ac-Bullet)) - Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3,
N- (, 3-Ac-Bullet)) - Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2CH3,
N- (3-Ac-Bullet)) - Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro-D-AlaNH2,
N-, 3-Ac-Bullet)) - Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-D-AlaNH2.
N-; 3-Ac-Bullet)) - Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2,
N-3-Ac-Bullet)) - Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2CH3,
N-; 3-Ac-Bullet)) - Sar-Gly-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3,
N-3-Ac-Bullet)) - Sar-Gly-Val-D-Pen-Thr-Nva-lle-Arg-ProNHCH2CH3,
N- '3-Ac-Bullet)) - Sar-Gly-Val-D-lle-Ser-Nva-lle-Arg-ProNHCH2CH3,
yg ^^^^ ü ^^ N- (3-Ac-Bullet) -Sar-Ala-Val-D-alolle-Ser-Nva-lle-Arg-ProNHCH2CH3, N- (3-Ac-Bullet) -Sar- Ala-Val-D-lle-Ser-Nva-lle-Arg-ProNHCH2CH3, N- (3-Ac-Bullet) -Sar-Ala-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2CH3, N- (3-Ac-Bullet) -Sar-Ala-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg- Pro-OH, N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-Pro-OH, N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-lle Arg-Pro-OH, N-Ac-Sar-Gly-Val-D-Pen-Thr-Nva-lle-Arg-Pro-OH, N-Ac-Sar-Gly-Val-D-Phe (3,4, 5-triF) -Thr-Nva-lle-Arg-Pro-OH, N-Ac-Sar-Gly-Val-D-lle-Thr-GIn-lle-Arg-Pro-OH, N-Ac-Sar-Gly -Val-D-Leu-Ser-Nva-lle-Arg-Pro-OH, N-Ac-Sar-Ala-Val-D-lle-Thr-Nva-lle-Arg-Pro-OH, N-Ac-Sar -Gly-Val-D-lle-Ser-GIn-lle-Arg-Pro-OH, N-Succinyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-OH, and N- Succinyl-Sar-G Iv-Val-D-Leu-Thr-GIn-lle-Arg-Pro-OH. Preferred compounds for the practice of the invention are: N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr -Nva-lle-Arg-ProNHCHzCHz-O -pyrrolidine) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNH (ethyl-l- (R) -cyclohexyl), N- Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNH2l N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2 (CH3) 2, N -Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Val-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac - Sar-Gly-Val-D-Nle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Phe-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar -Gly-Val-D-Cha-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-3,4-diCIPhe-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac -Sar-Gly-Val-D-3-CIPhe-Thr-N a-lle-Arg-ProNHCH2 CH3, N-Ac-Sar-Gly-Val-D-2-Thienylala-Thr-Nva-lle-Arg-ProNHCH2CH3 , N-Ac-Sar-Gly-Val-D-3-CNPhe-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Cha-lle-Arg-ProNHCH2CH3 , N [2-THFcarbonyl] - Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N [6-N-acetyl- (CH2); C (O)] - Sar-G ly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Hexanoyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N- [4-N-Aceti lami nobutyryl] -Sar-Gly-Val-D-lle-Thr-N va-I le-Arg-ProNHCH2CH3, N- [CH3C (O) NH- (CH2) 2-O- (CH2) 2-O-CH2 -C (O)] Gly-Val-D-lle-Thr-Nv &-He-ArgProNHCH2CH3, N-Ac-Pro-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac -NEtGly-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-ProNHCH2CH3, N-Ac-Sar -Gly-Val-DJIe-Thr-Ser-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-D-AlaNH2, N-Ac-Sar -Gly-Val-D-Leu-Thr-Nva-Lys (Ac) -Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Leu-Arg-ProNHCH2CH3, N-Ac- Sar-Gly-Val-D-Leu-Thr-Nva-1-Nal-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Allygly-Arg-ProNHCH2CH3, N-Ac-Sar- Gly-Val-D-Leu-Ala-Nva-lle-Arg-ProNHCH2CH3, N- -Ac-Sar-Gly-Val-D-Leu-Trp-Nva-lle-Arg-ProNHCH2CH3, N- -Ac-Sar- Gly-Val-D-Leu-Tyr-Nva-lle-Arg-ProNHCH2CH3, N- -Ac-Sar-Gly-Val-D-Leu-Gly-Nva-lle-Arg-ProNHCH2CH3, N- -Ac-Sar- Gly-Val-D-Leu-2Nal-Nva-ll e-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-Leu-1Nal-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-Leu-Octylgly-Nva-lle- Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-Leu-Allygly-Nva-lle-Arg- ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-Leu-D-Thr-Nva-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-lle-Thr-Tyr-lle-Arg- ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-lle-Thr-Glu-lle-Arg-ProNHCH2CH3, N -Ac-Sar-Gly-Val-D-lle-Thr-Propargylgly-lle-ArbProNHCH2CH3,
N -Ac-Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2CH3, N -Ac-Bullet-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Phenylacetyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3,
N -Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-AzaglyNH2, N -Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro- SerNH2, N - (6-Ac-Aca) -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2 (CH3) 2,
N - (6-Ac-Aca) 4-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3> 2,
N - (4-Ac-Gaba) -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2 (CH3) 2,
N - (4-Ac-Gaba) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2,
N - (2-Furoyl) -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2 (CH3) 2,
N - (2-Furoyl) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2,
N - (Sh? Kimil) -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2 (CH3) 2,
N - (Shikimil) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2, N- (Shikimil) -Sar-Gly-Val-D-Leu-Ser-Gln- lle-Arg-ProNHCH2 (CH3) 2, N- (Shikimil) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) z, N- (2-Me-nicotinyl) - Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg- ProNHCH2 (CH3) 2, N- (2-Me-nicotinyl) -Sar-Gly-Val-D-Leu-Ser-Nva-lle- Arg- ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-OH, N-Ac-Sar-Ala-Val-D-lle-Thr- Nva-lle-Arg-ProNHCHzCHa, N-Ac-Sar-Gly-Val-D-Pen-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Phe (3,4, 5-triF) -Thr-Nva-lle-Arg-ProNHCH2CH3, and N-Ac-Sar-Gly-Val-D-Phe (4-NH2) -Thr-Nva-lle-Arg-ProNHCH2CH3.
It is well known in the art that modifications and changes in the structure of a polypeptide can be made without substantially altering the biological function of that peptide. For example, certain amino acids may be substituted by other amino acids in a given polypeptide, without any appreciable loss of function. To make such changes, substitutions of similar amino acid residues can be made based on the relative similarity of side chain substituents, for example, their size, charge, hydrophobicity, hydrophilicity, and the like. In describing the invention, certain abbreviations are used for convenience throughout the specification, including the examples, to refer to reagents and compounds useful for preparing the compounds of the invention. When used like this, the following
•• * - ** rtt? -.
Abbreviations have the following meanings: DMF for dimethylformamide; DMA for dimethylacetamide; DIEA for diisopropylethylamine; HATU for O- (7-a2: a-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate; NMP for N-methylpyrrolidone; and TFA for trifluoroacetic acid.
Determination of Biological Activity Preparation of Pella 10 microliters of a mixture containing a final concentration of 1.5 or 10 mN of the peptides of the invention, 100 ng of bFGF (Collaborative Biomedical Products, Bedford, MA) were placed in a pipette. Hydron% (Sigma, St. Louis, MO) at the tip of a sterile Teflon rod. After drying for 1- 2 hours, the pellets were stored at 4 ° C.
Implantation of the pellet A small radial incision (approximately 2 mm) at 1 mm from the center of the cornea was performed on anesthetized Sprague Dawley rats. With a curved iris spatula, an intrastromal cavity was made at a distance of 1 mm from the edge from the circular blood vessels surrounding the cornea. Only one pellet was implanted. Antibiotic ointment (neosporin) was applied after surgery to the operated eye to prevent infection and reduce inflammation.
Data Analysis On the seventh day after implantation, neovascularization was measured through a slot lamp biomicroscope (Nikon NS-1), connected to an image analysis system (Leica Qwin). The response was calculated by colorimetrically detecting the area of the new blood spleens, and calculating the new surface area of the spleen in μm2. The compounds of the invention inhibit neovascularization of rat cornea as shown in Table 2.
Table 2 Effect of inhibition compounds on neovascularization of rat cornea
The compounds of the invention, including, but not limited to, those specified in the examples, possess anti-angiogenic activity. As inhibitors of angiogenesis, said compounds are useful in the treatment of primary tumors as metastatic, including carcinomas of the breast, colon, rectum, lung, oropharynx, hypopharynx, esophagus, stomach, pancreas, liver, gall bladder and bile ducts, small intestine, urinary tract (including kidney, bladder and urothelium), female genital tract (including cervix, uterus and ovaries, as well as choriocarcinoma and gestational trophoblastic disease), male genital tract (including seminal vesicle, testes and germ cell tumors), endocrine glands (including the thyroid, adrenal and pituitary glands), and skin, as well as hemangiomas, melanomas, sarcomas (including those arising from bones and soft tissues as well as Kaposi's sarcoma) and tumors of the brain, nerves, eyes and meninges (including astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas , neuroblastomas, Schwannomas, and meningiomas). Such compounds may also be useful for treating solid tumors arising from hematopoietic diseases such as leukemias (ie, chloromas, plasmacytomas and plaques and fungal tumors of mycosis and lymphoma / cutaneous T-cell leukemia) as well as in the treatment of lymphomas (both Hodkin lymphomas and non-Hodgkin lymphomas). In addition, these compounds may be useful for the prevention of metastasis of the tumors described above, either when used alone or in combination with radiotherapy and / or other chemotherapeutic agents. Other uses include the treatment and prophylaxis of autoimmune diseases such as rheumatoid arthritis, immune and degenerative; various ocular diseases such as diabetic retinopathy, premature type retinopathy, corneal graft rejection, retrolental fibroplacia, neobascular glaucoma, rubeosjis,
tf ^^ Mt-tMM retinal neovascularization due to macular degeneration, hipó < ia, angiogenesis in the eye associated with infection or surgical intervention and other conditions of abnormal neovascularization of the eye; skin diseases such as pessoriasis; diseases of blood spleens such as hemagiomas, and capillary proliferation within atherosclerotic plaques; Osler-Webber syndrome; starch angiogenesis; plaque neovascularization; telangiectasia, hemophiliac joints; angiofibroma; and wound granulation. Other uses include the treatment of diseases characterized by excessive or abnormal stimulation of endothelial cells, including, but not limited to, intestinal adhesions, Crohn's disease, atherosclerosis, scleroderma and hypertrophic scars, i.e. keloids. Another use is as a birth control agent, inhibiting ovulation and establishing the placenta. The compounds of the invention are also useful in the treatment of diseases having angiogenesis as a pathological consequence such as cat scratch disease (Róchele minalia quintosa) and ulcers (Helicobacter pylori). The compounds of the invention are also useful for reducing bleeding through administration anees of surgery, especially for the treatment of tumors capable of resection. The compounds of the invention can be used in combination with other compositions and methods for the treatment of diseases. For example, a tumor can be treated conventionally with surgery, radiation or chemotherapy combined with a peptide of the present invention and then a peptide of the present invention can be subsequently administered to the patient to extend the inactive period of micrometastasis and to stabilize and inhibit the growth of any residual primary tumor. In addition, the compounds of the invention can be combined with pharmaceutically acceptable excipients, and optionally sustained release matrices, such as biodegradable polymers, to form therapeutic compositions. A sustained release matrix as used herein is a matrix made of materials, usually polymers, which are degradable through enzymatic or acid-based hydrolysis or through dissolution. Once inserted into the body, the matrix is driven by enzymes and body fluids. A sustained release matrix is desirably chosen from biocompatible materials such as liposomes, polylactics (polylactic acid), polyglycolide (glycolic acid polymer), polylactide co-glycolide (copolymers of lactic acid and glycolic acid), polyanhydrides, poly (ortho) esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinylpropylene, polyvinylpyrrolidone and silicone. A preferred biodegradable matrix is a matrix of either polylactide either polyglycolide, or polylactic co-glycolide icopolymers of lactic acid and glycolic acid). When used in the above treatments or other treatments, a therapeutically effective amount of one of the compounds of the present invention may be employed in pure form or, when such a form exists, in a pharmaceutically acceptable salt form. By a "therapeutically effective amount" of the compound of the invention is meant a sufficient amount of the compound to treat an angiogenic disease (e.g., to limit tumor growth or to decrease or block tumor metastasis) to a ratio reasonable benefit / risk applicable to any medical treatment. However, it will be understood that the total daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope of the medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disease that will be treated and the severity of the disease; activity of the specific compound employed; the specific composition employed; body weight, general health, sex and diet of the patient; the time of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or according to the specific compound used; and similar factors well known in the art of medicine. For example, it is inside
from the experience of the technique start with doses of the compound at lower levels than those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved. The compounds of the present invention can be used in the form of salts derived from organic or inorganic acids. These salts include, but are not limited to the following: salts of acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptane, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinite, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate , glutamate, bicarbonate, p-toluenesulfonate, and undecanoate. In this way soluble products are obtained or dispersed in water or oil. Examples of acids that can be used to form pharmaceutically acceptable acidic adhesion salts include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid and organic acids such as acetic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals such as sodium, potassium, calcium or magnesium or with an organic base. Preferred salts of the compounds of the invention include phosphate, tris and acetate. Alternatively, a compound of the present invention can be administered as pharmaceutical compositions containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. A "pharmaceutically acceptable carrier or excipient" refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulation material or auxiliary of any kind. The compositions may be administered parenterally, intracisternally, intravaginally, intraperitoneally, topically (such as powders, ointments, or transdermal patch), rectally or buccally. The term "parenteral" as used herein, refers to modes of administration that include intravenous, intramuscular, intraperitoneal, intraestemal, subcutaneous and intraarticular injection and infusion. Pharmaceutical compositions for parenteral injection comprise sterile, pharmaceutically acceptable aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution in solutions: or sterile injectable dispersions before use. Examples of vehicles, solvent diluents or non-aqueous and aqueous carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil). , and injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, through the use of coating materials such as lecithin, through the maintenance of the required particle size in the case of dispersions, and through the use of surfactants. These compositions may also contain auxiliaries. such as preservatives, wetting agents, emulsifying agents and dispersing agents. The prevention of the action of microorganisms can be ensured through the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be produced through the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin. Injectable depot forms are made by forming microcapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly (orthoesters), poly (anhydride) and (poly) glycols such as PEG. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations can also be prepared by trapping the drug in liposomes or microemulsions, which are compatible with body tissues. Injectable formulations can be sterilized, for example, by filtration through a bacteria retention filter, or by incorporating sterilization agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other injectable medium. sterile just before use. Topical administration includes administration to the skin or mucosa, including surfaces of the lung and the eye. Compositions for topical administration, including those for inhalation, can be prepared as a dry powder, which can be pressurized or non-pressurized. In non-pressurized powder compositions, the active ingredient, in finely divided form, can be used in admixture with a pharmaceutically acceptable inert carrier, of larger size comprising particles having a size of, for example, up to 100 microns in diameter. Suitable inert carriers include sugars such as lactose. Desirably, at least 95% of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 microns.
Alternatively, the composition can be pressurized and contain a compressed gas, such as nitrogen or a liquefied gas propellant. The liquefied propellant medium and indeed the total composition preferably is such that the active ingredient does not dissolve therein to any substantial degree. The pressurized composition may also contain an active agent on the surface, such as an active agent on the liquid or solid nonionic surface, or it may be an active agent on the solid anionic surface. It is preferred to use the active agent on the solid anionic surface in the form of a sodium salt. An additional form of topical administration is for the eye. A compound of the invention is delivered in a pharmaceutically acceptable ophthalmic vehicle, such that the compound is kept in contact with the ocular surface for a sufficient period of time to allow the compound to penetrate the cornea and inner regions of the eye, for example , like the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris / ciliary, crystalline, choroid / retina and sclerotic membrane. The pharmaceutically acceptable ophthalmic vehicle, for example, can be an ointment, vegetable oil or an encapsulating material. Alternatively, the compounds of the invention can be injected directly into the vitreous body and aqueous fumes. Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or vehicles, such as cocoa butter, polyethylene glycol, or a suppository wax, which are solid to room temperature but liquid at body temperature and, therefore, melt in the rectum or vaginal cavity and release the active compound. The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed through mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid to form liposomes can be used. The compositions herein in liposome form may contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods for forming liposomes are well known in the art. See, for example, Prescott, Ed. Methods in Cell Biology, volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq. Although the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more agents that are conventionally administered to patients to treat angiogenic diseases. For example, the compounds of the invention are effective during the short period to make the tumors more sensitive to traditional cytotoxic therapies, such as chemicals and radiation. The compounds of the invention also improve the effectiveness of existing cytotoxic auxiliary cancer therapies. The compounds of the invention may also be combined with other anti-angiogenic agents to improve their effectiveness, or be combined with other anti-angiogenic agents and administered in conjunction with other cytotoxic agents. In particular, when used in the treatment of solid tumors, the compounds of the invention may be with IL-12, retinoids, interferons, angiostatin, endostatin, thalidomide, thrombospondin-1, thrombospondin-2, captopril, angioinhibines, TNP-470 , pentosan polysulfate, platelet factor 4, LM-609, SU-5416, CM-101, Tecogalan, plasminogen-K-5, vasostatin, vitaxin, vasculostaine, squalamine, marimastat or other MMP inhibitors, antineoplastic agents such as alpha interferon, COMP (cyclophosphamide, vincristine, methotrexate and prednisone), etoposide, mBACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone ), PRO-MACE / MOPP (prednisone, methotrexate, (w / leucovine, rescue), doxorubicin, cyclophosphamide, cisplatin, taxol, etoposide / meclorentamine, vincristine, prednisone and procarbazine), vincristine, vinblastine, and the like as well as radiation. The daily dose of the compositions of the invention which will be administered to a human or other host animal in individual or divided doses may be in amounts of, for example, 0.0001 to 300 mg / kg of body weight daily, and more usually 1 at 300 mg / kg of body weight. It will be understood that agents that can be combined with the compound of the present invention for the inhibition, treatment or prophylaxis of angiogenic diseases are not limited to those listed above, but include in principle any agent useful for any treatment or prophylaxis of angiogenic diseases. . The peptides of the invention can be used for the development of affinity columns for isolation of receptors important for the anti-angiogenic activity of the peptide of the invention, for example, TSP-1 receptor in, for example, cultured endothelial cells. As is known in the art, the isolation and purification of the receptor can be followed by amino acid sequencing to identify and isolate polynucleotides which encode the receptor. Recombinant expression of this receptor could allow large amounts of receptor to be produced, for example, to produce an amount sufficient to be used in high throughput screening assays to identify other angiogenesis inhibitors. The peptides of the present invention can be chemically coupled to isotopes, enzymes, carrier proteins, cytotoxic agents, fluorescent, chemiluminescent, bioluminescent, and other compounds for a variety of applications. For example, a peptide can be labeled to facilitate testing of its ability to bind antisera or to detect cell types that possess an important receptor. The coupling technique generally selected based on functional groups available on the amino acids of the peptide including, but not limited to, amino, sulfhydral, carboxyl, amide, phenol and imidazole. Several reagents for making such couplings include among others, glutaraldehyde, diasodized benzidine, carbodiimide, and p-benzoquinone. The efficiency of the coupling reaction is determined using different techniques appropriate for the specific reaction. For example, radio-labeling of the peptide with I 125 can be achieved using chloramine T and Nal 125 with high specific activity. The reaction is terminated with sodium metabisulfite and the mixture is desalted on disposable columns. The labeled peptide is eluted from the column and the fractions are collected. The aliquots are removed from each fraction and the radioactivity is measured in a gamma counter. In this way, a labeled peptide can be obtained, which is free of unreacted Nal125. The peptides of the present invention can also be used as antigens to generate polyclonal or monoclonal antibodies. Said antibodies can be used in diagnostic methods and equipment to detect or quantify the peptide of the invention, or peptides related thereto, in a fluid or tissue of the body. The results of these tests can be used to diagnose or determine the prognostic importance of said peptides. The use of the peptides of the present invention to generate monoclonal antibodies in animals such as mouse, rabbit or sheep follows techniques well known in the art. If desired, the antibodies can then be used to make anti-idiotype antibodies, which in turn can be humanized as is
^ t ^ gguisijmi ii ii i m known in the art to avoid immunological responses. Humanized antibodies can be used to inhibit angiogenesis or to make kits to detect the receptor as described herein. For the production of polyclonal antisera in rabbits, sheep, sheep or other animals, the peptides of the invention are coupled, for example, via lysine residues, to bovine serum albumin using glutaraldehyde. The efficiency of this reaction can be determined by measuring the incorporation of the radiolabelled peptide. The unreacted glutaraldehyde and the peptide can be separated through dialysis and the conjugate is stored for subsequent use. Serum samples from the generation of polyclonal antisera or media samples from the production of monoclonal antisera can be analyzed for the determination of antibody titration and in particular for the determination of high titre antisera. Subsequently, the highest titre antisera can be tested to establish the following: a) optimal dilution of antiserum for higher specific binding of antigen and lower non-specific binding, b) ability to bind increasing amounts of peptide in a displacement curve standard c) potential cross-reactivity with immunologically related peptides and proteins (including plasminogen, TSP-1, and TSP-1 of related species), and d) ability to detect the peptide of the invention in plasma, urine, tissue and media extracts of cell culture. Titration can be established through various means known in the art, such as through dot staining and density analysis, and also through precipitation of radiolabeled peptide / antibody complexes using protein A, secondary antisera, ethanol cold or carbon-dextran, followed by measurement of activity with a gamma counter. If desired, the highest titre antisera can be purified into affinity columns. For example, the peptides of the invention can be coupled to a commercially available resin and used to form an affinity column. The antiserum samples can then be passed through the column so that antibodies to the peptides of the invention are linked (via the peptide) to the column. These antibodies in laces are subsequently eluted, collected and evaluated for the determination of titration and specific character. The equipment for measuring the compounds of the invention are also contemplated as part of the present invention. Antisera having the highest titre and specific character and can detect the peptides of the invention in extracts of plasma, urine, tissues and in cell culture media, can be used to establish test equipment for rapid, reliable measurement, sensitive and specific and the location of peptides of the invention. These test kits may employ (but are not limited to) the following techniques: competitive and non-competitive assays, radioimmunoassay (RIA), bioluminescence and chemiluminescence assays, fluorometric assays, sandwich assays, immunoradiometric assays, dot assays, assays enzyme linked including ELISA, microtiter plates, antibody-coated strips or rods for rapid urine or blood verification and immunocytochemistry. For each piece of equipment, the scale, sensitivity, accuracy, reliability, specific character and reproducibility of the assay are established through means well known to those skilled in the art. The assay kit described above can provide instructions, antiserum, one or more peptides of the invention, and possibly radiolabelled peptides of the invention and / or reagents for the precipitation of linked peptide / antibody complexes. Such a kit could be useful for measuring the peptide of the invention in biological fluids and tissue extracts from animals and humans with and without tumors as is well known in the art. Another equipment can be used to visualize or locate the peptide of the invention in tissues and cells. Immunohistochemical techniques and equipment, for example, that employs techniques that are well known to those experts in the field. Such equipment provides antisera to the peptide of the invention, and possibly blocks the serum and secondary antiserum bound to a fluorescent molecule such as fluorescein isothioate, or some other reagent used to visualize the primary antiserum. Using this methodology, tumors from biopsies can be examined for peptide production sites or for peptide receptor sites. Alternatively, a kit can deliver radiolabelled nucleic acids for use in in situ hybridization to probe the messenger RNA encoding the compound of the invention.
Synthesis of the Peptides The polypeptides of the present invention can be used through any technique that is known to those skilled in the art. For the synthesis of solid phase peptide, a summary of the many techniques can be found in J.M. Stewart and J.D. Young, Solid Phase Peptide Synthesis, W.H. Freeman Co. (San Francisco), 1963 and J. Meienhofer, Hormonal Proteins and Peptides, vol. 2 P. 46, Academic Press (New York), 1973. For classical solution synthesis see G. Schroder and K. Lupke, The Peptides, vol. 1, Academic Press (New York), 1965. Reagents, resins, amino acids and amino acid derivatives are commercially available and can be purchased from Chen-Impex International, Inc. (Wood Dale, IL., USA) or Calbiochem-Novabioquem Corp. (San Diego, CA, USA), unless otherwise specified. In general, these methods comprise the sequential addition of one or more amino acids or amino acids suitably protected for a growing peptide chain. Normally, either the amino or carboxyl group of the first amino acid is protected by a suitable protecting group. The protected or derivatized amino acid can then be bound to an inert solid support or used in solution by adding the next amino acid in sequence having the complementary group (amino or carboxyl) suitably protected under suitable conditions to form the amide linkage. The protective group is then removed from this newly added amino acid residue and the next amino acid (suitably protected) is then added, and so on. After all the desired amino acids have been linked in the proper sequence, any remaining protecting group (and any solid support) is removed sequentially or concurrently to provide the final polypeptide. By simple modification of this general procedure it is possible to add more than one amino acid at a time to a developing chain, for example, by coupling (under conditions which do not racemize chiral centers) a tripeptide protected with an appropriately protected dipeptide to form, after the deprotection, a pentapeptide. A particularly preferred method for preparing compounds of the present invention involves solid phase peptide synthesis. In this particularly preferred method, the α-amino function is protected by a group sensitive to the acid or base. Sayings
-. * £ * * & & > ** protecting groups must have the properties of being stable to the conditions of peptide bond formation, while being easily removable without the destruction of the developing peptide chain or racemization of any of the chiral centers contained there. Suitable protecting groups are 9-fluorenylmethyloxycarbonyl (Fmoc), .butyloxycarbonyl (boc), benzyloxycarbonyl (Cbz), biphenylisopropyloxycarbonyl, t-amyloxycarbonyl, isobornyloxycarbonyl, (a, a) -dimethyl-3,5-dimethoxybenzyloxycarbonyl, o-nitrophenylsulfenyl, 2, -cyano-r-butyloxycarbonyl, and the like. The 9-fluorenylcarbonyl protecting group (Fmoc) is preferred. Particularly preferred side chain protecting groups are, for side chain amino groups such as lysine and arginine: 2,2,5,7,8-pentamethylchroman-6-sulfonyl (pmc), nitro, p-toluenesulfonyl, 4-methoxybenzenesulfonyl , Cbz, Boc, and adamantyloxycarbonyl; for tyrosine: benzyl, o-bromobenzyloxycarbonyl, 2,6-dichlorobenzyl, isopropyl, r-butyl, (t-Bu), cyclohexyl, cyclopentyl and acetyl (Ac); for serine: .butyl, benzyl and tetrahydropyranyl, for histidine: trifly, benzyl, Cbz, p-toluenesulfonyl and 2,4-dinitrophenyl; for tryptophan: formyl and Boc. In the solid phase peptide synthesis method, the C-terminal amino acid is attached to a suitable solid support or resin. Suitable solid supports useful for the above synthesis are those materials that are inert to the reactants; and reaction conditions of stepped condensate-deprotection reactions, just as it is insoluble in the medium used. The preferred support for the synthesis of C-terminal carboxy peptides is 4-hydroxymethyl-phenoxymethyl-copoly (1% styrene-divinylbenzene). The preferred solid support for C-terminal amide peptides is the 4- (2,4-dimethoxyphenyl-Fmoc-aminomethyl) phenoxy acetamidoethyl resin which is commercially available from Applied Biosystems. The C-terminal amino acid is coupled to the resin via N, N'-dichlohexylcarbodiimide (DCC), N, N'-disopropylcarbodiimide (DIC) or O-benzotrol azol-1-ylN, N, N 'hexafluorophosphate , N'-tetramethyluronium (HBTU), with or without 4-dimethylaminopyridine (DMAP) 1-hydroxybenzotriazole (HOBT), benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) or bis (2-) chloride oxo-3-oxasolidinyl) phosphine (BOPCI), mediated coupling of about 1 to 24 hours at a temperature of between 10 ° and 50 ° C in a solvent such as dichloromethane or DMF. When the solid support is the resin 4- (2 ', 4'-dimethoxyphenyl-Fmoc-aminomethyl) -phenoxyacetamidoethyl, the Fmoc group is cleaved with a secondary amine, preferably piperidine, before coupling with the C-terminal amino acid as described previously. The preferred method for coupling to the deprotected resin of 4- (2 ', 4'-dimethoxy fe nyl-Fmoc-am i nomethyl) phenoxyacetamidoethyl is O-benzotriazol-1-yl-N, N, N, N' hexafluorophosphate. N'-tetramethyluronium (HBTU, 1 equivalent) and 1-hydroxybenzotriazole (HOBT, 1 equivalent) in DMF..
The coupling of successive protected amino acids can be performed in an automatic polypeptide synthesizer as is well known in the art. In a preferred embodiment, the a-amino function in the amino acids of the developing peptide chain are protected with Fmoc. Removal of the Fmoc protecting group from the N-terminal side of the developing peptide is achieved through treatment with a secondary amine, preferably piperidine. Each protected amino acid is then introduced in a molar excess of about three times and the coupling is preferably carried out in DMF. The coupling agent is usually O-benzotriazole-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU, 1 equivalent) and 1-hydroxy-benzotriazole (HOBT, 1 equivalent). At the end of the solid phase synthesis, the polypeptide is removed from the resin and deprotected, either in succession or in an individual operation. Removal of the polypeptide and removal can be achieved in a single operation by treating the resin-bound polypeptide with a cleavage reagent, for example, tianizol, water, ethanedithiol, and trifluoroacetic acid. In cases where the C-terminus of the polypeptide is tub alkylamide, the resin is cleaved through aminolysis with an alkylamine. Alternatively, the peptide can be removed through transesterification, for example, with methanol, followed by aminolysis or through direct transamidation. The protected peptide can be purified at this point or taken to the next step
^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ The removal of side chain protecting groups is achieved using the cleavage cocktail described above. The fully deprotected peptide is purified through a sequence of chromatographic steps employing any or all of the following types: ionic change in a weakly basic resin in the acetate form; hydrophobic chromatography chromatography in non-derivatized polystyrene-divinylbenzene (for example, AMBERLITE®XAD); silica adsorption chromatography; ion exchange chromatography on carboxymethylcellulose; division chromatography, for example, in SEPHADEX® G-25, LH-20 or countercurrent distribution; high performance liquid chromatography (HPLC), especially reverse phase HPLC in the phase column gasket attached to HPLC in octyl- or octadecylsilyl-silica. The following examples will serve to further illustrate the preparation of the novel compounds of the invention.
Preparation of the Excision Reagent The cleavage reagent (2 ml) was prepared by mixing, in the following order, 100 μL of thioanisole, 50 μL of water, 50 μL of ethanedithiol and 1.8 mL of trifluoroacetic acid. The freshly prepared piss was cooled to -5 to -10 ° C and used as described below.
- "Zltá VI tlir -yy-y-" Excision and Deprotection Procedure A mixture of the polypeptide bound to the resin and cleavage reagent was stirred at 0 ° C for 10-15 minutes and then at room temperature for an additional 1.75 hours. The amount of time was increased by 0.5 hours for each additional arginine up to a total of 3 hours. The amount of cleavage reagent used is determined using the following formula:
The resin is then filtered and rinsed with net trifluoroacetic acid. The filtrate is then added in 0.5 ml portions to a centrifuge tube containing approximately 8 ml of cold diethyl ether. The suspension was then centrifuged and the supernatant was decanted. The pellet was resuspended in approximately 8 ml of ether, another 0.5 ml of the filtrate was added, and the process was repeated until all the peptide was precipitated. The precipitated filtrate was washed with ether, dried and lyophilized. If the peptide is not precipitated after addition to ether the mixture is stirred with 30% aqueous acid. The organic phase is then extracted twice with aqueous 30% acetic acid and the combined aqueous extracts are lyophilized.
Example 1 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 A synthetic column was placed in the peptide column position of a Perkin Elmer peptide synthesizer / Applied Biosynthesis SYNERGY® of peptide Pro (2-CITrt) (25 μM amino acid, Nova Biochem). The amino acids are added sequentially according to the following synthetic cycle: (1) Solve the resin using DMF for approximately
minutes; (2) Wash with DMF for approximately 5 minutes; (3) Activate the input Fmoc protected amino acid (75μM) using a 0.2M solution of HBTU (75μM) and HOBT (75μM) in DMSO-NMP (N-methylpyrrolidine); (4) Coupling using a DMF solution of the Fmoc-protected amino acid prepared as in step 3 above for about 30 minutes; (5) Wash with DMF for 5 minutes; and (6) For peptides blocked at their end with acetyl at the N-terminus, substitute acetic acid (87 μM) for an amino acid protected with Fmoc and using 87 μM each of HBTU and HOBT. (7) For peptides blocked at their end with ethylamide at the C terminus, add DMF to the resin followed by ByProp (1.1 equivalent) and ethylamine (20 equivalents) in THF. The amino acids were coupled to the resin in the following order using the indicated conditions.
After finishing the synthesis the resin was washed with THF for about 30 minutes to remove DMF and shrink the resin. The resin was then dried with argon gas for about 10 minutes and nitrogen for a further 10 minutes to provide the resin bound peptide (85 mg). Cleavage and deprotection are achieved using the procedure described above (40 mg of peptide bound to dry resin, 700μL of cleavage reagent, cleavage time 2.5 hours) to give the crude peptide (14 mg). Purification of HPLC using a 7μm Symmetry Prep C18 column (7.8 x 300 mm) with solvent mixtures varying in a gradient from 5% to 100% acetonitrile-water over a period of 50 minutes followed by lyophilization provided by the peptide wanted.
^^ um ^ - The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, as the trifluoroacetate salt: Rt = 26.5 min ( 10% to 40% acetonitrile in water containing 0.01% TFA, for a period of 30 minutes); MS (ESI) m / e 994 (M + H) +.
Example 2 piroGlu-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3
The desired peptide was prepared under the conditions described in Example 1. The amino acids were coupled to the resin in the following order using the indicated conditions. The pure fractions were lyophilized to produce piroGlu-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, as well as the trifluoroacetate salt: Rt = 23.5 (gradient from 10% to 40% acetonitrile in water containing 0.01% of TFA, during a period of 30 minutes);
MS (ESI) m / e 994 (M + H) \ Example 3 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH3 The procedure described in Example 1 was used substituting methylamine. (2.0 M solution in THF) for ethylamine. After cleavage of the peptide from the resin and removal of protecting groups, the crude product was purified from C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitoplo. -water containing 0.1% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH3 as the trifluoroacetate salt: Rt = 3.224 min (gradient from 20 to 95% acetonitrile in water containing 0.01 M NH Ac for a period of 10 months, MS (ESI) m / e 930 (M + H) +;
Amino acid analyzed: 1.09 Sar; 1.03 Gly; 0.98 Val; 0.98 lie; 0 54 Thr: 1.72 Nva; 1.01 Arg; 1.08 Pro.
Example 4 N-Ac-Sar-Gly-Val-lle-Thr-Nva-lle-Arg-ProNHCH2 (CH3) 2 The procedure described in Example 1 was used, but replacing isopropylamine for ethylamine. After the cleavage of the peptide from the resin and the removal of the protective groups, the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10 to 50% acetonitrile-water containing 1.01% TFA. The pure fractions were lyophilized to produce Nac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHIsopropyl as the trifluoroacetate salt: Rt = 3648min (gradient from 20% to 95% acetonitrile in water containing 0.01 M NH4Ac for a period of 10 minutes; Ms (ESI) m / e 1008 (M + H) +; Anal. Amino acid: 1.10 Sar; 0.99 Gly; 0.96 Val; 1.88 lie; 0.56 Thr; 1.67 Nva; 0 96 Arg; 1.09 Pro.
Example 5 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHethyl- (l-pyrrolidine) Preparation of the Resin The resin AM 4- (4-Formyl-3-methoxyphenoxy) was placed. ) butyryl (0.5 g, 0.54 mmoles / g of substitution) in a solid phase vessel containing (9: 1) DMA / acetic acid (4 ml). The mixture was stirred for 5 minutes. The resin was drained and this process was repeated three times. To the swollen resin were added 10-15 grains of activated 4A molecular sieves and (9: 1) of DMA / acetic acid (4 ml) and 10 molar equivalents of 1- (2-aminoethyl) pyrrolidine. The slurry was stirred for 1 hour at room temperature and 10 molar equivalents of sodium triacetoxyborohydride were added thereto. The slurry was stirred for 2 hours at room temperature. The resin was drained and washed three times with DMA, three times with methanol, three times with dichloromethane, three times with diethyl ether and dried under vacuum at room temperature overnight. The dried resin was swollen in DMA (4 ml) and stirred for 5 minutes. This process was repeated again.
Coupling of Fmoc-Pro The following chemicals were sequentially added to the swollen resin in the reaction vessel: DMA (4 ml), one equivalent of DIEA, a solution of DMA containing 3.0 equivalents of Fmoc-Pro, 3.0 equivalents of HATU, and 3.0 equivalents of DIEA. The slurry was stirred overnight. The resin was drained and washed three times with DMA, three times with methanol, three times with dichloromethane, three times with diethyl ether and dried under vacuum at room temperature overnight. A small portion of the resin was used to determine the charge of Fmoc-Pro. The rest of the resin was stirred with 4 ml of DMA three times for 5 minutes and then 1 hour at room temperature with a solution of (8: 1: 1) DMA / pyridine / acetic anhydride (5 ml). the resin was drained and washed with DMA, three times with methanol, three times with dichloromethane and three times with diethyl ether. The resin was dried under vacuum overnight at room temperature overnight and then used in subsequent solid phase peptide synthesis.
Synthesis of the Previous Peptide In the synthesis of the above peptide, the amino acids, the coupling conditions and the synthetic protocol used were identical to those described in Example 1. After finishing the synthesis, the peptide and protecting groups were split at room temperature using (95: 5) TFA / anisole (3 ml) for 3 hours. The resin was drained and washed three times with methanol. The combined filtrates were concentrated in vacuo and diethyl ether was added to the residue. The solid precipitate was filtered. The crude product was purified through C-18 column chromatography using a solvent mixture ranging in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-D-lle-Thr-Nva-lle-Arg-ProNHethyl (1-pyrrolidine) as the bis-trifluoroacetate salt: R1 = 4.40 min (gradient of 20 to 95% acetonitrile in water containing 0.01 M NH4Ac for a period of 10 minutes; MS (ESI) m / e 1063 (M + H) +; Anal.Amino acid: 0.95 Sar; 1.0 Gly; 0.86 Val; 1.63 lie; 0.56 Thr; 1.38 Nva; 0.88 Arg; 1.07 Pro.
Example 6 N-Ac-Sar-Gly-Val-DI le-Thr-N va-I le-Arg-ProNHethyl (1-piperidine) The procedure described in Example 5 was used psro substituting 1- (2-aminoethyl) piperidine for 1- (2-aminoethyl) -pyrrolidine in the reductive alkylation step. After separation of the peptide from the resin and removal of the protecting groups, the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile- aciua containing 0.01% TFA. The pure fractions were freeze-dried to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHethyl- (piperidine) as the bis-trifluoroacetate salt: R! = 4.437 min (gradient of 20% to 95% acetonitrile in water containing 0.01 M NH Ac for a period of 10 minutes), MS (ESI) m / e 1077 (M + H) +; Anal. Amino acid: 1.11 Sar; 1.04 Gly; 0.99 Val; 1.77 lie; 0.61 Thr; 1.61 Nva; 0.97 Arg; 1.10 Pro.
Example 7 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHmethylcyclopropyl The procedure described in Example 1 was used but substituting (aminoethyl) cyclopropane for 1 (2-aminoethylpyrrolidine). After separation of the peptide from the resin and removal of the protecting groups, the crude product was purified through chromatography of the C-18 column using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHmethylcyclopropyl as the trifluoroacetate salt: Rt = 3.615 min (gradient from 20% to 95% acetonitrile in water containing 0.01 M NH4Ac for a period of 10 min.); MS (ESI) m / e 1020 (M + H) +; Anal. Amino acid: 1.01 Sar; 0.96 Gly; 0.96 Val; 1.66 Me; 0.53 Thr; 1.65 Nva; 1.08 Arg; 1.09 Pro.
Example 8 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHethyl-1- (R) -cyclohexyl The procedure described in Example 5 was used but
zz? zt lUZ, substituting (R) -1-cycloxylethylamine for 1- (2-aminoethylpyrrolid? pa) After separating the peptide from the resin and removing the protecting groups, the crude product was purified through chromatography of C-18 column using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHethyl-1 - (R) -cyclohexyl as the trifluoroacetate salt: Rt = 5.196 min. (gradient from 20% to 95% acetonitrile in water containing 0.01 M NH Ac for a period of 10 minutes); MS (ESI) m / e 1076 (M + H) +; Anal. Amino acid: 1.19 Sar; 0.99 Gly; 0.62 Val; 1.47 lie, 0.48 Thr; 1.57 Nva; 1.01 Arg; 0.83 Pro.
Example 9 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNH (2-hydroxyethyl) The procedure described in Example 5 was used but replacing O-TBDMS-ethanolamine for 1- ( 2-aminoethylpyrrolidone). After separating the peptide from the resin and removing the protecting groups, the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNH (2-hydroxyethyl) as the trifluoroacetate salt: Rt = 4.04 min. (gradient from 20% to 95% acetonitrile in water containing 0.01 M NH Ac for a period of 10 minutes); MS (ESI) m / e 1010 (M + H) +; Anal. Amino acid: 1.04 Sar; 1.01 Gly; 0.98 Val; 1.59 lie; 0.44 Thr; 1.45 Nva; 0.99 Arg; 1.96 Pro.
Example 10 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNH2 The procedure described in Example 5 was used but replacing Fmoc-Pro-Síeber amide resin for the H-Pro resin -CITrt. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture. varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNH2 as the trifluoroacetate salt: Rt = 4.063 min. (gradient from 20% to 95% acetonitrile in aciua containing 0.01 M NH4Ac for a period of 10 minutes); MS (ESI) m / e 966 (M + H) +; Anal. Amino acid: 0.87 Sar; 0.98 Gly; 0.94 Val; 1.73 Me; 0.47 Thr; 1.35 Nva; 1.02 Arg; 1.05 Pro.
Example 11 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNH2CH2OCH3 The procedure described in Example 5 was used but substituting 2-methoxy-ethylamine for 1- (2-aminoethylpyrrolidine). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNH2CH2-OCH3 as the trifluoroacetate salt: Rt = 3.40 min. (gradient from 20% to 95% acetonitrile in water containing 0.01 M NH4Ac for a period of 10 minutes); MS (ESI) m / e 1024 (M + H) +; Anal. Amino acid: 1.02 Sar; 1.06 Gly; 0.97 Val; 1.54 lie; 0.47 Thr; 1.81 Nva; 0.97 Arg; 1 25 Pro.
Example 12 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH2-cyclohexyl The procedure described in Example 5 was used but replacing cyclohexylethylamine for 1- (2-aminoethylpyrrolidine, a).
After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH2-cyclohexyl as the trifluoroacetate salt: R, = 4.97 min .. (gradient of 20% to 95% acetonitrile in water containing 0.01 M NH Ac for a period
¿¿WÍOiMtiliíHMMa- of 10 minutes); MS (ESI) m / e 1076 (M + H) +; Anal Amino acid- 0 87 Sar; 1.00 Gly; 0.88 Val; 1.34 He; 0.44 Thr; 1.61 Nva; 1.07 Arg; 1.05 Pro.
Example 13 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH2CH3 The procedure described in Example 1 was used but replacing propylamine for ethylamine. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNH2CH2CH2CH3 as the trifluoroacetate salt: R, = 3.68 min .. (gradient from 20% to 95%). % acetonitrile in water containing 0.01 M NH4Ac for a period of 10 minutes); MS (ESI) m / e 1008 (M + H) +; Anal. Amino acid: 0.94 Sar; 1.09 Gly; 0.96 Val; 1.58 lie; 0.51 Thr; 1.78 Nva; 0.96 Arg; 1.23 Pro.
Example 14 N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCH2OCH3 The procedure described in Example 1 was used but replacing Fmoc-D-alolle for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonite ilo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-allolle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 22.5 min .. (gradient from 20% to 95% of acetonitrile in water containing 0.01 TFA over a period of 30 minutes); MS (ESI) m / e 994 (M + H) +; Anal. Amino acid: 0.95 Sar; 0.96 Gly; 0.97 Val; 0.99 lie; 0.54 Thr; 1.66 Nva; 1.14 Arg; 1.08 Pro.
Example 15 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2OCH3 The procedure described in Example 1 was used but replacing Fmoc-D-Leu for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2OCH3 as the trifluoroacetate salt: R, = 3.54 min. (gradient of 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 10 minutes); MS (ESI) m / e 094 (M + H) +; Anal. Amino Acid: 1.00 Sar; 0.93 Gly; 0.96 Val; 1.02 Leu;
0. 58 Thr; 1.50 Nva; 0.99 lie; 1.14 Arg; 1.08 Pro.
Example 16 N-Ac-Sar-Gly-Val-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-lle for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.28 min (gradient from 10% to 30% acetonitrile in water containing 0.01% of TFA during a period of 30 minutes); MS (ESI) m / e 994 (M + H) +; Anal. Amino acid: 095 Sar; 0.94 Gly; 0.89 Val; 1.70 Me; 0.52 Thr; 1.67 Nva; 0.99 Me; 1.27 Arg; 1.06 Pro.
Example 17 N-Ac-Sar-Gly-Val-Gly-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Gly for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-Gly-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 2.47 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 938 (M + Hf; Anal. Amino Acid: 1.10 Sar; 1.94 Gly; 1.03 Val; 0.98 Me; 0.54 Thr; 1.61 Nva; 1.28 Arg; 1.05 Pro.
Example 18 N-Ac-Sar-Gly-Val-D-Val-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Val for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% ac-tonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Val-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.13 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 980 (M + H) +; Anal. Amino acid: 1.07 Sar; 1.0 Gly; 2.01 Val; 0.99 Me; 0 62 Thr; 1.54 Nva; 1.49 Arg; 1.11 Pro.
Example 19 N-Ac-Sar-Gly-Val-allolle-Thr-Nva-lle-Arg-ProNHCH2OCH3 (SEQ ID NO: 5) The procedure described in Example 1 was used but replacing Fmoc-alolle for Fmoc-D-lle . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-allolle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.174 min.
(gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 994 (M + H) +; Anal. Amino acid: 1.02 Sar; 0.99 Gly; 0.95 Val; 1.29 Me;
0. 45 Thr; 1.52 Nva; 1.54 Arg; 1.07 Pro.
Example 20 N-Ac-Sar-Gly-Val-D-Ala-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Ala for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Val-D-Ala-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: R, = 3.826 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 952 (M) + and 908 (M-44) \
Example 21 N-Ac-Sar-Gly-Val-D-Lys-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Lys (Boc) for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Lys-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.544 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1009 (M) + and 965 (M-44) \
Example 22 N-Ac-Sar-Gly-Val-D-Met-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but
riittBMSMiiÉfa-iiM-N.MÍ-H ^^^^^^^. ^ U ^ substituting Fmoc-D-Met for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Met-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.141 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1C12 (Mf.
Example 23 N-Ac-Sar-Gly-Val-D-Nle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Nle for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Nle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.383 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 994 (M) +.
Example 24 N-Ac-Sar-Gly-Val-D-Phe-Thr-Nva-lle-Arg-ProNHCH2OCH3 The procedure described in Example 1 was used but replacing Fmoc-D-Phe for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Phe-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.476 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1028 (Mf.
Example 25 N-Ac-Sar-Gly-Val-D-Trp-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Trp (Boc) for Fmoc-D-lle . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Trp-Thr-Nva-Me-Arg-ProNHCH2CH3 as the trifluoroacetate salt. Rt = 4,430 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1024 (Mf.
Example 26 N-Ac-Sar-Gly-Val-D-Tyr-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Tyr (2-CITrt) for Fmoc-D -lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Tyr-Thr-Nva-Me-Arg-ProNHCH2CH3 as the trifluoroacetate salt: R, = 3,964 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1045 (Mf.
Example 27 N-Ac-Sar-Gly-Val-D-4,4'-Biphenylala-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-4,4'-biphenylala for Fmoc-D-lle. After separating the peptide from the resin and removing the groups
HEMMÉILHIMÉtMIHB «ÉKÍáBá protectores using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile -water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-4,4'-Biphenylalan-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 5.005 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1104 (Mf.
Example 28 N-Ac-Sar-Gly-Val-D-Cha-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Cha for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Cha-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 5.005 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1034 (f Example 29 N-Ac-Sar-Gly-Val-D-Chg-Thr-Nva-l le-Arg-ProN HCH2CH3 The procedure described in Example 1 was used but replacing Fmoc -D-Chg for Fmoc-D-lle After separating the peptide from the resin and removing the protective groups using (9: 1) TFA / anisole (3 ml), the crude product was purified by chromatography of column C-1 8 using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA.The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val- D-Chg-Thr-Nva-l le-Arg-ProN HCH2CH3 as the trifluoroacetate salt: Rt = 4.377 rr in. (Gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes ); MS (APCI) m / e 977 (Mf.
Example 30 N-Ac-Sar-Gly-Val-D-4-CI Phe-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-4-CI Phe for Fmoc- Dl him After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-1 column chromatography using a solvent mixture. varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Cl Phe-Thr-N va-Me-Arg-ProN HCH2CH3 as the trifluphroacetate salt: Rt = 4.674
- a ^ rf - »..
min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1018 (Mf.
Example 31 N-Ac-Sar-Gly-Val-D-Hphe-Thr-Nva-lle-Arg-ProNHCH2 (CH3) 2 The procedure described in Example 1 was used but replacing Fmoc-D-Hphe for Fmoc-D- lle After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Hphe-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.597 min.
(gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1042 (Mf and 998 (M-44f.
EXAMPLE 32 N-Ac-Sar-Gly-Val-D-Dehydroleu-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Dehydroleu for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through column chromatography of C-1 8 using a mixture of solvent varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Dehydroleu-Thr-Nva-l le-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.1707 min. (g radient from 10% to 30% acetonitrile in aciua containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 992 (Mf and 992 (M-44f.
Example 33 N-Ac-Sar-Gly-Val-D-3-CF3Phe-Thr-Nva-l le-Arg-ProN HCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-3-CF3Phe for Fmoc- Dl him After separating the peptide from the resin and removing the protective groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture. varying in a gradient from 10% to 50% acetonitrile-ag ua containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-3-CF3Phe-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.825 min. (gradient of 10% to 30% of acetonitrile in a g uua containing 0.01% of TFA during a period of 30 minutes); MS (APCI) m / e 1097 (Mf and 1053 (M-44f.
Example 34 N-Ac-Sar-Gly-Val-D-pentaFPhe-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-pentaFPhe for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-pentaFPhe-Thr-Nva-Me-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4810 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1118 (Mf and 1075 (M-44f.
Example 35 N-Ac-Sar-Gly-Val-D-3,4-diCIPhe-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-3,4-diCIPhe for Fmoc-D-lle. After separating the peptide from the resin and removing the protective groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-3,4-d? CIPhe-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4,911 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1100 (M + 3f.
Example 36 N-Ac-Sar-Gly-Val-D-3-CIPhe-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-3-CIPhe for Fmoc-D- lle After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-3-CIPhe-Thr-Nva-Me-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.689 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1062 (Mf.
Example 37 N-Ac-Sar-Gly-Val-D-2-Thienylala-Thr-Nva-lle-Arg-ProNHCH2CH; The procedure described in Example 1 was used but replacing Fmoc-D-2-Thienylala for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Val-D-2-T-enylala-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: R, = 4.388 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1034 (Mf.
Example 38 N-Ac-Sar-Gly-Val-D-3-CNPhe-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-3-CNPhe for Fmoc-D- lle After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crudc product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-3-CNPhe-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.361 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1009 (Mf.
Example 39 N-Ac-Sar-Gly-Val-D-3,3-Diphenylalan-Thr-Nva-lle-Arg-ProNHCH2CH; The procedure described in Example 1 was used but replacing Fmoc-D-3,3-Diphenylala for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Diphenylala-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4778 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); S (APCI) m / e 1104 (Mf.
Example 40 N-Ac-Sar-Gly-Val-D-3-Benzothienylala-Thr-Nva-lle-Arg-ProNHCH2CH3
The procedure described in Example 1 was used but replacing Fmoc-D-3-Benzothienylala for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Val-D-3-Benzothienylala-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.797 min. (10% to 30% gradient of acetonitrile in water containing 0.01% TFA for a period of 30 minutes); MS (APCI) m / e 1084 (Mf.
Example 41 N-Ac-Sar-Gly-Val-D-3,4-diF-Phe-Thr-Nva-l le-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-3, 4-diF-Phe for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-diF-Phe-Thr-Nva-l le-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.608 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1064 (Mf.
Example 42 N-Ac-Sar-Gly-Val-D-l le-Thr-DNva-l le-Arg-ProN HC HzCHa The procedure described in Example 1 was used but replacing Fmoc-DNva for Fmoc-Nva. After separating the peptide from the resin and removing the protective groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture. varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-DNva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.75 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 994 (M + Hf; Anal.Amino acid: 1.08 Sar, 0.96 Gly; 0.95 Val; 1.74 Lile; 0.50 Thr; 1.69 Nva; 1.26 Arg; 1.09 Pro.
Example 43 N-Ac-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Gln (Trt) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-GIn-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.047 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1023 (M + Hf; Anal Amino Acid: 1.15 Sar; 0.96 Gly; 0.63 Val; 1.7 He; 0.46 «• 112 Thr; 0.65 Glu; 1.45 Arg; 1.04 Pro.
Example 44 N-Ac-Sar-Gly-Val-D-lle-Thr-Cha-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Cha for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a mixture
of solvent varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Cha-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4503 min. (gradient from 10% to 30% acetonitrile in water containing 0.01%
of TFA over a period of 30 minutes); MS (ESI) m / e 1048 (M + Hf; Anal.Amino acid: 1.18 Sar, 0.94 Gly; 0.59 Val; 1.65 He; 0.45 Thr; 0.37 Cha; 1.45 Arg; 1.06 Pro.
Example 45 N-Ac-Sar-Gly-Val-D-lle-Thr-Gly-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Gly for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified
through C-18 column chromatography using a r-r * 113 mixture of solvent varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Val-D-lle-Thr-Gly-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.11 min. 5 (10% to 30% gradient of acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 952 (M + H) "
Example 46 N-Ac-Sar-Gly-Val-D-lle-Thr-Ala-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Ala for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a mixture
of solvent varying in a 10% to 50% acetonitoplo-water gradient containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Val-D-lle-Thr-Ala-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.16 min. (gradient from 10% to 30% acetonitrile in water containing 0.01%
of TFA over a period of 30 minutes); MS (ESI) m / e 966 (M + H) "
Example 47 N-Ac-Sar-Gly-Val-D-He-Thr-Val-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Val for Fmoc-Nva. After separating
^? Peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Val-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.36 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 994 (M + H) "
Example 48 N-Ac-Sar-Gly-Val-D-lle-Thr-Abu-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Abu for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Abu-lle-A, rg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.23 min. (gradient from 10% to 30% acetonitrile in water containing 0.C1% TFA over a period of 30 minutes); MS (ESI) m / e 380 (M + Hf.
áb ^ áá¡ái? - ^ * á »mi ^^ ¡a ^ - -a ^ i ^ 1 1 5 Example 49 N-Ac-Sar-Gly-Val-D-lle-Thr-Alilgly-lle-Arg-ProNHCHzCHa The procedure described in Example 1 was used but replacing Fmoc-Aiilgly for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were
lyophilized to produce N-Ac-Sar-Gly-Val-D-l le-Thr-Allygly-l le-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.40 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ES I) m / e 992 (M + Hf. 15 Example 50 N-Ac-Sar-Gly-Val-D-lle-Thr-Octylgly-lle-Arg-ProNHCHzCHa The procedure described in Example 1 was used but replacing Fmoc-Octilgly for Fmoc-Nva. After separating the
peptide from the resin and the removal of the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through column chromatography of C-1 8 using a solvent mixture varying in a radium of 10% to 50% acetonite 'ilo-water containing 0.01% TFA. The pure fractions were
lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Octylgly -l le-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 5.30 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1064 (M + Hf.
Example 51 N-Ac-Sar-Gly-Val-D-lle-Thr-Met-lle-Arg-ProNHCHzCHa The procedure described in Example 1 was used but replacing Fmoc-Met for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Met-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.48 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1027 (M + H + f.
Example 52 N-Cyclohexylacetyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing cyclohexylacetic acid for acetic acid. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Cyclohexyl acetyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCHzCH3 as the trifluoroacetate salt: Rt = 5.11 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1076 (M + H + f; Anal.Amino acid: 1.15 Sar; 0.97 Gly; 0.95 Val; 1.79 He; 0.54 Thr; 1.66 Nva; 1.28 Arg; 1.08 Pro.
Example 53 N- (2-Me-Nicotinyl) -Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but substituting 2-Me-nicotinic acid for acid acetic. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N- (2-Me-Nicotinyl) -Sar-Gly-Val-D-He-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt Rt = 5.11 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1071 (M + Hf; Anal. Amino Acid- 1.19 Sar; 1 01 Gly; C 99 Val; 1.79 He; 0.57 Thr; 1.70 Nva; 1.59 Arg; 1.17 Pro.
Example 54 N-Succinyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but acetylating the peptide resin after coupling and deprotection of Fmoc-Sar) with a mixture of (1: 1) succinic anhydride / pyridine (2 ml) overnight. After washing the resin and separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 2.72 min. (Gradually from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1052 (M + Hf; Anal.Amino acid: 1 16 Sar; 1.05 Gly; 0.95 Val; 1.85 He; 0.57 Thr; 1.70 Nva; 1.59 Arg; 1 17 Pro.
Example 55 N-Nicotinyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but substituting nicotinic acid for acetic acid in the last coupling. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-nicotinyl-Sar-Gly-Val-D-lle-Thr-Nva-He-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.6 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1057 (M + Hf; Anal.Amino acid: 1.03 Sar; 0.89 Gly; 0.81 Val; 1.48 He; 0.40 Thr; 1.46 Nva; 1.07 Arg; 1.04 Pro.
Example 56 N-propionyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but substituting propionic acid for acetic acid in the last coupling. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-propionyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.7 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1008 (M + Hf; Anal.Amino acid: 0.93 Sar; 0.97 Gly; 0.88 Val; 1.60 He; 0.44 Thr; 1.58 Nva; 1.17 Arg; 1 10 Pro.
Example 57 N-MeOacetyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but substituting methoxyacetic acid for acetic acid in the last coupling. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-MeOacetyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCHZCHa as the trifluoroacetate salt: Rt = 3.45 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1024 (M + Hf; Anal. Amino Acid: 1.12 Sar; 1.06 Gly; 0.94 Val; 1.62 He; 0.48 Thr; 1.91 Nva; 1.40 * Arg; 1.27 Pro.
Example 58 N-Shikimil-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCHzCHs The procedure described in Example 1 was used but replacing shikimic acid for acetic acid in the last coupling. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Shikimil-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.0 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1108 (M + Hf; Anal. Amino Acid: 1.22 Sar; 1.06 Gly; 0.94 Val; 1.80 He; 0.55 Thr; 1.70 Nva; 1.28 Arg; 1.26 Pro.
Example 59 N- (2-Furoyl) Nicotinyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg- ProNHCH2CH3 The procedure described in Example 1 was used but substituting 2-furoic acid for acetic acid in the last coupling. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N- (2-Furoyl) -Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.0 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1046 (M + Hf; Anal. Amino Acid: 1.02 Sar; 1.00 Gly; 0.99 Val; 1.66 Lie; 0.45 Thr; 1.75 Nva; 1.45 Arg; 1.21 Pro.
Example 60 N-Butyryl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but substituting butyric acid for acetic acid in the last coupling. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% of
TFA The pure fractions were lyophilized to produce N-Butyryl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.03 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1022 (M + Hf; Anal. Amino Acid: 1.13
HE; 0.99 Gly; 1.01 Val; 1.93 He; 0.67 Thr; 1.61 Nva; 1.45 Arg; 1.08
Pro.
^ z ^ x ^ x-- -,., ^ .., ...... ^ X Example 61 N- (Tetrahydro-2-fluoroyl) -Sar-Gly-Val-D-lle-Thr-Nva- lle-Arg- ProNHCH2CH3 The procedure described in Example 1 was used but replacing tetrahydro-2-furoic acid for acetic acid in the last coupling. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% of
TFA The pure fractions were lyophilized to produce N- (tetrahydro-2-fluoroyl) -Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg- ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.91 min.
(gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1050
(M + Hf; Anal. Amino acid: 1.12 Sar; 0.97 Gly; 0.88 Val; 1.41 He;
0. 42 Thr; 1.60 Nva; 1.43 Arg; 1.03 Pro.
Example 62 N- [CH3C (O) NH- (CH2) 2-O- (CH2) 2-O-CH2-C (O)] - Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg -ProNHCH2CH3 The procedure described in Example 1 was used but replacing with Fmoc-8-amino-3,6-dioxo-ocatnoic acid after coupling of Fco-Sar, after the removal of the terminal Fmoc, the peptide resin was coupled with acetic acid as
-Iá iHí tmm described above. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N- [CH3C (O) NH- (CH2) 2-O- (CH2) 2-O-CH2-C (O)] - Sar-Gly-Val-D-lle-Thr- Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.32 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1139 (M + Hf; Anal. Amino Acid: 1.04 Sar; 1.01 Gly; 0.91 Val; 1.67 He; 0.53 Thr; 1.77 Nva; 1.39 Arg; 1.02 Pro.
Example 63 N-te-N'-Acetyl-ICHJsCÍOH-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg- ProNHCH2CH3 The procedure described in Example 1 was used but replacing with Fmoc-6 acid amino-hexanoic after Fmoc-Sar coupling, after removal of the terminal Fmoc, the peptide resin was coupled with acetic acid as described above. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N- [6-N'-acetyl- (CH2) 5-C (O)] - Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the salt of trifluoroacetate: Rt = 3.60 min. (gradient of 10%> to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1107 (M + Hf; Anal. Amino Acid: 1.13 Sar; 0.96 Gly; 0.89 Val; 1.42 He; 0.43 Thr; 1.68 Nva; 1.44 Arg; 1.04 Pro.
Example 64 N-Hexanoyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but substituting hexanoic acid for acetic acid in the last coupling. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Hexanoyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.95 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1050 (M + Hf; Anal. Amino acid: 1.07 Sar; 0.93 Gly; 1.02 Val; 1.95 He; 0.56 Thr; 1.31 Nva; 1.52 Arg; 1.05 Pro.
Example 65 N- [4-N'-Acetyl-butyryl] -Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg- ProNHCH2CH3 The procedure described in Example 1 was used but replacing with Fmoc-4 acid -amino-butyric after the coupling of Fmoc-Sar, after the removal of the terminal Fmoc, the peptide resin was coupled with acetic acid as described above. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% of
TFA The pure fractions were lyophilized to produce N- [4-N'-Acetyl-butyryl] -Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.09 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1079 (M + Hf; Anal.
Amino acid: 1.03 Gaba; 1.07 Sar; 0.93 Gly; 1.00 Val; 1.90 He; 0.54
Thr; 1.30 Nva; 1.54 Arg; 1.06 Pro.
Example 66 H-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but omitting the coupling of acetic acid at the end. After separating the peptide from the resin and removing the groups
Protein using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce H-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the bistrifluoroacetate salt: Rt = 3.65 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 952 (M + Hf; Anal. Amino Acid: 1.00 Sar; 1.00 Gly; 0.99 Val; 1.67 He; 0.50 Thr; 1.76 Nva; 1.47 Arg; 1.22 Pro.
Example 67 N-Ac-Sar-Gly-Asn-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing with Fmoc-Asn (Trt) for Fmoc-Val. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Asn-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the bistrifluoroacetate salt: Rt = 2.45 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1C09 (M + Hf; Anal. Amino acid: 1.05 Sar; 0.98 Gly; 0.96 Asp; 1.7 lie;
^ gi ^^ g 0.48 Thr; 1.54 Nva; 1.32 Arg; 1.07 Pro.
EXAMPLE 68 N- [CH3C (O) NH- (CH2) 2-O- (CH2) 2-O-CH2-C (O)] - Gly-Val-D-lle-Thr-Nva-He-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing with Fmoc-8-amino-3,6-dioxo-octanoic acid for
Fmoc-Sar. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through column chromatography of
C-18 using a solvent mixture varying in a gradient of
% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N- [CH3C (O) NH- (CH2) 2-O- (CH2) 2-O-CH2-C (O)] - Gly-Val-D-lle-Thr-Nva- lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.12 min.
(gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1068
(M + Hf; Anal. Amino acid: 0.93 Gly; 1.02 Val; 1.97 He; 0.57 Thr;
1. 31 Nva; 1.54 Arg; 1.05 Pro.
Example 69 N-Ac-Pro-Gly-Asn-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing with Fmoc-Pro for Fmoc-Sar. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Pro-Gly-Asn-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.30 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1020 (M + Hf; Anal. Amino Acid: 0.92 Gly; 0.99 Val; 1.80 He; 0.50 Thr; 1.32 Nva; 1.53 Arg; 2 09 Pro.
Example 70 N-Ac-Gly-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing with Fmoc-Gly for Fmoc-Sar. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Gly-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.08 rrin. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 980 (M + Hf; Anal. Amino Acid: 1.89 Gly; 1.02 Val; 1.91 He; 0.52 Thr;
1. 35 Nva; 1.57 Arg; 1.09 Pro.
Example 71 N-Ac-Ala-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing with Fmoc-Ala for Fmoc-Sar. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Ala-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.00 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e £ 94 (M + Hf; Anal. Amino Acid: 1.01 Ala; 0.93 Gly; 1.01 Val; 1.92 He; 0.56 Thr; 1.30 Nva; 1.51 Arg; 1.05 Pro.
Example 72 N-Ac-NEtGly-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing with Fmoc-NEtGly for Fmoc-Sar. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a mixture
ÜHHMiíMkl mSttÉmámÉ m of solvent varying in a gradient of 10% to 50% of acetonitplo-agua containing 0.01% of TFA. The pure fractions were lyophilized to produce N-Ac-NEtGly-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 4.24 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1008 (M + Hf; Anal. Amino Acid: 0.95 Gly; 1.04 Val; 1.99 He; 0.59 Thr; 1.34 Nva; 1.50 Arg; 1.01 Pro.
Example 73 N-Ac-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing with Fmoc-Leu for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: R, = 4.348 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1008 (M + Hf; Anal. Amino Acid: 0.88 Sar; 0.99 Gly; 0.95 Val; 1.03 He; 0.55 Thr; 1.12 Leu; 1.53 Arg; 1.07 Pro.
» ^ -? M / i &k & amp; amp; amp; amp; amp; Example 74 N-Ac-Sar-Gly-Val-D-lle-Thr-Ser-lle-Arg-ProNHCHzCHs The procedure described in Example 1 was used but replacing with Fmoc-Ser (tBu) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Serle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: R, = 3.963 min.
(gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 982
(M + Hf; Anal. Amino acid: 0.91 Sar; 0.97 Gly; 1.00 Val; 1.03 lie; 0.56 Thr; 0.23 Ser; 1.52 Arg; 1.08 Pro.
Example 75 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-D-AlaNH2 The procedure described in Example 10 was used but replacing amide resin Fmoc-D-Ala-Sieber for amine resin Fmoc-Pro-Sieber. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole
(3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-D-AlaNH2 as the trifluoroacetate salt: Rt = 4.117 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1037 (M + Hf; Anal.Amino acid: 0 85 Sar; 0.94 Gly; 0.92 Val; 1.83 He; 0.54 Thr; 1.18 Nva; 1.01 Arg; 1 04 Pro; 1.01 Ala.
Example 76 10 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-D-ProNHCH2CH3 The procedure described in Example 10 was used but replacing amine resin Fmoc-D-Pro-Sieber for Fmoc-Pro-Sieber ethylamide resin. After separating the peptide from the resin and removing the protective groups using (9: 1)
TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-acua containing 0.01% TFA. The pure fractions were freeze-dried to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-D-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 4.20 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 994 (M + Hf.
* - • "- ^^^^" Example 77 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-AbuNHCH2CH3 The procedure described in Example 10 was used but replacing ethylamide resin Fmoc -Abu-Sieber for Fmoc-Pro-Sieber amide resin After separating the peptide from the resin and removing the protective groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through of C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA.The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val D-lle-Thr-Nva-lle-Arg-AbuNHCH2CH3 as the trifluoroacetate salt: R, = 4.35 min. (Gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 982 (M + Hf.
Example 78 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-PheNHCH2CH3 The procedure described in Example 10 was used but replacing ethylamide resin Fmoc-Phe-Sieber for Fmoc amide resin Pro-Sieber. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole
(3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-PheNHCH2CH3 as the trifluoroacetate salt: Rt = 4.73 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1044 (M + Hf.
Example 79 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Tic-NHCH 2 CH 3 The procedure described in Example 10 was used but replacing ethylamide resin Fmoc-Tic-Sieber for amide resin Fmoc-Pro-Sieber. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Tic-NHCH2CH3 as the trifluoroacetate salt: R, = 4.68 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1056 (M + Hf.
Example 80 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Hyp-NHCH 2 CH 3 The procedure described in Example 10 was used but replacing ethylamide resin Fmoc-Hyp-Sieber for amide resin Fmoc-Pro-Sieber. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Hyp-NHCH2CH3 as the trifluoroacetate salt: Rt = 3.95 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1010 (M + Hf.
Example 81 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Aib-NHCH 2 CH 3 The procedure described in Example 10 was used but replacing ethylamide resin Fmoc-Aib-Sieber for amide resin Fmoc-Pro-Sieber. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Aib-NHCH2CH3 as the trifluoroacetate salt: Rt = 4.25 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 982 (M + Hf.
m ^^^^^ u ^ l ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ - - - 7r- ~ • -fr Example 82 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-D-Ala-NHCH 2 CH 3 The procedure described in Example 10 was used but replacing resin of ethylamide Fmoc-D-Ala-Sieber for amide resin Fmoc-Pro-Sieber. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-D-Ala -NHCH2CH3 as the trifluoroacetate salt: R, = 2.95 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 968 (M + Hf.
Example 83 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pip-NHCH 2 CH 3 The procedure described in Example 10 was used but replacing ethylamide resin Fmoc-Pip-Sieber for amide resin Fmoc-Pro-Sieber. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole
(3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pip-NHCHzCHa as the trifluoroacetate salt: R = 3.30 min (gradient from 10% to 30% of acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1008 (M + Hf.
Example 84 N-Ac-Sar-Gly-Val-D-Tyr (Et) -Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Tyr (Et) for Fmoc- D-lle. After separating the peptide from the resin and removing the protectoid groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Tyr (Et) -Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 6.01 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1072 (Mf.
Example 85 N-Ac-Sar-Gly-Val-D-Cys (tBu) -Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Cys (tBu) for Fmoc- D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Cys (tBu)) - Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: R, = 5.96 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1040 (Mf.
Example 86 N-Ac-Sar-Gly-Val-D-Cys (Acm) -Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Cys (Acm) for Fmoc- D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Cys (Acm) -Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: R, = 5 12 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) n / a 1044 (Mf.
^^ MH-TM- ^ UIB Example 87 N-Ac-Sar-Gly-Val-D-Tyr (Bzl) -Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc- D-Tyr (Bzl) for Fmoc-D-lle. After separating the peptide from the resin and removing the protective groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Tyr (Bzl) -Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 6.74 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) rn / e 1135 (Mf.
Example 88 N-Ac-Sar-Gly-Val-D-Ser (Bzl) -Thr-N va-I le-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Ser (Bzl) for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Ser (Bzl) -Thr-Nva-lle-Arg-Pro-NHCH 2 CH 3 as the trifluoroacetate salt: R, = 5 97 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1058 (Mf.
Example 89 N-Ac-Sar-Gly-Val-D-1Nal-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-1Nal for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-1 Nal-Thr-Nva-lle-A g-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 6.30 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1081 (Mf.
Example 90 N-Ac-Sar-Gly-Val-D-t-Butylgly-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-tBitilgly for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-t-Butylgly-Thr-Nvale-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 5.46 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 994 (Mf.
Example 91 N-Ac-Sar-Gly-Val-D-Orn-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Orn (Boc) for Fmoc-D-lle . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Orn-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: R, = 1.69 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 995 (Mf.
Example 92 N-Ac-Sar-Gly-Val-D-Thr (Bzl) -Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Thr (Bzl) for Fmoc- D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Val-D-Thr (Bzl) -Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: R, = 6.10 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1072 (Mf.
Example 93 N-Ac-Sar-Gly-Val-D-2Nal-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-2Nal for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-2Nal-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 6.33 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (APCI) m / e 1078 (M) "
Example 94 N-Ac-Sar-Gly-Val-D-Phe (4-Me) -Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Phe (4-Me ) for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Phe (4-Me) -Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3.654 min. (gradient of 10% to 30% of acetonitrile in aciua containing 0.01% of TFA during a period of 30 minutes); MS (ESI) m / e 1042 (Mf.
Example 95 N-Ac-Sar-Gly-Val-D-Phe (3,4-diMeO) -Thr-Nva-lle-Arg-ProNHCH2CH3
The procedure described in Example 1 was used but replacing Fmoc-D-Phe (3,4-diMeO) for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Phe (3,4-diMeO) -Thr-Nva-lle-Arg-Pro-NHCH 2 CH 3 as the trifluoroacetate salt: R, = 3,006 min . (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1088 (Mf.
Example 96 N-Ac-Sar-Gly-Val-D-Phe (3,4,5-triF) -Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Phe (3,4,5-triF) for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Phe (3,4,5-triF) -Thr-Nva-lle-Arg-Pro-NHCH 2 CH 3 as the trifluoroacetate salt: R, = 3,848 min (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1082 (Mf.
^ MHÉ-UÍÍ-1ÍJ Example 97 N-Ac-Sar-Gly-Val-D-Phe (4-NO2) -Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D -Phe (4-NO2) for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Val-D-Phe (4-NO 2) -Thr-Nva-lle-Arg-Pro-NHCH 2 CH 3 as the trifluoroacetate salt: Rt = 3,483 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1073 (Mf.
Example 98 N-Ac-Sar-Gly-Val-D-Pen-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Pen (Trt) for Fmoc-D-lle . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Pen-Thr-Nvale-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2928 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1012 (Mf.
Example 99 N-Ac-Sar-Gly-Val-D-Pen (Acm) -Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Pen (Acm) for Fmoc- D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Pen (Acm) -Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.415 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1083 (Mf.
Example 100 N-Ac-Sar-Gly-Val-D-Pen (Bzl) -Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Pen (Bzl) for Fmoc- D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Val-D-Pen (Bzl) -Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 4.124 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1102 (Mf.
Example 101 N-Ac-Sar-Gly-Val-D-Abu-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used to substitute Fmoc-D-Abu for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Abu-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.533 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 966 (Mf.
MTMTM Example 102 N-Ac-Sar-Gly-Val-D-Phe (4-NH 2) -Thr-Nva-lle-Arg-ProNHCH 2 CH 3 The procedure described in Example 1 was used but replacing Fmoc-D-Phe (4- Boc-NH2) for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were chosen to produce N-Ac-Sar-Gly-Val-D-Phe (4-NH 2) -Thr-Nva-lle-Arg-Pro-NHCH 2 CH 3 as the trifluoroacetate salt. R | = 2,545 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1043 (Mf.
Example 103 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ala-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Ala for Fmoc-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ala-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.675 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 952 (Mf.
Example 104 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Gln-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Gln (Trt) for Fmoc-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Gln-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.46 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1009 (M.
Example 105 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Met-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Met for Fmoc-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a mixture.
-77 »z-Sixuiz V of solvent varying in a gradient of 10% to 50% of acetonitoplo-water containing 0.01% of TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Met-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: R = 3.219 rrin. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1012 (M.
Example 106 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Phe-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Phe for Fmoc-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Phe-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: R = 3.579 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1028 (Mf.
Example 107 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Pro-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Pro for Fmoc-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Pro-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.704 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 978 (Mf.
Example 108 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ser-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Ser (tBu) for Fmoc-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Ser-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.510 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 968 (Mf.
Example 109 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Trp-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Trp (Boc) for Fmoc-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Trp-A-g-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3.625 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1067 (Mf.
Example 110 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Tyr-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Tyr (tBu) for Fmoc-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Tyr-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: R, = 3.017 min.
(gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1044 (Mf.
Example 111 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Nva-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Nva for Fmoc-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Nva-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3.139 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 980 (Mf.
Example 112 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Asp-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Asp (OtBu) -OH) for Fmoc-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Asp-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: R, = 2.082 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 996 (Mf.
Example 113 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Gly-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Gly for Fmoc-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Gly-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2623 min.
(gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 938 (Mf.
Example 114 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Lys (Ac) -Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Lys (Ac) for Fmoc-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisoJ (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Lys (AC-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2599 min. (10% gradient to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1051 (M.
Example 115 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Leu-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Leu for Fmoc-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Leu-Ai g-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3.403 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 994 (Mf Example 116 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-2Nal-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-2Nal for Fmoc-lle After separating the peptide from the resin and removing the protected groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography. using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA.The pure fractions were
lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-2Nal-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 4.198 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1078 (M.
Example 117 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-1Nal-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-1Nal for Fmoc-lle. After separating the peptide from the resin and removing the protective groups
Using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-containing water. 0.01% of TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-1 Nal-Arg-25 Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 4.217 min.
^^^^. ^^^ ¡¡¡¡¡¡¡¡¡¡yX ^ X ^^ Xz (10% to 30% gradient of acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1078 (Mf.
Example 118 N-Ac-Sar-Gly-Val-D-Leu-Thr-N a-Allygly-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Alilgly for Fmoc-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Allygly-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2993 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 978 (Mf.
Example 119 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Cit-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Cit for Fmoc-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Cit-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.408 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1038 (M) +.
Example 120 N-Ac-Sar-Gly-Val-D-Leu-Ala-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Ala for Fmoc-Thr (tBu) After separating the Peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Ala-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3.481 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 964 (Mf.
Example 121 N-Ac-Sar-Gly-Val-D-Leu-Pro-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Pro for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Pro-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3621 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 990 (Mf.
Example 122 N-Ac-Sar-Gly-Val-D-Leu-Trp-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Trp (Boc) for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Trp-Nva-pe-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 4.378 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1079 (Mf.
Example 123 N-Ac-Sar-Gly-Val-D-Leu-Tyr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Tyr (tBu) for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Tyr-N lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: R, = 3.606 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) rn / e 1056 (Mf.
Example 124 N-Ac-Sar-Gly-Val-D-Leu-Nva-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Nva for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Nva-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3.870 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 992 (Mf.
Example 125 N-Ac-Sar-Gly-Val-D-Leu-Gly-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Gly for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude prodwas purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Gly-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: R, = 3.397 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 950 (Mf.
Example 126 N-Ac-Sar-Gly-Val-D-Leu-Lys (Ac) -Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Lys (Ac) for Fmoc-Thr ( tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude prodwas purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Lys (Ac) -Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3365 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1063 (Mf.
Example 127 N-Ac-Sar-Gly-Val-D-Leu-2Nal-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-2Nal for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude prodwas purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Val-D-Leu-2Nal-Nva-lle-Arg-Pro-NHCH 2 CH 3 as the trifluoroacetate salt: R = 4,992 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1090 (Mf.
Example 128 N-Ac-Sar-Gly-Val-D-Leu-1Nal-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-1Nal for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude prodwas purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-1 Nal-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 5.032 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1090 (M.
Example 129 N-Ac-Sar-Gly-Val-D-Leu-Octylgly-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Octilgly for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude prodwas purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Octylgly-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 5.90 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1062 (M.
M * ^ -U Example 130 N-Ac-Sar-Gly-Val-D-Leu-Gln-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Gln (Trt) for Fmoc -Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-GIn-Nva-lle-Arg-Pro-NHCH 2 CH 3 as the trifluoroacetate salt: R, = 3,323 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) rn / e 1021 (Mf.
Example 131 N-Ac-Sar-Gly-Val-D-Leu-Met-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Met for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Met-Nva-He-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3,901 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1024 (Mf.
Example 132 N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Ser (tBu) for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3.414 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 980 (Mf.
Example 133 N-Ac-Sar-Gly-Val-D-Leu-Allygly-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Alilgly for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Allygly-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3,801 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 990 (Mf.
Example 134 N-Ac-Sar-Gly-Val-D-Leu-lle-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-lle for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a silica gel. solvent varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-lle-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 4.028 rnin. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1006 (Mf.
Example 135 N-Ac-Sar-Gly-Val-D-Leu-D-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but
-rftt * i- ^ - ^ - ^^ - - ^ ™ _. ^ _ ^^ _ ^^ Éiííliííííííííáá * i¿á & í ?? ii * - replacing Fmoc-D-Thr ( tBu) for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-D-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: R, = 3.437 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 994 (Mf.
Example 136 N-Ac-Sar-Gly-Val-D-lle-Thr-lle-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-lle for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-lle-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3.54 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1008 (Mf; Anal.
Amino acid: 1.07 Sar; 0.94 Gly; 0.91 Val; 3.02 He; 0.47 Thr; 1.24 Arg; 1.04 Pro.
Example 137 N-Ac-Sar-Gly-Val-D-lle-Thr-Nle-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Nle for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitide-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nle Jle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3.80 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1006 (Mf.
Example 138 N-Ac-Sar-Gly-Val-D-lle-Thr-Cit-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Cit for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Cit-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.83 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1052 (Mf; Anal, acid: 1.05 Sar; 1.00 Gly; 1.00 Val; 2.13 He; 0.65 Thr; 1.11 Cit; 1.49 Arg; 1.10 Pro.
Example 139 N-Ac-Sar-Gly-Val-D-lle-Thr-Met (O2) -lle-Arg-ProNHCH2CH3
1 The procedure described in Example 1 was used but replacing Fmoc-Met (O2) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Met (O2) -lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.701 rnin. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1058 (Mf; Anal, acid: 1.36 Sar; 0.94 Gly; 0.62 Val; 2.06 He; 0.13 Thr; 0.66 Met (O2); 1.50 Arg; 0.68 Pro.
Example 140 N-Ac-Sar-Gly-Val-D-lle-Thr-Arg-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Arg (Pmc) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Arg-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 0.54 min. (gradient of 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1049 (Mf; Anal, acid: 0.92 Sar; 0.74 Gly; 0.86 Val; 2.00 He; 0.49 Thr; 2.67 Arg; 1.00 Pro.
Example 141 N-Ac-Sar-Gly-Val-D-lle-Thr-Tyr-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Tyr (tBu) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Tyr-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3.048 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1058 (Mf; Anal, acid: 0.88 Sar; 0.99 Gly; 0.97 Val; 1.97 He; 0.52 Thr; 0.92 Tyr; 1.58 Arg; 1.08 Pro.
Example 142 N-Ac-Sar-Gly-Val-D-lle-Thr-Glu-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Glu (OtBu) -OH for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Val-D-lle-Thr-Glu le-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: R, = 2348 min.
(gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1024 (Mf;
Anal, acid: 1.05 Sar; 1.024 Gly; 0.94 Val; 2.67 lie; 0.47 Thr; 0.94
Glu; 2.20 Arg; 1.09 Pro.
Example 143 N-Ac-Sar-Gly-Val-D-lle-Thr-Lys (Ac) -lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Lys (Ac) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Lys (Ac) -lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2744 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1065 (Mf; Anal, acid: 1.03 Sar; 0.99 Gly; 0.95 Val; 2.04 He; 0.66 Thr; 1.05 Lys; 1.41 Arg; 1.02 Pro.
Example 144 N-Ac-Sar-Gly-Val-D-lle-Thr-Propargylgly-lle-Arg-ProNHCH2CH;, The procedure described in Example 1 was used but replacing Fmoc-Propargilgly for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Propargylgly-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: o: Rt = 3,003 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 990 (Mf; Anal, acid: 1.05 Sar; 1.00 Gly; 0.93 Val; 2.10 He; 0.54 Thr; 1.71 Arg; 0.97 Pro.
Example 145 N-Ac-Sar-Gly-Val-D-Alolle-Thr-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Alolle for Fmoc-D-lle and Fmoc- Gln (Trt) for
Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of
% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Val-D-Alolle-Thr-Gln-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.704 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1023 (Mf; Anal, acid: 0.93 Sar;
Gly; 0.94 Val; 2.10 lie; 0.51 Thr; 0.87 Glu; 1.45 Arg; 1.03 Pro.
. • 'v jsaaMMMfa Example 146 N-Ac-Sar-Gly-Val-D-Leu-Thr-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Gln (Trt) for Fmoc-Nva . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-GIn-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2685 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1023 (Mf; Anal, acid: 0.98 Sar; 0.74 Gly; 0.95 Val; 1.04 lie; 0.49 Thr; 1 04 Leu; 0.94 Glu; 1.63 Arg; 0.97 Pro.
Example 147 N-Ac-Bullet-Sar-Gly-Val-D-pe-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 65 was used but replacing Fmoc-beta-alanine for Fmoc-4-am acid non-butyric
After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA.
jj ^^^ j ^ H ^^ pure fractions were lyophilized to produce N-Ac-Bala-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: R, = 2.92 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1065 (Mf; Anal, acid: 0.99 Sar; 0.99 Gly; 1.00 Val; 1.86 lie; 0.49 Thr; 1.07 Nva; 1.51 Arg; 1.02 Pro.
Example 148 N-Phenylacetyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 60 was used but substituting phenylacetic acid for butyric acid. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Phenylacetic-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt =
3. 83 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS
(ESI) m / e 1070 (Mf; Anal, acid: 1.04 Sar; 0.979 Gly; 1.01 Val;
1. 90 lie; 0.59 Thr; 1.09 Nva; 1.53 Arg; 1.03 Pro.
Example 149 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-Azagly-NH2 To a solution of N-Ac-Sar-Gly-Val-D-lle-Thr (tBu ) -Nva-lle-Arg (Pmc) -Pro-OH (0.1288 g) in DMF was added semicarbazide hydrochloride (0.222 g) followed by DIEA (0.346 ml) and PyBrop (0.513). The solution was stirred at room temperature for 36 hours. The solvent was removed in vacuo and the residue was treated with diethyl ether. The solid was filtered and then treated with (9: 1) TFA / anisole (3 ml) at room temperature for 4 hours. The solvent was again removed in vacuo and the residue was treated with diethyl ether. The precipitate was filtered to give the crude product as a solid. This was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-AzaglyN2 as the trifluoroacetate salt: Rt = 2.67 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1024 (Mf; Anal, acid: 0.99 Sar; 0.98 Gly; 1.00 Val; 2.13 Hertz; 0.56 Thr; 1.09 Nva; 0.92 Arg; 1.02 Pro.
EXAMPLE 150 N-Ac-Sar-Gly-Val-D-lle-Thr-N a-lle-Arg-Sar-NHCH2CH3 The procedure described in Example 76 was used but replacing ethylamide resin from Fmoc-Sar-Sieber for res .ina of ethylamide Fmoc-D-Pro-Sieber. After separating the peptide from the resin and removing the protecting groups using (9 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were freeze-dried to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Sar-NHCH2C H3 as the trifluoroacetate salt: Rt = 2.93 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 968 (Mf; Anal, acid: 1 96 Sar; 0.96 Gly; 0.98 Val; 2.07 lie; 0.55 Thr; 1.55 Nva; 1.49 Arg.
Example 151 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-SerNH2 The procedure described in Example 75 was used but replacing amide resin Fmoc-Ser (tBu) -Sieber for ammo resin Fmoc-D-Ala-Sieber. After separating the peptide from the resin and removing the protective groups using (9: 1)
TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a 10% to 50% gradient of acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-SerNH2 as the trifluoroacetate salt: Rt = 2.65 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1053 (Mf; Anal, acid: 0.99 Sar; 0.95 Gly; 1.00 Val; 1.96 Lie; 0.57 Thr; 1.12 Nva; 1.03 Arg; 1.03 Pro; 0.27 Ser.
Example 152 N-Succinyl-Sar-Gly-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 54 was used but replacing Fmoc-D-Leu for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-Leu-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.85 min (gradient from 10% to 30% of acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1052 (M, Anal, acid: 1.01 Sar; 0.93 Gly; 0.95 Val; 1.16 Leu; 1.10 He; 0 51 Thr; 1.04 Nva; 1.67 Arg; 0.96 Pro.
Example 153 N-Ac-Sar-Ala-Val-D-He-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Ala for Fmoc-Gly. After separating the peptide from the resin and removing the protective groups
• ITtfaMia ^ B ^ MMfa using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% of acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Ala-Val-D-lle-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3.056 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1008 (Mf; Anal, acid: 1.32 Sar; 0.96 Ala; 0.94 Val; 2.10 He; 0.52 Thr; 0.98 Nva; 1.65 Arg; 1.01 Pro.
Example 154 N-Ac-Sar-Leu-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Frnoc-Leu for Fmoc-Gly. After separating the peptide from the resin and removing the protectoid groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Leu-Val-D-lle-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3628 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes), MS (ESI) m / e 1050 (Mf.
Example 155 N-Ac-Sar-Ser-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Ser (tBu) for Fmoc-Gly. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Ser-Val-D-lle-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.995 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1024 (Mf.
Example 156 N-Ac-Sar-Phe-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Phe for Fmoc-Gly. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Phe-Val-D-lle-Thr-Nva-lle-Ar g-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3.83 mm.
(gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1084 (Mf.
Example 157 N-Ac-Sar-Glu-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Glu (OtBu) -OH for Fmoc-Gly. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through cold chromatography of C-18 using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Glu-Val-D-lle-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: R, = 3.08 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1065 (Mf.
Example 158 N-Ac-Sar-Pro-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Pro for Fmoc-Gly and Fmoc-D-Leu for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10%
^^ üt ?? üü-tiMh to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Pro-Val-D-Leu-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3343 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1034 (Mf.
Example 159 N-Ac-Sar-Asn-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Asn (Trt) for Fmoc-Gly and Fmoc-D -Leu for
Fmoc-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of
% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Asn-Val-D-Leu-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt-Rt = 3.112 min. (gradient of 10% to 30% acetonitrile in water containing 0 01% TFA over a period of 30 minutes); MS (ESI) m / e 1051 (Mf.
Example 160 N-Ac-Sar-Asp-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Asp (OtBu) for Fmoc-Gly and Fmoc-D -Leu for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Asp-Val-D-Leu-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.9113 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1052 (Mf.
Example 161 N-Ac-Asn-Gly-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Asn (Trt) for Fmoc-Sar and Fmoc-D -Leu for
Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% of
TFA The pure fractions were lyophilized to produce N-Ac-Asn-Gly-Val-D-Leu-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: R = 3.06 min. (gradient of 10% to 30% acetonitrile in water containing 0.01% TFA over a period
^^ & ^ n ^ 30 minutes); MS (ESI) m / e 1037 (M) '
Example 162 N-Ac-Gln-Gly-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used to substitute Fmoc-Gln (Trt) for Fmoc-Sar and Fmoc-D -Leu for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Gln-Gly-Val-D-Leu-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3.10 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1051 (Mf.
Example 163 N-Ac-Ser-Gly-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Ser (tBu) for Fmoc-Sar and Fmoc-D -Leu for Fmoc-D-lle After separating the peptide from the resin and removing the protective groups using (9: 1) TFA / aniso? (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Ser-Gly-Val-D-Leu-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3.15 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1010 (Mf.
Example 164 N-Ac-Cit-Gly-Val-D-pe-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Cit for Fmoc-Sar. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Cit-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.97 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1080 (Mf.
Example 165 N-Ac-Glu-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Glu (tBu) -OH for Fmoc-Sar. After
- .. • ...
Separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a 10% to 50% gradient of acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Glu-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.69 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1052 (M.
Example 166 N-Ac-Gaba-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-gamma-aminobutyric acid for Fmoc-Sar. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Gaba-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3.17 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1008 (Mf.
Example 167 N-Ac-Bullet-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-beta-alanine for Fmoc-Sar. After separating the peptide from the resin and removing the protective groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Bala-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3 14 min. (10% to 30% gradient of acetonitrile in water containing 0.01%) of TFA over a period of 30 minutes); MS (ESI) m / e 994 (Mf.
Example 168 N-Ac-Gln-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Gln (Trt) for Fmoc-Sar. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-GIn-Gly-Val-D-lle-Thr-Nva-lle-Arg-
| a | atfefl ||||| HHg | MHjMH ^^ M | HH | ^^^ Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 3.00 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1051 (Mf.
Example 169 N-Ac-Sar-Gly-Gly-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Gly for Fmoc-Val. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Gly-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.46 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 952 (Mf.
EXAMPLE 170 N-Ac-Sar-Gly-Glu-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Glu (OtBu) -OH for Fmoc-Val. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using
zz £ r a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Glu-D-lle-Thr-Nva-lle-Arg-Pro-NHCH2CH3 as the salt of tpfluoroacetate: Rt = 1.74 min (gradient from 10% to 30%). % acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1024 (Mf.
Example 171 N-Ac-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2 The procedure described in Example 4 was used but replacing Fmoc-Gln (Trt) for Fmoc-Nva . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-GIn-lle-Arg-Pro-NHCH2 (CH3) 2 as the trifluoroacetate salt: Rt = 2.80 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1037 (Mf; Anal, acid: 0.98 Sar; 0.94 Gly, 0.97 Val; 2.23 He; 0.51 Thr, 0 90 Glu; 1.16 Arg; 1.03 Pro.
Example 172 N-Ac-Sar-Gly-Val-D-Leu-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2 The procedure described in Example 4 was used but replacing Fmoc-D-Leu for Fmoc-lle and Fmoc-Gln (Trt) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through column chromatography of
C-18 using a solvent mixture varying in a gradient of
% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Gln-lle-Arg-Pro-NHCH2 (CH3) 2 as the trifluoroacetate salt: Rt = 2.90 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1037 (Mf; Anal, acid: 1.05 Sar; 0.97 Gly; 0.99 Val; 1.30 Leu; 0.52 Thr; 0.89 Glu; 1.20 Arg; 1.04 Pro.
Example 173 H-Sar-Gly-Val-D-Leu-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2 The procedure described in Example 172 was used but omitting the latter coupling with acetic acid. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions
MB-ÜIHMKM were lyophilized to produce H-Sar-Gly-Val-D-Leu-Thr-Gln-I le-Arg-Pro-NHCH2 (CH3) 2 as the trifluoroacetate salt: Rt = 2.55 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 981 (Mf; Anal, acid: 1.02 Sar; 0.93 Gly; 1.02 Val; 1.05 Leu; 1.02 He; 0.55 Thr; 0.84 Gln; 1.31 Arg; 1.03 Pro.
Example 174 N-Succinyl-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Gln (Trt) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-lle-Thr-GIn-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.02 min.
(gradient from 10% to 30% acetonitrile in water containing 0.C1% TFA over a period of 30 minutes); MS (ESI) m / e 1081 (Mf;
Anal, acid: 1.00 Sar; 0.94 Gly; 1.00 Val; 2.00 He; 0.52 Thr; 0.87
Gln; 1.37 Arg; 1.05 Pro.
Example 175 N-Succinyl-Sar-Gly-Val-D-Leu-Thr-Gly-lle-Arg-ProNHCH2CH3 The procedure described in Example 174 was used but replacing Fmoc-D-Leu for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-Leu-Thr-GIn-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.284 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1081 (Mf.
Example 176 N-Succinyl-Sar-Gly-Val-D-Leu-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2 The procedure described in Example 4 was used but replacing Fmoc-D-Leu for Fmoc-D- lle and Fmoc-Gln (Trt) for Fmoc-Nva. Following coupling with Fmoc-Sar and protection, the resin was treated with succinic anhydride / pipdin as described in Example 54. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitoplo-water
• • • - - containing 0.01% TFA The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-Leu-Thr-GIn-lle-Arg-Pro-NHCH2 (CH3) 2 as the salt of trifluoroacetate: Rt = 2.56 min. (gradient of 10% to 30% acetonitrile in water containing 0.0 '?% TFA over a period of 30 minutes); MS (ESI) m / e 1095 (Mf; Anal, acid: 0.95 Sar; 0.94 Gly; 1.02 Val; 1.02 Leu; 1.05 lie; 0.56 Thr; 0.86 Gln; 1.00 Arg; 1.07 Pro.
Example 177 N-Ac-Sar-Gly-Val-D-Leu-Thr-Asp-lle-Arg-ProNHCH2CH3 The procedure described in Example 146 was used but replacing Fmoc-Asp (OtBu) -OH for Fmoc-Gln (Trt ). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Asp-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.53 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1010 (Mf; 1.00 Sar; 0.95 Gly; 1.01 Val; 1.02 Leu; 1.00 He; 0.56 Thr; 0.99 Asp; 1.43 Arg; 1.03 Pro.
HIHMi ilMálÍltMMM- &MM-a Example 178 N-Ac-Sar-Gly-Val-D-lle-Thr-Asp-lle-Arg-ProNHCH2CH3 The procedure described in Example 142 was used but replacing Fmoc-Asp (OtBu) -OH for Fmoc-Glu (OtBu) -0 H. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through column chromatography of C-18 using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Asp-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.455 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1010 (Mf.
Example 179 N-Ac-Sar-Gly-Val-D-lle-Thr-Asn-lle-Arg-ProNHCH2CH3 The procedure described in Example 43 was used but replacing Fmoc-Asn (Trt) for Fmoc-Gln (Trt). After separating the peptide from the resin and removing the protective groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Asn-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.68 min. (gradient of 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1009 (Mf.
Example 180 N-Ac-Sar-Gly-Val-D-lle-Thr-Met (O) -lle-Arg-ProNHCH2CH3 The procedure described in Example 139 was used but replacing Fmoc-Met (O) for Fmoc-Met ( O2). After separating the peptide from the resin and removing the protectoid groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a mixture of solvent varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Met (O) -lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: Rt = 2.713 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1042 (Mf.
Example 181 N-Ac-Sar-Gly-Val-D-Leu-Thr-Asn-lle-Arg-ProNHCH2CH3 The procedure described in Example 146 was used but replacing Fmoc-Asn (Trt) for Fmoc-Gln (Trt). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Asn-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt: R, = 2752 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) rr / e 1009 (Mf.
Example 182 The procedure described in Example 1 was used but replacing separately in the Fmoc-D-lle synthesis with the following amino acids Fmoc-D-Thr (tBu), Fmoc-D-Ser (tBu), Fmoc-D- Hser (tBu), Fmoc-D-Gln (Trt), Fmoc-D-Asn (Trt), Fmoc-D-Cit, Fmoc-D-HCit, Fmoc-D-Hle, Fmoc-D-Neopentylgly. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the trifluoroacetate salt of the following peptides: N-Ac-Sar-Gly-Val-D-Thr-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Giy-Val- D-Ser-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Hser-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D- Gln-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Asn-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Cit- Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Hcy-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Hle-Thr- Nva-lle-Arg-ProNHCH2CH3, and N-Ac-Sar-Gly-Val-D-Neopentylgly-Thr-Nva-lle-Arg-ProNHCH2CH3.
Example 183 N-Ac-Sar-Gly-Val-D-lle-Thr-Phe (4-CONH2) -lle-Arg-ProNHCH2CH: The procedure described in Example 43 was used but replacing Fmoc-Phe [4-CONH ( Trt)] for Fmoc-Gln (Trt). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Phe (4-CONH2) -lle-Arg-ProNHCH2CH3.
Example 184 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-His-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-His (Boc) for Fmoc-Arg (Pmc). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-His-ProNHCH2CH3.
Example 185 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Lys (lsp) -ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Lys (N-epsilon-lsp, N -Epsilon-Boc) for Fmoc-Arg (Pmc). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Lys (lsp) -ProNHCH2CH3.
Example 186 The procedure described in Example 185 was used but replacing separately in the synthesis Fmoc-Lys (N-epsilon-nicotinyl), Fmoc-Orn (N-delta-nicotinil), Fmoc-Orn- (N-delta- lsp, N-epsilon-Boc), Fmoc-Phe (4-N-lsp, 4-Nboc), Fmoc-Cha- (4-N-lsp, 4-Boc) instead of Fmoc-Lys (N-epsilon- lsp, N-epsilon-Boc). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the trifluoroacetate salt of the following peptides: N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Lys (Nic) -ProNHCH2CH3, N-Ac-Sar-Gly -Val-D-lle-Thr-Nva-lle-Orn (Nic) -ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Orn (lsp) -ProNHCH2CH3, N-Ac - Sar-Gly-Val-D-lle-Thr-Nva-lle-Phe-ProNHCH2CH3, and N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Cha (4-Nlsp) -ProNHCH2CH3 .
Example 187 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Harg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Harg (Pmc) for Fmoc-Arg (Pmc). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Harg-ProNHCH2CH3.
Example 188 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Norarg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Norarg (N, N-bis-Boc) for Fmoc -Arg (Pmc). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-va-lle-Norarg-ProNHCH2CH3.
Example 189 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Cit-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Cit for Fmoc-Arg (Pmc). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Cit-ProNHCH2CH3.
Example 190 N-Ac-Sar-Gly-Val-D-lle-Thr-N a-lle-Lys-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Lys (Boc) for Fmoc-Arg (Pmc) . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Lys-ProNHCH2CH3.
Example 191 N-Ac-Sar-Gly-Val-D-lle-Phe (4-CH 2 OH) -Nva-lle-Arg-ProNHCH 2 CH 3 The procedure described in Example 1 was used but replacing Fmoc-Phe [4-CH 2 O (Trt ) for Fmoc-Thr (Trt). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Phe (4-CH2OH) -Nva-lle-Arg-ProNHCH2CH3.
Example 192 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Phe (4-guanidino) -ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Phe (4-bis-Boc). -guanidino) for Fmoc-Arg (Pmc). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Phe (4-guanidino) -ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.423 (gradient of 10% a 30% acetonitrile-water containing 0.01% TFA over a period of 30 minutes: MS (ESI) m / e 1042 (M + Hf.
Example 193 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Aminopyrimidinylbutanoyl- ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-2-amino-4 - [(2-amino ) -pyrimidinyl] butanoic acid for Fmoc-Arg (Pmc). After separating the peptide from the resin and removing the protecting groups using (9 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-aminopyriminidyl-butanoyl-ProNHCH2CH3 as the trifluoroacetate salt: R, = 3.303 (gradient from 10% to 30% in acetonitoplo-water containing 0.01% TFA over a period of 30 minutes: MS (ESI) m / e 1016 (M + Hf.
Example 194 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Phe (4-CH2NHIsp) -ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Phe (4-CH2Nlsp-Boc ) for Fmoc-Arg (Pmc). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Phe (-CH2NHIsp) -ProNHCH2CH3 as the trifluoroacetate salt.
Example 195 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Gly [4-Pip (N-amidino)] - ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Gly- 4-piper? Dinil [N-am? Do (BOC) 2 for Fmoc-Arg (Pmc). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Gly (4-Pip-amidino-ProNHCH2CH3 as the trifluoroacetate salt.
Example 196 N-Ac-Sar-Gly-Val-D-lle-Thr-N a-lle-Ala [4-Pip (N-amdino)] - ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc -Ala- [4-piperidinyl- (N ', N "-bis-Boc-amidino)] for Fmoc-Arg (Pmc) After separating the peptide from the resin and removing the protective groups using (9: 1 TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. Pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Ala [4-Pip (N-amidino)] - ProNHCH2CH; as the trifluoroacetate salt.
Example 197 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Ala (3-guanidino) -ProNHCH2CH3 The procedure described in Example 1 was used but
^ UMMMU. ^^ MBdiaEMMdiMIlt substituting Fmoc-Ala- [3- (b? S-Boc) guanidino] for Fmoc-Arg (Pmc). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Ala (3-guanidino) -ProNHCH2CH3 as the trifluoroacetate salt.
Example 198 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Ala (3-pyrrol idini lam ino) - ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Ala [3- pyrroli-dinyl (2-N, N'-bis-Boc-amidino)] for Fmoc-Arg (Pmc). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Ala- (3-pyrrolidinyl-amidino) -ProNHCH2CH3 as the trifluoroacetate salt.
Example 199 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Orn (2-? M? Dazo) -ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Orn- [N -2- (1-Boc) imidazolinyl] for Fmoc-Arg (Pmc). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Orn (2-imidazo) -ProNHCH2CH3 as the trifluoroacetate salt.
Example 200 N-Succinyl-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 54 was used but replacing Fmoc-D-alolle for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-Alolle-Thr-Nva-He-Argo NHCH2CH3 as the trifluoroacetate salt.
- ^ i ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^ ~ ^^^^^^^ i ^^^^^^^ Example 201 N-Succinyl-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 54 was used but replacing Fmoc-Gln (Trt) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-lle-Thr-GIn-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 202 N-Succinyl-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 75 was used but replacing Fmoc-Gln (Trt) for Fmoc-Nva, and. after coupling with Fmoc-Sar, acylate the peptide resin with succinic anhydride as described in Example 54. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole ( 3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-lle-T r-25 Gln-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
M ^ ^^ naia? Liß ^ M ^ _ ^ Bil ^^ _ K ^^ _ É ^^ aÉáiiM ^^? ^^ i ^^^^^^ É? AUMH «? Example 203 N-Succinyl-Sar-Gly-Val-D-Alolle-Thr-GIn-lle-Arg-ProNHCHzCHs The procedure described in Example 201 was used but replacing Fmoc-D-Alolle for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-alolle-Thr-GIn-He-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 204 N-Succinyl-Sar-Gly-Val-D-Alolle-Thr-Gln-lle-Arg-Pro-D-AlaNH2 The procedure described in Example 202 was used but replacing Fmoc-D-Alolle for Fmoc-D- lle After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-alolle-Thr-GIn-He-Arg-Pro-D-AlaNH2 as the trifluoroacetate salt.
Example 205 N-Succinyl-Sar-Gly-Val-D-Alolle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) :, The procedure described in Example 175 was used but replacing Fmoc-D-Alolle for Fmoc-D -Leu After separating the peptide from the resin and removing the protectoid groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-allolle-Thr-Gln-He-Arg-ProNHCH2 (CH3) 2 as the trifluoroacetate salt.
Example 206 N-Succinyl-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2 The procedure described in Example 205 was used but replacing Fmoc-D-lle for Fmoc-D- alolle After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-lle-Thr-GIn-lle-Arg-ProNHCH2 (CH3) 2 as the trifluoroacetate salt.
Example 207 N-Ac-Sar-Gly-Val-D-Alolle-Thr-Nva-lle-Arg-Pro-D-AlaNH2 The procedure described in Example 75 was used but replacing Fmoc-D-Alolle for Fmoc-D- lle After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were cleaved to produce N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-Pro-D-AlaNH2 as the trifluoroacetate salt.
Example 208 N-Ac-Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2 The procedure described in Example 4 was used but replacing Fmoc-D-Alolle for Fmoc-D- lle After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-alolle-Thr-GIn-He-Arg-ProNHCH2 (CH3) 2 as the trifluoroacetate salt.
_ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ -Gln-lle-Arg-Pro-D-AlaNH2 The procedure described in Example 75 was used but replacing Fmoc-Gln (Trt) for Fmoc-Nva. After separating the peptide from the resin and removing the protecto-es groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a mixture of solvent varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-GIn-lle-Arg-Pro-D-AlaNH2 as the trifluoroacetate salt.
Example 210 N-Ac-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2 The procedure described in Example 201 was used but replacing Fmoc-Gln (Trt) for Fmoc-Nva . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-GIn-lle-Arg-ProNHCH2 (CH3) 2 as the trifluoroacetate salt.
Example 211 N-Ac-Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-D-AlaNH2 The procedure described in Example 209 was used but replacing Fmoc-D-Alolle for Fmoc-D- lle After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alolle-Thr-GIn-lle-A'g-Pro-D-AlaNH2 as the trifluoroacetate salt.
Example 212 N-Ac-Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2 The procedure described in Example 210 was used but replacing Fmoc-D-Alolle for Fmoc-D- lle After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alolle-Thr-GIn-lle-Arg-ProNHCH2 (CH3) 2 as the trifluoroacetate salt.
Example 213 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProSarNH2 The procedure described in Example 75 was used but replacing Fmoc-Sar-Seiber amide resin for Fmoc amide resin D-Ala-Seiber. After separating the peptide from the resin and removing the protecting groups using (9 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProSarNH2 as the trifluoroacetate salt.
Example 214 N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-SarNH2 The procedure described in Example 213 was used but replacing Fmoc-D-Alolle for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-Pro-SarNH2 as the trifluoroacetate salt.
Example 215 N-Ac-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-SarNH2 The procedure described in Example 213 was used but replacing Fmoc-Gln (Trt) for Fmoc- Nva After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% of acetonitr-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-GIn-lle-Arg-SarNH2 as the trifluoroacetate salt.
Example 216 N-Ac-Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-SarNH2 The procedure described in Example 215 was used but replacing Fmoc-D-alolle for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alolle-Thr-GIn-lle-Arg-Pro-SarNH2 as the trifluoroacetate salt.
Example 217 N-Ac-Sar-Gly-Val-D-alole-Thr-Ser-lle-Arg-Pro-D-AlaNH2 The procedure described in Example 207 was used but replacing Fmoc-Ser (tBu) for Fmoc-Nva . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture. varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alolle-Thr-Ser-lle-A 'g-Pro-D-AlaNH2 as the trifluoroacetate salt.
Example 218 N-Ac-Sar-Gly-Val-D-alolle-Thr-Ser-lle-Arg-ProNHCH2 (CH3) 2 The procedure described in Example 208 was used to substitute Fmoc-Ser (tBu) for Fmoc-Nva . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile or water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alolle-Thr-Ser-lle-Arg-ProNHCH2 (CH3) 2 as the trifluoroacetate salt.
Example 219 N-Ac-Sar-Gly-Val-D-alolle-Thr-Ser-lle-Arg-ProNHCH2CH3 The procedure described in Example 15 was used but replacing Fmoc-Ser (tBu) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alolle-Thr-Ser-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 220 N-Ac-Sar-Gly-Val-D-lle-Thr-Orn (Ac) -lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Orn (Ac) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Orn (Ac) -lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.iiMá-M É-áBiaí-iMi rikiai-i Example 221 N-Ac-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro-AzaglyNH2 The procedure described in Example 149 was used but replacing Fmoc-Gln (Trt) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-GIn-lle-Arg-Pro-AzaglyNH2 as the trifluoroacetate salt.
Example 222 N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-Pro-AzaglyNH2 The procedure described in Example 149 was used but replacing Fmoc-D-alolle for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a mixture of solvent varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-Pro-AzaglyNH2 as the trifluoroacetate salt.
Example 223 N-Ac-Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-AzaglyNH2 The procedure described in Example 222 was used but replacing Fmoc-Gln (Trt) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alolle-Thr-GIn-lle-Arg-Pro-AzaglyNH2 as the trifluoroacetate salt.
Example 224 N- (2-THFcarbonyl) -Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg- ProNHCH2CH3 The procedure described in Example 61 was used but replacing tetrahydro-2-furoic acid for acetic acid. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N- (2-THFcarbonyl) -Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 225 N- (2-THFcarbonyl) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 61 was used but replacing Fmoc-Gln (Trt) for Fmoc-Nva . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were freeze-dried to produce N- (2-THFcarbon? L) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 226 N- (2-THFcarbonyl) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg- ProNHCH2CH3 The procedure described in Example 225 was used but replacing Fmoc-D-alolle for Fmoc-D- lle After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N- (2-THFcarbonyl) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
^ MMk ai my Example 227 N- (2-THFcarbonyl) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro-D-AlaNH2 The procedure described in Example 209 was used but replacing tetrahydro acid -2-furoic for acetic acid. After separating the peptide from the resin and removing the protective groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N- (2-THFcarbon? L) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro-D-AlaNH2 as the trifluoroacetate salt.
Example 228 N- (2-THFcarbonyl) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-D-AlaNH2 The procedure described in Example 227 was used but replacing Fmoc-D-alolle for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N- (2-THFcarbonyl) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-D-AlaNH2 as the trifluoroacetate salt.
Example 229 NJ2-TH Fea rbon il) -Sar-Gly-Val-D-allolle-Thr-GI nl le-Arg- ProNHCH2 (CH3) 2 The procedure described in Example 4 was used but replacing Fmoc-D-alolle for Fmoc-D-lle, Fmoc-Gln (Trt) for Fmoc-Nva and tetrahydro-2-furoic acid for acetic acid. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N- (2-THFcarbonyl) -Sar-Gly-Val-D-allolle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2 as the trifluoroacetate salt.
Example 230 The procedures described in Examples 224, 225, 226,
227, 228 and 229 were used but replacing N-acetyl-6-aminocaproic acid (6-Ac-Aca) instead of tetrahydro-2-furoyl. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the following peptides as s. to trifluoroacetate: N- (6-Ac-Aca) -Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCH2CH3, N- (6-Ac-Aca) -Sar-Gly-Val- D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, N- (6-Ac-Aca) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2CH3, N- (6-Ac -Aca) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProAlaNH2, N- (6-Ac-Aca) -Sar-Gly-Val-D-alolle-Thr-Gln-lle- Arg-Pro-D-AlaNH2, and N- (6-Ac-Aca) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2CH3.
Example 231 The procedures described in Examples 224, 225, 226,
227, 228 and 229 were used but replacing N-acetyl-4-aminobutyric acid (4-Ac-Gaba) instead of N-acetyl-6-amicaprioic acid. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the following peptides as the trifluoroacetate salt: N- (4-Ac-Gaba) -Sar-Gly-Val-D-Alolle-Thr-Nva-lle-Arg-ProNHCH2CH3, N- (4 -Ac-Gaba) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, N- (4-Ac-Gaba) -Sar-Gly-Val-D-Alolle-Thr-Gln- lle-Arg-ProNHCH2CH3 N- (4-Ac-Gaba) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, N- (4-Ac-Gaba) -Sar -Gly-Val-D-Alolle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, and N- (4-Ac-Gaba) -Sar-Gly-Val-D-Alolle-Thr-Gln-lle- Arg-ProNHCH2CH3
Example 232 The procedures described in Examples 224, 225, 226, 227, 228 and 229 were used but replacing furoic acid in place of tetrahydro-2-furoic acid. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture. varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the following peptides as the trifluoroacetate salt: N- (2-Furoyl) -Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCH2CH3, N- (2-Furoil ) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, N- (2-Furoyl) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2CH3, N- (2-Furoyl) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, N- (2-Furoyl) -Sar-Gly-Val-D-alolle- Thr-Gln-lle-Arg-Pro-D-AlaNH2 and N- (2-Furoyl) -Sar-Gly-Val-D-alolle-Thr-Gln-pe-Arg-ProNHCH2 (CH3) 2.
Example 233 The procedures described in Examples 224, 225, 226,
227, 228 and 229 were used but replacing shikimic acid instead of tetrahydro-2-furoic acid. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the following peptides as the trifluoroacetate salt: N- (Shikimil) -Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCH2CH3,
N- (Shikimil) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, N- (Shikimil) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg- ProNHCH2CH3,
N- (Shikimil) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, N- (Shikimil) -Sar-Gly-Val-D-alolle-Thr-Gln- lle-Arg-Pro-D-AlaNH2 and
N- (Sh? K¡m1) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2
Example 234 The procedures described in Examples 224, 225, 226, 227, 228 and 229 were used but substituting 2-me ?: il-nicotinic acid instead of tetrahydro-2-furoic acid. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the following peptides as the trifluoroacetate salt: N (2-Me-Nicotinyl) -Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCH2CH3, N (2-Me -Nicotinyl) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, N (2-Me-Nicotinyl) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg - ProNHCH2CH3, N (2-Me-Nicotinyl) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, N (2-Me-Nicotinyl) -Sar-Gly-Val -D-alolle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, and Ñ (2-Me-Nicotinyl) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2 (CH3 )2.
Example 235 N-Ac-Sar-Gly-Val-D-Alolle-Thr-Leu-lle-Arg-Pro-D-AlaNH2 The procedure described in Example 75 was used but replacing Fmoc-D-alolle for Fmoc-D- lle and Fmoc-Leu for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Allolle-Thr-Leu-lle-Arg-Pro-D-AlaNH2 as the trifluoroacetate salt.
Example 236 N-Ac-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-Pro-NHCH2 (CH3) 2 The procedure described in Example 4 was used but replacing Fmoc-4 for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-Pro-NHCH2 (CH3) 2 as the trifluoroacetate salt.
Example 237 N-Ac-Sar-Gly-Val-D-alolle-Thr-Leu-lle-Arg-Pro-NHCH2CH3 The procedure described in Example 73 was used but replacing Fmoc-D-alolle for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alolle-Thr-Leu-lle-Arg-Pro-NHCH2CH3 as the trifluoroacetate salt.
Example 238 N-Ac-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-Pro-D-AlaNH2 The procedure described in Example 75 was used but replacing Fmoc-Leu for Fmoc-Nva. After separating the peptide from the resin and removing the protectoies using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-Pro-D-AlaNH2 as the trifluoroacetate salt.
Example 239 N-Succinyl-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-Pro-D-AlaNH2 The procedure described in Example 75 was used but replacing Fmoc-Leu for Fmoc-Nva, and acetylating with succinic anhydride after coupling with Fmoc-Sar and deprotection as described in Example 54. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the Crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-Pro-D-AlaNH2 as the trifluoroacetate salt.
Example 240 N-Succinyl-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-ProNHCH2 (CH3) 2 The procedure described in Example 206 was used but replacing Fmoc-Leu for Fmoc-Gln (Trt) , and acetylating with
».A.fe > . ...
Vtr ** 229 succinic anhydride after coupling with Fmoc-Sar and deprotection as described in Example 54. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-ProNHCH2 (CH3) 2 as the trifluoroacetate salt. Example 241 The procedures described in Examples 201, 202 and 203 were used but replacing Fmoc-Leu instead of Fmoc-Gln (Trt). After separating the peptide from the resin and removing the
protective groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile- water containing 0.01% TFA. The pure fractions were lyophilized to produce the following
peptides: N-Succinyl-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Gly-Val-D-alolle-Thr-Leu-lle-Arg-ProNHCH2CH3 , and N-Succinyl-Sar-Gly-Val-D-alolle-Thr-Leu-lle-Arg-Pro-D-AlaNH2.
| kS ^ Mtetf? g8gí ^ ß ^ H | MBMtaMMHa ||| aai tj || fa ía S- 230 Example 242 N-Succinyl-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg- ProAzaglyNH2 The procedure described in Example 149 was used but replacing Fmoc-Leu for Fmoc-Nva, and acetylating with succinic anhydride after coupling with Fmoc-Sar and deprotection as described in Example 54. After separating the peptide from the resin and the removal of protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture.
varying in a gradient of 10% to 50% acetonitoplo-a? Ua containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-ProAzaglyNH2 as the trifluoroacetate salt.
Example 243 N-Ac-Sar-G ly-Val-D-alolle-Thr-N va-I le-Arg-ProNHethyl- (1-pyrrole id i na) The procedure written in Example 5 was used but replacing Fmoc -D-alolle for Fmoc-D-lle. After separating the peptide from the resin and removing the protective groups
Using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-containing water. 0.01%) of TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-25 ProNHethyl- (l-pyrrolidine) as the trifluoroacetate salt.
"fc 231 Example 244 N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNH (ethyl-l-cyclohexyl) The procedure written in Example 8 was used but replacing Fmoc- D-alolle for Fmoc-D-lle After separating the peptide from the resin and removing the protective groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through column chromatography of C-18 using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA.g to.
lyophilized to produce N-Ac-Sar-Gly-Vai-D-alolle-Thr-Nva-lle-Arg-ProNH (ethyl-1-cyclohexyl) as the trifluoroacetate salt.
Example 245 N-Ac-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHethyl- (l-pyrrolidine) The procedure written in Example 5 was used but replacing Fmoc-Gln (Trt) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture. varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-GIn-lle-Arg-ProNHethyl- (l-pyrrolidine) as the trifluoroacetate salt.
Example 246 N-Ac-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNH (ethyl-l-cyclohexyl) The procedure written in Example 8 was used but replacing Fmoc-Gln- (Trt ) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-GIn-lle-Arg-ProNH (ethyl-1-cyclohexyl) as the trifluoroacetate salt.
Example 247 N-Succinyl-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNH (ethyl-l-cyclohexyl) The procedure described in Example 246 was used but acylating the peptide resin with succinic anhydride after coupling with Fmoc-Sar and deprotection as described in
Example 54. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a mixture of solvent varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% of
TFA The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNH (ethyl-l-cyclohexyl) as the trifluoroacetate salt.
Example 248 The procedures described in Example 11 were used but replacing the appropriate protected amino acids as described in Examples 14, 43, 74, 73, 54, 174 and 132, respectively. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the following peptides as the trifluoroacetate salt: N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCH2CH2OCH3, N-Ac-Sar-Gly-Val- D-lle-Thr-Gln-lle-Arg-ProNHCH2CH2OCH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Ser-lle-Arg-ProNHCH2CH2OCH3, N-Ac-Sar-Gly-Val-D- lle-Thr-Leu-lle-Arg-ProNHCH2CH2OCH3, N-Succinyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH2OCH3, N-Succinyl-Sar-Gly-Val-D-lle Thr-Gln-lle-Arg-ProNHCH2CH2OCH3, N-Succinyl-Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2CH2OCH:?, N-Ac-Sar-Gly-Val-D-lle Ser-Nva-lle-Arg-ProNHCH2CH2OCH3, and N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2CH2OCH3.
Example 249 The procedures described in Example 49 were used but replacing the appropriate protected amino acids as described in Examples 14, 4, 75, 54 and 132 respectively.
After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the following peptides as the trifluoroacetate salt: N-Ac-Sar-Gly-Val-D-alolle-Thr-Aligly-lle-Arg-ProNHCH2CH2OCH3, N-Ac-Sar-Gly-Val- D-lle-Thr-Aligly-lle-Arg-ProNHCH2CH2 (OCH3) 2, N-Ac-Sar-Gly-Val-D-lle-Thr-Aligly-lle-Arg-Pro-D-AlaNH2, N-Ac- Sar-Gly-Val-D-alolle-Thr-Aligly-lle-Arg-Pro-D-AlaNH2, N-Succinyl-Sar-Gly-Val-D-lle-Thr-Aligly-lle-Arg-Pro-D- AlaNH2, N-Ac-Sar-Gly-Val-D-lle-Ser-Aligly-lle-Arg-Pro-ProNHCH2CH3, and N-Ac-Sar-Gly-Val-D-Leu-Ser-Aligly-lle-Arg -Pro-ProNHCH2CH3.
Example 250 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-D-SerNH2 The procedure described in Example 75 was used but replacing amide resin Fmoc-D-Ser (tBu ) -Sieber for amide resin Fmoc-D-Ala-Sieber. After separating the peptide from the resin and removing the protective groups using (9: 1)
TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-D-SerNH2 as the trifluoroacetate salt.
Example 251 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHOH The procedure described in Example 149 was used but replacing hydroxylamine hydrochloride for semicarbazide hydrochloride. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHOH as the trifluoroacetate salt.
Example 252 N-Ac-Sar-Gly-Val-D-lle-Ser-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 132 was used but replacing Fmoc-D-lle for Fmoc-D-Leu. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D Jle-Ser-Nva-lle-Arg ProNHCH2CH3 as the trifluoroacetate salt
Example 253 N-Ac-Sar-Gly-Val-D-alolle-Ser-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 132 was used but replacing Fmoc-D-alolle for Fmoc-D-Leu. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alolle-Ser-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 254 N-Ac-Sar-Gly-Val-D-Leu-Hser-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 132 was used but replacing Fmoc-Hser (tBu) for Fmoc (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Hser-Nva-lle-Arg-
x ^^^^ jg & St ^^^^^^^^^^^^^^^^^ ProNHCH2CH3 as the trifluoroacetate salt
Example 255 N-Ac-Sar-Gly-Gln-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Gln (Trt) for Fmoc-Val. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% > of TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-GIn-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 2.36 min. (gradient of 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1023 (Mf.
Example 256 N-Ac-Sar-Gly-Nva-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Nva for Fmoc-Val. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Nva-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.28 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 994 (M.
Example 257 N-Ac-Sar-Gly-lle-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-lle for Fmoc-Val. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01%) of TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-lle-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: R, = 3.55 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1008 (Mf.
Example 258 N-Ac-Sar-Gly-Phe-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Phe for Fmoc-Val. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified
• A "'-" - • • through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Phe-D-lle-Thr-Nva-lie-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.77 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1042 (Mf.
Example 259 N-Ac-Sar-Gly-Leu-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Leu for Fmoc-Val. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Leu-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.56 mln. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 1008 (Mf.
Example 260 N-Ac-Sar-Gly-Ser-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Ser (tBu) for Fmoc-Val. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Ser-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 2.41 min. (gradient from 10% to 30% acetonitrile in water containing 0.01% TFA over a period of 30 minutes); MS (ESI) m / e 982 (M) J
Example 261 N-Ac-Thr-Gly-Val-D-Leu-Thr-N a-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Thr (tBu) for Fmoc-Sar and Fmoc- D-Leu for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Thr-Gly-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt: Rt = 3.33 min. (10% to 30% gradient of acetonitrile in water containing 0.01%) of TFA over a period of 30 minutes); MS (ESI) m / e 1024 (Mf.
Example 262 The procedures described in Example 46 were used but replacing the appropriate protected amino acids as described in Examples 75, 4, 54 and 132. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the following peptides as the trifluoroacetate salt: N-Ac-Sar-Gly-Val-D-alolle-Thr-Ala-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- D-lle-Thr-Ala-lle-Arg-ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Val-D-lle-Thr-Ala-lle-Arg-Pro-D-AlaNH2, N-Ac- Sar-Gly-Val-D-alolle-Thr-Ala-lle-Arg-Pro-D-AlaNH2, N-Succinyl-Sar-Gly-Val-D-lle-Thr-Ala-lle-Arg-Pro-D- AlaNH2, N-Ac-Sar-Gly-Val-D-lle-Ser-Ala-lle-Arg-ProNHCH2CH3, and N-Ac-Sar-Gly-Val-D-Leu-Ser-Ala-lle-Arg-ProNHCH2CH3 .
Example 263 The procedures described in Example 262 were used but replacing Fmoc-Val for Fmoc-Ala. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a mixture
of solvent varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the following peptides as the trifluoroacetate salt: N-Ac-Sar-Gly-Val-D-alolle-Thr-Val-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- D-lle-Thr-Val-lle-Arg-ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Val-D-lle-Thr-Val-lle-Arg-Pro-D-AlaNH2, N-Ac- Sar-Gly-Val-D-alolle-Thr-Val-lle-Arg-Pro-D-AlaNH2, N-Succinyl-Sar-Gly-Val-D-lle-Thr-Val-lle-Arg-Pro-D- AlaNH2, N-Ac-Sar-Gly-Val-D-lle-Ser-Val-lle-Arg-ProNHCH2CH3, and N-Ac-Sar-Gly-Val-D-Leu-Ser-Val-lle-Arg-ProNHCH2CH3 .
Example 264 The procedures described in Example 263 were used but replacing Fmoc-DNva for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the following peptides as the trifluoroacetate salt: N-Ac-Sar-Gly-Val-D-alolle-Thr-D-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly- Val-D-lle-Thr-D-Nva-lle-Arg-ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Val-D-lle-Thr-DN a-lle-Arg-Pro-AlaNH2,
j N-Ac-Sar-Gly-Val-D-alolle-Thr-D-Nva-lle-Arg-Pro-D-AlaNH2, N-Succinyl-Sar-Gly-Val-D-lle-Thr-D-Nva -lle-Arg-Pro-D-AlaNH2, N-Ac-Sar-Gly-Val-D-lle-Ser-D-Nva-lle-Arg-ProNHCH2CH3, and N-Ac-Sar-Gly-Val-D- Leu-Ser-D-Nva-lle-Arg-ProNHCH2CH3.
Example 265 N-Ac-Sar-Gly-Val-D-lle-Ser-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 132 was used but replacing Fmoc-D-lle for Fmoc-D-Leu and Fmoc- Gln (Trt) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10%) to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Ser-Gln-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 266 N-Ac-Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 132 was used but replacing Fmoc-Gln (Trt) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-
- ^^ mÉm ^ i? jm im ii ia.
water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Ser-GIn-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 267 N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-Pro-D-AlaNH2 The procedure described in Example 75 was used but replacing Fmoc-D-Leu for Fmoc-D- lle and Fmoc-Ser (tBu) for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-Pro-D-AlaNH2 as the trifluoroacetate salt.
Example 268 N-Ac-Sar-Gly-Val-D-lle-Ser-Nva-lle-Arg-Pro-D-AlaNH2 The procedure described in Example 267 was used but replacing Fmoc-D-lle for Fmoc-D- Leu and Fmoc-Ser (tBu) for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Ser-Nva-lle-Arg-Pro-D-AlaNH2 as the trifluoroacetate salt.
Example 269 N-Succinyl-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 54 was used but replacing Fmoc-D-Leu for Fmoc-D-lle and Fmoc- Ser (tBu) for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lysed to produce N-Succinyl-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 270 N-Succinyl-Sar-Gly-Val-D-lle-Ser-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 269 was used but replacing Fmoc-D-lle for Fmoc-D-Leu After separating Peptide from the resin and removal of the protected groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-lle-Ser-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 271 N-Succinyl-Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 270 was used but replacing Fmoc-D-Leu for Fmoc-D-lle and Fmoc- Gln (Trt) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-S-ar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 272 N-Succinyl-Sar-Gly-Val-D-lle-Ser-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 270 was used but replacing Fmoc-Gln (Trt) for Fmoc-Nva. After separating the peptide from the resin and removing the protected groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a mixture
'*' J? Or.- and y-? Z of solvent varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-lle-Ser-GIn-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 273 N-Ac-Sar-Gly-Val-D-lle-Ser-Ser-lle-Arg-ProNHCH2CH3 The procedure described in Example 265 was used but replacing Fmoc-Ser (tBu) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Ser-Ser-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 274 N-Ac-Sar-Gly-Val-D-Leu-Ser-Ser-lle-Arg-ProNHCH2CH3 The procedure described in Example 266 was used but replacing Fmoc-Ser (tBu) for Fmoc-Nva. After separating the peptide from the resin and removing the protected groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a mixture of solvent varying in a gradient of 10% to 50% acetonitoplo- water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Ser-Ser-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 275 N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2 The procedure described in Example 13 was used to substitute Fmoc-D-Leu for Fmoc- lle and Fmoc-Ser (tBu) for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2 as the trifluoroacetate salt.
Example 276 N-Ac-Sar-Gly-Val-D-lle-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2 The procedure described in Example 13 was used but replacing Fmoc-Ser (tBu) for Fmoc-Thr (tBu) After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% of
^^ 1 acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2 as the trifluoroacetate salt.
Example 277 N-Ac-Sar-Gly-Val-D-Leu-Ser-Leu-lle-Arg-ProNHCH2CH3 The procedure described in Example 132 was used but replacing Fmoc-D-Leu for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Ser-Leu-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 278 N-Ac-Sar-Gly-Val-D-lle-Ser-Leu-lle-Arg-ProNHCH2CH3 The procedure described in Example 277 was used but replacing Fmoc-D-lle for Fmoc-D-Leu. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a metal: of solvent varying in a 10% to 50% gradient of acetonitoplo-water containing 0.01% TFA The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Ser-Leu-lle-Arg- ProNHCH2CH3 as the trifluoroacetate salt.
Example 279 N-Ac-Sar-Gly-Val-D-alolle-Ser-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 132 was used but replacing Fmoc-D-alolle for Fmoc-D-Leu. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alolle-Ser-GIn-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 280 N-Ac-Sar-Gly-Val-D-alolle-Ser-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 265 was used but replacing Fmoc-D-alolle for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-allolle-Ser-GIn-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 281 N-Succinyl-Sar-Gly-Val-D-alolle-Ser-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 270 was used but replacing Fmoc-D-alolle for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Succinyl-Sar-Gly-Val-D-alolle-Ser-Nva-He-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 282 N-Ac-Sar-Gly-Val-D-alolle-Ser-N a-lle-Arg-ProNHCH2 (CH3) 2 The procedure described in Example 276 was used but replacing Fmoc-D-alolle for Fmoc-D -lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alolle-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2 as the trifluoroacetate salt.
Example 283 N-Ac-Sar-Gly-Val-D-alolle-Ser-Nva-lle-Arg-Pro-D-AlaNH2 The procedure described in Example 268 was used but replacing Fmoc-D-alolle for Fmoc-D- lle After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alolle-Ser-Nva-lle-Arg-Pro-D-AlaNH2 as the trifluoroacetate salt.
Example 284 N-Ac-Sar-Gly-Val-D-alolle-Ser-Leu-lle-Arg-ProNHCH2CH3 The procedure described in Example 265 was used but replacing Fmoc-D-alolle for Fmoc-D-lle and Fmoc- Leu for Fmoc-Gln (Trt). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alope-Ser-Leu-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
MMMMÍiÜ-MkMIMta Example 285 N-Ac-Sar-Gly-Val-D-alolle-Ser-Ser-lle-Arg-ProNHCH2CH3 The procedure described in Example 276 was used but replacing Fmoc-D-alolle for Fmoc-D-lle . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01%) of TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alolle-Ser-Ser-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 286 The procedure described in Example 125 was used but separately by replacing Fmoc-lle and Fmoc-allo, respectively, for Fmoc-D-Leu. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the following peptides as the trifluoroacetate salt: N-Ac-Sar-Gly-Val-D-lle-Gly-Nva-lle-Arg-ProNHCH2CH3, and N-Ac-Sar-Gly-Val -D-alolle-Gly-Nva-lle-Arg-ProNHCH2CH3.
Example 287 The procedure described in Examples 125 and 186 was used but separately replacing Fmoc-lle and Fmoc-alolle, respectively, for Fmoc-D-Leu and substituting Fmoc-Gln (T? T) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the trifluoroacetate salt: N-Ac-Sar-Gly-Val-D-Leu-Gly-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle Gly-Gln-lle-Arg-ProNHCH2CH3, and N-Ac-Sar-Gly-Val-D-allolle-Gly-Gln-lle-Arg-ProNHCH2CH3.
Example 288 The procedure described in Example 123 was used but separately by replacing Fmoc-lle and Fmoc-alolle, respectively, for Fmoc-D-Leu. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the trifluoroacetate salt:
N-Ac-Sar-Gly-Val-D-lle-Tyr-Nva-lle-Arg-ProNHCH2CH3, and N-Ac-Sar-Gly-Val-D-al lol le-Ty rN va-I le-Arg- ProNHCH2CH3.
Example 289 The procedure described in Examples 123 and 288 was used but separately replacing Fmoc-lle and Fmoc-alolle, respectively, for Fmoc-D-Leu and substituting Fmoc-Gln (Trt) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the trifluoroacetate salt: N-Ac-Sar-Gly-Val-D-Leu-Tyr-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle Tyr-Gln-lle-Arg-ProNHCH2CH3, and N-Ac-Sar-Gly-Val-D-allolle-Tyr-Gln-lle-Arg-ProNHCH2CH3.
Example 290 N-Ac-Sar-Gly-Val-D-Ser-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Ser (tBu) for Fmoc-D-lle . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using
r-t? - •• jrnirüMt, - rr a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Val-D-Ser-Thr-Nva-He-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 291 N-Ac-Sar-Gly-Val-D-Thr-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Thr (tBu) for Fmoc-D-lle . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Thr-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate sai.
Example 292 N-Ac-Sar-Gly-Val-D-Gln-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Gln (Trt) for Fmoc-D-lle . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Gln-Thr-Nva-He-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 293 N-Ac-Sar-Gly-Val-D-Asn-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Asn (Trt) for Fmoc-D-lle . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Asn-Thr-Nva-He-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 294 N-Ac-Sar-Gly-Val-D-Arg-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Arg (Pmc) for Fmoc-D-lle . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Arg-Thr-Nva-He-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 295 N-Ac-Sar-Gly-Val-D-3-Pal-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-3-Pal for Fmoc-D- lle After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-3-Pal-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 296 N-Ac-Sar-Gly-Val-D-Glu-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Glu (OtBu) -OH for Fmoc-D -lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Glu-Thr-Nva-He-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 297 N-Ac-Sar-Gly-Val-D-Asp-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Asp (OtBu) -OH for Fmoc-D -lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Asp-Thr-Nva-He-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 298 N-Ac-Sar-Gly-Val-D-His-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-His (Boc) for Fmoc-D-lle . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-His-Thr-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 299 N-Ac-Sar-Gly-Val-D-Hser-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-Hser / tBu) for Fmoc-D-lle . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Hser-Thr-Nva-He-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 300 N-Ac-Sar-Gly-Val-D-alo-Thr-Thr-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-aloThr (tBu) for Fmoc-D-lle . After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-alo-Thr-Thr-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 301 N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-D-lle for Fmoc-D-lle. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-A-g-ProNHCH2CH3 as the trifluoroacetate salt.
Example 302 N-Ac-Sar-Gly-Val-D-Ser-Thr-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 290 was used but replacing Fmoc-Gln (Trt) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Ser-Thr-GIn-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
WMUMliaittitttftahkttta glM | k ^^ | ^^ H | ^ Example 303 N-Ac-Sar-Gly-Val-D-Thr-Thr-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 291 was used but replacing Fmoc- Gln (Trt) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Thr-Thr-GIn-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 304 N-Ac-Sar-Gly-Val-D-aloThr-Thr-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 300 was used but replacing Fmoc-Gln (Trt) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% of acetonitr-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-aloThr-Thr-GIn-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
^^^^ * - ^^ Example 305 N-Ac-Sar-Gly-Val-D-Ser-Ser-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 290 was used but replacing Fmoc-Ser (tBu) for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Ser-Ser-Nva-He-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 306 N-Ac-Sar-Gly-Val-D-Thr-Ser-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 291 was used but replacing Fmoc-Ser (tBu) for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Thr-Ser-N »a-He-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 307 N-Ac-Sar-Gly-Val-D-aloThr-Ser-Nva-lle-Arg-ProNHCH2CH3 The procedure described in Example 300 was used but replacing Fmoc-Ser (tBu) for Fmoc-Thr (tBu). After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-aloThr-Ser-Nva-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 308 N-Ac-Sar-Gly-Val-D-AloThr-Ser-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 304 was used but replacing Fmoc-Gln (Trt) for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-AloThr-Ser-GIn-l le-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 309 N-Ac-Sar-Gly-Val-D-Thr-Ser-Gln-lle-Arg-ProNHCH2CH3 The procedure described in Example 303 was used but replacing Fmoc-Gln for Fmoc-Nva. After separating the peptide from the resin and removing the protecting groups using (9: 1) TFA / anisole (3 ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Thr-Ser-GIn-lle-Arg-ProNHCH2CH3 as the trifluoroacetate salt.
Example 310 The procedure described in Examples 132 and 266 was used but replacing N-acetyl-6-aminocaproic acid (6-Ac-Aca) for acetic acid. After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield the following peptides as the trifluoroacetate salt: N- (6-Ac-Aca) -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2 (CH3) 2, and N- (6-Ac-Aca) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2.
Example 311 The procedure described in Example 310 was used but replacing N-acetyl-gamma-aminobutyric acid (4-Ac-Gaba) in place of N-acetyl-6-aminocaproic acid. After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile or water containing 0.01% TFA. The pure fractions were lyophilized to yield the following peptides as the trifluoroacetate salt: N- (4-Ac-Gaba) -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2 (CH3) > , and N- (4-Ac-Gaba) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2.
Example 312 The procedure described in Example 311 was used but replacing 2-furoic acid in place of N-acetyl-gamma-aminobutyric acid. After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the following peptides as the trifluoroacetate salt:
N- (2-furoyl) -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2 (CH3) 2, and N- (2-furoyl) -Sar-Gly-Val-D-Leu -Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2.
Example 313 The procedure described in Example 311 was used but replacing shikimic acid instead of 2-furoic acid. After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield the following peptides as the trifluoroacetate salt: N- (Shikimil) -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2 (CH3) 2, and N- ( Shikimil) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2.
Example 314 The procedure described in Example 311 was used but replacing shikimic acid in place of 2-furoic acid. After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield the following peptides as the trifluoroacetate-N- (Shikimil) salt -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2 (CH3) 2, and N- ( Shikimil) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2.
Example 315 The procedure described in Example 312 was used but substituting 2-methyl-nicotinic acid for 2-furoic acid. After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield the following peptides as the trifluoroacetate salt: N- (2-Me-nicotinyl) -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2 (CH3) 2, and N- (2-Me-nicotinyl) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2.
Example 316 N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHethyl-1- (R) -cyclohexyl
The procedure described in Example 8 was used but replacing Fmoc-D-Leu for Fmoc-Dile and Fmoc-Ser (tBu) for
Fmoc-Thr (tBu). After separation of the peptide from the resin and removal of the protecting groups using (9 1) TFA / anisole (3
M & Ü & ..
ml) The crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHethyl-1- (R) -cyclohexyl as the trifluoroacetate salt.
Example 317 N-Ac-Sar-Gly-Val-Dlle-Thr-Ser-lle-Arg-ProNHethyl-1- (R) -cyclohexyl The procedure described in Example 8 was used but replacing Fmoc-Ser (tBu) for Fmoc -Nava After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Val-Dlle-Thr-Ser-lle-Ai g-ProNHethyl-1 - (R) -cyclohexyl as the trifluoroacetate salt.
Example 318 N-Ac-Sar-Gly-Val-Dlle-Thr-Leu-lle-Arg-ProNHethyl-1- (R) -cyclohexyl
The procedure described in Example 8 was used but replacing Fmoc-Leu for Fmoc-Nva. After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-DHe-Leu-lle-Arg-ProNHethyl-1 - (R) -cyclohexyl as the trifluoroacetate salt.
Example 319 N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-lle-Arg-ProNHethyl-1- (R) -cyclohex? L The procedure described in Example 8 was used but replacing Fmoc-D- Leu for Fmoc-Dlle. After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50%) of acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Thr-Ser-lle-Arg-ProNHethyl-1 - (R) -cyclohexyl as the trifluoroacetate salt.
Example 320 N-Ac-Sar-Gly-Val-D-Leu-Ser-Ser-lle-Arg-ProNHethyl-1- (R) -cyclohe > il
The procedure described in Example 316 was used but replacing Fmoc-Ser (tBu) for Fmoc-Nva. After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using
- * * * "•" - - • * »" »- *" * • "- a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Ser-Ser-lle-Arg-ProNHethyl-1- (R) -cyclohexyl as the trifluoroacetate salt.
Example 321 N-Ac-Sar-Gly-Val-D-Leu-Ser-Gln-Arg-ProNHethyl-1- (R) -cyclohexyl The procedure described in Example 316 was used but replacing Fmoc-Gln (Trt) for Fmoc -Nava After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01%) of TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Ser-GIn-Arg-ProNHethyl-1 - (R) -cyclohexyl as the Grifluoroacetate salt.
Example 322 Nac-Sar-Gly-Val-Dile-Thr-Nva-lle-Arg-ProNHethyl-1- (S) -cyclohexyl The procedure described in Example 8 was used but replacing (S) -l-cycloxylethylamine for (R ) -1-cycloxylethylamine a. After separation of the peptide from the resin and removal of the protecting groups, the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitoplo-a ua containing 0.01% TFA. The pure fractions were lyophilized to produce Nac-Sar-Gly-Val-Dile-Thr-Nva-lle-Arg-ProNHethyl-1 - (S) -cyclohexyl as the trifluoroacetate salt.
Example 323 The procedures described in Example 98 were used but replacing the appropriate protected amino acids as described in Examples 132, 43, 54 and 75. After separation of the peptide from the resin and removal of the protecting groups using (9) : 1) TFA / anisole (3-ml), the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acrylonitrile-water containing 0.01% of TFA The pure fractions were lyophilized to yield the following peptides as the trifluoroacetate salt: N-Ac-Sar-Gly-Val-D-Pen-Ser-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- D-Pen-Gly-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Pen-Thr-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D- Pen-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2, N-Succinyl-Sar-Gly-Val-D-Pen-Ser-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- D-Pen-Ser-Nva-lle-Arg-Pro-D-AlaNH2, N-Ac-Sar-Gly-Val-D-Pen-Ser-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly- Val-D-Pen-Gly-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Pen-Ser-Ser-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- D-Pen-Thr-Ser-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Pen-Ser-Leu-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Gly-Val-D- Pen-Ser-Ser-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Gly-Val-D-Pen-Ser-Leu-lle-Arg-ProNHCH2CH3, and N-Succinyl-Sar-Gly-Val-D-Pen -Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2.
Example 324 N-Ac-Sar-Gly-Val-D-Cys-Thr-Nva-lle-Arg-Pro ProNHCH2CH3 The procedure described in Example 98 was used but replacing Fmoc-D-Cys (Trt) for Fmoc-D-pen (Trt). After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Cys-Thr-Nva-lle-Arg-Pro ProNHCH2CH3 as the trifluoroacetate salt.
Example 325 The procedures described in Example 324 were used but replacing the appropriate protected amino acids as described in Examples 132. 43, 54 and 75. After separation of the peptide from the resin and removal of the protecting groups using (9) : 1) TFA / anisole (3 ml) The crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield the following peptides as the trifluoroacetate salt: N-Ac-Sar-Gly-Val-D-Cys-Ser-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- D-Cys-Gly-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Cys-Thr-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D- Cys-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2, N-Succinyl-Sar-Gly-Val-D-Cys-Ser-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- D-Cys-Ser-Nva-lle-Arg-Pro-AlaNH2, N-Ac-Sar-Gly-Val-D-Cys-Ser-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- D-Cys-Gly-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Cys-Ser-Ser-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D- Cys-Thr-Ser-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Cys-Thr-Leu-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Cys- Ser-Leu-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Gly-Val-D-Cys-Ser-Ser-lle-Arg-ProNHCH2CH3, and N-Succinyl-Sar-Gly-Val-D-Cys-Ser -Leu-lle-Arg-ProNHCH2CH3.
Example 326 N-Ac-Sar-Gly-Pen-Dlle-Thr-Nva-lle-Arg-Pro ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Pen (Trt) for Fmoc-Val. After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using
lH ^ n a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Pen-Dlle-Thr-Nva-lle-Arg-Pro ProNHCH2CH3 as the trifluoroacetate salt.
Example 327 N-Ac-Sar-Gly-Cys-Dlle-Thr-Nva-lle-Arg-Pro ProNHCH2CH3 The procedure described in Example 1 was used but replacing Fmoc-Cys (Trt) for Fmoc-Val. After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield N-Ac-Sar-Gly-Cys-Dlle-Thr-Nva-lle-Arg-Pro ProNHCH2CH3 as the trifluoroacetate salt.
Example 328 The procedures described in Example 326 were used but replacing the appropriate protected amino acids as described in Examples 14, 15, 132, 43, 54 and 75. After separation of the peptide from the resin and removal of the groups Protectants using (9: 1) TFA / anisole (3 ml) The crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01 % of TFA. The pure fractions were lyophilized to yield the following peptides as the trifluoroacetate salt: N-Ac-Sar-Gly-Pen-D-allolle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Pen- D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Pen-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Pen-D- lle-Ser-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Pen-D-lle-Thr-Nva-lle-Arg-ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Pen- D-lle-Thr-Nva-lle-Arg-Pro-D-AlaNH2, N-Succinyl-Gly-Pen-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Gly-Pen- D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, and N-Succinyl-Sar-Gly-Pen-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3.
Example 329 N-Ac-Sar-Gly-Val-D-Leu-Pen-Nva-lle-Arg-Pro ProNHCH2CH3 The procedure described in Example 120 was used but replacing Fmoc-Pen (Trt) for Fmoc-Ala. After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Leu-Pen-Nva-I le-Arg-Pro ProNHCH2CH3 as the trifluoroacetate salt.
miir _iit M || iiiMiM-ia-ii-a ^^ Example 330 The procedures described in Example 329 were used but replacing the appropriate protected amino acids as described in Examples 14, 15, 132, 43, 54 and 75. After of the separation of the peptide from the resin and the removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the following peptides as the trifluoroacetate salt: N-Ac-Sar-Gly-Val-D-lle-Pen-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- D-allolle-Pen-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Pen-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D- lle-Pen-Ser-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Pen-Leu-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle Pen-Nva-lle-Arg-ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Val-D-lle-Pen-Nva-lle-Arg-Pro-D-AlaNH2, N-Succinyl-Sar-Gly- Val-D-lle-Pen-Nva-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Gly-Val-D-lle-Pen-Gln-lle-Arg-ProNHCH2CH3, and N-Succinyl-Sar-Gly -Val-D-lle-Pen-Gln-lle-Arg-ProNHCH2 (CH3) 2.
Example 331 N-Ac-Sar-Gly-Val-D-lle-Thr-Pen-lle-Arg-Pro ProNHCH2CH3 The procedure described in Example 11 was used but
^^^^ j ^^ replacing Fmoc-Pen (Trt) for Fmoc-Nva. After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-lle-Thr-Pen-lle-Arg-Pro ProNHCH2CH3 as the trifluoroacetate salt.
Example 332 The procedures described in Example 331 were used but replacing the appropriate protected amino acids as described in Examples 14, 15, 132, 43, 54 and 75. After separation of the peptide from the resin and removal of the groups Protectants using (9: 1) TFA / anisole (3 ml) The crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01 % of TFA. The pure fractions were lyophilized to yield the following peptides as the trifluoroacetate salt: N-Ac-Sar-Gly-Val-D-allolle-Thr-Pen-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- D-Leu-Thr-Pen-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Pen-lle-Arg-Pro-D-AlaNH2, N-Succinyl-Sar-Gly- Val-D-lle-Thr-Pen-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Pen-He-Arg-ProNHCH2 (CH3) 2, N-Ac-Sar- Gly-Val-D-Leu-Ser-Pen-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Leu-Gly-Pen-lle-Arg-ProNHCH2CH3, and N-Succinyl-Sar-Gly -Val-D-Leu-Ser-Pen-lle-Arg-ProNHCH2CH3.
Example 333 N-Ac-Sar-Gly-Val-D-Phe (3,4,5-triF) -Thr-Gln-lle-Arg-Pro ProNHCH2CH3 The procedure described in Example 96 was used but replacing Fmoc-Gln ( Trt) for Fmoc-Nva. After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D-Phe (3,4,5-triF) -Trr-Gln-lle-Arg-Pro ProNHCH2CH3 as the trifluoroacetate salt.
Example 334 The procedures described in Example 333 were used but replacing the appropriate protected amino acids as described in Examples 132, 43, 54 and 75. After separation of the peptide from the resin and removal of the protecting groups using (9) : 1) TFA / anisole (3 ml) The crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield the following peptides as the trifluoroacetate salt: N-Ac-Sar-Gly-Val-D-Phe (3,4,5-triF) -Ser-Nva-lle-Arg-ProNHCH2CH3
N-Ac-Sar-Gly-Val-D-Phe (3,4,5-triF) -Gly-Nva-lle-Arg-ProNHCH2CH3,
N-Ac-Sar-Gly-Val-D-Phe (3,4,5-triF) -Ser-Leu-lle-Arg-ProNHCH2CH3,
N-Ac-Sar-Gly-Val-D-Phe (3,4,5-triF) -Ser-Nva-lle-Arg-Pro-D-AlaNH2,
N-Succinyl-Sar-Gly-Val-D-Phe (3,4,5-triF) -Thr-Gln-lle-Arg- ProNHCH2CH3, N-Succ? N? L-Sar-Gly-Val-D-Phe (3,4,5-tr? F) -Ser-Gln-lle-Arg- ProNHCH2CH3, N-Succinyl-Sar-Gly-Val-D-Phe (3,4,5-triF) -Thr-Gln-lle -Arg- ProNHCH2 (CH3) 2, N-Ac-Sar-Gly-Val-D-Phe (3,4,5-triF) -Ser-Gln-lle-Arg-ProNHCH2CH3, and
N-Ac-Sar-Gly-Val-D-Phe (3,4,5-triF) -Ser-Ser-lle-Arg-ProNHCH2CH3
Example 335 N-Ac-Sar-Ala-Val-D-alolle-Thr-Nva-lle-Arg-Pro ProNHCH2CH3 The procedure described in Example 153 was used but replacing Fmoc-Dalolle for Fmoc-DHe. After separation of the peptide from the resin and removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce N-Ac-Sar-Ala-Val-D-allolle-Thr-Nva-lle-Arg-Pro ProNHCH2CH3 as the trifluoroacetate salt.
Example 336 The procedures described in Example 335 were used but replacing the appropriate protected amino acids as described in Examples 132, 43, 54 and 75. After separation of the peptide from the resin and removal of the protecting groups using (9) : 1) TFA / anisole (3 ml) The crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to yield the following peptides as the trifluoroacetate salt: N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val- D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Val-D- Leu-Ser-Gln-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Ala-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Ala-Val-D-lle Thr-Gln-Nva-lle-Arg-ProNHCH2CH3, N-Succinyl-Sar-Ala-Val-D-lle-Thr-Gln-va-lle-Arg-ProNHCH2 (CH3) 2, and N-Succinyl-Sar-Ala -Val-D-lle-Thr-Gln-Nva-lle-Arg-ProNHCH2CH3.
Example 337 The procedures described in Example 231 were used
LÉb = HiMtiühri riUÉAi B-ü-ÉHÉii-tt-? íÉf «IMÍiM but replacing N-acetyl-beta-alanine (3-Ac-Bala) for N-acetyl-4-aminobutyric acid After separation of the peptide from the resin and the removal of the protecting groups using (9: 1) TFA / anisole (3 ml) the crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient of 10% to 50% of acetonitrile-water containing 0.01% TFA. The pure fractions were lyophilized to produce the following peptides as the trifluoroacetate salt: N- (3-Ac-Bullet -Sar-Gly-Val-D-allolle-Thr-Nva-lle-Arg-ProNHCH2CH3l N- (3-Ac -Bala-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, N- (3-Ac-Bullet -Sar-Gly-Val-D-allolle-Thr-Gln-lle-Arg- ProNHCH2CH3, N- (3-Ac-Bullet -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, N- (3-Ac-Bullet -Sar-Gly-Val- D-allolle-Thr-Nva-lle-Arg-ProNHCH2CH3, N- (3-Ac-Bullet-Sar-Gly-Val-D-allolle-Thr-Gln-lle-Arg-Pro-DAIaNH2, N- (3- Ac-Bullet -Sar-Gly-Val-D-allolle-Thr-GIn-lle-Arg- ProNHCH2 (CH3) 2, N- (3-Ac-Bullet -Sar-Gly-Val-D-Leu-Ser-Nva -lle-Arg-ProNHCH2CH3,
N- (3-Ac-Bullet -Sar-Gly-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3,
N- (3-Ac-Bullet -Sar-Gly-Val-D-Pen-Thr-Nva-lle-Arg-ProNHCH2CH3,
N- (3-Ac-Bullet -Sar-Gly-Val-D-lle-Ser-Nva-lle-Arg-ProNHCH2CH3,
N- (3-Ac-Bullet -Sar-Ala-Val-D-allolle-Ser-Nva-lle-Arg-ProNHCH2CH3,
N- (3-Ac-Bullet -Sar-Ala-Val-D-lle-Ser-Nva-lle-Arg-ProNHCH2CH3,
N- (3-Ac-Bullet -Sar-Ala-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2CH3, and
N- (3-Ac-Bullet -Sar-Ala-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2CH3 Example 338 N-Ac-Sar-Gly-Val-D-lle-Thr-N a-lle -Arg-Pro-OH The procedure described in Example 1 was used but replacing and omitting the coupling with ethylamine After the separation of the peptide from the resin and the removal of the protective groups, the crude product was purified by chromatography of C-18 column using a solvent mixture varying in a gradient of 10% to 50% acetonitrile-water containing 0.01% TFA.The pure fractions were lyophilized to produce N-Ac-Sar-Gly-Val-D- lle-Thr-Nva-lle-Arg-Pro-OH as the S. to I of trifluoroacetate.
Example 339 The procedures described in Example 338 were used but replacing the appropriate protected amino acids as described in Examples 14, 15, 132, 43, 54 and 75. After separation of the peptide from the resin and removal of the groups Protectants using (9: 1) TFA / anisole (3 ml) The crude product was purified through C-18 column chromatography using a solvent mixture varying in a gradient from 10% to 50% acetonitrile-water containing 0.01 % of TFA. The pure fractions were lyophilized to produce the following peptides as the trifluoroacetate salt: N-Ac-S-Gly-Val-D-allolle-Thr-Nva-lle-Arg-Pro-OH, N-Ac-S-Gly- Val-D-Leu-Thr-Nva-lle-Arg-Pro-OH,
^^^ g¡! ^^^^^^ t ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ , N-Ac-Sar-Gly-Val-D-Phe (3,4,5-triF) -Thr-Nva-lle-Arg-Pro-OH, N-Ac-Sar-Gly-Val-D-lle Thr-GIn-lle-Arg-Pro-OH, N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-Pro-OH, N-Ac-Sar-AI-Val-D- lle-Thr-Nva-lle-Arg-Pro-OH, N-Ac-Sar-Gly-Val-D-lle-Ser-GIn-lle-Arg-Pro-OH, N-Succinimil-Sar-Gly-Val- D-lle-Thr-Nva-lle-Arg-Pro-OH, and N-Succinimil-Sar-Gly-Val-D-Leu-Thr-GIn-lle-Arg-Pro-OH.
In Vitro Assay for Anqiogenic Activity The human microbascular endothelial migration assay (HMVEC) was performed according to the S.S. Tolsma, O. V. Volert, D. J. Good, W. F. Fraizer, P. J. Polverini and N, Bouck, J. Cell Biol. 122, 497-511 (1993). The HMVEC migration assay was performed using human-dermal microbascular endothelial cells (individual donor) and human microbascular endothelial cells (neonatal). BCE or HMVED cells were left without food overnight in DME containing 0.1% bovine serum albumin (BSA). The cells were then harvested with trypsin and resuspended in DME with 0.1% BSA at a concentration of 1.5 x 106 cells per ml. The cells were added to the bottom of a modified Boyden chamber with 48 cavities (Nucleopore Corporation, cabin John, MD). The chamber was assembled and inverted, and the cells were allowed to bind for 2 hours at 37 ° C to chemotaxis membranes
tr- -7-, ^^^^ M ^ _ ^^ iÉTIÉ |MMMÉ | at¿t ^ of polycarbonate (pore size 5 μ) that were soaked in 0.1% gelatin overnight and dried. The chamber was then inverted again, and the test substances (total volume of 50 μl), including activators, 15 ng / ml bFGF / VEGF, were added to the cavities of the upper chamber. The apparatus was incubated for 4 hours at 37 ° C. The membranes were recovered, fixed and stained (Dic Quick, Fisher Scientific) and a number of cells that migrated to the upper chamber by three high energy fields were counted. Previous migration to DME + 0.1 BSA was subtracted and the data reported as the number of cells migrated per 100 high energy fields (400X) or, when the results of multiple experiments were combined, as the percentage of migration inhibition compared to a positive control The compounds described in Examples 1 to 339 inhibited the migration of human endothelial cell in the above assay from about 30% to about 95% inhibition when tested at concentrations of 10 nM or 20 nM, as reported in Table 3 to continuation.
'^^ a. ^ ** 3fe & ^ Table 3 In Vitro Angiogenic Activity
LIST OF SEQUENCES
< 110 > Abbott Laboratories Henkin, J. Haviv, F. Bradley, M. F. Kalvin, D. M. Schneider, A. J. < 120 > Peptide Antiangiogenic Peptides < 130 > 6356. PC.01 < 140 > PCT / US99 / 11448 < 141 > 1999-05-21 < 150 > US 09 / 277,466 < 151 > 1998-03-26 < 150 > Us 09 / 250,574 < 151 > 1998-02-16 < 150 > US 09 / 083,745 < 151 > 1998-05-22 < 160 > 6 < 170 > FastSEC for Windows Version 3.0 < 210 > 1 < 211 > 10 < 212 > PRT < 213 > Artificial Sequence < 220 >
^ _ ^ ^ AÉjBtt¡ ^ ^ HtÉfMiiÉiiÉii < 221 > PEPTIDE < 222 > (1) (1) < 223 > Xaa is Ala, Asx, citrulil (Cit), Glx, EtGly, Met, N-methylAla (MeAla), Pro, pyro-Glx, MeGly, Ser, or Thr
< 221 > PEPTIDE < 222 > (2) ... (2) < 223 > Xaa is Ala, Asx, Glx, Leu, Met, Phe, Pro or Ser
< 221 > PEPTIDE < 222 > (3) ... (3) < 223 > Xaa is Ala, Asx, Cit, Cha, cicIohexilGIy, Glx, Gly, He, Leu, Met, Nva, Phe, Ser, t-byGly, Thr, Val or Cys
< 221 > PEPTIDE < 222 > (4) ... (4) < 223 > Xaa in position 4 can also be D-3- (4,4'-biphenyl) Ala,
D-chloroPhe, D-3- (3-trifluoromethylphenyl) Ala, D-3J3-cyanophenyl) Ala,
< 221 > PEPTIDE < 222 > (4) ... (4) < 223 > Xaa at position 4 can also be D-3- (3,4-difluorophenyl) Ala, D-Cit, D-Cha, D-cyclohexyl-GIy, D-Cys, D-Cys (St-bu), D-Glx, D-His, D-homolle, D-homoPhe, D-homoSer, D-lle, < 221 > PEPTIDE < 222 > (4) ... (4) < 223 > Xaa in position 4 can also be D-Leu, D-Lys (N-epsilon-nicotinil), D-Lys, D-Met, D-neopentylGy, D-Nle, D- Nava, D-Orn, D-Phe , D-3- (4-aminophenyl) Ala, D-3J4-aminophenyl) Ala, D-3- (4-methylphenyl) Ala,
< 221 > PEPTIDE < 222 > (4) ... (4) < 223 > Xaa in position 4 can also be D-3- (4-nitrophenyl) Ala, D-3- (3,4-dimethoxyphenyl) Ala, D-3- (3,4, 5-trif luorofenil) Al a, D-Pro, D-Ser,
< 221 > PEPTIDE < 222 > (4) ... (4) < 223 > Xaa in position 4 can also be D-Ser (O-benzyl), Dt-buGly, D-thienylAla, D-Thr, D-Thr (O-benzyl), D-Trp, D-Tyr (O-benzyl) , D-Tyr (O-ethyl), D-Tyr, or D-Val
< 221 > PEPTIDE < 222 > (5) ... (5)
N ^^ ái ^ < 223 > Xaa is Ala, (3- pi rid i I) Al a, 3- (naft-1 -il) Ala, 3- (naft-2-il) Ala, alloThr, alilGIy, Glx, Gly, His, homoSer, He , Lys (N-epsilon-acetyl), Met, Nava, octiGly, Orn, 3- (4-hydroxymethylphenyl) Ala,
< 221 > PEPTIDE < 222 > (5) ... (5) < 223 > Xaa in position 5 can also be Pro, Ser, Thr, Tip, Tyr, D-alloThr, D-homoSer, D-Ser, D-Thr, or Cys
< 221 > PEPTIDE < 222 > (6) ... (6) < 223 > Xaa is Ala, 3- (naft-1-yl) Ala, 3- (naft-2-yl) Ala, (3-pi rid i I) Al a, Abu, ally GIy, Arg, Asx, Cit, Cha, Glx , Gly, His, homoAla, homoLeu, homoSer, He, Leu,
< 221 > PEPTIDE < 222 > (6) ... (6) < 223 > Xaa in position 6 can also be Lys (N-epsilon-acetyl), Lys (N-epsilon-isopropyl), Met (sulfone), Met (sulfoxide), Met, NIe, Nva, octylGy, Phe,
< 221 > PEPTIDE < 222 > (6) ... (6) < 223 > Xaa in position 6 can also be 3- (4- carboxamidaphenyl) Ala, propargylGly, Ser, Thr, Trp, Tyr, Val, D- 3- (naft-1-yl) Ala, D-3- (naft-2) -il) Ala, D-Glx, D-homoSer, D-Leu,
< 221 > PEPTIDE < 222 > (6) ... (6) < 223 > Xaa in position 6 can also be D-Nva, D-Ser, or Cys
< 221 > PEPTIDE < 222 > (7) .. (7) < 223 > Xaa is Ala, alilGIy, Asx, Cit, cidohexylGly, Glx, Gly, homoSer, He, alie, Leu, Lys (N-epsilon-acetyl), Met, 3- (naft-1- il) Ala, 3- (naft -2-il) Wing, Nva, Phe, Pro, Ser, Pro, Ser, t-buGly,
< 221 > PEPTIDE < 222 > (7) ... (7) < 223 > Xaa in position 7 can also be Trp, Tyr, Val, D-alle, or Cys
• i tó21 > PEPTIDE < 222 > (8) ... (8) < 223 > Xaa is Ala (3-guanidino), Ala [3-pyrrolidinyl (2-N-amidino], Ala [4-piperidinyl (N-amidino)], Arg,
< 221 > PEPTIDE < 222 > (8) ... (8) < 223 > Xaa in position 8 can also be Arg (NGNG'dietil), Cit,
3- (cyclohexyl) Ala (4-N'-isopropyl), Gly [4-piperidinyl (N-amidino)],
His, homoArg,
< 221 > PEPTIDE < 222 > (8) ... (8) < 223 > Xaa in position 8 can also be Lys, Lys (N-epsilon-isopropyl), Lys (N-epsilon-nicotinyl), norArg, Orn (N-delta, isopropyl), Orn (N-delta-nicotinyl),
< 221 > PEPTIDE < 222 > (8) ... (8) < 223 > Xaa at position 8 can also be Orn [N-delta- (2-imidazolinyl)], [(4-amino (N-isopropyl) methyl) phenyl] Ala, 3- (4-guanidinophenyl) Ala, or
< 221 > PEPTIDE < 222 > (8) ... (8) < 223 > Xaa in position 8 can also be 3- (4-amino-N-isopropylphenyl) Ala
< 221 > PEPTIDE < 222 > (9) ... (9) < 223 > Xaa is Abu, Aib, homoPro, hydroxyPro, He, Leu, Phe, P ^ o, Ser, t-buGly, Thr, Val, D-Ala, or Pro
< 221 > PEPTIDE < 222 > (10) ... (10) < 223 > Xaa is azaGyamide, D-Alaamide, D-Alaethylamide, GIyamide,
Glyethylamide, MeGyamide, Seramide, or D-Seramide < 400 > Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10
< 210 > 2 < 211 > 9 < 212 > PRT < 213 > Artificial Sequence < 220 > < 221 > PEPTIDE < 222 > (1) ... (1) < 223 > Xaa is MeGly
< 221 > PEPTIDE < 222 > (4) ... (4) < 223 > Xaa in position 4 here is the same as position 4 in SEQ ID NO: 1
my"! i.-rÉÉláii '"ii É líí LL ___ LÍ_ < 221 > PÉPTIDO < 222 > (5) .. (5) < 223 > Xaa in position 5 here is the same as position 5 in SEC ID NO: 1
< 221 > PEPTIDE < 222 > (6) ... (6) < 223 > Xaa in position 6 here is the same as position 6 in SEC
ID NO: 1 < 400 > 2 Xaa Gly Val Xaa Xaa Xaa He Arg Pro 1 5
< 210 > 3 < 211 > 9 < 212 > PRT < 213 > Artificial Sequence < 220 > < 221 > PEPTIDE < 222 > (1) ... (1) < 223 > Xaa is MeGly
< 221 > PEPTIDE < 222 > (6) ... (6) < 223 > Xaa is Nva < 400 > 3 Xaa Gly Val He Thr Xaa He Arg Pro 1 5
< 210 > 4 < 211 > 9 < 212 > PRT < 213 > Artificial Sequence < 220 > < 221 > PEPTIDE < 222 > (1) ... (1) < 223 > Xaa is MeGly
< 221 > PEPTIDE < 222 > (6) ... (6) < 223 > Xaa is Nva < 400 > 4 Xaa Gly Val Thr Xaa He Arg Pro 1 5
< 210 > 5 < 211 > 9 < 212 > PRT < 213 > Artificial Sequence < 220 >
~ ^^^^ < 221 > PEPTIDE < 222 > (1) . (1) < 223 > Xaa is MeGly
< 221 > PEPTIDE < 222 > (4) ... (4) < 223 > Xaa is alie < 221 > PEPTIDE < 222 > (6) ... (6) < 223 > Xaa is Nva < 400 > 5 Xaa Gly Val Xaa Thr Xaa He Arg Pro 1 5
< 210 > 6 < 211 > 9 < 212 > PRT < 213 > Artificial Sequence < 220 > < 221 > PEPTIDE < 222 > (1) ... (1) < 223 > Xaa is MeGly
< 221 > PEPTIDE < 222 > (4) ... (4)
ÉM ^ SlÜiÜÍSÍH < 223 > Xaa is dehydroLeu < 221 > PEPTIDE < 222 > (6) ... (6) < 223 > Xaa is Nva < 400 > 6 Xaa Gly Val Xaa Thr Xaa lie Arg Pro 1 5
Claims (17)
1. A compound of the formula: Ao-A1-A2-A3-A4-A5-A6-A7-A8-A9-A1o or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, wherein: A0 is hydrogen or a acyl group selected from: (3) R- (CH2) nC (O); wherein n is an integer from 0 to 8 and R is selected from hydroxyl; methyl; N-acetylamine; methoxy, carboxyl; cyclohexyl optionally containing one or two double bonds and optionally substituted with 1 to 3 hydroxyl groups; and a 5- or 6-membered aromatic or non-aromatic ring optionally containing one or two heterogeneous atoms selected from nitrogen, oxygen and sulfur, wherein the ring is optionally substituted with a selected portion of alkyl, alkoxy, and halogen; and (4) R1-CH2CH2- (OCH2CH2O) p-CH2-C (O) -; wherein R is selected from hydrogen, alkyl, N-acetylamino, and p is an integer from 1 to 8; Ai is an aminoacyl residue selected from: 1) alanyl, 2) asparaginyl, 3) citrulil, 4) glutaminyl, 5) glutamyl, 6) N-ethylgyl, 7) methionyl, 8) N-metalalanyl, 9) prolyl , 10) pyro-glutamyl, 11) sarcosyl, 12) seryl, 10 13) threonyl, 14) -HN- (CH2) qC (O) -, where q is 1 to 8, and 15) -HN-CH2CH2- (OCH2CH2O) r-CH2-C (O) -, wherein r is 1 to 8; A2 is an amino acyl residue selected from: 1) alanyl, 2) asparaginyl, 3) aspartyl, 4) glutaminyl, 5) glutamyl, 6) leucyl, 7) methionyl, 8) phenylalanyl, 9) prolyl, ) seryl, 11) -HN- (CH2) qC (O), where q is 1 to 8, and 12) -HN-CH2CH2- (OCH2CH2O) r -CH2-C (O) -, where r is 1 to 8; A3 is an amino acyl selected from. I) Alanyl; 2) asparaginyl, 3) citrulil, 4) cyclohexylalanyl, 5) cyclohexylglycyl, 6) glutaminyl, 7) glutamyl, 8) glycyl, 9) isoleucyl, 10) leucyl, II) methionyl, 12) norvalyl, 13) phenylalanyl, 14) seryl, 15) t-butylglycyl, 16) threonyl, 17) vallyl, 18) penicillaminyl, and 19) cystyl; A4 is an amino acyl residue of the L or D configuration selected from: 1) allo-isoleucyl, "* -tr jüC--. 2) glycyl, 3) isoleucyl, 4) prolyl, 5) dehydroleucyl, 6) D-alanyl, 7) D-3- (naphth-1-yl) alanyl, 8) D-3- (naphth-2-yl) alanyl, 9) D (3-pyridyl) -alanyl, 10) D-2-aminobutyryl, 10 11) D-alo-isoleucyl, 12) D-allo-threonyl, 13) D-ali Ig ricyl, 14) D- asparaginyl, 15) D-aspartyl, 15 16) D-benzothienylalanyl, 17) D-3- (4,4-biphenyl) alanyl, 18) D-chlorophenylalanyl, 19) D-3- (3-trifluoromethylphenyl) alanyl, ) D-3- (3-cyanophenyl) alanyl, 20 21) D-3- (3,4-difluorophenyl) alanyl, 22) D-citrulil, 23) D-cyclohexylalanyl, 24) D-cyclohexylglycyl, 25) D- cystyl, 25 26) D-cystyl (S-butyl), m! i¡y¿ ^^^^^^ m 27) D-glutaminyl, 28) D-glutamyl, 29) D-histidyl, 30) D-homoisoleucyl, 31) D-homophenylalanyl, 32) D-homoseryl, 33) D-isoleucyl, 34) D-leucyl, 35) D-lysyl (N-epsilon-nicotilino), 10 36) D-lysyl, 37) D-methionyl, 38) D-neopentyl glycyl, 39) D-nor! Eucyl, 40) D-norvalyl, 15 41) D-ornylyl, 42) D-penicillaminyl, 43) D- penicillaminyl (acetamidomethyl), 44) D-penicillaminyl (S-benzyl), 45) D-phenylalanyl, 46) D-3- (4-aminophenyl) alanyl, 47) D-3- (4-methylphenyl) alanyl, 48 ) D-3 (4-nitrophenyl) alanyl, 49) D-3 (3,4-dimethoxyphenyl) alanyl, 50) D-3 (3,4,5-trofluorophenyl) alanyl, 25 51) D-prolyl, H ^ ityia «liYMaIIyMtHiFeiHi'i» il 52) D-seryl, 53) D-seryl (O-benzyl), 54) Df-butyglycyl, 55) D-thienylalanyl, 56) D-threonyl, 57) D-threonyl (O -benzyl), 58) D-triptyl, 59) D-tyrosyl (O-benzyl), 60) D-tyrosyl (O-ethyl), 61) D-tyrosyl, and 62) D-valyl; A5 is an amino acyl residue of the L or D configuration selected from: I) alanyl, 2) (3-pyridinyl) alanyl, 3) 3- (naphth-1-yl) alanyl, 4) 3- (naphth-2-) il) alanyl, 5) allo-threonyl, 6) allylglycyl, 7) glutaminyl, 8) glycyl, 9) histidyl, 10) homoseryl, II) isoleucyl, 12) lysyl (N-epsilon-acetyl), 13) methionyl, ) norvalil, 15) octi tg licit, 16) ornitil, 17) 3- (4-hydroxylphenyl) alanyl, 18) prolyl, 19) seryl, 20) threonyl, 21) triptyl, 22) tyrosyl, 23) D-allo-threonyl, 24) D-homoseryl, 25) D-seryl, 26) D-threonyl, 27) penicillaminyl, and 28) cystyl: A6 is an amino acyl residue of the L or D configuration of the selected configuration of: 1) alanilo. 2) 3- (naphth-1-yl) alanyl, 3) 3- (naphth-2-yl) alanyl, 4) (3-pyridyl) alanyl, 5) 2-aminobutyryl, 6) allyl glycyl, 7) arginyl , 8) asparaginyl, 9) aspartyl, 10) citrulil, 11) cyclohexylalanyl, 12) glutaminyl, 13) glutamyl, 14) glycyl, 15) histidyl, 16) homoalanyl, 10 17) homoleucyl, 18) homoseryl, 19) isoleucyl, 20) leucyl, 21) lysyl (N-epsilon-acetyl), 15 22) lysyl (N-epsilon-isopropyl), 23) methionyl (sulfone), 24) methionyl (sulfoxide), 25) methionyl, 26) norleucyl, 27) norvalyl, 28) octylglycyl, 29) phenylalanyl, 30) 3- (4-carboxyamidaphenyl) alanyl, 31) propalg i Ig lici I, 25 32) seryl, - - ^ "^^ - ^ - ^ 33) threonyl, 34) tyl, 35) tyrosyl, 36) vally, 37) D-3- (naft-1-? L) alanyl, 38) D-3- ( naphth-2-yl) alanyl, 39) D-glutaminyl, 40) D-homoseryl, 41) D-leucyl, 42) D-norvalyl, 43) D-seryl, 44) penicillaminyl, and 45) cystyl; A7 is an amino acyl residue of the L or D configuration selected from: 1) alanyl, 2) allyl glyc, 3) aspartyl, 4) citrulil, 5) cyclohexylglycyl, 6) glutamyl, 7) glycyl, 8) homoseryl, ) isoleucyl, 10) alo-isoleucyl, 11) leucyl, 12) l? yesl (N-epsilon-acetyl), 13) methionyl, 14) 3- (naphth-1-? l) alanyl, 15) 3- (naft) -2-? L) alanyl, 16) norvalyl, 17) phenylalanyl, 18) prolyl, 19) seplo, 10 20) f-butylglyc, 21) tyl, 22) tyrosyl, 23) valyl, 24) D-alo-isoleucyl , 15 25) D-isoleucyl, 26) penicillaminyl, and 27) cystyl; A8 is an amino acyl residue selected from: 1) 2-amino-4 - [(2-amino) -pyrimidinyl] butanoyl, 2) alanyl (3-guanidino), 3) alanyl [3-pyrrolidinyl (2-N-amidino)], 4) alanyl [4-piperidinyl (N-amidino)], 5) arginyl, 6) arginyl (NGNG ' diethyl), 25 7) citrulil, ^ jjj ^ S¿5 ^ or? ^ lg i * I ^^^ £ a ^ g ^^^^^ j ^^ j ^^^^^^ 8) 3- (cyclohexyl) alanyl (4-N-sopropyl), 9) glycyl [4-piperidinyl (N- amidino)], 10) histidyl, 11) homoarginyl, 12) lysyl, 13) lysyl (N-epsilon-isopropyl), 14) lysyl (N-epsilon-nicotinyl), 15) norargylyl, 16) ornithyl (N-delta- isopropyl), 17) ornithyl (N-delta-nicotinyl), 18) ornithyl [N-delta- (2-imidazolinyl)], 19) [4-amino (N-isopropyl) methyl) phenyl] alanyl, 20) 3- (4-guanidinophenyl) alanyl, and 21) 3- (4-amino-N-isopropylphenyl) alanyl; A9 is an amino acyl residue of the L or D configuration selected from: 1) 2-amino-butyryl, 2) 2-amino-isobutyral, 3) homoprolyl, 4) hydroxyprolyl, 5) isoleucyl, 6) leucyl, 7) phenylalanyl, 8) prolyl, 9) seryl, 10) r-butylglycyl, 11) 1,2,3,4-tetrahydroxyaquinoline-3-carbonyl, 12) threonyl, 13) valyl, 14) D-alanyl, and ) D-propyl; and A10 is a hydroxyl group or an amino acid amide and is selected from: 1) azaglycylamide, 2) D-alanylamide, 3) D-alanyl ethylamide, 4) glycylamide, 5) glycylethylamide, 6) sarcosylamide, 7) serylamide, ) D-serylamide, 9) a group represented by the formula: R 'NH- (CH2) S-CHRJ and (10) a group represented by the formula -NH-R wherein is an integer selected from 0 to 8, R2 is selected from hydrogen, alkyl and a cycloalkyl ring of 5 to 6 members, R3 is selected from hydrogen, hydroxy, alkyl, phenyl, alkoxy, and a 5- to 6-membered ring optionally containing one to two heterogeneous atoms selected from oxygen, nitrogen and sulfur, provided that s is not 0 when R3 is hydroxy or alkoxy; and R4 is selected from hydrogen and hydroxy.
2. A compound according to claim 1, wherein A is sarcosyl, A2 is glycyl, A3 is valyl, A7 is isoleucyl, A8 is arginyl, A9 is propyl and A0, A4, A5, A6 and A10 are as were defined in claim 1.
3. A compound according to claim 2, wherein A is an aminoacyl residue having a D configuration selected from: (1) D-alanyl, (2) D-3- ( naphth-1-yl) alanyl, (3) D-3- (naphth-2-yl) alanyl, (4) D (3-pyridyl) -alanyl, (5) D-2-aminobutyryl, (6) D- allo-isoleucyl, (7) D-allo-threonyl, (8) D-allyl glyc, (9) D-asparaginyl, (10) D-aspartyl, (11) D-chlorophenylalanyl, (12) D- 3- (3) -trif luoromethylphenyl) alanyl, (13) D-3- (3-cyanophenyl) alanyl, (14) D-3- (3,4-difluorophenyl) alanyl, (15) D-cyclohexylalanyl, (16) D-cyclohexylglycyl, (17) D -cycryl, (18) D-glutaminyl, (19) D-glutamyl, (20) D-histidyl, (21) D-homoisoleucyl, ( 22) D-homophenylalanyl, (23) D-homoseryl, (24) D-isoleucyl, (25) D-leucyl, (26) D-lysyl (N-epsilon-nicotilino), (27) D-methionyl, (28) D-neopentyl glycyl, (29) D-norleucyl, (30) D-norvalyl, (31) D-penicillaminyl, (32) D-penicillaminyl (acetamidomethyl), (33) D-penicillaminyl (S-benzyl), (34) D-phenylalanyl, (35) D-3- (4-aminophenyl) alanyl, (36) D-3- (4-methylphenyl) alanyl, (37) D-3 (4-nitrophenyl) alanyl, (38) D-3 (3,4-dimethoxyphenyl) alanyl, (39) D-3 (3,4,5-trof luorofenil) ala ni lo, (40) D -prolyl, (41) D-seryl, (42) D-seryl (O-benzyl), (43) D-butylglyc, (44) D-thienylalanyl, (45) D-threonyl, (46) D-threonyl ( O-benzyl), (47) D-tisoryl (O-ethyl), (48) D-tyrosyl, and (49) D-valyl;
4. A compound according to claim 3, wherein A4 is an aminoacyl residue having a D configuration selected from: (1) D-Alo-isoleucyl, (2) D-Allylglycyl, (3) D-3 - (3-cyanophenyl) alanyl, (4) D-cystyl (5) D-isoleucyl, (6) D-leucyl, (7) D-pencylaminyl, (8) D-phenylalanyl, (9) D-3- ( 3,4,5-trifluorophenyl) alanyl, and (10) D-3- (4-aminophenyl) alanyl.
5. A compound according to claim 2, wherein A5 is selected from: (1) glycyl, (2) octylcyclic, (3) penicilaminyl, (4) seryl, (5) threonyl, and (6) tyrosyl.
6. A compound according to claim 2, wherein A6 is selected from: (1) glutaminyl, (2) leucyl, (3) norvalyl, and (4) seryl.
7. A compound according to claim 3, wherein A0 is selected from: (1) acetyl, (2) butyryl, (3) caprolyl, (4) (4-N-acetylamino) butyryl, (5) N -acetyl-beta-alanyl, (6) (6-N-acetylamino) caproyl, (7) chloromicotinyl, (8) cyclohexylacetyl, (9) furoyl, (10) gamma-aminobutyryl, (11) 2-methoxyacetyl, (12) ) methylnicotinyl, (13) nicotinyl, (14) (8-N-acetylamino) -3,6-dioxo-octanoyl, (15) phenylacetyl, (16) propionyl, (17) shikimil, (18) succinyl, and (19) ) tetrahydrofuroyl.
8. A compound according to claim 3, wherein A10 is selected from: (1) D-alanylamide, (2) aglylamide, (3) serylamide, (4) eilamide, (5) hydroxylamide, (6) ) iopropylamide, (7) propylamide, (8) 2- (cyclohexyl) ethylamide, (9) 2- (1-pyrrolidine) ethylamide, (10) 1 - (cyclohexyl) et? lide, (11) 2- (methoxy) ethylamide, EMI ^^ (12) 2- (hydroxy) ethylamide, (13) 2- (2-pyrrolidine) ethylamide, (14) (2-pyridine) methylamide, (15) 2 (3-pyridine) ethylamide, (16 2- (2- (1-methyl) pyrrolidine) ethylamide, (17) 2- (N-morpholine) ethylamide, and (18) cyclopropylmethylamide.
9. A compound according to claim 1, wherein A4 is an aminoacyl residue having a D configuration selected from: (1) D-alo-isoleucyl, (2) D-allylglycosyl, (3) D- 3- (3-cyanophenyl) alanyl, (4) D-cysylo, (5) D-isoleucyl, (6) D-leucyl, (7) D-pencylaminyl, (8) D-phenylalanyl, (9) D-3 - (3,4,5-trifluorophenyl) alanyl, and (10) D-3- (4-aminophenyl) alanyl; A5 is an aminoacyl residue selected from: (1) otilglycyl, (2) glcil, (3) pencylaminyl, (4) seplo, (5) threonyl, and (6) tyrosyl; and A6 is an aminoacyl residue selected from: (1) glutaminyl, (2) leucyl, (3) norvalyl, and (4) seryl.
10. A compound according to claim 9, wherein A0 is selected from: (1) acetyl, (2) butyryl, (3) caprolyl, (4) (4-N-acetylamino) butyryl, (5) N -acetyl-beta-alanyl, (6) (6-N-acetylamino) caprolyl, (7) chloromicotinyl, (8) cyclohexylacetyl, (9) furoyl, (10) gamma-aminobutyryl, (11) 2-methoxyacetyl, (12) ) methylnicotinyl, (13) nicotinyl, (14) (8-N-acetylamino) -3,6-dioxo-octanoyl, (15) phenylacetyl, (16) propionyl, - m (17) shikimil, (18) succinyl, and (19) tetrahydrofuroyl.
11. A compound according to claim 9, wherein A? 0 is selected from: (1) D-alanylamide, (2) azaglycylamide, (3) serylamide, (4) ethylamide, (5) hydroxylamide, (6) ) isopropylamide, (7) propylamide, (8) 2- (cyclohexyl) ethylamide, (9) 2- (1-pyrrolidine) ethylamide, (10) 1- (cyclohexyl) ethylamide, (11) 2- (n-heptoxy) ethylamide, (12) 2- (hydroxy) ethylamide, (13) 2- (2-pyridine) ethylamide, (14) (2-pyridine) methylamide, (15) 2. (3-pyridine) ethylamide, (16) 2- ( 2- (1-methyl) pyrrolidine) ethylamide, (17) 2- (N-morpholine) ethylamide, and (18) cyclopropylmethylamide.
12. A compound or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof selected from: MafcaMii-ÍÉiiMüi (1) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, (2) piroGlu-Gly-Val-D-lle-Thr-Nva-lle-Arg -ProNHCH2CH3, (3) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH3, (4) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva -lle-Arg-ProNHCH2 (CH3) 2, (5) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH2- (1- pyrrolidine), (6) N-Ac -Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHethylpiperidine, (7) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHmethylcyclopropyl, (8) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNH (ethyl-1- (R) -cyclohexyl), (9) N-Ac-Sar-Gly-Val -D-lle-Thr-Nva-lle-Arg-ProNH2, (10) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH2OCH3, (11) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH2 cyclohexyl, (12) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle -Arg-ProNHCH2 (CH3) 2, (13) N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCH2CH3, (14) N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3, (15) N-Ac-Sar-Gly-Val-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, (16) N-Ac-Sar-Gly-Val-Gly-Thr-Nva-lle-Arg-ProNHCH2CH3, (17) N-Ac-Sar-Gly-Val-D-Val-Thr-Nva-lle-Arg-ProNHCH2CH3, (18) N-Ac-Sar-Gly-Val-D-Ala-Thr-Nva-lle-Arg-ProNHCH2CH3, (19) N-Ac-Sar-Gly-Val-D-Met-Thr-N va-I le-Arg -Pro NHCH2CH3, (20) N-Ac-Sar-Gly-Val-D-Nle-Thr-Nva-lle-Arg-ProNHCH2CH3, (21) N-Ac-Sar-Gly-Val-D-Phe-Thr-Nva-1 le-Arg-Pro NHCH2CH3, (22) N-Ac-Sar-Gly-Val-D-Tyr-Thr-Nva- lle-Arg-ProNHCH2CH3, (23) N-Ac-Sar-Gly-Val-D-4,4-Biphenylala-Thr-Nva-lle-Arg- ProNHCH2CH3, (24) N-Ac-Sar-Gly-Val- D-Cha-Thr-Nva-lle-Arg-ProNHCH2CH3, (25) N-Ac-Sar-Gly-Val-D-Chg-Thr-Nva-lle-Arg-ProNHCH2CH3, (26) N-Ac-Sar- Gly-Val-D-4-CIPhe-Thr-Nva-lle-Arg-ProNHCH2CH3, (27) N-Ac-Sar-Gly-Val-D-Hphe-Thr-Nva-lle-Arg-ProNHCH2CH3, (28) N-Ac-Sar-Gly-Val-Dehydroleu-Thr-Nva-lle-Arg-ProNHCH2CH3, (29) N-Ac-Sar-Gly-Val-D-3-CF3Phe-Thr-Nva-lle-Arg-ProNHCH2CH :, (30) N-Ac-Sar-Gly-Val-D-pentaFPhe-Thr-Nva-lle-Arg-ProNHCH2CH3, (31) N-Ac-Sar-Gly-Val-D-3,4-diCIPhe-Thr-Nva-lle-Arg- ProNHCH2CH3, (32) N-Ac-Sar-Gly-Val-D-3-CIPhe- Thr-Nva-lle-Arg-ProNHCH2CH3, (33) N-Ac-Sar-Gly-Val-D-2-Thienylala-Thr-Nva-lle-Arg-ProNHCH2CH3, (34) N-Ac-Sar-Gly-Val-D-3-CNPhe-Thr-Nva-lle-Arg-ProNHCH2CH3, (35) N-Ac-Sar-Gly-Val-D-lle-Thr-D-Nva-1 le-Arg-Pro NHCH2CH3, (36) N-Ac-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, (37) N-Ac-Sar-Gly-Val-D-lle-Thr-Cha-lle- Arg-ProNHCH2CH3, (38) N-Ac-Sar-Gly-Val-D-lle-Thr-Gly-lle-Arg-ProNHCH2CH3, (39) N-Ac-Sar-Gly-Val-D-lle-Thr- Ala-lle-Arg-ProNHCH2CH3, (40) N-Ac-Sar-Gly-Val-D-lle-Thr-Val-lle-Arg-ProNHCH2CH3, (41) N-Ac-Sar-Gly-Val-D- 1 le-Thr-Abu-l le-Arg-ProNHCH2CH3, (42) N-Ac-Sar-Gly-Val-D-lle-Thr-Allylyly-lle-Arg-ProNHCH2CH3, (43) N-Ac-Sar-Gly-Val D-lle-Thr-Octylgly-lle-Arg-ProNHCH2CH3, (44) N-Ac-Sar-Gly-Val-D-lle-Thr-Met-lle-Arg-ProNHCH2CH3, (45) N-Cyclohexylacetyl-Sar-Gly-Val-D-lle-Thr-Nva-lle Arg- ProNHCH2CH3, (46) N- (2-Me-Nicotinyl) -Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg- ProNHCH2CH3, (47) N-Succinyl-Sar-Gly-Val- D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, (48) NN icotinyl-Sar-Gly-Val-D-lle-Thr-N va-I le-Arg-ProNHCH2CH3, (49) N-Propionyl-Sar -Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3 (50) N- (Meo) acetyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, (51 ) N- (Shikimil) -Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH:?, (52) N- (2-Furoyl) -Sar-Gly-Val-D-lle- Thr-Nva-lle-Arg-ProNHCH2CH3, (53) N-Butyryl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, (54) N [2-THFcarbonyl] -Sar-Gly -Val-D-lle-Thr-Nva-lle-Arg- ProNHCH-CH3, (55) N- [CH3C (O) NH- (CH2) 2-O- (CH2) 2-O-CH2-C (O )] - Sar-Gly-Val-D-He-Thr-Nva-lle-Arg-ProNHCH2CH3, (56) N [6-N-acetyl- (CH2) 5C (O)] - Sar-Gly-Val-D -pe-Thr-Nva-lle-Arg- ProNHCH2CH3, (57) N-Hexanoyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, (58) N- [4-N- Acetylaminobutyryl] -Sar-G ly-Val-D-lle-Thr-N va-I le-Arg ProNHCH2CH3, (59) H-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, (60) N-Ac -Sar-Gly-Asn-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, (61) N- [CH3C (O) NH- (CH2) 2-O- (CH2) 2-O-CH2-C (O)] - Gly-Val-D-lle-Thr-Nva-He-Arg-ProNHCH2CH3, (62) N-Ac-Pro-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, (63) N-Ac-Gly-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, (64) N-Ac-Ala-Gly-Val-D-lle-Thr-Nva-lle Arg-ProNHCH2CH3, (65) N-Ac-NEtGly-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, (66) N-Ac-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-ProNHCH2CH3, (67) N-Ac-Sar-Gly-Val-D-lle-Thr-Ser-pe- Arg-ProNHCH2CH3, (68) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-D-AlaNH2, (69) N-Ac-Sar-Gly-Val-D- lle-Thr-Nva-lle-Arg-D-ProNHCH2CH3, (70) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-AbuNHCH2CH3, (71) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle Arg-Phe-NHCH2CH3, (72) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Tic-NHCH2CH3, (73) N-Ac-Sar-Gly-Val-D- lle-Thr-Nva-lle-Arg-Hyp-NHCH2CH3, (74) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Aib-NHCH2CH3, (75) N-Ac- Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-D-Ala-NHCH2CH3, (76) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pip-NHCH2CH3, (77) N-Ac-Sar-Gly-Val-D-Tyr (Et) -Thr -Nva-lle-Arg-ProNHCH2CH3, (78) N-Ac-Sar-Gly-Val-D-Cys (tBu) -Thr-Nva-lle-Arg-ProNHCH2CH3, (79) N-Ac-Sar-Gly-Val-D-Cys-Thr-Nva-lle-Arg-ProNHCH2CH3, (80) N-Ac-Sar-Gly-Val-D-Tyr (Bzl) -Thr-Nva -lle-Arg-ProNHCH2CH3, (81) N-Ac-Sar-Gly-Val-D-Ser (Bzl) -Thr-Nva-lle-Arg-ProNHCH2CH3, (82) N-Ac-Sar-Gly-Val-D-1Nal-Thr-Nva-lle-Arg-ProNHCH2CH3, (83) N-Ac-Sar-Gly-Val-D-tBut? Lgly-Thr-Nva- lle-Arg-ProNHCH2CH3, (84) N-Ac-Sar-Gly-Val-D-Orn-Thr-Nva-lle-Arg-ProNHCH2CH3, (85) N-Ac-Sar-Gly-Val-D-Thr (Bzl) -Thr-Nva -lle-Arg-ProNHCH2CH3, (86) N-Ac-Sar-Gly-Val-D-2Nal-Thr-Nva-lle-Arg-ProNHCH2CH3, (87) N-Ac-Sar-Gly-Val-D-Phe (4-Me) -Thr-Nva-lle-Arg-ProNHCH2CH3, (88) N-Ac-Sar-Gly-Val-D-Phe (3) , 4-d? MeO) -Thr-Nva-lle-Arg- ProNHCH2CH3, (89) N-Ac-Sar-Gly-Val-D-Phe (3,4,5-triF) -Thr-Nva-lle Arg- ProNHCH2CH3, (90) N -Ac-Sar-Gly-Val D-Phe (4-NO2) -Thr-Nva-lle-Arg-ProNHCH2CH3 (91) N -Ac-Sar-Gly-Val D-Pen-Thr-Nva-lle-Arg-ProNHCH2CH3, (92) N -Ac-Sar-Gly-Val D-Pen (Acm) -Thr-Nva-lle -Arg-ProNHCH2CH3, (93) N -Ac-Sar-Giy- Val D-Abu-Thr-Nva-lle-Arg-ProNHCH2CH3, (94) N -Ac-Sar-Gly- Val D-Phe (4-NH2) -Thr-Nva -lle-Arg-ProNHCH2CH3, (95) N -Ac-Sar-Gly-Val D-Leu-Thr-Nva-Ala-Arg-ProNHCH2CH3, (96) N -Ac-Sar-Gly -Val D-Leu-Thr-Nva-Met- Arg-ProNHCH2CH3, (97) N -Ac-Sar-Gly - Val D-Leu-Thr-Nva-Phe-Arg-ProNHCH2CH3, (98) N -Ac-Sar-Gly - Val D-Leu-Thr-Nva-Tyr-Arg-ProNHCH2CH3, (99) N -Ac-Sar-Giy -Val D-Leu-Thr-Nva-Nva-Arg -ProNHCH2CH3, (100) N -Ac-Sar-Gly -Val D-Leu-Thr-Nva-Asp-Arg-ProNHCH2CH3, (101) N -Ac-Sar-Gly -V to l-D-Leu-Thr-Nva-Gly-Arg-ProNHCH2CH3, (102) N -Ac-Sar-Giy -Val -D-Leu-Thr-Nva-Lys (Ac) -Arg-ProNHCH2CH3, (103) N -Ac-Sar-Giy -Val -D-Leu-Thr-Nva -Leu-Arg-ProNHCH2CH3, (104) N -Ac-Sar-Giy -Val -D-Leu-Thr-Nva-2Nal-Arg-ProNHCH2CH3, (105) N -Ac-Sar-Giy -Val -D-Leu -Thr-Nva-1Nal-Arg-ProNHCH2CH3, (106) N -Ac-Sar-Giy -Val -D-Leu-Thr-Nva-Allygly-Arg-ProNHCH2CH3, (107) N -Ac-Sar-Giy -Val -D-Leu-Thr-Nva-Cit-Arg-ProNHCH2CH3, (108) N -Ac-Sar-Giy -Val -D-Leu-Ala-Nva-lle- Arg-ProNHCH2CH3, (109) N -Ac-Sar-Giy -Val -D-Leu-Pro-Nva-I le-Arg -ProNHCH2CH3, (110) N -Ac-Sar-Giy -Val -D-Leu-Trp -Nva-lle-Arg-ProNHCH2CH3, (111) N -Ac-Sar-Giy -Val -D-Leu-Tyr-Nva-I le-Arg- ProNHCH2CH 3, N-Ac-Sar-G ly-Val-D -Leu-Nva-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D-Leu-Gly-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D -Leu-Lys (Ac) -Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D-Leu-2Nal-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly- Val-D-Leu-1Nal-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D-Leu-Octylgly-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly- Val-D-Leu-Gln-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D-Leu-Met-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly- Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D-Leu-Allygly-Nva-lle-Arg-ProNHCH-CH3, N-Ac-Sar-G ly-Val-D-Leu-lle-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D-Leu-D-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar -G ly-Val-D-lle -Thr-lle-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D-lle-Thr-Nle-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D-lle -Thr-Cit-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D-lle-Thr-Met (O2) -lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val- D-lle-Thr-Arg-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D-lle-Thr-Tyr-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val- D-lle-Thr-Glu-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D-lle-Thr-Lys (Ac) -lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly -Val-D-lle-Thr-Propargylgly-lle-Arg-ProNHCH2CH3, N-Ac-Sar-G ly-Val-D-alolle-Thr-GIn-l le-Arg -Pro NHCH2CH3, N-Ac-Sar-G ly-Val-D-Leu-Thr-Gln-lle-Arg- ProNHCH2CH3, N-Ac-Bullet-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Phenylacetyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg- ProNHCH2CH3, - -tßmmñf'-nr * - \ í N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-AzaglyNH2, N-Ac-Sar-Gly-Val-D-lle -Thr-Nva-lle-Arg-Sar-NHCH2CH3, N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-SerNH2, N-Succinyl-Sar-Gly-Val-D -Leu-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Ala-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Leu-Val-D-lle -Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Phe-Val-D-He-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Glu-Val-D-lle-Thr -Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Pro-Val-D-Leu-Thr-Nva-I le-Arg -Pro NHCH2CH 3, N-Ac-Sar-Asn-Val-D-Leu Th rN va-I le-Arg-ProNHCH2CH3, N-Ac-Sar-Asp-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Asn-Gly-Val-D-Leu-Thr -Nva-lle-Arg-ProNHCH2CH3, N-Ac-Gin-Gly-Val-D-Leu-Thr-Nva-I le-Arg-ProNHCH2CH3, N-Ac-Ser-Gly-Val-D-Leu-Thr- Nva-lle-Arg-ProNHCH2CH3, N-Ac-Cit-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Glu-Gly-Val-D-lle-Thr-Nva- lle-Arg-ProNHCH2CH3, N-Ac-Gaba-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Bullet-Gly-Val-D-1 le-Th rN va-l le-Arg-ProNHCH2CH3, N-Ac-Gln-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, N-Ac-Sar-Gly-Gly-DJ le-Th rN va-lle-Arg-ProNHCH2CH3, N-Ac -Sar-Gly-Glu-DI le-Th r-Nva-l le-Arg-ProNHCH2CH 3, N-Ac-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2 , N-Succinyl-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, N-Succ? Nil-Sar-Gly-Val-D-Leu-Thr-Gln-lle-Arg-ProNHCH2CH3 , N-Succin? L-Sar-Gly-Val-D-Leu-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2, 162) N-Ac-Sar-Gly-Val-D-Leu-Thr-Asp -lle-Arg-ProNHCH2CH3, 163) N-Ac-Sar-Gly-Val-DI le-Th r-Asp-lle-Arg-ProNHCH2CH3, 164) N-Ac-Sar-Gly-Val-D-lle-Thr -Asn-lle-Arg-ProNHCH2CH3, 165) N-Ac-Sar-Gly-Val-D-lle-Thr-Met (O) -lle-Arg-ProNHCH2CH3, 166) N-Ac-Sar-Gly-Val- D-Leu-Thr-Asn-lle-Arg-ProNHCH2CH3, 167) N-Ac-Sar-Gly-Val-D-Thr-Thr-Nva-lle-Arg-ProNHCH2CH3, 168) N-Ac-Sar-Gly-Val-D-Ser-Thr-Nva-lle-Arg -ProNHCH2CH3, 169) N-Ac-Sar-Gly-Val-D-Hser-Thr-Nva-lle-Arg-ProNHCH2CH3, 170) N-Ac-Sar-Gly-Val-D-Gln-Thr-Nva-lle -Arg-ProNHCH2CH3, (171) N-Ac-Sar-Gly-Val-D-Asn-Thr-Nva-lle-Arg-ProNHCH2CH3, 172) N-Ac-Sar-Gly-Val-D-Cit-Thr- Nva-lle-Arg-ProNHCH2CH3, 173) N-Ac-Sar-Gly-Val-D-Hcy-Thr-N va-I le-Arg-ProNHCH2CH3, 174) N-Ac-Sar-Gly-Val-D- Hle-Thr-Nva-lle-Arg-ProNHCH2CH3, 175) N-Ac-Sar-Gly-Val-D-Neopentylgly-Thr-Nva-lle-Arg- ProNHCH2CH3, 176) N-Ac-Sar-Gly-Val- DI le-Th r-Phe (4-CONH2) -lle-Arg- ProNHCH2CH3, 177) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-His-ProNHCH2CH3, .178) N- Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Lys (lsp) -ProNHCH2CH3, (179) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Lys ( Nic) -ProNHCH2CH3, 180) N-Ac-Sar-Gly-Val-D-lle-Thr-N a-lle-Orn (Nic) -ProNHCH2CH3, 181) N-Ac-Sar-Gly-Val-DI le-Th rN va-I le-Orn (I sp) -ProNHCH2CH3, 182) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Phe (4-Nlsp) -PrONHCH2CH3,; i83) N-Ac-Sar- Gly-Val-D-lle-Thr-Nva-lle-Cha (4-Nlsp) -PrONHCH2CH3, (184) N-Ac-Sar-Gly-Val-D-lle-Thr-N a-lle-Harg-ProNHCH2CH3 , (185) N-Ac-Sar-Gly-Val-D-lle -Thr-Nva-lle-Norarg-ProNHCH2CH3, (186) N-Ac-Sar-Gly-Val-D-lle -Thr-Nva-lle-Cit-ProNHCH2CH3, (187) N-Ac-Sar-Gly-Val-D-lle -Thr-Nva-lle- Lys-ProNHCH2CH3, (188) N-Ac-Sar-Gly-Val-D-lle -Phe (4-CH2OH) -Nva-lle-Arg-ProNHCH2CH3, (189) N-Ac-Sar-Gly-Val-D -lle -Thr-Nva-lle-Phe (4-guanidino) - PrONHCH2CH3, (190) N-Ac-Sar-Gly-Val-D-lle -Thr-Nva-lle-Aminopyrimidinylbutanoyl- ProNHCH2CH3, (191) N- Ac-Sar-Gly-Val-D-lle -Thr-Nva-ile-Phe (4-CH2NHIsp) - ProNHCH2CH3, (192) N-Ac-Sar-Gly-Val-D-lle -Thr-Nva-lle- Gly [4-Pip (N-amidino)] - ProNHCH2CH3, (193) N-Ac-Sar-Gly-Val-D-lle -Thr-Nva-lle-Ala [4-Pip (N-amidino)] - ProNHCH2CH3 , (194) N-Ac-Sar-Gly-Val-D-lle -Thr-Nva-lle-Ala (3-guanidino) -ProNHCH2CH3, (195) N-Ac-Sar-Gly-Val-D-lle- Thr-Nva-Ala-Ala (3-pyrrole dinylamidino) - ProNHCH2CH3, (196) N-Ac-Sar-Gly-Val-D-lle -Thr-Nva-lle-Orn (2-im? Dazo) - ProNHCH2CH3 , (197) N-Succinyl-Sar-Gly-Val-D-alolle-Thr-N a-lle-Arg-ProNHCH2CH3, (198) N-Succinyl-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, (199) N-Succinyl-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, (200) N-Succinyl-Sar-Gly-Val-D-alolle-Thr- Gin-lle-Arg-ProNHCH2CH3, ÜMl ^ ÉIIIIÍÉI ^ AÉ ^ MttÉtaÉHitel ^^ k (201) N-Succinyl-Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, (202) N-Succinyl-Sar-Gly-Val-D-alolle-Thr-GIn-lle-Arg-ProNHCH2 (CH3) 2, (202) N-Succinyl-Sar-Gly-Val-D-lle-Thr- Gln-lle-Arg-ProNHCH2 (CH3) 2, (204) N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-Pro-D-AlaNH2, (205) N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCH2 (CH3) 2, (206) N-Ac-Sar-Gly-Val-DI le-Th r-Gln-lle-Arg-Pro-D-AlaNH2, (207) N-Ac-Sar-Gly-Val-DI le-Th r- GI nl le-Arg-ProNHCH2 (CH3) 2, (208) N-Ac-Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, (209) N-Ac-Sar-Gly-Val-D-alolle-Thr- Gln-lle-Arg-ProNHCH2 (CH3) 2, (210) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-SarNH2, (211) N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva- lle-Arg-Pro-SarNH2, (212) N-Ac-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro-SarNH2, (213) N-Ac-Sar-Gly-Val- D-alolyl-Thr-Gln-lle-Arg-Pro-SarNH2, (214) N-Ac-Sar-Gly-Val-Da lol le-Th r-Ser-lle-Arg-Pro-D-AlaNH2, (215) N-Ac-Sar-Gly-Val-D-alolle-Thr-Ser-lle-Arg-ProNHCH2 (CH3) 2, (216) N-Ac-Sar-Gly-Val-D-alolle-Thr-Ser-lle-Arg-ProNHCH2CH3, (217) N-Ac-Sar-Gly-Val-D-lle-Thr-Orn (Ac) -lle-Arg-ProNHCH2CH3, (218) N-Ac-Sar-Gly-Val-DI le-Th r-GI nl le-Arg-Pro-AzaglyNH2, (219) N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva- lle-Arg-Pro-AzaglyNH2, (220) N-Ac-Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-AzaglyNH2, (221) N- (2-TH Fea rbon il) -Sar-Gly-Val-D-alol le-Th r-Nva-l le-Arg -Pro NHCH2CH3, (222) N- (2-THFcarbon? L) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg- ProNHCH2CH3, (223) N- (2-THFcarbonyl) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg- Pro NHCH2CH3, (224) N- (2-TH Fea rbonyl) -Sar-Gly-Val-Dl le-Th r -GIn-l le-Arg-Pro-D-AlaNH2, (225) N- (2-THFcarbonil ) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-DAIaNH2, (226) N- (2.THFcarbonil) -Sar-Gly-Val-D-alolle-Thr-Gln-lle -Arg-Pro-NHCH2 (CH3) 2, (227) N- (6-Ac-Aca) -S a r-Gly-Va I-D-alol le-Th rN va-l le-Arg-ProNHCH2CH3, ( 228) N- (6-Ac-Aca) -Sar-Gly-Val-D-lle-T r-Gln-lle-Arg- ProNHCH2CH3, (229) N- (6-Ac-Aca) -Sar-Gly- Val-D-alol le-Th r-GIn-ile-Arg- ProNHCH2CH3, (230) N- (6-Ac-Aca) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-Pro -D-AlaNH2, (231) N- (6-Ac-Aca) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-D- AlaNH2, (232) N- (6-Ac-Aca) - Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg- ProNHCH2 (CH3) 2. (233) N- (4-Ac-Gaba) -Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg- ProNHCH2CH3, (234) N- (4-Ac-Gaba) -Sar-Gly- Val-D-lle-Thr-Gln-lle-Arg- ProNHCH2CH3, (235) N- (4-Ac-Gaba) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg- ProNHCH2CH3, ( 236) N- (4-Ac-Gaba) -Sar-Gly-Val-Dl le-Th rG I nl le-Arg -Pro-D-AlaNH2 (237) N- (4-Ac-Gaba) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-D- AlaNH2, (238) N- (4-Ac-Gaba) - Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro NHCH2 (CH3) 2, (239) N- (2-Furoyl) -Sar-Gly-Val-D-alolle-Thr-Nva- lle-Arg- ProNHCH2CH3, (240) N- (2-Furoyl) -Sar-Gly-Val-Dl le-Th r-GI nl le-Arg-ProNHCH2CH3, (241) N- (2-Furoyl) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg- ProNHCH2CH3, (242) N- (2-Furoyl) -Sar-Gly-Val-D- lle-Thr-Gln-lle-Arg-Pro-D-AlaNH2, (243) N- (2-Furoyl) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-D-AlaNH2 , (244) N- (2-Furoyl) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg- ProNHCH2 (CH3) 2, (245) N- (Shikimil) -Sar-Gly-Val -D-alolle-Thr-Nva-lle-Arg- ProNHCH2CH3, (246) N- (Shikimil) -Sar-Gly-Val-Dl le-Th r-Gi nl le-Arg-ProNHCH2CH3, (247) N- (Shikimil) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg- ProNHCH2CH3, (248) N- (Shikimil) -Sar-Gly-Val-Dl le-Th rG In - 1 le-Arg -Pro- D-Ala NH2, (249) N- (Shikimil) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro-D- AlaNH2, (250) N- (Shikimil) -Sar-Gly-Vai D-alolyl-Thr-Gln-lle-Arg- ProNHCH2 (CH3) 2, (251) N- (2-Me-N -cyninyl) -Sar-Gly-Val-D-alolle-Thr-Nva-lie-Arg -Pro ^ M-m ------- ^^^^ - ^ m ^^^ - ^ - -? aaim *? mii * * * átem ^ NHCH2CH3, (252) N- (2-Me-Nicotinyl) -Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg- ProNHCH2CH3, (253) N- (2-Me-Nicotinyl) -Sar-Gly-Val-D-alol le-Th rG I nl le-Arg -Pro NHCH2CH3, (254) N- (2-Me-Nicotinyl) -Sar-Gly-Val-D -lle-Thr-Gln-lle-Arg-Pro-D- AlaNH2, (255) N- (2-Me-Nicotinyl) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-Pro- D AlaNH2, (256) N- (2-Me-Nicotinyl) -Sar-Gly-Val-D-alolle-Thr-GI nl le-Arg -Pro NHCH2 (CH3) 2, (257) N-Ac-Sar- Gly-Val-D-alolle-Thr-Leu-lle-Arg-Pro-D-AlaNH2, (258) N-Ac-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-ProNHCH2 (CH3 ) 2, (259) N-Ac-Sar-Gly-Val-D-alol le-Th r-Leu-lle-Arg-ProNHCH2CH3, (260) N-Ac-Sar-Gly-Val-D-lle-Thr -Leu-lle-Arg-Pro-D-AlaNH2, (261) N-Succinyl-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-Pro-D-AlaNH2, (262) N-Succinyl-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-ProNHCH2 (CH3) 2, (263) N-Succinyl-Sar-Gly-Val-D-I le-Th r-Leu-lle-Arg-ProNHCH2CH3, (264) N-Succinyl-Sar-Gly-Val-D-alolle-Thr-Leu-lle-Arg-ProNHCH2CH3, (265) N-Succinyl-Sar-Gly-Val-D-alolle-Thr-Leu-lle Arg-Pro-D-AlaNH2, (266) N-Succinyl-Sar-Gly-Val-D-lle-Thr-Leu-lle-Arg-Pro-AzaglyNH2, (267) N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNHethyl- (1- pyrrolidine), (268) N-Ac-Sa rG ly-Vai-D-alol -Th rN va-I le-Arg-ProNH (eti 1-1-cyclohexyl), (269 N-Ac-Sar-Gly-Val-DI le-Th rG I nl le-Arg- ProNHethyl- (1-pyrrolidine) , (270 N -Ac-Sar-G ly- Va lD- 1 le-Th rG I nl le-Arg -Pro NH (eti 1-1-cyclohexyl), (271 N-Succi ni l-Sar-Gly-Val -D-lle-Thr-GIn-lle-Arg-ProNH (ethyl-1-cyclohexyl), (272 N-Ac-Sar-Gly-Val-D-alo I le-Th rN va-I le-Arg-ProNHCH2CH2OCH3, (273 N-Ac-Sar-Gly-Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH2OCH3, (274 N-Ac-Sar-Gly-Val-D-lle-Thr-Ser-l le-Arg -Pro NHCH2CH2OCH3, (275 N-Ac-Sar-Gly-Val-DI le-Th r-Leu-lle-Arg-ProNHCH2CH2OCH3, (276 N-Succinyl-Sar-Gly-Val-D-lle-Thr-Nva- lle-Arg- ProNHCH2CH2OCH3, (277 N-Succinyl-Sar-Gly-Val-D-lle-Thr-GIn-lle-Arg- ProNHCH2CH2OCH3, (278 N-Succinyl-Sar-Gly-Val-D-alolle-Thr- GIn-lle-Arg- ProNHCH2CH2OCH3, (279 N-Ac-Sar-Gly-Val-D-lle-Ser-Nva-lle-Arg-ProNHCH2CH2OCH3, (280 N-Ac-Sar-Gly-Val-D-Leu Ser-Nva-lle-Arg-ProNHCH2CH2OCH3, (281 N-Ac-Sar-Gly-Val-D-alol le-Th r-Aligly-l le- Arg-ProNHCH? CH3, (282 N-Ac-Sar-Gly-Val-D-lle-Thr-Aligly-lle -Arg-ProNHCH2 (CH3) 2, (283 N-Ac-Sar-Gly-Val-DI le-Th r-Aligly-l le-Arg-Pro-D-AI to NH2, (284 N-Ac-Sar- Gly-Val-D-alolle-Thr-Aligly-lle-Arg-Pro-D-AlaNH2, (285 N-Succin i l-Sar-Gly-Val-Dl le-Th r-Aligly-l I e-Arg- Pro-D-AlaNH2, (286 N-Ac-Sar-Gly-Val-D-lle-Ser-Aligly-lle-Arg-Pro-ProNHCH2CH3 (287 N-Ac-Sar-Gly-Val-D-Leu-Ser -Aligly-lle-Arg-Pro-ProNHCH2CH3, (288) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-SarNH2, (289) N-Ac-Sar-Gly -Val-DI le-Th rN va-lle-Arg-ProNHOH, (290) N-Ac-Sar-Gly-Val-D-lle-Ser-Nva-lle-Arg-ProNHCH2CH3, (291) N-Ac- Sar-Gly-Val-D-alolle-Ser-Nva-lle-Arg-ProNHCH2CH3, (292) N-Ac-Sar-Gly-Val-D-Leu-Hser-Nva-lle-Arg-ProNHCH2CH3, (293) N-Ac-Sar-Gly-Gln-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, (294) N-Ac-Sar-Gly-Nva-DI le-Th rN va-I le-Arg-ProNHCH2CH3 , (295) N-Ac-Sar-Gly-lle-Dl le-Th rN va-I le-Arg-ProNHCH2CH3, (296) N-Ac-Sar-Gly-Phe-DI le-Th rN va-lle- Arg-ProNHCH2CH3, (297) N-Ac-Sa rG ly-Leu-Dl le-Th rN va-I le-Arg-ProNHCH2CH3, (298) N-Ac-Sar-Gly-Ser-D-lle-Thr-Nva-lle Arg-ProNHCH2CH3, (299) N-Ac-Thr-Gly-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3, (300) N-Ac-Sar-Gly-Val-D-alolle-Thr-Ala-He -Arg-ProNHCH2CH3, (301) N-Ac-Sar-Gly-Val-DI le-Th r-Ala-l le-Arg-ProNHCH2 (CH3) 2, (302) N-Ac-Sar-Gly-Val- D-lle-Thr-Ala-lle-Arg-Pro-D-AlaNH2, (303) N-Ac-Sar-Gly-Val-D-alolle-Thr-Ala-lle-Arg-Pro-D-AlaNH2, ( 304) N-Succinyl-Sar-Gly-Val-D-lle-Thr-Ala-1 le-Arg-Pro-D-AlaNH2, (305) N-Ac-Sar-Gly-Val-D-lle-Ser- AI aIle-Arg-ProNHCH2CH3, (306) N-Ac-Sar-Gly-Val-D-Leu-Ser-Ala-lle-Arg-ProNHCH2CH3, (307) N-Ac-Sar-Gly-Val-D- alolle-Thr-Val-l le-Arg- ProNHCH2CH3, (308) N-Ac-Sar-Gly-Val-DI le-Th r-Val-lle-Arg-ProNHCH2 (CH3) 2, (309) N-Ac -Sar-Gly-Val-DI le-Th r-Val-l le-Arg -Pro-D-AlaNH2, (310) N-Ac-Sa rG ly-Val-Da lol le-Th r-Va ll le- Arg-Pro-D-AlaNH2, (311) N-Succ? N? L-Sar-Gly-Val-DI le-Th r-Val-lle-Arg-Pro-D-AlaNH2, (312) N-Ac- Sar-Gly-Val-D-lle-Ser-Val-lle-Arg-ProNHCH2CH3, AÉÜÉÉllMIMIÉkr (313) N-Ac-Sar-Gly-Val-D-Leu-Ser-Val-lle-Arg-ProNHCH2CH3, (314) N-Ac-Sar-Gly-Val-D-Alolle-Thr-D-Nva -lle-Arg-ProNHCH2CH3, (315) N-Ac-Sar-Gly-Val-D-lle-Thr-D-Nva-lle-Arg-ProNHCH2 (CH3) 2, (316) N-Ac-Sar-Gly-Val-DI le-Th rDN va-I le-Arg-Pro-D-AlaNH2, (317) N-Ac-Sar-Gly-Val-D-alo I le- Th rDN va-I le-Arg-Pro-D-AlaNH2, (318) N-Succinyl-Sar-Gly-Val-D-lle-Thr-D-Nva-lle-Arg-Pro-D-AlaNH2, (319) N-Ac-Sar-Gly-Val-D-lle-Ser-D-Nva-lle-Arg-ProNHCH2CH3, (320) N-Ac-Sar-Gly-Val-D-Leu-Ser-D-Nva-lle-Arg-ProNHCH2CH3, (321) N-Ac-Sar-Gly-Val-D-lle-Ser-Gln-lle-Arg-ProNHCH2CH3, (322) N-Ac-Sar-Gly-Val-D-Leu-Ser-Gln-lle Arg-ProNHCH2CH3, (323) N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-Pro-D-AlaNH2, (324) N-Ac-Sar-Gly-Val-D- lle-Ser-Nva-lle-Arg-Pro-D-AlaNH2, (325) N-Succinyl-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2CH3, (326) N-Succinyl-Sar-Gly-Val-D-lle-Ser-Nva-lle-Arg-ProNHCH2CH3, (327) N-Succinyl-Sar-Gly-Val-D-Leu-Ser-Gln-lle Arg-ProNHCH2CH3, (328) N-Succinyl-Sar-Gly-Val-D-lle-Ser-Gln-lle-Arg-ProNHCH2CH3, (329) N-Ac-Sar-Gly-Val-D-lle-Ser-Ser-lle-Arg-ProNHCH2CH3, (330) N-Ac-Sar-Gly-Val-D-Leu-Ser-Ser-lle- Arg-ProNHCH2CH3, (331) N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2, (332) N-Ac-Sar-Gly-Val-D- lle-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2, (333) N-Ac-Sar-Gly-Val-D-lle-Ser-Leu-lle-Arg-ProNHCH2CH3, (334) N-Ac-Sar-Gly-Val-D-lle-Ser-Leu-lle Arg-ProNHCH2CH3, (335) N-Ac-Sar-Gly-Val-D-alolle-Ser-Nva-lle-Arg-ProNHCH2CH3, (336) N-Ac-Sar-Gly-Val-D-alolle-Ser-Gln-He-Arg-ProNHCH2CH3, (337) N-Succinyl-Sar-Gly-Val-D-alolle-Ser-N a-lle -Arg-ProNHCH2CH3, (338) N-Ac-Sar-Gly-Val-D-alolle-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2, (339) N-Ac-Sar-Gly-Val-D-alolle-Ser-Nva-lle-Arg-Pro-D-AlaNH2, (340) N-Ac-Sar-Gly-Val-D-alolle-Ser-Leu-lle-Arg-ProNHCH2CH3, (341) N-Ac-Sar-Gly-Val-D-alolle-Ser-Ser-lle-Arg-ProNHCH2CH3, (342) N-Ac-Sar-Gly-Val-D-lle-Gly-Nva-lle- Arg-ProNHCH2CH3, (3431 N-Ac-Sar-Gly-Val-D-alolle-Gly-Nva-lle-Arg-ProNHCH2CH3, (3441 N-Ac-Sar-Gly-Val-D-Leu-Gly-Gln-lle-Arg-ProNHCH2CH3, (345 N-Ac-Sar-Gly-Val-D-lle-Gly-Gln-lle-Arg-ProNHCH2CH3, (346 N-Ac-Sar-Gly-Val-D-alolle-Gly-Gln-lle-Arg-ProNHCH2CH3, (347) N-Ac-Sar-Gly-Val-D-lle-Tyr-Nva-lle-Arg -ProNHCH2CH3, (348) N-Ac-Sar-Gly-Val-D-alolle-Tyr-Nva-lle-Arg-ProNHCH2CH3, (349) N-Ac-Sar-Gly-Val-D-Leu-Tyr-GI n-l le-Arg-ProNHCH2CH3, (350) N-Ac-Sar-Gly-Val-D-lle-Tyr-Gln-lle-Arg-ProNHCH2CH3, (351) N-Ac-Sar-Gly-Val-D-alolle-Tyr-Gln-lle-Arg-ProNHCH2CH3, (352) N-Ac-Sar-Gly-Val-D-Ser-Thr-Nva-lle Arg-ProNHCH2CH3, (353) N-Ac-Sar-Gly-Val-D-Thr-Thr-Nva-lle-Arg-ProNHCH2CH3, (354) N-Ac-Sar-Gly-Val-D-Gln-Thr-Nva-lle-Arg-ProNHCH2CH3, (355) N-Ac-Sar-Gly-Val -D-Asn-Thr-Nva-lle-Arg-ProNHCH2CH3, (356) N-Ac-Sar-Gly-Val-D-Arg -Th rN va-I le-Arg-ProNHCH2CH3, (357) N-Ac-Sar-Gly-Val-D-3-Pal-Thr-Nva -lle-Arg-ProNHCH2CH3, (358) N-Ac-Sar-Gly-Val-D-Glu-Thr-Nva-lle-Arg-ProNHCH2CH3, (359) N-Ac-Sar-Gly-Val-D-Asp-Th r-N va-I le-Arg-ProNHCH2CH 3, (360) N-Ac-Sar-Gly-Val-D-His-Th r -N va-I le-Arg-ProNHCH2CH3, (361) N-Ac-Sar-Gly-Val-D-Hser-Thr-Nva-lle-Arg-ProNHCH2CH3, (362) N-Ac-Sar-Gly-Val-D-aloThr-Thr-Nva-lle Arg-ProNHCH2CH3, (363) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-D-lle-Arg-ProNHCH2CH3, (364) N-Ac-Sar-Gly-Val-D-Ser-Thr-Gln-lle-Arg-ProNHCH2CH3, (365) N-Ac-Sar-Gly-Val-D-Thr-Thr-Gln-lle Arg-ProNHCH2CH3, (366) N-Ac-Sar-Gly-Val-D-aloThr-Thr-Gln-lle-Arg-ProNHCH2CH3, (367) N-Ac-Sar-Gly-Val-D-Ser-Ser- Nva-lle-Arg-ProNHCH2CH3, (368) N-Ac-Sar-Gly-Val-D-Thr-Ser-Nva-lle-Arg-ProNHCH2CH3, (369) N-Ac-Sar-Gly-Val-D- aloThr-Ser-Nva-lle-Arg-ProNHCH2CH3, (370) N-Ac-Sar-Gly-Val-D-aloThr-Ser-Gln-lle-Arg-ProNHCH2CH3, (371) N-Ac-Sar-Gly- Val-D-Thr-Ser-Gln-lle-Arg-ProNHCH2CH3, (372) N- (6-Ac-Aca) -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg- ProNHCH2 (CH3 ) 2, (373) N- (6-Ac-Aca) -Sar-Gly-Val-D-Leu-Ser-Nva-l le-Arg-ProNHCH2 (CH3) 2, (374) N- (4-Ac -Gaba) -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg- ProNHCH2 (CH3) 2, -r (375) N- (4-Ac-Gaba) -Sar-Gly-Val-D -Leu-Ser-Nva-lle-Arg- ProNHCH2 (CH3) 2, (376) N- (2-Furoyl) -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg- ProNHCH2 (CH3) 2, (377) N- (2-Furoyl) -Sar-Gly-Val-D-Leu-Ser-N va-I le-Arg-ProNHCH2 (CH3) 2, (378) N- (Shikimil) -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2 (CH3) 2, (379) N- (Shikimil) -Sar-Gly-Val-D-Leu-Se rN va-I le-Arg-ProNHCH2 (CH3) 2, (380) N- (Shikimil) -Sar- Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2 (CH3) 2, (381) N- (Shikimil) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2, (382) \ l- (2-Me-Nicotinyl) -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg- ProNHCH2 (CH3) 2, (383) N- (2 -Me-Nicotinyl) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2, (384) N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva -lle-Arg-ProNHethyl-l- (R) -cyclohexyl, (385) N-Ac-Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHethyl-l- (R) -cyclohexyl, (386) N-Ac-Sar-Gly-Val-D-lle-Thr-Ser-lle-Arg-ProNHethyl-l- (R) -cyclohexyl, (387) N-Ac-Sar-Gly-Val-D- Leu-Thr-Nva-lle-Arg-ProNHethyl-l- (R) -cyclohexyl, (388) N-Ac-Sar-Gly-Val-D-Leu-Ser-Ser-lle-Arg-ProNHethyl-l- ( R) - cyclohexyl, (389) N-Ac-Sar-Gly-Val-DI le-Th rN va-I le-Arg-ProNH ethyl 1- (S) -cyclohexyl, (390) N-Ac-Sar- Gly-Val-D-Pen-Ser-Nva-lle-Arg-ProNHCH2CH3, (391) N-Ac-Sar-Gly-Val-D-Pen-Gly-Nva-lle-Arg-ProNHCH2CH3, (392) N-Ac-Sar-Gly-Val-D-Pen-Thr-GI n-l le-Arg-ProNHCH2CH 3, (393) N-Ac-Sar-Gly-Val-D-Pen-Ser-Nva-I le-Arg-ProNHCH2 (CH 3) 2, (394) N-Succinyl-Sar-Gly-Val-D-Pen Ser-N a-lle-Arg-ProNHCH2CH3, ^^^ (395)) N-Ac-Sar-Gly-Val-D-Pen-Ser-Nva-lle-Arg-Pro-D-AlaNH2, (396)) N-Ac-Sar-Gly-Val-D -Pen-Ser-Gln-lle-Arg-ProNHCH2CH3, (397)) N-Ac-Sar-Gly-Val-D-Pen-Gly-Gln-lle-Arg-ProNHCH2CH3, (398)) N-Ac-Sar -Gly-Val-D-Pen-Ser-Ser-lle-Arg-ProNHCH2CH3, (399)) N-Ac-Sar-Gly-Val-D-Pen-Thr-Ser-lle-Arg-ProNHCH2CH3, (400) ) N-Ac-Sar-Gly-Val-D-Pen-Thr-Leu-lle-Arg-ProNHCH2CH3, (401)) N-Ac-Sar-Gly-Val-D-Pen-Ser-Leu-lle-Arg -ProNHCH2CH3, (402)) N-Succinyl-Sar-Gly-Val-D-Pen-Ser-Ser-lle-Arg-ProNHCH2CH3, (403)) N-Succinyl-Sar-Gly-Val-D-Pen-Ser-Leu-lle-Arg-ProNHCH2CH3 (404)) N-Succinyl-Sar-Gly-Val-D-Pen-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2, (405)) N-Ac-Sar-Gly-Vai-D-Cys-Th r -N va-l le-Arg- ProNHCH2CH3, (406)) N-Ac-Sar-Gly-Val-D-Cys-Ser-Nva-lle-Arg-ProNHCH2CH3, (407)) N-Ac-Sar-Gly-Val-D-Cys-Gly-Nva- lle-Arg-ProNHCH2CH3, (408)) N-Ac-Sar-Gly-Val-D-Cys-Thr-Gln-lle-Arg-ProNHCH2CH3, (409)) N-Ac-Sar-Gly-Val-D- Cys-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2, (410)) N-Succinyl-Sar-Gly-Val-D-Cys-Ser-N a-lle-Arg-ProNHCH2CH3, (411)) N-Ac-Sar-Gly-Val-D-Cys-Ser-Nva-lle-Arg-Pro-D-AlaNH2, (412)) N-Ac-Sar-Gly-Val-D-Cys- Ser-G I nl le-Arg-ProNHCH2CH3, (413)) N-Ac-Sar-Gly-Val-D-Cys-Gly-Gln-lle-Arg-ProNHCH2CH3, (414)) N-Ac-Sar-Gly -Val-D-Cys-Ser-Ser-lle-Arg-ProNHCH2CH3, (415)) N-Ac-Sar-Gly-Val-D-Cys-Thr-Ser-lle-Arg-ProNHCH2CH3, (416)) N -Ac-Sar-Gly-Val-D-Cys-Thr-Leu-lle-Arg-ProNHCH2CH3, (417)) N-Ac-Sar-Gly-Val-D-Cys-Ser-Leu-lle-Arg-ProNHCH2CH3 , (418)) N-Succ? N? L-Sar-Gly-Val-D-Cys-Ser-Ser-lle-Arg-ProNHCH2CH3, (419)) N-Succ? Nyl-Sar-Gly-Val-D-Cys-Ser-Leu-lle-Arg-ProNHCH2CH3, (420) N-Ac-Sar-Gly-Pen-D-lle-Thr-Nva -lle-Arg-ProNHCH2CH3, (421) N-Ac-Sar-Gly-Cys-DI le-Th rN va-I le-Arg -Pro NHCH2CH3, (422) N-Ac-Sar-Gly-Pen-D- alolle-Thr-Nva-lle-Arg-ProNHCH2CH3, (423) N-Ac-Sar-Gly-Pen-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3, (424) N-Ac-Sar-Gly-Pen-D-lle-Thr-G i nl le-Arg -Pro NHCH2CH3, (425) N-Ac-Sar-Gly-Pen-D-lle-Ser-Nva- lle-Arg-ProNHCH2CH3, (426) N-Ac-Sar-Gly-Pen-D-lle-Thr-Nva-lle-Arg-ProNHCH2 (CH3) 2, (427) N-Ac-Sar-Gly-Pen-D-lle-Thr-Nva-lle-Arg-Pro-D-AlaNH2, (428) N-Succinyl-Gly-Pen-DI le-Th rN va-I le-Arg-ProNHCH2CH3, (429) N-Succinyl-Sar-Gly-Pen-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, (430) N-Succi ni l-Sa r-G ly-Pen-D-l le-Th r-G I n-l le-Arg-ProNHCH2 (CH3) 2, (431) N-Ac-Sar-Gly-Val-D-Leu-Pen-Nva-lle-Arg-ProNHCH2CH3, (432) N-Ac-Sar-Gly-Val-D-lle-Pen-Nva-lle-Arg-ProNHCH2CH3, (433) N-Ac-Sar-Gly-Val-D-alolie-Pen-Nva-lle Arg-ProNHCH2CH3, (434) N-Ac-Sar-Gly-Val-D-lle-Pen-Gln-lle-Arg-ProNHCH2CH3, (435) N-Ac-Sar-Gly-Val-D-lle-Pen-Ser-l le -Arg-ProNHCH2CH3, (436) N-Ac-Sar-Gly-Val-D-lle-Pen-Leu-lle-Arg-ProNHCH2CH3, (437) N-Ac-Sar-Gly-Val-D-lle-Pen -Nva-lle-Arg-ProNHCH2 (CH3) 2, (438) N-Ac-Sar-Gly-Val-D-lle-Pen-Nva-lle-Arg-Pro-D-Ala NH2, (439) N-Succinyl-Sar-Gly-Val-D-lle -Pen-Nva-lle-Arg-ProNHCH2CH3, (440) N-Succinyl-Sar-Gly-Val-D-lle-Pen-Gln-lle-Arg-ProNHCH2CH3, (441) N-Succinyl-Sar-Gly-Val-D-lle-Pen-Gln-lle-Arg-ProNHCH2 (CH3) 2, (442) N-Ac-Sar-Gly-Val-DI le-Th r-Pen-l le-Arg-ProNHCH2CH3, (443) N-Ac-Sar-Gly-Val-D-alolle-Thr-Pen-lle -Arg-ProNHCH2CH3, (444) N-Ac-Sa r-G I y-Va I -D-Leu -Thr- Pen -I le-Arg -Pro NHCH 2 CH 3, NayíaWéilÉilÉllil (445) N-Ac-Sar-Gly-Val-D-lle-Thr-Pen-lle-Arg-Pro-D-AlaNH2, (446) N-Succinyl-Sar-Gly-Val-D-lle-Thr -Pen-lle-Arg-ProNHCH2CH3, (447) N-Ac-Sar-Gly-Val-DI le-Th r-Pen-lle-Arg-ProNHCH2 (CH3) 2, (448) N-Ac-Sar-Gly -Val-D-Leu-Ser-Pen-lle-Arg-ProNHCH2CH3, (449) N-Ac-Sar-Gly-Val-D-Leu-Gly-Pen-lle-Arg-ProNHCH2CH3, (450) N-Succinyl-Sar-Gly-Val-D-Leu-Ser-Pen-lle-Arg-ProNHCH2CH3, (451) N-Ac-Sar-Gly-Val-D-Phe (3,4,5- triF) -Thr-Gln-lle-Arg-ProNHCH2 CH3, (452) N-Ac-Sar-Gly-Val-D-Phe (3, 4, 5-tri F) -Ser-Nva-I le-Arg -Pro NHCH2 CH3, (453) N-Ac-Sar -Gly-Val-D-Phe (3,4,5-triF) -Gly-Nva-lle-Arg-ProNHCH2 CH3, (454) N-Ac-Sar-Gly-Val-D-Phe (3,4, 5-triF) -Ser-Leu-lle-Arg-ProNHCH2 CH3, (455) N-Ac-Sar-Gly-Val-D-Phe (3,4,5-tr? F) -Ser-Nva-lle- Arg-Pro-D- AlaNH2, (456) N-Succin I-Sar-Gly-Val-D-Phe (3,4, 5-tri F) -Thr-GI nl le-Arg ProNHCH2CH3, (457) N -Succinyl-Sar-Gly-Val-D-Phe (3,4, 5-tri F) -Se rG I nl le-Arg ProNHCH2CH3, (458) N-Succinyl-l-Sar-Gly-Val-D-Phe (3,4,5-tr? F) -Thr-Gln-lle-Arg- ProNHCH2 (CH3) 2, (459) N-Ac-Sar-Gly-Val-D-Phe (3,4,5-tr F) -Ser-Gln-lle-Arg-ProNHCH2 CH3, (460) N-Ac-Sar-Gly-Val-D-Phe (3,4,5-tr? F) -Ser-Ser-lle-Arg -ProNHCH2 CH3, (461) N-Ac-Sar-Ala-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCH2CH3, (462) N-Ac-Sar-Ala-Val-D-Leu-Thr-Nva-lle-Arg-ProNHCH2CH3, (463) N-Ac-Sar-Ala-Val-D-lle-Thr-Gln-lle Arg-ProNHCH2CH3, (464) N-Ac-Sar-Ala-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2CH3, (465) N-Ac-Sar-Ala-Val-D-Leu-Ser- Gln-lle-Arg-ProNHCH2CH3, (466) N-Succinyl-Sar-Ala-Val-DI le-Th rN va-I le-Arg-ProNHCH2CH3, (467) N-Succinyl-Sar-Ala-Val-D-lle-Thr-Gln-Nva-lle-Arg-ProNHCH2 CH3, (468) N-Succinyl-Sar-Ala-Val-D-lle-Thr-Gln -Nva-lle-Arg-ProNHCH2 (CH3) 2, (469) N-Succinyl-Sar-Ala-Val-D-lle-Thr-Gln-Nva-lle-Arg-Pro-D-AlaNH2 (470) N- (3-Ac-Bullet) -Sar-Gly-Val-D-alolle-Thr-Nva-lle-Arg-ProNHCH2 CH3, (471) N- (3-Ac-Bullet) -Sar-Gly -Val-D-lle-Thr-Gln-lle-Arg-ProNHCH2CH3, (472) N- (3-Ac-Bullet) -Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2 CH3, (473) N- (3-Ac-Bullet) -Sar-Gly -Val-D-lle-Thr-Gln-lle-Arg-Pro-DAIaNH2, (474) N- (3-Ac-Bullet) -Sar-Gly-Val-D-alol le-Th rG In-I le-Arg -Pro- DAIaNH2, (475) N- (3-Ac-Bullet) - Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2 (CH3) 2, (476) N- (3-Ac-Bullet) -Sar-Gly-Val-D-Leu-Ser-Nva -lle-Arg-ProNHCH2 CH3, (477) N- (3-Ac-Bullet) -Sar-Gly-Val-D-Leu-Thr-Nva-lle-Arg-ProN? CH2 CH3, (478) N- ( 3-Ac-Bullet) -Sar-Gly-Val-D-Pen-Thr-Nva-lle-Arg-ProNHCH2 CH3, (479) N- (3-Ac-Bullet) -Sar-Gly-Val-D-lle Ser-Nva-lle-Arg-ProNHCH2CH3 (480) N- (3-Ac-Bullet) -Sar-Ala-Val-D-alolle-Ser-Nva-lle-Arg-ProNHCH2 CH3, (481) N- ( 3-Ac-Bala) -Sa r-Ala-Val-Dl le-Ser-N va-I le-Arg- ProNHCH2CH3 (482) N- (3-Ac-Bullet) -Sar-Ala-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 CH3, (483) N- (3-Ac-Bullet) -Sar-Ala -Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2 CH3, (484) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-OH, (485) N-Ac-Sa rG ly-Val-D-alol le-Th rN va-lle-Arg-Pro-OH, (486) N -Ac-S a rG I y-Va I- D-Leu-Th rN va -lle-Arg-Pro-OH, (487) N-Ac-Sar-Gly-Val-D-Pen-Th rN va-lle-Arg-Pro-OH, (488) N-Ac-Sar-Gly-Val -D-Phe (3, 4, 5-triF) -Thr-N va-lle-Arg-Pro-OH, (489) N-Ac-Sar-Gly-Val-D-lle-Thr-Gin-lle Arg-Pro-OH, (490) N -Ac-S a rG I y-Va I -D- Le u-Se rN va-lle-Arg-Pro-OH, (491) N -Ac-S a r- AI a-Va I -D- 1 le-Th rN va-lle-Arg-Pro-OH, (492) N-Ac-Sar-Gly-Val-D-lle-Ser-GIn-lle-Arg-Pro- OH, (493) N-Succinyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-OH, and (494) N-Succinyl-Sar-Gly-Val-D-Leu-Thr -GIn-lle-Arg-Pro-OH 13.- A compound according to claim 12, which is selected from (1) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle -Arg-ProNHCH2CH3, gM ^ Müaüüüü (2) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH2- (1- pyrrolidine), (3) N-Ac-Sar-Gly-Val-DI le-Th rN va-lle-Arg-ProN H (eti 1-1 - (R) -cyclohexyl), (4) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg- ProNH2, (5) N-Ac-Sar-Gly-Val-DI le-Th r-Nva-l le-Arg-Pro NHCH2 (CH3) 2, (6) N-Ac-Sar-Gly-Val-D-alolle-Thr-Nva-l le-Arg-ProNHCH2CH3, (7) N-Ac-Sar-Gly-Val-D-Val-Thr-Nva-lle-Arg-ProNHCH2CH3, (8) N-Ac-Sar-Gly-Val-D-Nle-Thr-N va-I le-Arg-ProNHCH2CH3, (9) N-Ac-Sar-Gly-Val-D-Phe-Thr-Nva-I le-Arg-ProNHCH-CH3, (10) N-Ac-Sar-Gly-Val-D -Cha-Thr-Nva-I le-Arg-ProNHCH2CH3, (11) N-Ac-Sar-Gly-Val-D-3,4-diCIPhe-Thr-Nva-lle-Arg-ProNHCH2CH3 (12) N-Ac-Sar-Gly-Val-D-3-CIPhe-Thr-Nva-lle-Arg-ProNHCH2CH3, (13) N-Ac-Sar-Gly-Val-D-2-Thienylala-Thr-Nva-lle-Arg-ProNHCH2 CH3, (14) N-Ac-Sar-Gly-Val-D-3-CNPhe-Thr -Nva-lle-Arg-ProNHCH2CH3, (15) N-Ac-Sar-Gly-Val-DI le-Th rCha-lle-Arg-ProNHCH2CH3, (16) N [2-THF-C (O)] -Sar-Gly-Val-D-lle-Thr-N a-lle-Arg-ProNHCH2 CH3, (17) N [6-N-acetyl- (CH2) 5C (O)] - Sar-Gly-Val-D -lle-Thr-Nva-lle-Arg ProNHCH2CH3, (18) N-Hexanoyl-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, (19) N- [4-N-Acetylaminobutyryl] ] -Sar-Gly- Val- Dl le-Th rN va- 1 le-Arg ProNHCH2CH3, (20) N- [CH3C (O) NH- (CH2) 2-O- (CH2) 2-0-CH2-C (O)] - Gly-Val-D-lle- Thr-Nva-lle-Arg-ProNHCH2CH3, (21) N-Ac-Pro-Gly-Val-DI le-Th rN va-lle-Arg-ProNHCH2CH3, ( 22) N-Ac-NEtGly-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, (23) N-Ac-Sar-Gly-Val-DI-Th r-Leu-lle-Arg-ProNHCH2CH3, (24) N-Ac-Sar-Gly-Val-D-lle-Thr-Ser-l le -Arg-ProNHCH2CH3, (25) N-Ac-Sar-Gly-Val-DI le-Th rN va-lle-Arg-Pro-D-AlaNH2, (26) N-Ac-Sar-Gly-Val-D- Leu-Thr-Nva-Lys (Ac) -Arg-ProNHCH2CH3, (27) N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Leu-Arg-ProNHCH2CH3, (28) N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-1Nal-Arg-ProNHCH2CH3, (29) N-Ac-Sar-Gly-Val-D-Leu-Thr-Nva-Allygly-Arg-ProNHCH2CH3, (30) N-Ac-Sar-Gly-Val-D-Leu-Ala-Nva-lle-Arg-ProNHCH2CH3, (31) N-Ac-Sar-Gly-Val-D-Leu-Trp-Nva-lle Arg-ProNHCH2CH3, (32) N-Ac-Sar-Gly-Val-D-Leu-Tyr-Nva-lle-Arg-ProNHCH2CH3, (33) N-Ac-Sar-Gly-Val-D-Leu-Gly- N va-I le-Arg-ProNHCH2CH 3, (34) N-Ac-Sar-Gly-Val-D-Leu-2Nal-Nva-lle-Arg-ProNHCH2CH3, (35) N -Ac-S to r-G ly-Val-D-Leu-1 Nal-N va- 1 le-Arg-ProNHCH2CH3, (36) N-Ac-Sar-Gly-Val-D-Leu-Octylgly-Nva-lle-Arg-ProNHCH2CH3, (37) N-Ac-Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2CH3, (38) N-Ac-Sar-Gly-Val-D-Leu-Allygly-Nva-lle Arg-ProNHCH2CH3, (39) N-Ac-Sar-Gly-Val-D-Leu-D-Thr-Nva-lle-Arg-ProNHCH2CH3, (40) N-Ac-Sar-Gly-Val-D-lle-Thr-Tyr-lle-Arg-ProNHCH2CH3, (41) N-Ac-Sar-Gly-Val-DI le-Th rG I u- 1 le -Arg -ProNHCH2CH3, (42) N-Ac-Sar-Gly-Val-D-lle-Thr-Propargylgly-lle-Arg-ProNHCH2CH3, (43) N-Ac-Sar-Gly-Val-D-alolle-Thr-Gln-lle-Arg-ProNHCH2CH3, (44) N-Ac-Bala-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-ProNHCH2CH3, (45) N-Phenylacetyl-Sar-Gly-Val-D-lle-Thr-Nva- lle-Arg-ProNHCH2 CH3, (46) N-Ac-Sar-Gly-Val-DI le-Th rN va-l le-Arg-Pro-AzaglyNH2, (47) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-SerNH2, (48) N- (6-Ac-Aca) -Sar-Gly-Val-D- Leu-Ser-Gln-lle-Arg-ProNHCH2 (CH3) 2, (49) N- (6-Ac-Aca) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2, (50) N- (4-Ac-Gaba) -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2 (CH3) 2, (51) N- (4- Ac-Gaba) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2, (52) N- (2-Furoyl) -Sar-Gly-Val-D-Leu Ser-Gln-lle-Arg-ProNHCH2 (CH3) 2, (53) N- (2-Furoyl) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2, ( 54) N- (Shikimil) -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2 (CH3) 2, (55) N- (Shikimil) -Sar-Giy-Val-D-Leu Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2, (56) N- (Shikimil) -Sar-Gly-Val-D-Leu-Ser-Gln-lle-Arg-ProNHCH2 (CH3) 2, (57 ) N- (Shikim? L) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg-ProNHCH2 (CH3) 2, (58) N- (2-Me-Nicotinyl) -Sar-Gly- Val-D-Leu-Ser-Gln-lle-Arg- ProNHCH2 (CH3) 2, (59) N- (2-Me-Nicotinyl) -Sar-Gly-Val-D-Leu-Ser-Nva-lle-Arg - ProNHCH2 (CH3) 2, 5 (60) N-Ac-Sar-Gly-Val-D-lle-Thr-Nva-lle-Arg-Pro-OH, (61) N-Ac-Sar-Ala-Val- DI le-Th rN va-I le-Arg-Pro NHCH2CH3, (62) N-Ac-Sar-Gly-Val-D-Pen-Th rN va-i le-Arg-ProNHCH2CH3, (63) N-Ac- Sar-Gly-Val-D-Phe (3,4,5-triF) -Thr-Nva-lle-Arg- ProNHCH2CH3 10 (64) N-Ac-Sar-Gly -Val-D-Phe (4-NH2) -T r-Nva-lle-Arg-ProNHCH2CH3. 14. A pharmaceutical composition comprising a compound of Formula 1 and a pharmaceutically acceptable carrier. 15. A method for treating a patient with the need for anti-angiogenesis therapy comprising administering to the patient the need for a therapeutically effective amount of a compound of claim 1. 16. A composition for the treatment of a selected cancer disease, arthritis, psoriasis, angiogenesis of the eye associated with infection or surgical intervention, macular degeneration and diabetic retinopathy, comprising a peptide according to claim 1, in combination with a pharmaceutically acceptable carrier. 17. A method for isolating a receptor from an endothelial cell, which comprises binding a peptide as defined in É > li fi-li & claim 1 to the receptor to form a peptide receptor complex; isolate the peptide receptor complex; and purify the receiver.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/083,745 | 1998-05-22 | ||
| US09/250,574 | 1999-02-16 | ||
| US09/277,466 | 1999-03-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00011490A true MXPA00011490A (en) | 2001-11-21 |
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