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US20130046077A1 - Dolastatin 15 derivatives - Google Patents

Dolastatin 15 derivatives Download PDF

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US20130046077A1
US20130046077A1 US13/447,529 US201213447529A US2013046077A1 US 20130046077 A1 US20130046077 A1 US 20130046077A1 US 201213447529 A US201213447529 A US 201213447529A US 2013046077 A1 US2013046077 A1 US 2013046077A1
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US13/447,529
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Bernd Janssen
Teresa Barlozzari
Andreas Haupt
Thomas Zierke
Andreas Kling
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AbbVie Deutschland GmbH and Co KG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/26—Preparation of nitrogen-containing carbohydrates
    • C12P19/28—N-glycosides
    • C12P19/30—Nucleotides
    • C12P19/34—Polynucleotides, e.g. nucleic acids, oligoribonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Dolastatins 1-10 U.S. Pat. No. 4,816,444, issued to Pettit et al
  • Dolastatin-15 European Patent Application No. 398558
  • Compounds of the present invention include cell growth inhibitors which are peptides of Formula I,
  • L is a monovalent radical, such as, for example, an amino group, an N-substituted amino group, a ⁇ -hydroxylamino group, a hydrazido group, an alkoxy group, a thioalkoxy group, an aminoxy group, or an oximato group.
  • compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.
  • An additional embodiment of the present invention is a method for treating cancer in a mammal, such as a human, comprising administering to the manvnal an effective amount of a compound of Formula I in a pharmaceutically acceptable composition.
  • the present invention relates to peptides having antineoplastic activity. It also includes pharmaceutical compositions comprising these compounds and methods for treating cancer in a mammal, including a human, by administration of these compositions to the mammal.
  • Dolastatin 15 a peptide isolated from the sea hare Dolabella auricularia, is a potent inhibitor of cell growth. This compound, however, is present in trace quantities in the sea hare, and is thus difficult to isolate. Dolastatin 15 is also expensive to synthesize and suffers from poor aqueous solubility. As shown herein, however, Dolastatin 15 can serve as a starting point for the development of compounds which overcome these disadvantages while retaining antineoplastic activity or exhibiting greater antineoplastic activity than the natural product. Applicants have discovered that certain structural modifications of Dolastatin 15 provide compounds with a surprisingly improved therapeutic potential for the treatment of neoplastic diseases as compared to Dolastatin 10 and Dolastatin 15. Furthermore, the compounds of the present invention can be conveniently synthesized, as described below in detail.
  • the term “monovalent radical” is intended to mean an electrically neutral molecular fragment capable of forming one covalent bond with a second neutral molecular fragment.
  • Monovalent radicals include the hydrogen atom, alkyl groups, such as methyl, ethyl and propyl groups, halogen atoms, such as fluorine, chlorine and bromine atoms, aryl groups, such as phenyl and naphthyl groups, and alkoxy groups, such as methoxy and ethoxy groups.
  • Two monovalent radicals on adjacent sigma-bonded atoms can also together form a pi bond between the adjacent atoms.
  • Two monovalent radicals may also be linked together, for example, by a polymethylene unit, to form a cyclic structure.
  • the unit —N(R)R′, wherein R and R′ are each a monovalent radical can, together with the nitrogen atom, form a heterocyclic ring.
  • two monovalent radicals bonded to the same atom can together form a divalent radical, such as an oxygen atom or an alkylidene group, for example, a propylidene group.
  • normal alkyl refers to an unbranched, or straight chain, alkyl group, for example, normal propyl (n-propyl, —CH 2 CH 2 CH 3 ).
  • the compounds of the present invention can be represented by Formula I,
  • A, B, D, E, F, G, and K are ⁇ -amino acid residues; s and r are each, independently, 0 or 1; and L is a monovalent radical such as an amino group, an N-substituted amino group, a ⁇ -hydroxylamino group, a hydrazido group, an alkoxy group, a thioalkoxy group, an aminoxy group, or an oximato group.
  • the peptides of Formula I are generally composed of L-amino acids but they can contain one or more D-amino acids.
  • reference to a particular amino acid includes both enantiomers unless a specific enantiomer is indicated.
  • the present compounds can also be present as salts with physiologically-compatible acids, including hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine.
  • physiologically-compatible acids including hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, benzoic acid, glucuronic acid
  • A is a proline derivative of Formula II a ,
  • R a is a monovalent radical, such as a hydrogen atom or an unsubstituted or fluorine-substituted alkyl group, for example a normal, branched or cyclic C 1 -C 3 -alkyl group which is, optionally, substituted by from 1 to about 3 fluorine atoms; suitable examples include methyl, ethyl, isopropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl, 1-fluoromethyl-2-fluoroethyl or cyclopropyl; methyl, ethyl or isopropyl are preferred;
  • R 1 a is a monovalent radical, such as a hydrogen atom, an alkyl group, such as a methyl, ethyl or propyl group, or a phenyl group.
  • the phenyl group can be substituted; suitable substituents include one or more halogen atoms, with fluorine, chlorine and bromine atoms preferred, C 1 -C 4 -alkyl groups, methoxy, ethoxy, trifluoromethyl or nitro groups.
  • R a and R 1 a together can also form a propylene bridge.
  • R 2 a , R 3 a , R 4 a and R 5 a are each, independently, a monovalent radical, such as a hydrogen atom or an alkyl, preferably, methyl, group.
  • A is a substituted glycine derivative of Formula III a ,
  • R a has the meaning stated for R a in Formula II a and, R 1 a , is a monovalent radical, for example, a hydrogen atom or a C 1 -C 6 -alkyl group, preferably a methyl, ethyl or propyl group.
  • R 6 a is a monovalent radical, such as an alkyl, substituted alkyl, alkenyl, phenyl or substituted phenyl group. Suitable examples include methoxymethyl, 1-methoxyethyl, 1,1-dimethyl-hydroxymethyl, 1-trifluoromethylethyl, 1-trifluoromethyl-2,2,2-trifluoroethyl, vinyl, and 1-methylvinyl. Phenyl substituents can include one or more halogen atoms, preferably fluorine, chlorine or bromine atoms, and alkyl, methoxy, ethoxy, trifluoromethyl, and nitro groups.
  • R 6 a can also be a C 1 -C 6 -alkyl, cycloalkyl, unsubstituted benzyl or substituted benzyl group.
  • Suitable benzyl substituents include one or more halogen atoms, such as fluorine, chlorine or bromine atoms, C 1 -C 4 -alkyl groups, and methoxy, ethoxy, trifluoromethyl and nitro groups.
  • R 7 a is a monovalent radical, preferably a methyl, ethyl or isopropyl group.
  • A is an ⁇ -amino acid derivative of Formula IV a ,
  • m a is an integer, preferably 1 or 2, and R a and R 7 a have the meanings stated for these substituents in Formula III a .
  • A is an ⁇ -amino acid derivative of Formula V a ,
  • R a and R 7 a have the meanings stated for R a and R 7 a , in Formula III a .
  • A is a substituted proline derivative of Formula VI a ,
  • R a and R 1 a have the meanings stated for R a and R 1 a in Formula II a
  • X a is a monovalent radical, preferably a hydroxyl, alkoxy, for example, methoxy or ethoxy, group or a fluorine atom.
  • A is a thiaprolyl derivative of Formula VII a ,
  • R a , R 1 a , R 2 a , R 3 a , R 4 a and R 5 a have the meanings stated for the respective substituents in Formula II a .
  • A is a 1,3-dihydroisoindole derivative of Formula VIII a
  • R a has the meaning stated for R a for Formula II a .
  • A is a 2-azabicyclo[2.2.1]heptane-3-carboxylic acid derivative of Formula IX a ,
  • Z a is a single or double bond and R a has the meaning stated for Formula II a .
  • the 3-carbonyl substituent can have either the exo or endo orientation.
  • A is an ⁇ -amino acid derivative of Formula X a ,
  • n a has the meaning as stated for n a for Formula II a
  • R 7 a has the meanings as stated for R 7 a and R a for Formula III a .
  • B is a valyl, isoleucyl, allo-isoleucyl, norvalyl, 2-tert-butylglycyl or 2-ethylglycyl residue.
  • B can also be an ⁇ -amino acid residue of Formula II b ,
  • R 1 b and R 2 b are each a monovalent radical.
  • R 1 b is, preferably, a hydrogen atom and R 2 b is, for example, an alkyl, alkoxyalkyl or alkenyl group.
  • R 2 b is a cyclopropyl group, a normal or branched butyl, preferably tertiary-butyl, group, a methoxymethyl group, a 1-methoxyethyl group or a 1-methylvinyl group.
  • R 1 b and R 2 b together can be an isopropylidene group.
  • D is an N-alkylvalyl, N-alkyl-2-ethylglycyl, N-alkyl-2-tert-butylglycyl, N-alkyl-norleucyl, N-alkyl-isoleucyl, N-alkyl-allo-isoleucyl or N-alkyl-norvalyl residue, where the N-alkyl group is preferably a methyl group or an ethyl group.
  • D is an ⁇ -amino acid residue of Formula II d ,
  • R d has the meaning stated for R a in Formula III a
  • R 1 d is a monovalent radical, preferably a hydrogen atom
  • R 2 d is a monovalent radical, for example, an alkyl, alkoxyalkyl or alkenyl group.
  • R 2 d is a cyclopropyl group, a normal or branched butyl, preferably tertiary-butyl, group, a methoxymethyl group, a 1-methoxyethyl group or a 1-methylvinyl group such as a cyclopropyl group, a methoxymethyl group, a 1-methoxyethyl group or a 1-methylvinyl group.
  • R 1 d and R 2 d together can form an isopropylidene group.
  • D can be a proline derivative of Formula III d ,
  • n d is an integer, for example, 1 or 2, and R 3 b has the meaning stated for R 1 a in Formula III a .
  • X d is a monovalent radical, preferably a hydrogen atom, and, in the case where n d equals 1, can also be a hydroxy or alkoxy, for example, methoxy or ethoxy, group or a fluorine atom.
  • E is a prolyl, thiazolidinyl-4-carbonyl, homoprolyl or hydroxyprolyl residue, or a cyclic ⁇ -amino carboxylic acid residue of Formula II e ,
  • R 1 e has the meaning stated for R 1 a in Formula III a .
  • R 2 e , and R 3 e are each a monovalent radical, and can be, independently, a hydrogen atom or an alkyl, preferably methyl, group.
  • R 4 e is a monovalent radical, preferably a hydrogen atom, a hydroxy, alkoxy, for example, methoxy or ethoxy, group or a fluorine atom.
  • R 5 e is a monovalent-radical, preferably a hydrogen atom or a fluorine atom.
  • n e 1, R 3 e and R 4 e can together form a double bond, or R 4 e , and R 5 e can together be a double-bonded oxygen radical.
  • R 1 e and R 2 e can together form a double bond.
  • E is a 2- or 3-amino-cyclopentanecarboxylic acid residue of Formula III e ,
  • R e is an alkyl group, such as methyl or ethyl, and R 1 e has the meaning stated for R 1 a , in Formula III a .
  • F is a prolyl, thiazolidinyl-4-carbonyl, homoprolyl or hydroxyprolyl residue.
  • F can also be a cyclic ⁇ -amino acid residue of Formula II,
  • R 1 f has the meaning stated for R 1 a in Formula III a .
  • R 2 f and R 3 f are each a monovalent radical, and can be, independently, a hydrogen atom or an alkyl, preferably methyl, group.
  • R d f is a monovalent radical, preferably a hydrogen atom, a hydroxy, alkoxy, for example, methoxy or ethoxy, group or a fluorine atom.
  • R 5 f is a monovalent radical, preferably a hydrogen atom or a fluorine atom.
  • R 3 f and R 4 f together can form a double bond or R 4 f and R 5 f can together be a double-bonded oxygen radical.
  • R 1 f and R 2 f can together form a double bond.
  • F is a 2- or 3-amino-cyclopentanecarboxylic acid residue of Formula III f
  • R f is a monovalent radical, such as a methyl or ethyl group, and R 2 f has the meaning stated for R 1 a in Formula II.
  • F is an N-alkylglycyl or N-alkylalanyl residue
  • the alkyl group is, preferably, a methyl group or an ethyl group.
  • G is an ⁇ -amino acid residue of Formula II g .
  • R 1 g is a hydrogen atom, or an alkyl group, for example, methyl, ethyl or n-propyl.
  • R 2 g can be, for example, a hydrogen atom, or an alkyl, arylalkyl, heteroarylalkyl or aryl group.
  • R 2 g is an ethyl, isopropyl, tert-butyl, isobutyl, 2-methylpropyl, cyclohexylmethyl, benzyl, thiazolyl-2-methyl, pyridyl-2-methyl, n-butyl, 2,2-dimethylpropyl, naphthylmethyl, or n-propyl group, or a substituted or unsubstituted phenyl group.
  • Suitable phenyl substituents include one or more halogen, preferably fluorine, chlorine or bromine, atoms, C 1 -C 4 -alkyl groups, methoxy, ethoxy, nitro or trifluoromethyl groups or a dioxomethylene group.
  • R 1 g and R 2 g can, together with the ⁇ -carbon atom, form a cyclopentane or cyclohexane ring or a benzo-fused cyclopentane ring, such as, for example, the indanyl group.
  • K is an ⁇ -amino acid residue of Formula II k ,
  • R 1 k has the identity stated for R 1 g in Formula II g
  • R 2 k has the identity stated for R 2 g in Formula II g .
  • L is an amino or substituted amino group of Formula II l ,
  • R 1 l is a monovalent radical, such as a hydrogen atom, a normal or branched, saturated or unsaturated C 1 -C 18 -alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted aryl-C 1 -C 6 -alkoxy group, or a substituted or unsubstituted aryloxy-C 1 -C 6 — alkoxy or heteroaryl-C 1 -C 6 -alkoxy group.
  • the aryl group is preferably a phenyl or naphthyl group.
  • the heteroaryl group is a 5- or 6-membered, preferably nitrogen-, oxygen- or sulfur-containing, ring system, such as, for example, a heteroaryl group derived from imidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine.
  • Suitable aryl substituents include one or more halogen, preferably fluorine, bromine or chlorine, atoms, C 1 -C 4 -alkyl groups, methoxy, ethoxy or trifluoromethyl groups, a dioxymethylene group or nitro groups.
  • R 2 l is a monovalent radical, such as a hydrogen atom, a normal or branched, saturated or unsaturated C 1 -C 18 -alkyl group, a C 3 -C 10 -cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.
  • the aryl group is preferably a phenyl or naphthyl group.
  • the heteroaryl group is a 5- or 6-membered, preferably nitrogen-, oxygen- or sulfur-containing, ring system, such as, for example, a heteroaryl group derived from imidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine.
  • Suitable aryl substituents include one or more halogen, preferably fluorine, bromine or chlorine, atoms, C 1 -C 4 -alkyl groups, methoxy, ethoxy or trifluoromethyl groups, a dioxymethylene group or nitro groups.
  • R 2 l can, alternately, be of Formula II r ,
  • R 3 t is a monovalent radical, preferably a lower alkyl group, such as a methyl, ethyl, propyl or isopropyl group.
  • R 4 l is a monovalent radical, which can be a saturated or partially unsaturated carbocyclic system comprising from about 3 to about 10 carbon atoms, a substituted or unsubstituted aryl or heteroaryl group, with aryl and heteroaryl and preferred substituents having the meaning stated for R 2 l in Formula II l .
  • R 2 l can also be a substituent of Formula III r ,
  • W l is an oxygen or sulfur atom or an N—R 6 l group.
  • R 5 l is a monovalent radical, such as a hydrogen atom, a C 1 -C 4 -alkyl or C 3 -C 7 -cycloalkyl group or a substituted or unsubstituted aryl or arylmethyl group, with aryl and its preferred substituents having the meaning stated for R 2 l from Formula II l .
  • R 6 l is a monovalent radical, preferably a hydrogen atom, a C 1 -C 4 -alkyl group or a C 3 -C 7 -cycloalkyl group, a C 1 -C 18 -alkanoyl group, a benzoyl group or a substituted or unsubstituted aryl or arylmethyl group, with aryl and its preferred substituents having the meaning stated for R 2 l in Formula II l .
  • R 2 l can, alternately, be a substituent of Formula IV r ,
  • Z l can be a monovalent radical such as a formyl, aminocarbonyl or hydrazinocarbonyl group, or a cyclic or acyclic acetal or thioacetal group.
  • R 2 l can also be a substituent of Formula V r ,
  • R 7 l can be a monovalent radical, such as a polyglycol group of the formula —O—(CH 2 —CH 2 —O) d l —CH 3 , where d l is an integer; preferably in the range from about 2 to about 4 or from about 40 to about 90.
  • R 2 l can further be a carbohydrate of Formula VI r ,
  • R 2 l is a monovalent radical, such as a hydrogen atom, a C 1 -C 4 -alkanoyl or alkyl group, a benzoyl group or a benzyl group.
  • L can also be a ⁇ -hydroxylamino group of Formula III l ,
  • R 2 l is a monovalent radical such as a hydrogen atom, a C 1 -C 6 -alkyl group or a substituted or unsubstituted aryl group, with aryl and its preferred substituents having the meaning stated for R 2 l -R 10 l is a monovalent radical, preferably a hydrogen atom, alkyl, for example, methyl, or a phenyl group.
  • L can also be an amino group of Formula IV l ,
  • R 2 l and R 4 l are each a monovalent radical.
  • R 2 l and R 4 l can also be linked by a carbon-carbon bond.
  • Another subclass of compounds of this invention includes peptides of Formula I wherein L is a hydrazido group of Formula V l ,
  • R 11 l is a monovalent radical, preferably a hydrogen atom.
  • R 12 l can be a monovalent radical such as a hydrogen atom, a normal or branched C 1 -C 8 -alkyl group, a C 1 -C 3 -cycloalkyl group, a C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl group or a substituted or unsubstituted aryl, heteroaryl, aryl-C 1 -C 4 -alkyl or heteroaryl-C 1 -C 4 -alkyl group, where aryl, heteroaryl and their preferred substituents can be selected from among the options listed for R 2 l .
  • R 11 l can also be selected from among the options listed above for R 12 l , and the two radicals together can additionally form a propylene or butylene bridge.
  • L is a monovalent radical of the formula —O—R 13 l or the formula —S—R 13 l , where R 13 l is a monovalent radical, such as a C 3 -C 10 -cycloalkyl group, a normal or branched C 2 -C 16 -alkenylmethyl group or a C 1 -C 16 -alkyl group which can be substituted by from 1 to about 5 halogen, preferably fluorine, atoms.
  • R 13 l can also be the radical —(CH 2 ) e —R 14 l , where e is an integer, preferably 1, 2 or 3.
  • R 14 l is a monovalent radical, preferably a saturated or partially unsaturated C 3 -C 11 -carbocycle.
  • R 13 l can further be the monvalent radical —[CH 2 —CH ⁇ C(CH 3 )—CH 2 ] l —H, where f is an integer, preferably 1, 2, 3 or 4.
  • R 13 l can also be the radical —[CH, —CH 2 —O] g —CH 3 , where g is an integer, preferably in the range from 1 to about 5.
  • R 13 l can also be the radical —(CH 2 ) h -aryl or —(CH 2 ) h -heteroaryl, where aryl and heteroaryl can also be substituted and, along with their preferred substituents, can be selected from the group listed for R 2 l .
  • h is an integer, preferably 0, 1, 2 or 3.
  • R 13 l can further be the radical —(CH 2 ) b —W l —R 5 l .
  • W l and R 5 l can each be selected from among the options described for Formula IV l .
  • L is an aminoxy group of the formula —O—N(R 15 l )(R 16 l ), where R 15 l and R 16 l are each a monovalent radical, which can independently be a hydrogen atom, a normal or branched C 1 -C 8 -alkyl group, which can be substituted by halogen, preferably fluorine, atoms, a C 3 -C 8 -cycloalkyl group, a C 3 -C 8 -cycloalkyl-C 1 -C 4 -alkyl group, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted aryl-C 1 -C 4 -alkyl group.
  • Aryl and heteroaryl groups and the preferred substituents thereof can be selected from the options listed for R 2 l .
  • R 16 l can be selected from among the options listed for R 15 l . Additionally, R 15 l and R 16 l can together form a 5-, 6- or 7-membered heterocycle.
  • the compounds of the present invention further comprise the salts of the compounds described above with physiologically tolerated acids.
  • R 15 l and R 16 l can be selected from among the options listed above and, additionally, can together form a cyclic system comprising, preferably, from about 3 to about 7 ring atoms.
  • This cyclic system can additionally be fused to one or more aromatic rings. Particularly preferred cyclic systems are shown below.
  • the invention provides compounds of Formula I wherein A is an amino acid derivative selected from among N-alkyl-D-prolyl, N-alkyl-L-prolyl, N-alkyl-D-piperidine-2-carbonyl, N-alkyl-L-piperidine-2-carbonyl, N,N-dialkyl-D-2-ethyl-2-phenylglycyl and N,N-dialkyl-L-2-ethyl-2-phenylglycyl, wherein alkyl is methyl, ethyl or isopropyl; and 13 is a valyl, isoleucyl or 2-t-butyl-L-glycyl residue.
  • A is an amino acid derivative selected from among N-alkyl-D-prolyl, N-alkyl-L-prolyl, N-alkyl-D-piperidine-2-carbonyl, N-alkyl-L-piperidine-2-carbonyl, N,N
  • Preferred compounds of the invention include compounds of Formula I wherein r and s are each 0.
  • A is an amino acid derivative selected from among D-N-methyl-piperidine-2-carbonyl, L-N-methyl-piperidine-2-carbonyl, N,N-dimethylamino-iso-butyryl, N-methyl-L-prolyl, N-methyl-L-thiazolidine-4-carbonyl, N,N-dimethyl-glycyl, L-prolyl, L-piperidine-2-carbonyl, N-propyl-D-piperidine-2-carbonyl, D-piperidine-2-carbonyl, N-ethyl-D-piperidine-2-carbonyl, N-methyl-[2,2,5,5-tetramethyl]-L-thiazolidine-2-carbonyl, N-isopropyl-D-piperidine-2-carbonyl, N,N-dimethyl-2-cyclopropylglycyl, N,N-
  • B is valyl, isoleucyl or 2-tert-butylglycyl.
  • D is N-methylvalyl, N-methyl-2-t-butylglycyl or N-methylisoleucyl.
  • E and F are each, independently, prolyl, thiaprolyl, homoprolyl, hydroxyprolyl, 3,4-didehydroprolyl, 4-fluoroprolyl, and 3-methylprolyl.
  • L is an alkoxy group or an amino group of the formula R 1 l —N—R 2 l , wherein R 1 l and R 2 l are independently selected from the group consisting of hydrogen, alkoxy, hydroxy, alkyl and alkylaryl.
  • L is a C 1 -C 6 -alkoxy group or an amino group of the formula R 1 l —N—R 2 l , wherein R 1 l and R 2 l are each independently selected from the group consisting of hydrogen, C 1 -C 6 -alkoxy, hydroxy, normal, cyclic or branched C 1 -C 12 -alkyl, and phenylalkyl.
  • the compounds of the present invention can be prepared by known methods of peptide synthesis.
  • the peptides can be assembled sequentially from individual amino acids or by linking suitable small peptide fragments.
  • sequential assembly the peptide chain is extended stepwise, starting at the C-terminus, by one amino acid per step.
  • fragment coupling fragments of different lengths can be linked together, and the fragments in turn can be obtained by sequential assembly from amino acids or by fragment coupling of still shorter peptides.
  • Preferred methods include the azide method, the symmetric and mixed anhydride method, the use of in situ generated or preformed active esters, the use of urethane protected N-carboxy anhydrides of amino acids and the formation of the amide linkage using coupling reagents, such as carboxylic acid activators, especially dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), pivaloyl chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), n-propanephosphonic anhydride (PPA), N,N-bis(2-oxo-oxazolidinyl)amidophosphoryl chloride (BOP—Cl), bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBrop),
  • the coupling reagents can be employed alone or in combination with additives such as N,N-dimethyl-4-aminopyridine (DMAP), N-hydroxy-benzotriazole (HOBt), N-hydroxyazabenzotriazole (HOAt), N-hydroxybenzotriazine (HOOBt), N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine.
  • DMAP N,N-dimethyl-4-aminopyridine
  • HABt N-hydroxy-benzotriazole
  • HOAt N-hydroxyazabenzotriazole
  • HOOBt N-hydroxybenzotriazine
  • HSu N-hydroxysuccinimide
  • 2-hydroxypyridine 2-hydroxypyridine
  • Solvents suitable for peptide synthesis include any solvent which is inert under the reaction conditions, especially water, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dichloromethane (DCM), 1,4-dioxane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP) and mixtures of these solvents.
  • solvents suitable for peptide synthesis include any solvent which is inert under the reaction conditions, especially water, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dichloromethane (DCM), 1,4-dioxane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP) and mixtures of these solvents.
  • Peptide synthesis on the polymeric support can be carried out in a suitable inert organic solvent in which the amino acid derivatives starting materials are soluble.
  • preferred solvents additionally have resin-swelling properties, such as DMF, DCM, NMP, acetonitrile and DMSO, and mixtures of these solvents.
  • resin-swelling properties such as DMF, DCM, NMP, acetonitrile and DMSO, and mixtures of these solvents.
  • the cleavage reactions most commonly used are acid- or palladium-catalyzed, the former being conducted in, for example, liquid anhydrous hydrogen fluoride, anhydrous trifluoromethanesulfonic acid, dilute or concentrated trifluoroacetic acid, and acetic acid/dichloromethane/trifluoroethanol mixtures.
  • the latter can be carried out in THF or THF-DCM-mixtures in the presence of a weak base, such as morpholine. Certain protecting groups are also cleaved off under these conditions.
  • Partial deprotection of the peptide may also be necessary prior to certain derivatization reactions.
  • peptides dialkylated at the N-terminus can be prepared by coupling the appropriate N,N-di-alkylamino acid to the peptide in solution or on the polymeric support, by reductive alkylation of the resin-bound peptide in DMF/1% acetic acid with NaCNBH 3 and the appropriate aldehyde or by hydrogenation of the peptide in solution in the presence of the appropriate aldehyde or ketone and Pd/carbon.
  • amino acid building blocks with R 1 and R 2 groups can be prepared according to the method described by Wuensch and Weyl, Methoden der Organische Chemie , vol. XV, Springer Verlag: Stuttgart, p. 306 (1974) and references cited therein.
  • the present invention comprises a method for partially or totally inhibiting formation of, or otherwise treating (e.g., reversing or inhibiting the further development of) solid tumors (e.g., tumors of the lung, breast, colon, prostate, bladder, rectum, or endometrial tumors) or hematological malignancies (e.g., leukemias, lymphomas) in a mammal, for example, a human, by administering to the mammal a therapeutically effective amount of a compound or a combination of compounds of Formula I.
  • the compound(s) may be administered alone or in a pharmaceutical composition comprising the compound(s) and an acceptable carrier or diluent.
  • Administration can be by any of the means which are conventional for pharmaceutical, preferably oncological, agents, including oral and parenteral means, such as subcutaneously, intravenously, intramuscularly and intraperitoneally, nasally or rectally.
  • the compounds may be administered alone or in the form of pharmaceutical compositions containing a compound or compounds of Formula I together with a pharmaceutically accepted carrier appropriate for the desired route of administration.
  • Such pharmaceutical compositions may be combination products, i.e., they may also contain other therapeutically active ingredients.
  • the dosage to be administered to the mammal will contain a therapeutically effective amount of a compound described herein.
  • therapeutically effective amount is an amount sufficient to inhibit (partially or totally) formation of a tumor or a hematological malignancy or to reverse development of a solid tumor or other malignancy or prevent or reduce its further progression.
  • the dosage is determined empirically, using known methods, and will depend upon factors such as the biological activity of the particular compound employed; the means of administration; the age, health and body weight of the recipient; the nature and extent of the symptoms; the frequency of treatment; the administration of other therapies; and the effect desired.
  • a typical daily dose will be from about 0.05 to about 50 milligrams per kilogram of body weight by oral administration and from about 0.01 to about 20 milligrams per kilogram of body weight by parenteral administration.
  • the compounds of the present invention can be administered in conventional solid or liquid pharmaceutical administration forms, for example, uncoated or (film-) coated tablets, capsules, powders, granules, suppositories or solutions. These are produced in a conventional manner.
  • the active substances can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, sustained release compositions, antioxidants and/or propellant gases (cf. H. Sücker et al.: Pharmazeutician Technologie, Thieme-Verlag, Stuttgart, 1978).
  • the administration forms obtained in this way typically contain from about 1 to about 90% by weight of the active substance.
  • the peptides of the invention are synthesized either by classical solution synthesis using standard Z- and Boc-methodology as described above or by standard methods of solid-phase synthesis using Boc and Fmoc protective group techniques.
  • the N,N-dialkyl-penta- or hexapeptide acids are liberated from the solid support and further coupled with the corresponding C-terminal amines in solution.
  • BOP—Cl and PyBrop were used as reagents for coupling of the amino acid following the N-methylamino acids. The reaction times were correspondingly increased.
  • the peptide-resin was deprotected at the N terminus and then reacted with a 3-fold molar excess of aldehyde or ketone in DMF/1% acetic acid with addition of 3 equivalents of NaCNBH 3 . After the reaction was complete (negative Kaiser test) the resin was washed several times with water, isopropanol, DMF and dichloromethane.
  • Valyl-N-methylvalyl-prolyl-prolylbenzylamide hydrochloride for example was prepared according to methods disclosed in German Patent Application No. DE 19527575 A1.
  • the purity of the resulting products was determined by analytical HPLC (stationary phase: 100 2.1 mm VYDAC C-18, 5 micron, 300 A; mobile phase: acetonitrile-water gradient, buffered with 0.1% TFA, 40° C.; or 3.9 mm VYDAC C-18, 30° C.). Characterization was by fast atom bombardment mass spectroscopy and NMR-spectroscopy.
  • N-Methyl-piperidine-2-carboxylic acid ethyl ester (5.1 g) was dissolved in a mixture of 100 ml methanol and 10 ml water. NaOH (8 g) was added and the reaction mixture was stirred at room temperature overnight. The solution was then neutralized with hydrochloric acid, evaporated to dryness, and evaporated four times with toluene. The resulting powdery residue was used directly in the next step.
  • 2-Amino-isobutyric acid (10.3 g) was dissolved in 200 ml methanol. After addition of 25 ml aqueous formaldehyde and 1 g 10% Pd/C, the reaction mixture was hydrogenated overnight at room temperature. The catalyst was filtered, and the filtrate was evaporated to dryness. The residue was crystallized from isopropanal to give 4.8 g of the desired product.
  • the ether extracts were washed with 1 N NaOH (1 ⁇ ) and aqueous NaCl (3 ⁇ ), then dried over sodium sulfate and evaporated to dryness under reduced pressure.
  • isomer 1 is the diastereomer with the shorter retention time on the reversed phase analytical HPLC system. Fast atom bombardment-mass spectrometry results for selected compounds are provided in Table 2.
  • Xai L-piperidine-2-carboxylic acid
  • Xak 2-[N,N-dimethylamino]-isobutyric acid
  • Xal L-thiazolidine-4-carboxylic acid
  • Xam N-propyl-D-piperidine-2-carboxylic acid
  • Xan L-3,4-didehydroproline
  • Xao D-piperidine-2-carboxylic acid
  • Xap proline tert.butylester
  • Xaq N-ethyl-D-piperidine-2-carboxylic acid
  • Xar N-methyl-[2,2,5,5-tetramethyl]-L-thiazolidine-2-carboxylic acid
  • Xas N-isopropyl-D-piperidine-2-carboxylic acid
  • Xat N,N-dimethyl-2-cyclopropyl-glycine
  • Xau N,N-dimethyl-2-
  • Xaw N-methyl-D-pro line
  • Xax N,N-dimethyl-2-[2-fluoro]phenyl-glycine
  • Xay 1-aza-[3,3,0]bicyclooctyl-5-carboxylic acid
  • Xaz N,N-dimethyl-2-[4-fluoro]phenyl-glycine
  • Xba N-methyl-[2,2,5,5-tetramethyl]-thiazolidine-2-carboxylic acid
  • Xbb 2-(R,S)-ethyl-2-phenyl-glycine
  • Xbc D,L-1-aminoindane-1-carboxylic acid
  • Xbd N,N-dimethyl-2-(R,S)-methyl-2-phenyl-glycine
  • Xbe 2-[N,N-dimethylamino]indane-2-carboxylic acid
  • Xbf 5-[N,N-di
  • Xbt proline-[5-phenyl]isoxazolidinyl
  • Xbu N-methyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid
  • Xbv N-methyl-azetidine-2-carboxylic acid
  • Xbw N-isopropyl-azetidine-2-carboxylic acid
  • Xbx proline-tert-butylamide
  • Xbz N,N-dimethyl-[O-methyl]threonine
  • Xca N-methyl-1,2,3,4-tetrahydro isoquino line-3-carboxylic acid
  • Xcb proline-pentyl(3)amide
  • Xcc proline-(R)-phenethylamide
  • Xcd proline-(S)-phenethylamide
  • Xce 1-[N,N-di
  • Cytotoxicity was measured using a standard methodology for adherent cell lines, such as the microculture tetrazolium assay (MTT). Details of this assay have been published (Alley, M. C. et al., Cancer Research 48: 589-601, (1988)). Exponentially growing cultures of HT-29 colon carcinoma cells were used to make microtiter plate cultures. Cells were seeded at 5000-20,000 cells per well in 96-well plates (in 150 mL of media), and grown overnight at 37° C. Test compounds were added, in 10-fold dilutions varying from 10 ⁇ 4 M to 10 ⁇ 10 M. Cells were then incubated for 48 hours.
  • MTT microculture tetrazolium assay
  • the MTT dye was added (50 mL of a 3 mg/mL solution of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide in saline). This mixture was incubated at 37° C. for 5 hours, and then 50 mL of 25% SDS, pH 2, was added to each well. After an overnight incubation, the absorbance of each well at 550 nm was read using an ELISA reader. The values for the mean+/ ⁇ SD of data from replicated wells were calculated, using the formula % T/C (% viable cells treated/control). The concentration of test compound which gives a T/C of 50% growth inhibition was designated as the IC 50 .
  • Table 3 presents the IC 50 values determined in the HT-29 assay for a series of compounds of the invention.
  • Compounds of this invention may be further tested in any of the various preclinical assays for in vivo activity which are indicative of clinical utility.
  • Such assays are conducted with nude mice into which tumor tissue, preferably of human origin, has been transplanted (“xenografted”), as is well known in this field.
  • Test compounds are evaluated for their anti-tumor efficacy following administration to the xenograft-bearing mice.
  • human tumors grown in athymic nude mice can be transplanted into new recipient animals, using tumor fragments which are about 50 mg in size.
  • the day of transplantation is designated as day O, Six to ten days later, the mice are treated with the test compounds given as an intravenous or intraperitoneal injection, in groups of 5-10 mice at each dose. Compounds are given daily for 5 days, 10 days or days, at doses from 10-100 mg/kg body weight. Tumor diameters and body weights are measured twice weekly. Tumor masses are calculated using the diameters measured with Vernier calipers, and the formula:
  • Mean tumor weights are then calculated for each treatment group, and T/C values are determined for each group relative to the untreated control tumors.

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Abstract

Compounds of the present invention include cell growth inhibitors which are peptides of Formula I,

A-B-D-E-F-(G)r-(K)s-L  (I),
and acid salts thereof, wherein A, B, D, E, F, G and K are α-amino acid residues, and s and r are each, independently, 0 or 1. L is a monovalent radical, such as, for example, an amino group, an N-substituted amino group, a β-hydroxylamino group, a hydrazido group, an alkoxy group, a thioalkoxy group, an aminoxy group, or an oximato group. The present invention also includes a method for treating cancer in a mammal, such as a human, comprising administering to the mammal an effective amount of a compound of Formula I in a pharmaceutically acceptable composition.

Description

    RELATED APPLICATIONS
  • This application is a continuation of U.S. application Ser. No. 12/648,446, filed Dec. 29, 2009, which is a continuation of U.S. application Ser. No. 11/406,512 filed Apr. 18, 2006, which is a continuation of U.S. application Ser. No. 10/255,118 filed Sep. 25, 2002, which is a continuation of U.S. application Ser. No. 09/618,694 filed Jul. 18, 2000, which is a continuation of U.S. application Ser. No. 08/896,394 filed Jul. 18, 1997, the entire contents of which are incorporated herein by reference.
    • BACKGROUND OF THE INVENTION
  • A number of short peptides with significant activity as inhibitors of cell growth have been isolated from the Indian Ocean sea hare Dolabella auricularia (Bai et al., Biochem. Pharmacolog_v, 40: 1859-1864 (1990); Beckwith et al., J. Natl. Cancer Inst., 85: 483-488 (1993) and references cited therein). These include Dolastatins 1-10 (U.S. Pat. No. 4,816,444, issued to Pettit et al) and Dolastatin-15 (European Patent Application No. 398558). Dolastatin 15, for example, markedly inhibits the growth of the National Cancer Institute's P388 lymphocytic leukemia (PS system) cell line, a strong predictor of efficacy against various types of human malignancies.
  • The exceedingly small amounts of the various Dolastin peptides present in Dolahella auricularia (about 1 mg each per 100 kg sea hare) and the consequent difficulties in purifying amounts sufficient for evaluation and use, have motivated efforts toward the synthesis of these compounds (Roux et al., Tetrahedron 50: 5345-5360 (1994); Shioiri et al., Tetrahedron 49: 1913-24 (1993); Patino et al., Tetrahedron 48: 4115-4122 (1992) and references cited therein). Synthetic Dolastatin 15, however, suffers from drawbacks which include poor solubility in aqueous systems and the need for expensive starting materials for its synthesis. These, in turn, have led to the synthesis and evaluation of structurally modified Dolastatin 15 derivatives [cf.: Biorg. Med. Chem. Lett. 4: 1947-50 (1994); WO 93 03054; JP-A-06234790; WO 93 23424].
  • However, there is a need for synthetic compounds with the biological activity of Dolastatin 15 which have useful aqueous solubility and can be produced efficiently and economically.
    • SUMMARY OF THE INVENTION
  • Compounds of the present invention include cell growth inhibitors which are peptides of Formula I,

  • A-B-D-E-F-(G),-(K)5-L
  • and acid salts thereof, wherein A, B, D, E, F, G and K are a-amino acid residues, and s and r are each, independently, 0 or 1. L is a monovalent radical, such as, for example, an amino group, an N-substituted amino group, a β-hydroxylamino group, a hydrazido group, an alkoxy group, a thioalkoxy group, an aminoxy group, or an oximato group.
  • Another aspect of the present invention includes pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier. An additional embodiment of the present invention is a method for treating cancer in a mammal, such as a human, comprising administering to the manvnal an effective amount of a compound of Formula I in a pharmaceutically acceptable composition.
    • DETAILED DESCRIPTION OF THE INVENTION
  • The present invention relates to peptides having antineoplastic activity. It also includes pharmaceutical compositions comprising these compounds and methods for treating cancer in a mammal, including a human, by administration of these compositions to the mammal.
  • Dolastatin 15, a peptide isolated from the sea hare Dolabella auricularia, is a potent inhibitor of cell growth. This compound, however, is present in trace quantities in the sea hare, and is thus difficult to isolate. Dolastatin 15 is also expensive to synthesize and suffers from poor aqueous solubility. As shown herein, however, Dolastatin 15 can serve as a starting point for the development of compounds which overcome these disadvantages while retaining antineoplastic activity or exhibiting greater antineoplastic activity than the natural product. Applicants have discovered that certain structural modifications of Dolastatin 15 provide compounds with a surprisingly improved therapeutic potential for the treatment of neoplastic diseases as compared to Dolastatin 10 and Dolastatin 15. Furthermore, the compounds of the present invention can be conveniently synthesized, as described below in detail.
  • For the purposes of the present invention, the term “monovalent radical” is intended to mean an electrically neutral molecular fragment capable of forming one covalent bond with a second neutral molecular fragment. Monovalent radicals include the hydrogen atom, alkyl groups, such as methyl, ethyl and propyl groups, halogen atoms, such as fluorine, chlorine and bromine atoms, aryl groups, such as phenyl and naphthyl groups, and alkoxy groups, such as methoxy and ethoxy groups. Two monovalent radicals on adjacent sigma-bonded atoms can also together form a pi bond between the adjacent atoms. Two monovalent radicals may also be linked together, for example, by a polymethylene unit, to form a cyclic structure. For example, the unit —N(R)R′, wherein R and R′ are each a monovalent radical, can, together with the nitrogen atom, form a heterocyclic ring. In addition, two monovalent radicals bonded to the same atom can together form a divalent radical, such as an oxygen atom or an alkylidene group, for example, a propylidene group.
  • For the purposes of the present invention, the term “normal alkyl” refers to an unbranched, or straight chain, alkyl group, for example, normal propyl (n-propyl, —CH2CH2 CH3).
  • The compounds of the present invention can be represented by Formula I,

  • A-B-D-E-F-(G)r-(K)s-L  (I),
  • wherein A, B, D, E, F, G, and K are α-amino acid residues; s and r are each, independently, 0 or 1; and L is a monovalent radical such as an amino group, an N-substituted amino group, a β-hydroxylamino group, a hydrazido group, an alkoxy group, a thioalkoxy group, an aminoxy group, or an oximato group.
  • The peptides of Formula I are generally composed of L-amino acids but they can contain one or more D-amino acids. In the following discussion, reference to a particular amino acid includes both enantiomers unless a specific enantiomer is indicated. The present compounds can also be present as salts with physiologically-compatible acids, including hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine.
  • The following is a description of the present invention, including a detailed description of individual components and of methods of using the claimed compounds.
    • Compounds of the Present Invention Identity of A
  • In one embodiment, A is a proline derivative of Formula IIa,
  • Figure US20130046077A1-20130221-C00001
  • where n, is an integer, preferably 0, 1, 2, or 3. Ra is a monovalent radical, such as a hydrogen atom or an unsubstituted or fluorine-substituted alkyl group, for example a normal, branched or cyclic C1-C3-alkyl group which is, optionally, substituted by from 1 to about 3 fluorine atoms; suitable examples include methyl, ethyl, isopropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1-methyl-2-fluoroethyl, 1-fluoromethyl-2-fluoroethyl or cyclopropyl; methyl, ethyl or isopropyl are preferred;
  • In this embodiment, R1 a, is a monovalent radical, such as a hydrogen atom, an alkyl group, such as a methyl, ethyl or propyl group, or a phenyl group. The phenyl group can be substituted; suitable substituents include one or more halogen atoms, with fluorine, chlorine and bromine atoms preferred, C1-C4-alkyl groups, methoxy, ethoxy, trifluoromethyl or nitro groups. Ra and R1 a together can also form a propylene bridge.
  • R2 a, R3 a, R4 a and R5 a, are each, independently, a monovalent radical, such as a hydrogen atom or an alkyl, preferably, methyl, group.
  • In another embodiment, A is a substituted glycine derivative of Formula IIIa,
  • Figure US20130046077A1-20130221-C00002
  • where Ra has the meaning stated for Ra in Formula IIa and, R1 a, is a monovalent radical, for example, a hydrogen atom or a C1-C6-alkyl group, preferably a methyl, ethyl or propyl group.
  • In this embodiment, R6 a is a monovalent radical, such as an alkyl, substituted alkyl, alkenyl, phenyl or substituted phenyl group. Suitable examples include methoxymethyl, 1-methoxyethyl, 1,1-dimethyl-hydroxymethyl, 1-trifluoromethylethyl, 1-trifluoromethyl-2,2,2-trifluoroethyl, vinyl, and 1-methylvinyl. Phenyl substituents can include one or more halogen atoms, preferably fluorine, chlorine or bromine atoms, and alkyl, methoxy, ethoxy, trifluoromethyl, and nitro groups.
  • When R1 a is an alkyl group, R6 a, can also be a C1-C6-alkyl, cycloalkyl, unsubstituted benzyl or substituted benzyl group. Suitable benzyl substituents include one or more halogen atoms, such as fluorine, chlorine or bromine atoms, C1-C4-alkyl groups, and methoxy, ethoxy, trifluoromethyl and nitro groups.
  • R7 a is a monovalent radical, preferably a methyl, ethyl or isopropyl group.
  • In another embodiment, A is an α-amino acid derivative of Formula IVa,
  • Figure US20130046077A1-20130221-C00003
  • where ma is an integer, preferably 1 or 2, and Ra and R7 a have the meanings stated for these substituents in Formula IIIa.
  • In another embodiment, A is an α-amino acid derivative of Formula Va,
  • Figure US20130046077A1-20130221-C00004
  • where Ra and R7 a have the meanings stated for Ra and R7 a, in Formula IIIa.
  • In a further embodiment, A is a substituted proline derivative of Formula VIa,
  • Figure US20130046077A1-20130221-C00005
  • where Ra and R1 a have the meanings stated for Ra and R1 a in Formula IIa, and Xa is a monovalent radical, preferably a hydroxyl, alkoxy, for example, methoxy or ethoxy, group or a fluorine atom.
  • In another embodiment, A is a thiaprolyl derivative of Formula VIIa,
  • Figure US20130046077A1-20130221-C00006
  • where Ra, R1 a, R2 a, R3 a, R4 a and R5 a have the meanings stated for the respective substituents in Formula IIa.
  • In another embodiment, A is a 1,3-dihydroisoindole derivative of Formula VIIIa
  • Figure US20130046077A1-20130221-C00007
  • where Ra has the meaning stated for Ra for Formula IIa.
  • In another embodiment, A is a 2-azabicyclo[2.2.1]heptane-3-carboxylic acid derivative of Formula IXa,
  • Figure US20130046077A1-20130221-C00008
  • where Za is a single or double bond and Ra has the meaning stated for Formula IIa. The 3-carbonyl substituent can have either the exo or endo orientation.
  • In another embodiment, A is an α-amino acid derivative of Formula Xa,
  • Figure US20130046077A1-20130221-C00009
  • where na has the meaning as stated for na for Formula IIa, and R7 a, and Ra have the meanings as stated for R7 a and Ra for Formula IIIa.
    • Identity of B
  • B is a valyl, isoleucyl, allo-isoleucyl, norvalyl, 2-tert-butylglycyl or 2-ethylglycyl residue. B can also be an α-amino acid residue of Formula IIb,
  • Figure US20130046077A1-20130221-C00010
  • in which R1 b and R2 b are each a monovalent radical. R1 b is, preferably, a hydrogen atom and R2 b is, for example, an alkyl, alkoxyalkyl or alkenyl group. In preferred embodiments, R2 b is a cyclopropyl group, a normal or branched butyl, preferably tertiary-butyl, group, a methoxymethyl group, a 1-methoxyethyl group or a 1-methylvinyl group. Additionally, R1 b and R2 b together can be an isopropylidene group.
    • Identity of D
  • D is an N-alkylvalyl, N-alkyl-2-ethylglycyl, N-alkyl-2-tert-butylglycyl, N-alkyl-norleucyl, N-alkyl-isoleucyl, N-alkyl-allo-isoleucyl or N-alkyl-norvalyl residue, where the N-alkyl group is preferably a methyl group or an ethyl group.
  • In another embodiment, D is an α-amino acid residue of Formula IId,
  • Figure US20130046077A1-20130221-C00011
  • where Rd has the meaning stated for Ra in Formula IIIa, R1 d is a monovalent radical, preferably a hydrogen atom, and R2 d is a monovalent radical, for example, an alkyl, alkoxyalkyl or alkenyl group. In preferred embodiments, R2 d is a cyclopropyl group, a normal or branched butyl, preferably tertiary-butyl, group, a methoxymethyl group, a 1-methoxyethyl group or a 1-methylvinyl group such as a cyclopropyl group, a methoxymethyl group, a 1-methoxyethyl group or a 1-methylvinyl group. Additionally, R1 d and R2 d together can form an isopropylidene group.
  • Alternatively, D can be a proline derivative of Formula IIId,
  • Figure US20130046077A1-20130221-C00012
  • where nd is an integer, for example, 1 or 2, and R3 b has the meaning stated for R1 a in Formula IIIa. Xd is a monovalent radical, preferably a hydrogen atom, and, in the case where nd equals 1, can also be a hydroxy or alkoxy, for example, methoxy or ethoxy, group or a fluorine atom.
    • Identity of E
  • E is a prolyl, thiazolidinyl-4-carbonyl, homoprolyl or hydroxyprolyl residue, or a cyclic α-amino carboxylic acid residue of Formula IIe,
  • Figure US20130046077A1-20130221-C00013
  • where ne is an integer, preferably 0, 1 or 2. R1 e has the meaning stated for R1 a in Formula IIIa. R2 e, and R3 e are each a monovalent radical, and can be, independently, a hydrogen atom or an alkyl, preferably methyl, group. R4 e, is a monovalent radical, preferably a hydrogen atom, a hydroxy, alkoxy, for example, methoxy or ethoxy, group or a fluorine atom. R5 e, is a monovalent-radical, preferably a hydrogen atom or a fluorine atom. In the case where ne is 1, R3 e and R4 e can together form a double bond, or R4 e, and R5 e can together be a double-bonded oxygen radical. In the case where ne has the value 1 or 2, R1 e and R2 e can together form a double bond.
  • In another embodiment, E is a 2- or 3-amino-cyclopentanecarboxylic acid residue of Formula IIIe,
  • Figure US20130046077A1-20130221-C00014
  • where Re is an alkyl group, such as methyl or ethyl, and R1 e has the meaning stated for R1 a, in Formula IIIa.
    • Identity of F
  • F is a prolyl, thiazolidinyl-4-carbonyl, homoprolyl or hydroxyprolyl residue. F can also be a cyclic α-amino acid residue of Formula II,
  • Figure US20130046077A1-20130221-C00015
  • where nf is an integer, preferably 0, 1 or 2. R1 f has the meaning stated for R1 a in Formula IIIa. R2 f and R3 f are each a monovalent radical, and can be, independently, a hydrogen atom or an alkyl, preferably methyl, group. Rd f is a monovalent radical, preferably a hydrogen atom, a hydroxy, alkoxy, for example, methoxy or ethoxy, group or a fluorine atom. R5 f is a monovalent radical, preferably a hydrogen atom or a fluorine atom. In the case where nr has the value 1, R3 f and R4 f together can form a double bond or R4 f and R5 f can together be a double-bonded oxygen radical. In the case where nf has the value 1 or 2, R1 f and R2 f can together form a double bond.
  • In another embodiment, F is a 2- or 3-amino-cyclopentanecarboxylic acid residue of Formula IIIf
  • Figure US20130046077A1-20130221-C00016
  • where Rf is a monovalent radical, such as a methyl or ethyl group, and R2 f has the meaning stated for R1 a in Formula II.
  • In another embodiment, F is an N-alkylglycyl or N-alkylalanyl residue, and the alkyl group is, preferably, a methyl group or an ethyl group.
    • Identity of G
  • G is an α-amino acid residue of Formula IIg,
  • Figure US20130046077A1-20130221-C00017
  • wherein R1 g is a hydrogen atom, or an alkyl group, for example, methyl, ethyl or n-propyl. R2 g can be, for example, a hydrogen atom, or an alkyl, arylalkyl, heteroarylalkyl or aryl group. Preferably, R2 g is an ethyl, isopropyl, tert-butyl, isobutyl, 2-methylpropyl, cyclohexylmethyl, benzyl, thiazolyl-2-methyl, pyridyl-2-methyl, n-butyl, 2,2-dimethylpropyl, naphthylmethyl, or n-propyl group, or a substituted or unsubstituted phenyl group. Suitable phenyl substituents include one or more halogen, preferably fluorine, chlorine or bromine, atoms, C1-C4-alkyl groups, methoxy, ethoxy, nitro or trifluoromethyl groups or a dioxomethylene group. Alternately, R1 g and R2 g can, together with the α-carbon atom, form a cyclopentane or cyclohexane ring or a benzo-fused cyclopentane ring, such as, for example, the indanyl group.
    • Identity of K
  • K is an α-amino acid residue of Formula IIk,
  • Figure US20130046077A1-20130221-C00018
  • wherein R1 k has the identity stated for R1 g in Formula IIg, and R2 k has the identity stated for R2 g in Formula IIg.
    • Identity of L
  • In one embodiment, L is an amino or substituted amino group of Formula IIl,
  • Figure US20130046077A1-20130221-C00019
  • where R1 l is a monovalent radical, such as a hydrogen atom, a normal or branched, saturated or unsaturated C1-C18-alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted aryl-C1-C6-alkoxy group, or a substituted or unsubstituted aryloxy-C1-C6— alkoxy or heteroaryl-C1-C6-alkoxy group. The aryl group is preferably a phenyl or naphthyl group. The heteroaryl group is a 5- or 6-membered, preferably nitrogen-, oxygen- or sulfur-containing, ring system, such as, for example, a heteroaryl group derived from imidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine. Suitable aryl substituents include one or more halogen, preferably fluorine, bromine or chlorine, atoms, C1-C4-alkyl groups, methoxy, ethoxy or trifluoromethyl groups, a dioxymethylene group or nitro groups.
  • R2 l is a monovalent radical, such as a hydrogen atom, a normal or branched, saturated or unsaturated C1-C18-alkyl group, a C3-C10-cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. The aryl group is preferably a phenyl or naphthyl group. The heteroaryl group is a 5- or 6-membered, preferably nitrogen-, oxygen- or sulfur-containing, ring system, such as, for example, a heteroaryl group derived from imidazole, isoxazole, isothiazole, thiazole, oxazole, pyrazole, thiophene, furan, pyrrole, 1,2,4- or 1,2,3-triazole, pyrazine, indole, benzofuran, benzothiophene, indole, isoindole, indazole, quinoline, pyridazine, pyrimidine, benzimidazole, benzopyran, benzothiazole, oxadiazole, thiadiazole or pyridine. Suitable aryl substituents include one or more halogen, preferably fluorine, bromine or chlorine, atoms, C1-C4-alkyl groups, methoxy, ethoxy or trifluoromethyl groups, a dioxymethylene group or nitro groups.
  • R2 l can, alternately, be of Formula IIr,
  • Figure US20130046077A1-20130221-C00020
  • where al is an integer, such as 0, 1, 2, 3, 4 or 5. R3 t is a monovalent radical, preferably a lower alkyl group, such as a methyl, ethyl, propyl or isopropyl group. R4 l is a monovalent radical, which can be a saturated or partially unsaturated carbocyclic system comprising from about 3 to about 10 carbon atoms, a substituted or unsubstituted aryl or heteroaryl group, with aryl and heteroaryl and preferred substituents having the meaning stated for R2 l in Formula IIl.
  • R2 l can also be a substituent of Formula IIIr,

  • —(CH2)2—Wl—R5 l  (IIIr),
  • wherein Wl is an oxygen or sulfur atom or an N—R6 l group. R5 l is a monovalent radical, such as a hydrogen atom, a C1-C4-alkyl or C3-C7-cycloalkyl group or a substituted or unsubstituted aryl or arylmethyl group, with aryl and its preferred substituents having the meaning stated for R2 l from Formula IIl. R6 l is a monovalent radical, preferably a hydrogen atom, a C1-C4-alkyl group or a C3-C7-cycloalkyl group, a C1-C18-alkanoyl group, a benzoyl group or a substituted or unsubstituted aryl or arylmethyl group, with aryl and its preferred substituents having the meaning stated for R2 l in Formula IIl.
  • R2 l can, alternately, be a substituent of Formula IVr,

  • —(CH2)b l —Zl  (IVr),
  • where bl is an integer, preferably 2, 3 or 4. Zl can be a monovalent radical such as a formyl, aminocarbonyl or hydrazinocarbonyl group, or a cyclic or acyclic acetal or thioacetal group.
  • R2 l can also be a substituent of Formula Vr,
  • Figure US20130046077A1-20130221-C00021
  • in which bl has the above-mentioned meaning. R7 l can be a monovalent radical, such as a polyglycol group of the formula —O—(CH2—CH2—O)d l —CH3, where dl is an integer; preferably in the range from about 2 to about 4 or from about 40 to about 90.
  • R2 l can further be a carbohydrate of Formula VIr,
  • Figure US20130046077A1-20130221-C00022
  • where R2 l is a monovalent radical, such as a hydrogen atom, a C1-C4-alkanoyl or alkyl group, a benzoyl group or a benzyl group.
  • L can also be a β-hydroxylamino group of Formula IIIl,
  • Figure US20130046077A1-20130221-C00023
  • where R2 l is a monovalent radical such as a hydrogen atom, a C1-C6-alkyl group or a substituted or unsubstituted aryl group, with aryl and its preferred substituents having the meaning stated for R2 l-R10 l is a monovalent radical, preferably a hydrogen atom, alkyl, for example, methyl, or a phenyl group.
  • When r and/or s is l, L can also be an amino group of Formula IVl,
  • Figure US20130046077A1-20130221-C00024
  • where R2 l and R4 l are each a monovalent radical. R2 l and R4 l can also be linked by a carbon-carbon bond.
  • Another subclass of compounds of this invention includes peptides of Formula I wherein L is a hydrazido group of Formula Vl,
  • Figure US20130046077A1-20130221-C00025
  • and R11 l is a monovalent radical, preferably a hydrogen atom. R12 l can be a monovalent radical such as a hydrogen atom, a normal or branched C1-C8-alkyl group, a C1-C3-cycloalkyl group, a C3-C8-cycloalkyl-C1-C4-alkyl group or a substituted or unsubstituted aryl, heteroaryl, aryl-C1-C4-alkyl or heteroaryl-C1-C4-alkyl group, where aryl, heteroaryl and their preferred substituents can be selected from among the options listed for R2 l.
  • When r and/or s is l, R11 l can also be selected from among the options listed above for R12 l, and the two radicals together can additionally form a propylene or butylene bridge.
  • Another subclass of compounds of this invention includes peptides of Formula I wherein L is a monovalent radical of the formula —O—R13 l or the formula —S—R13 l, where R13 l is a monovalent radical, such as a C3-C10-cycloalkyl group, a normal or branched C2-C16-alkenylmethyl group or a C1-C16-alkyl group which can be substituted by from 1 to about 5 halogen, preferably fluorine, atoms.
  • R13 l can also be the radical —(CH2)e—R14 l, where e is an integer, preferably 1, 2 or 3. R14 l is a monovalent radical, preferably a saturated or partially unsaturated C3-C11-carbocycle.
  • R13 l can further be the monvalent radical —[CH2—CH═C(CH3)—CH2]l—H, where f is an integer, preferably 1, 2, 3 or 4.
  • R13 l can also be the radical —[CH, —CH2—O]g—CH3, where g is an integer, preferably in the range from 1 to about 5.
  • R13 l can also be the radical —(CH2)h-aryl or —(CH2)h-heteroaryl, where aryl and heteroaryl can also be substituted and, along with their preferred substituents, can be selected from the group listed for R2 l. h is an integer, preferably 0, 1, 2 or 3.
  • R13 l can further be the radical —(CH2)b—Wl—R5 l. b, Wl and R5 l can each be selected from among the options described for Formula IVl.
  • Another subclass of compounds of this invention includes peptides of Formula I in which L is an aminoxy group of the formula —O—N(R15 l)(R16 l), where R15 l and R16 l are each a monovalent radical, which can independently be a hydrogen atom, a normal or branched C1-C8-alkyl group, which can be substituted by halogen, preferably fluorine, atoms, a C3-C8-cycloalkyl group, a C3-C8-cycloalkyl-C1-C4-alkyl group, a substituted or unsubstituted aryl or heteroaryl group or a substituted or unsubstituted aryl-C1-C4-alkyl group. Aryl and heteroaryl groups and the preferred substituents thereof can be selected from the options listed for R2 l. R16 l can be selected from among the options listed for R15 l. Additionally, R15 l and R16 l can together form a 5-, 6- or 7-membered heterocycle. The compounds of the present invention further comprise the salts of the compounds described above with physiologically tolerated acids.
  • Another subclass of compounds of this invention includes peptides of Formula I wherein L is an oximato group of the formula —O—N═C(R15 l)(R16 l), R15 l and R16 l can be selected from among the options listed above and, additionally, can together form a cyclic system comprising, preferably, from about 3 to about 7 ring atoms. This cyclic system can additionally be fused to one or more aromatic rings. Particularly preferred cyclic systems are shown below.
  • Figure US20130046077A1-20130221-C00026
  • In one embodiment, the invention provides compounds of Formula I wherein A is an amino acid derivative selected from among N-alkyl-D-prolyl, N-alkyl-L-prolyl, N-alkyl-D-piperidine-2-carbonyl, N-alkyl-L-piperidine-2-carbonyl, N,N-dialkyl-D-2-ethyl-2-phenylglycyl and N,N-dialkyl-L-2-ethyl-2-phenylglycyl, wherein alkyl is methyl, ethyl or isopropyl; and 13 is a valyl, isoleucyl or 2-t-butyl-L-glycyl residue.
  • Preferred compounds of the invention include compounds of Formula I wherein r and s are each 0. A is an amino acid derivative selected from among D-N-methyl-piperidine-2-carbonyl, L-N-methyl-piperidine-2-carbonyl, N,N-dimethylamino-iso-butyryl, N-methyl-L-prolyl, N-methyl-L-thiazolidine-4-carbonyl, N,N-dimethyl-glycyl, L-prolyl, L-piperidine-2-carbonyl, N-propyl-D-piperidine-2-carbonyl, D-piperidine-2-carbonyl, N-ethyl-D-piperidine-2-carbonyl, N-methyl-[2,2,5,5-tetramethyl]-L-thiazolidine-2-carbonyl, N-isopropyl-D-piperidine-2-carbonyl, N,N-dimethyl-2-cyclopropylglycyl, N,N-dimethyl-L-2-ethyl-2-phenylglycyl, N,N-dimethyl-D-2-ethyl-2-phenylglycyl, D-prolyl, N-methyl-D-prolyl, N,N-dimethyl-2-(2-fluorophenyl)glycyl, 1-aza-[3,3,0]bicyclooctyl-5-carbonyl, N,N-dimethyl-2-[4-fluoro]phenyl-glycyl, N-methyl-[2,2,5,5-tetrameramethyl]-thiazolidine-2-carbonyl, 2-(R,S)-ethyl-2-phenylglycyl, D,L-1-aminoindane-1-carbonyl, N,N-dimethyl-2-(R,S)-methyl-2-phenylglycyl, 2-[N,N-dimethylamino]indane-2-carbonyl, 5-[N,N-dimethylamino]-5,6,7,8-tetrahydro-naphthalene-5-carbonyl, N-isopropyl-2-(R,S)-ethyl-2-phenylglycyl, 1-[N,N-dimethyl-amino]indane-2-carbonyl, N,N-dimethyl-2-propyl-2-phenylglycyl, N,N-dimethyl-2-[4-methoxy]phenyl-glycyl, N-methyl-3-hydroxy-D,L-valyl, N,N-dimethyl-D,L-2-isopropyl-2-phenylglycyl, N-methylpiperidine-2-carbonyl, N-methyl-L-prolyl, N-methyl-1,2,3,4-tetrahydroisoquinoline-1-carbonyl, N-methylazetidine-2-carbonyl, N-isopropylazetidine-2-carbonyl, N,N-dimethyl-[O-methyl]seryl, N,N-dimethyl-[O-methyl]threonyl, N-methyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl, 1-[N,N-dimethylamino]cyclohexyl-1-carbonyl, 1-[N,N-dimethylamino]cyclopentyl-1-carbonyl and 1,2,3,4-tetrahydroisoquinoline-3-carbonyl. B is valyl, isoleucyl or 2-tert-butylglycyl. D is N-methylvalyl, N-methyl-2-t-butylglycyl or N-methylisoleucyl. E and F are each, independently, prolyl, thiaprolyl, homoprolyl, hydroxyprolyl, 3,4-didehydroprolyl, 4-fluoroprolyl, and 3-methylprolyl. L is an alkoxy group or an amino group of the formula R1 l—N—R2 l, wherein R1 l and R2 l are independently selected from the group consisting of hydrogen, alkoxy, hydroxy, alkyl and alkylaryl.
  • In a particularly preferred subset of the compounds of the invention, r and s are each 0. A is an amino acid derivative selected from among D-N-methyl-piperidine-2-carbonyl, N-ethyl-D-piperidine-2-carbonyl, N-isopropyl-D-piperidine-2-carbonyl, N,N-dimethyl-2-cyclopropyl-glycyl, N-methyl-D-prolyl, L-aza-[3,3,0]bicyclooctyl-5-carbonyl, N-methyl-[2,2,5,5-tetramethyl]-thiazolidine-2-carbonyl, 2-(R,S)-ethyl-2-phenylglycyl, D,L-1-aminoindane-1-carbonyl, N,N-dimethyl-2-(R,S)-methyl-2-phenylglycyl, 5-[N,N-dimethylamino]-5,6,7,8-tetrahydro-naphthalene-5-carbonyl, 1-[N,N-dimethylamino]indane-2-carbonyl, N,N-dimethyl-2-propyl-2-phenylglycyl, N,N-dimethyl-L-2-ethyl-2-phenylglycyl, N,N-dimethyl-D-2-ethyl-2-phenylglycyl, N-methyl-3-hydroxy-D,L-valyl, N,N-dimethyl-D,L-2-isopropyl-2-phenylglycyl, N-methyl-piperidine-2-carbonyl, N-methyl-D,L-prolyl, N-methyl-1,2,3,4-tetra-hydroisoquinoline-1-carbonyl, N-methylazetidine-2-carbonyl, N-isopropylazetidine-2-carbonyl, N,N-dimethyl-[O-methyl]seryl, 1-[N,N-dimethylamino]cyclohexyl-1-carbonyl and L-[N,N-dimethylamino]cyclopentyl-1-carbonyl. B is valyl; D is N-methylvalyl; and E and F are each prolyl. L is a C1-C6-alkoxy group or an amino group of the formula R1 l—N—R2 l, wherein R1 l and R2 l are each independently selected from the group consisting of hydrogen, C1-C6-alkoxy, hydroxy, normal, cyclic or branched C1-C12-alkyl, and phenylalkyl.
    • Synthetic Methods
  • The compounds of the present invention can be prepared by known methods of peptide synthesis. Thus, the peptides can be assembled sequentially from individual amino acids or by linking suitable small peptide fragments. In sequential assembly, the peptide chain is extended stepwise, starting at the C-terminus, by one amino acid per step. In fragment coupling, fragments of different lengths can be linked together, and the fragments in turn can be obtained by sequential assembly from amino acids or by fragment coupling of still shorter peptides.
  • In both sequential assembly and fragment coupling it is necessary to link the units by forming an amide linkage, which can be accomplished via a variety of enzymatic and chemical methods. Chemical methods for forming the amide linkage are described in detail in standard references on peptide chemistry, including Miller, Methoden der organischen Chemie Vol. XV/2, 1-364, Thieme Verlag, Stuttgart, (1974); Stewart and Young, Solid Phase Peptide Synthesis, 31-34 and 71-82, Pierce Chemical Company, Rockford, Ill. (1984); Bodanszky et al., Peptide Synthesis, 85-128, John Wiley & Sons, New York, (1976). Preferred methods include the azide method, the symmetric and mixed anhydride method, the use of in situ generated or preformed active esters, the use of urethane protected N-carboxy anhydrides of amino acids and the formation of the amide linkage using coupling reagents, such as carboxylic acid activators, especially dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), pivaloyl chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), n-propanephosphonic anhydride (PPA), N,N-bis(2-oxo-oxazolidinyl)amidophosphoryl chloride (BOP—Cl), bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBrop), diphenyl-phosphoryl azide (DPPA), Castro's reagent (BOP, PyBop), O-benzotriazolyl-N,N,N′,N′-tetramethyluronium salts (HBTU), O-azabenzotriazolyl-N,N,N′,N′-tetramethyluronium salts (HATU), diethylphosphoryl cyanide (DEPCN), 2,5-diphenyl-2,3-dihydro-3-oxo-4-hydroxythiophene dioxide (Steglich's reagent; HOTDO), and 1,1-carbonyldi-imidazole (CDI). The coupling reagents can be employed alone or in combination with additives such as N,N-dimethyl-4-aminopyridine (DMAP), N-hydroxy-benzotriazole (HOBt), N-hydroxyazabenzotriazole (HOAt), N-hydroxybenzotriazine (HOOBt), N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine.
  • Although the use of protecting groups is generally not necessary in enzymatic peptide synthesis, reversible protection of reactive groups not involved in formation of the amide linkage is necessary for both reactants in chemical synthesis. Three conventional protective group techniques are preferred for chemical peptide synthesis: the benzyloxycarbonyl (Z), the t-butoxycarbonyl (Boc) and the 9-fluorenylmethoxy-carbonyl (Fmoc) techniques. Identified in each case is the protective group on the α-amino group of the chain-extending unit. A detailed review of amino-acid protective groups is given by Müller, Methoden der organischen Chemie Vol. XV/1, pp 20-906, Thieme Verlag, Stuttgart (1974). The units employed for assembling the peptide chain can be reacted in solution, in suspension or by a method similar to that described by Merrifield, J. Am. Chem. Soc. 85: (1963) 2149.
  • Solvents suitable for peptide synthesis include any solvent which is inert under the reaction conditions, especially water, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dichloromethane (DCM), 1,4-dioxane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP) and mixtures of these solvents.
  • Peptide synthesis on the polymeric support can be carried out in a suitable inert organic solvent in which the amino acid derivatives starting materials are soluble. However, preferred solvents additionally have resin-swelling properties, such as DMF, DCM, NMP, acetonitrile and DMSO, and mixtures of these solvents. Following synthesis, the peptide is removed from the polymeric support. The conditions under which this cleavage is accomplished for various resin types are disclosed in the literature. The cleavage reactions most commonly used are acid- or palladium-catalyzed, the former being conducted in, for example, liquid anhydrous hydrogen fluoride, anhydrous trifluoromethanesulfonic acid, dilute or concentrated trifluoroacetic acid, and acetic acid/dichloromethane/trifluoroethanol mixtures. The latter can be carried out in THF or THF-DCM-mixtures in the presence of a weak base, such as morpholine. Certain protecting groups are also cleaved off under these conditions.
  • Partial deprotection of the peptide may also be necessary prior to certain derivatization reactions. For example, peptides dialkylated at the N-terminus can be prepared by coupling the appropriate N,N-di-alkylamino acid to the peptide in solution or on the polymeric support, by reductive alkylation of the resin-bound peptide in DMF/1% acetic acid with NaCNBH3 and the appropriate aldehyde or by hydrogenation of the peptide in solution in the presence of the appropriate aldehyde or ketone and Pd/carbon.
  • The various non-naturally occurring amino acids as well as the various non-amino acid moieties disclosed herein can be obtained from commercial sources or synthesized from commercially available staring materials using methods known in the art. For example, amino acid building blocks with R1 and R2 groups can be prepared according to the method described by Wuensch and Weyl, Methoden der Organische Chemie, vol. XV, Springer Verlag: Stuttgart, p. 306 (1974) and references cited therein.
    • Methods of Use of the Claimed Compounds
  • In another embodiment, the present invention comprises a method for partially or totally inhibiting formation of, or otherwise treating (e.g., reversing or inhibiting the further development of) solid tumors (e.g., tumors of the lung, breast, colon, prostate, bladder, rectum, or endometrial tumors) or hematological malignancies (e.g., leukemias, lymphomas) in a mammal, for example, a human, by administering to the mammal a therapeutically effective amount of a compound or a combination of compounds of Formula I. The compound(s) may be administered alone or in a pharmaceutical composition comprising the compound(s) and an acceptable carrier or diluent. Administration can be by any of the means which are conventional for pharmaceutical, preferably oncological, agents, including oral and parenteral means, such as subcutaneously, intravenously, intramuscularly and intraperitoneally, nasally or rectally. The compounds may be administered alone or in the form of pharmaceutical compositions containing a compound or compounds of Formula I together with a pharmaceutically accepted carrier appropriate for the desired route of administration. Such pharmaceutical compositions may be combination products, i.e., they may also contain other therapeutically active ingredients.
  • The dosage to be administered to the mammal, such as a human, will contain a therapeutically effective amount of a compound described herein. As used herein, “therapeutically effective amount” is an amount sufficient to inhibit (partially or totally) formation of a tumor or a hematological malignancy or to reverse development of a solid tumor or other malignancy or prevent or reduce its further progression. For a particular condition or method of treatment, the dosage is determined empirically, using known methods, and will depend upon factors such as the biological activity of the particular compound employed; the means of administration; the age, health and body weight of the recipient; the nature and extent of the symptoms; the frequency of treatment; the administration of other therapies; and the effect desired. A typical daily dose will be from about 0.05 to about 50 milligrams per kilogram of body weight by oral administration and from about 0.01 to about 20 milligrams per kilogram of body weight by parenteral administration.
  • The compounds of the present invention can be administered in conventional solid or liquid pharmaceutical administration forms, for example, uncoated or (film-) coated tablets, capsules, powders, granules, suppositories or solutions. These are produced in a conventional manner. The active substances can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, sustained release compositions, antioxidants and/or propellant gases (cf. H. Sücker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way typically contain from about 1 to about 90% by weight of the active substance.
  • The present invention will now be illustrated by the following examples, which are not limiting.
    • EXAMPLES
  • The proteinogenous amino acids are abbreviated in the examples using the known three-letter code. Other abbreviations employed are: TFA=trifluoroacetic acid, Ac=acetic acid, DCM=dichloromethane, DMSO=dimethylsulfoxide, Bu=butyl, Et=ethyl, Me=methyl, Bzl=benzyl. In the compounds listed, all proteinogenous amino acids are L-amino acids unless otherwise noted. Other abbreviations used: Me2Val=N,N-dimethylvaline, MeVal=N-methylvaline, Bn=benzyl, Me2Aib=[2-N,N-dimethylamino]-isobutyric acid.
    • General Procedures
  • The peptides of the invention are synthesized either by classical solution synthesis using standard Z- and Boc-methodology as described above or by standard methods of solid-phase synthesis using Boc and Fmoc protective group techniques.
  • In the case of solid phase synthesis, the N,N-dialkyl-penta- or hexapeptide acids are liberated from the solid support and further coupled with the corresponding C-terminal amines in solution. BOP—Cl and PyBrop were used as reagents for coupling of the amino acid following the N-methylamino acids. The reaction times were correspondingly increased. For reductive alkylation of the N-terminus, the peptide-resin was deprotected at the N terminus and then reacted with a 3-fold molar excess of aldehyde or ketone in DMF/1% acetic acid with addition of 3 equivalents of NaCNBH3. After the reaction was complete (negative Kaiser test) the resin was washed several times with water, isopropanol, DMF and dichloromethane.
  • In solution synthesis, the use of either Boc-protected amino acid NCAs (N-tert.-butyloxycarbonyl-amino acid-N-carboxy-anhydrides), Z-protected amino acid NCAs (N-benzyloxycarbonyl-amino acid-N-carboxy-anhydrides), or the use of pivaloyl chloride as condensing agent respectively is most advantageous for coupling of the amino acid following the N-methylamino acids. Reductive alkylation of the N terminus can e.g. be achieved by reaction of the N-terminally deprotected peptides or amino acids with the corresponding aldehydes or ketones using NaCNBH3 or hydrogen-Pd/C.
  • Valyl-N-methylvalyl-prolyl-prolylbenzylamide hydrochloride for example was prepared according to methods disclosed in German Patent Application No. DE 19527575 A1.
    • Purification and Characterization of the Peptides
  • Peptide purification was carried out by gel chromatography (SEPHADEX G-10, G-15/10% HOAc, SEPHADEX LH20/MeOH), medium pressure chromatography (stationary phase: HD-SIL C-18, 20-45 micron, 100 Angstrom; mobile phase: gradient with A=0.1% TFA/MeOH, B=0.1% TFA/water), preparative HPLC (stationary phase: Waters Delta-Pak C-18, 15 micron, 100 Angstrom; mobile phase: gradient with A=0.1% TFA/MeOH, B=0.1% TFA/water), or by crystallization.
  • The purity of the resulting products was determined by analytical HPLC (stationary phase: 100 2.1 mm VYDAC C-18, 5 micron, 300 A; mobile phase: acetonitrile-water gradient, buffered with 0.1% TFA, 40° C.; or 3.9 mm VYDAC C-18, 30° C.). Characterization was by fast atom bombardment mass spectroscopy and NMR-spectroscopy.
    • Example 1 Synthesis of [N-Methyl-L-piperidine-2-carbonyl]-Val-MeVal-Pro-Pro-NHBn (Compound 1) and [N-Methyl-D-piperidine-2-carbonyl]-Val-MeVal-Pro-Pro-NHBn (Compound 2) Preparation of N-methyl-piperidine-2-carboxylic acid
  • N-Methyl-piperidine-2-carboxylic acid ethyl ester (5.1 g) was dissolved in a mixture of 100 ml methanol and 10 ml water. NaOH (8 g) was added and the reaction mixture was stirred at room temperature overnight. The solution was then neutralized with hydrochloric acid, evaporated to dryness, and evaporated four times with toluene. The resulting powdery residue was used directly in the next step.
    • Preparation of [N-Methyl-piperidine-2-carbonyl]-Val-MeVal-Pro-Pro-NHBn
  • The residue prepared as described above (5.05 g) and H-Val-MeVal-Pro-Pro-NHBn×HCl (4.88 g) were dissolved in 50 ml dry DMF. After cooling the solution in an ice bath, 1.52 g DEPCN and 2.66 ml triethylamine were added. The reaction mixture was stirred at 0° C. for 2 h and then at room temperature overnight. The DMF was removed by evaporation under reduced pressure. The residue was diluted with dichloromethane and the organic phase was washed with aqueous hydrochloric acid (pH 2) and water, dried over sodium sulfate and evaporated to dryness. The diastereomeric mixture was then separated by flash chromatography with a gradient using heptane/ethyl acetate and dichloromethane/methanol. Under the HPLC conditions described in the previous section (C-18 reverse phase) isomer 1 has a retention time of 14.9 minutes, and isomer 2 has a retention time of 15.8 minutes. Both isomers were characterized by fast atom bombardment mass spectrometry ([M+H]+=639).
    • Example 2 Preparation of Me2Aib-Val-MeVal-Pro-Pro-NHBn (Compound 3) Preparation of 2-[N,N-dimethylamino]-isobutyric acid
  • 2-Amino-isobutyric acid (10.3 g) was dissolved in 200 ml methanol. After addition of 25 ml aqueous formaldehyde and 1 g 10% Pd/C, the reaction mixture was hydrogenated overnight at room temperature. The catalyst was filtered, and the filtrate was evaporated to dryness. The residue was crystallized from isopropanal to give 4.8 g of the desired product.
    • Preparation of Me2Aib-Val-MeVal-Pro-Pro-NHBn×HCl
  • 2-[N,N-Dimethylamino]-isobutyric acid (1.3 g, 10 mmol) and 5.5 g (10 mmol) H-Val-MeVal-Pro-Pro-NHBn×HCl were dissolved in 50 ml dry DMF. After cooling to 0° C., 1.6 g DEPCN (10 mmol) and 2.9 ml triethylamine were added to the reaction mixture. The resulting mixture was stirred at 0° C. for 2 h and at room temperature overnight. Ice water (50 mL) was then added, and the resulting mixture was extracted twice with diethyl ether. The ether extracts were washed with 1 N NaOH (1×) and aqueous NaCl (3×), then dried over sodium sulfate and evaporated to dryness under reduced pressure. The product was crystallized from 100 ml diethyl ether with HCl/ether, and recrystallized from acetone to give 1.2 g of the desired product, which was characterized by fast atom bombardment mass spectrometry ([M+H]+=627).
    • Example 3 Preparation of [N,N-dimethyl-2-ethyl-2-phenylglycyl]-Val-MeVal-Pro-Pro-NHBn×HCl (Compound 4) Preparation of [N,N-dimethyl-2-ethyl-2-phenylglycyl]-Val-MeVal-Pro-Pro-NHBn×HCl
  • 2.07 g (10 mmol) N,N-Dimethyl-2-ethyl-2-phenylglycine and 5.5 g (10 mmol) H-Val-MeVal-Pro-Pro-NHBn×HCl were dissolved in 100 ml dry DMF. After cooling to 0° C., 1.6 g DEPCN (10 mmol) and 2.9 ml triethylamine were added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature overnight, then worked up as described above. The crude product was crystallized from diethyl ether with HCl/ether to give 4 g of the desired product, which was characterized by fast atom bombardment mass spectrometry ([M+H]+=703).
    • Example 4 Preparation of [N-Methyl-D-Pro]-Val-MeVal-Pro-Pro-NHBn (Compound 5) Preparation of Z-D-Pro-Val-MeVal-Pro-Pro-NHBn
  • 3.74 g Z-D-Pro-OH (15 mmol, BACHEM) and 8.25 g H-Val-MeVal-Pro-Pro-NHBn×HCl (15 mmol) were dissolved in 80 ml dry DMF. After cooling to 0° C., 2.4 g DEPCN (2.25 ml, 15 mmol) and 4.2 ml triethylamine (30 mmol) were added. The reaction mixture was stirred at 0° C. for several hours and room temperature overnight, then the DMF was evaporated under reduced pressure. The residue was diluted with ethyl acetate and thoroughly washed with dilute aqueous HCl (pH 2), water, dilute aqueous NaOH (pH 9-10), and water. The organic phase was dried over sodium sulfate and evaporated to dryness to yield 9.2 g of the desired protected pentapeptide.
    • Preparation of D-Pro-Val-MeVal-Pro-Pro-NHBn×HCl
  • 8.2 g (11 mmol) Z-D-Pro-Val-MeVal-Pro-Pro-NHBn was dissolved in 70 ml methanol. After addition of 0.7 ml concentrated hydrochloric acid and 0.3 g 10% Palladium/charcoal to the solution, the resulting mixture was hydrogenated. Filtration and evaporation of the solvent gave a residue which was dissolved in water, adjusted to pH 2 and extracted twice with ethyl acetate. The aqueous phase was adjusted to pH 9-10 and extracted twice with dichloromethane. The organic extracts were evaporated and the residue was redissolved in diethylether and crystallized by addition of HCl/ether as the hydrochloride salt to give 6.5 g of the desired product.
    • Preparation of [N-methyl-D-Pro]-Val-MeVal-Pro-Pro-NHBn×HCl
  • 1.94 g (3 mmol) of D-Pro-Val-MeVal-Pro-Pro-NHBn×HCl was dissolved in 30 ml methanol. To this solution was then added 0.3 g 10% Pd/charcoal and 1.5 ml aqueous formaldehyde solution and the reaction mixture was hydrogenated. Following filtration and evaporation of the solvents, the resulting residue was dissolved in water, adjusted to pH 2 and extracted twice with diethyl ether and several additional times with dichloromethane. The aqueous phase was adjusted to pH 9-10 and extracted twice with dichloromethane. The organic extracts were dried over sodium sulfate and evaporated to dryness. The residue was crystallized as the hydrochloride salt to give 0.5 g of the desired product which was characterized by fast atom bombardment mass spectrometry ([M+H]+=625).
  • The compounds listed in Table 1 were prepared according to the methods described in Examples 1-4. Where compounds are referred to as “isomer 1” or “isomer 2”, isomer 1 is the diastereomer with the shorter retention time on the reversed phase analytical HPLC system. Fast atom bombardment-mass spectrometry results for selected compounds are provided in Table 2.
  • TABLE 1
    Compound No. Compound
    6 Xah Val Xaa Pro Xab
    7 Xai Val Xaa Pro Xab
    8 Xae Val Xaa Pro Xab
    9 Xad Val Xaa Pro Xbr
    10 Xam Val Xaa Pro Xab
    11 Xaw Ile Xaa Pro Xbx
    12 Xao Val Xaa Pro Xab
    13 Xad Val Xaa Pro Xap
    14 Xaq Val Xaa Pro Xab
    15 Xar Val Xaa Pro Xab
    16 Xas Val Xaa Pro Xab
    17 Xat Val Xaa Pro Xab isomer 1
    18 Xat Val Xaa Pro Xab isomer 2
    19 Xaf Val Xaa Pro Xab
    20 Xav Val Xaa Pro Xab
    21 Xag Val Xaa Pro Xab
    22 Xax Val Xaa Pro Xab isomer 1
    23 Xax Val Xaa Pro Xab isomer 2
    24 Xay Val Xaa Pro Xab
    25 Xaz Val Xaa Pro Xab isomer 1
    26 Xaz Val Xaa Pro Xab isomer 2
    27 Xba Val Xaa Pro Xab
    28 Xbb Val Xaa Pro Xab
    29 Xbc Val Xaa Pro Xab
    30 Xbd Val Xaa Pro Xab isomer 1
    31 Xbd Val Xaa Pro Xab isomer 2
    32 Xbe Val Xaa Pro Xab isomer 1
    33 Xbe Val Xaa Pro Xab isomer 2
    34 Xbf Val Xaa Pro Xab isomer 1
    35 Xbg Val Xaa Pro Xab
    36 Xbh Val Xaa Pro Xab isomer 1
    37 Xbh Val Xaa Pro Xab isomer 2
    38 Xbi Val Xaa Pro Xab isomer 1
    39 Xbi Val Xaa Pro Xab isomer 2
    40 Xbk Val Xaa Pro Xab isomer 1
    41 Xbk Val Xaa Pro Xab isomer 2
    42 Xbl Val Xaa Pro Xab
    43 Xbf Val Xaa Pro Xab isomer 2
    44 Xbm Val Xaa Pro Xab
    45 Xaw Val Xaa Pro Xbn
    46 Xbo Val Xaa Pro Xbn isomer 1
    47 Xbo Val Xaa Pro Xbn isomer 2
    48 Xaw Val Xaa Pro Xbp
    49 Xbo Val Xaa Pro Xbp isomer 1
    50 Xbo Val Xaa Pro Xbp isomer 2
    51 Xaw Val Xaa Pro Xbq
    52 Xaw Val Xaa Pro Xbr
    53 Xbs Val Xaa Pro Xbt isomer 1
    54 Xbl Val Xaa Pro Xab isomer 1
    55 Xbl Val Xaa Pro Xab isomer 2
    56 Xbu Val Xaa Pro Xab isomer 1
    57 Xbv Val Xaa Pro Xab
    58 Xbw Val Xaa Pro Xab isomer 1
    59 Xbw Val Xaa Pro Xab isomer 2
    60 Xbs Val Xaa Pro Xbt isomer 2
    61 Xbu Val Xaa Pro Xab isomer 2
    62 Xbo Val Xaa Pro Xbr isomer 1
    63 Xbo Val Xaa Pro Xbr isomer 2
    64 Xbo Val Xaa Pro Xbq isomer 1
    65 Xbo Val Xaa Pro Xbq isomer 2
    66 Xaw Val Xaa Pro Xbx
    67 Xby Val Xaa Pro Xab
    68 Xbz Val Xaa Pro Xab
    69 Xca Val Xaa Pro Xab isomer 1
    70 Xca Val Xaa Pro Xab isomer 2
    71 Xbo Val Xaa Pro Xbx isomer 1
    72 Xbo Val Xaa Pro Xbx isomer 2
    73 Xau Val Xaa Pro Xbp
    74 Xau Val Xaa Pro Xbx
    75 Xbi Val Xaa Pro Xbx isomer 2
    76 Xau Val Xaa Pro Xab isomer 1
    77 Xau Val Xaa Pro Xab isomer 2
    78 Xau Val Xaa Pro Xcb
    79 Xbi Val Xaa Pro Xcb isomer 1
    80 Xbi Val Xaa Pro Xcb isomer 2
    81 Xbi Val Xaa Pro Xcc isomer 1
    82 Xbi Val Xaa Pro Xcc isomer 2
    83 Xbi Val Xaa Pro Xcd
    84 Xbk Val Xaa Pro Xcc isomer 1
    85 Xbk Val Xaa Pro Xcc isomer 2
    86 Xax Val Xaa Pro Xbp isomer 1
    87 Xax Val Xaa Pro Xbp isomer 2
    88 Xbk Val Xaa Pro Xcb isomer 1
    89 Xbk Val Xaa Pro Xcb isomer 2
    90 Xau Val Xaa Pro Xcc
    91 Xau Val Xaa Pro Xcd
    92 Xba Val Xaa Pro Xcb isomer 1
    93 Xba Val Xaa Pro Xcb isomer 2
    94 Xbo Val Xaa Pro Xbp isomer 1
    95 Xbo Val Xaa Pro Xbp isomer 2
    96 Xau Val Xaa Pro Xbp isomer 1
    97 Xau Val Xaa Pro Xbp isomer 2
    98 Xbi Val Xaa Pro Xcd isomer 2
    99 Xbk Val Xaa Pro Xcd
    100 Xba Val Xaa Pro Xbp isomer 1
    101 Xba Val Xaa Pro Xbp isomer 2
    102 Xba Val Xaa Pro Xcc isomer 1
    103 Xba Val Xaa Pro Xcc isomer 2
    104 Xba Val Xaa Pro Xcd
    105 Xce Val Xaa Pro Xab
    106 Xcf Val Xaa Pro Xab
    107 Xcg Val Xaa Pro Xab isomer 1
    108 Xcg Val Xaa Pro Xab isomer 2
    109 Xaw Val Xaa Pro Xch
    110 Xaw Val Xaa Pro Xci
    111 Xaw Val Xaa Pro Xck
    112 Xaw Val Xaa Pro Xcl
    113 Xaw Val Xaa Pro Xcm
    114 Xaw Val Xaa Pro Xcn
    115 Xaw Val Xaa Pro Xco
    116 Xaw Val Xaa Pro Xcp
    117 Xaw Val Xaa Pro Xcq
    118 Xaw Val Xaa Pro Xcr
    119 Xad Val Xaa Pro Xch
    120 Xad Val Xaa Pro Xci
    121 Xad Val Xaa Pro Xck
    122 Xad Val Xaa Pro Xcl
    123 Xad Val Xaa Pro Xcm
    124 Xad Val Xaa Pro Xcn
    125 Xad Val Xaa Pro Xco
    126 Xad Val Xaa Pro Xcp
    127 Xad Val Xaa Pro Xcq
    128 Xad Val Xaa Pro Xcr
    129 Xad Val Xaa Pro Xbx
    130 Xau Val Xaa Pro Xch
    131 Xau Val Xaa Pro Xci
    132 Xau Val Xaa Pro Xck
    133 Xau Val Xaa Pro Xcl
    134 Xau Val Xaa Pro Xcm
    135 Xau Val Xaa Pro Xcn
    136 Xau Val Xaa Pro Xco
    137 Xau Val Xaa Pro Xcp
    138 Xau Val Xaa Pro Xcq
    139 Xau Val Xaa Pro Xcr
    140 Xau Val Xaa Pro Xbr
    141 Xad Val Xaa Xal Xbx
    142 Xau Val Xaa Xal Xbx
    143 Xaw Val Xaa Xal Xbx
    144 Xad Val Xaa Xal Xch
    145 Xau Val Xaa Xal Xch
    146 Xaw Val Xaa Xal Xch
    147 Xad Val Xaa Xal Xcr
    148 Xau Val Xaa Xal Xcr
    149 Xaw Val Xaa Xal Xcr
    150 Xad Val Xaa Xan Xbx
    151 Xau Val Xaa Xan Xbx
    152 Xaw Val Xaa Xan Xbx
    153 Xad Val Xaa Xan Xch
    154 Xau Val Xaa Xan Xch
    155 Xaw Val Xaa Xan Xch
    156 Xad Val Xaa Xan Xcr
    157 Xau Val Xaa Xan Xcr
    158 Xaw Val Xaa Xan Xcr
    159 Xau Ile Xaa Pro Xbx
    160 Xad Ile Xaa Pro Xbx
    161 Xaw Ile Xaa Pro Xch
    162 Xad Ile Xaa Pro Xch
    163 Xau Ile Xaa Pro Xch
    164 Xaw Xcs Xaa Pro Xch
    165 Xad Xcs Xaa Pro Xch
    166 Xau Xcs Xaa Pro Xch
    167 Xaw Xcs Xaa Pro Xbx
    168 Xad Xcs Xaa Pro Xbx
    169 Xau Xcs Xaa Pro Xbx
    170 Xaw Val Xct Pro Xch
    171 Xad Val Xct Pro Xch
    172 Xau Val Xct Pro Xch
    173 Xaw Val Xct Pro Xbx
    174 Xad Val Xct Pro Xbx
    175 Xau Val Xct Pro Xbx

    The symbols Xaa in Table 1 represent the following amino acids or residues thereof:
    • Xaa: N-methyl-valine Xab: Prolyl N-benzylamide
  • Xac: L-N-methyl-piperidine-2-carboxylic acid
    Xad: D-N-methyl-piperidine-2-carboxylic acid
    • Xae: N-methyl-L-proline
  • Xaf: N-methyl-L-thiazolidine-4-carboxylic acid
    • Xag: N,N-dimethylglycine Xah: L-proline
  • Xai: L-piperidine-2-carboxylic acid
    Xak: 2-[N,N-dimethylamino]-isobutyric acid
    Xal: L-thiazolidine-4-carboxylic acid
    Xam: N-propyl-D-piperidine-2-carboxylic acid
    Xan: L-3,4-didehydroproline
    Xao: D-piperidine-2-carboxylic acid
    Xap: proline tert.butylester
    Xaq: N-ethyl-D-piperidine-2-carboxylic acid
    Xar: N-methyl-[2,2,5,5-tetramethyl]-L-thiazolidine-2-carboxylic acid
    Xas: N-isopropyl-D-piperidine-2-carboxylic acid
    Xat: N,N-dimethyl-2-cyclopropyl-glycine
    Xau: N,N-dimethyl-2-ethyl-2-phenyl-glycine
    • Xav: D-proline
  • Xaw: N-methyl-D-pro line
    Xax: N,N-dimethyl-2-[2-fluoro]phenyl-glycine
    Xay: 1-aza-[3,3,0]bicyclooctyl-5-carboxylic acid
    Xaz: N,N-dimethyl-2-[4-fluoro]phenyl-glycine
    Xba: N-methyl-[2,2,5,5-tetramethyl]-thiazolidine-2-carboxylic acid
    Xbb: 2-(R,S)-ethyl-2-phenyl-glycine
    Xbc: D,L-1-aminoindane-1-carboxylic acid
    Xbd: N,N-dimethyl-2-(R,S)-methyl-2-phenyl-glycine
    Xbe: 2-[N,N-dimethylamino]indane-2-carboxylic acid
    Xbf: 5-[N,N-dimethylamino]-5,6,7,8-tetrahydro-naphthalene-5-carboxylic acid
    Xbg: N-isopropyl-2-(R,S)-ethyl-2-phenyl-glycine
    Xbh: 1-[N,N-dimethylamino]indane-2-carboxylic acid
    Xbi: N,N-dimethyl-2-propyl-2-phenyl-glycine
    Xbk: N,N-dimethyl-2-[4-methoxy]phenyl-glycine
    Xbl: N-methyl-3-hydroxy-D,L-valine
    Xbm: N,N-dimethyl-D,L-2-isopropyl-2-phenyl-glycine
    Xbn: proline-N-methoxy-N-methyl-amide
    Xbo: N-methyl-piperidine-2-carboxylic acid
    Xbp: proline-isopropylamide
    Xbq: proline-isoxazolidinyl
    Xbr: proline-N-methoxy-N-benzylamide
    • Xbs: N-methyl-D,L-proline
  • Xbt: proline-[5-phenyl]isoxazolidinyl
    Xbu: N-methyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid
    Xbv: N-methyl-azetidine-2-carboxylic acid
    Xbw: N-isopropyl-azetidine-2-carboxylic acid
    Xbx: proline-tert-butylamide
    Xby: N,N-dimethyl-[O-methyl]serine
    Xbz: N,N-dimethyl-[O-methyl]threonine
    Xca: N-methyl-1,2,3,4-tetrahydro isoquino line-3-carboxylic acid
    Xcb: proline-pentyl(3)amide
    Xcc: proline-(R)-phenethylamide
    Xcd: proline-(S)-phenethylamide
    Xce: 1-[N,N-dimethylamino]cyclohexyl-1-carboxylic acid
    Xcf: 1-[N,N-dimethylamino]cyclopentyl-1-carboxylic acid
    Xcg: 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
    • Xch:
  • Figure US20130046077A1-20130221-C00027
    • Xci:
  • Figure US20130046077A1-20130221-C00028
    • Xck:
  • Figure US20130046077A1-20130221-C00029
    • Xcl:
  • Figure US20130046077A1-20130221-C00030
    • Xcm:
  • Figure US20130046077A1-20130221-C00031
    • Xcn:
  • Figure US20130046077A1-20130221-C00032
    • Xco:
  • Figure US20130046077A1-20130221-C00033
    • Xcp:
  • Figure US20130046077A1-20130221-C00034
    • Xcq: N
  • Figure US20130046077A1-20130221-C00035
    • Xcr:
  • Figure US20130046077A1-20130221-C00036
  • Xcs: L-2-tert-butyl-glycine
    • Xct: N-methyl-L-Isoleucine
  • TABLE 2
    Results of FAB-MS analysis of selected compounds
    Compound No. Mol. weight measured
    1 639
    2 639
    3 627
    4 703
    5 625
    6 611
    7 625
    8 625
    10 667
    12 625
    13 606
    14 653
    15 699
    16 667
    17 639
    18 639
    19 643
    20 611
    21 599
    22 693
    23 693
    24 651
    25 693
    26 693
    27 699
    28 675
    29 673
    30 689
    31 689
    32 701
    33 701
    34 715
    35 717
    36 701
    37 701
    38 717
    39 717
    40 705
    41 705
    42 643
    43 715
    44 703
    45 579
    46 593
    47 593
    48 577
    49 591
    50 591
    51 591
    52 655
    53 667
    54 657
    55 657
    56 687
    57 611
    58 639
    59 639
    60 667
    61 687
    62 669
    63 669
    64 605
    65 605
    66 591
    67 643
    68 657
    69 687
    70 687
    71 605
    72 605
    73 655
    74 669
    75 683
    76 703
    77 703
    78 683
    79 697
    80 697
    81 731
    82 731
    83 731
    84 719
    85 719
    86 645
    87 645
    88 685
    89 685
    90 717
    91 717
    92 679
    93 679
    94 591
    95 591
    96 655
    97 655
    98 731
    99 719
    100 651
    101 651
    102 713
    103 713
    104 713
    105 666
    106 653
    107 687
    108 687
    • Example 5 Evaluation of Biological Activity In Vitro Methodology
  • Cytotoxicity was measured using a standard methodology for adherent cell lines, such as the microculture tetrazolium assay (MTT). Details of this assay have been published (Alley, M. C. et al., Cancer Research 48: 589-601, (1988)). Exponentially growing cultures of HT-29 colon carcinoma cells were used to make microtiter plate cultures. Cells were seeded at 5000-20,000 cells per well in 96-well plates (in 150 mL of media), and grown overnight at 37° C. Test compounds were added, in 10-fold dilutions varying from 10−4 M to 10−10 M. Cells were then incubated for 48 hours. To determine the number of viable cells in each well, the MTT dye was added (50 mL of a 3 mg/mL solution of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide in saline). This mixture was incubated at 37° C. for 5 hours, and then 50 mL of 25% SDS, pH 2, was added to each well. After an overnight incubation, the absorbance of each well at 550 nm was read using an ELISA reader. The values for the mean+/−SD of data from replicated wells were calculated, using the formula % T/C (% viable cells treated/control). The concentration of test compound which gives a T/C of 50% growth inhibition was designated as the IC50.
  • Table 3 presents the IC50 values determined in the HT-29 assay for a series of compounds of the invention.
  • TABLE 3
    Compound No. HT-29 [IC50]
    1 4.7 × 10−8
    2  6.8 × 10−10
    3 3.5 × 10−8
    4 1.2 × 10−9
    5 5.0 × 10−9
    8 5.1 × 10−7
    10 1.3 × 10−7
    12 3.7 × 10−7
    13 1.0 × 10−9
    14 1.5 × 10−9
    15 1.7 × 10−7
    16  7.3 × 10−10
    17 6.3 × 10−8
    18 8.8 × 10−9
    22 6.4 × 10−7
    24 2.8 × 10−8
    27 3.7 × 10−8
    28 4.9 × 10−8
    29 3.6 × 10−8
    30 6.1 × 10−9
    31 2.0 × 10−7
    32 8.5 × 10−7
    33 1.2 × 10−6
    34 5.0 × 10−9
    35 1.4 × 10−7
    36 6.2 × 10−9
    37 1.9 × 10−7
    38 7.3 × 10−7
    39 2.5 × 10−8
    40 5.6 × 10−7
    41 7.3 × 10−6
    42 3.4 × 10−7
    43 5.9 × 10−8
    44 4.8 × 10−8
    45 5.6 × 10−8
    46 7.2 × 10−7
    47 2.3 × 10−8
    48 2.5 × 10−8
    49 8.8 × 10−8
    50 8.9 × 10−8
    51 4.6 × 10−8
    52 3.4 × 10−7
    53 5.0 × 10−9
    54 4.2 × 10−9
    55 5.6 × 10−8
    57 2.5 × 10−8
    58 6.3 × 10−8
    59 1.9 × 10−7
    60 1.8 × 10−9
    62 9.9 × 10−8
    63 5.6 × 10−8
    64 1.7 × 10−6
    65 9.7 × 10−8
    66 3.4 × 10−7
    67 3.4 × 10−7
    68 4.2 × 10−7
    70 7.1 × 10−6
    72 1.2 × 10−7
    73 1.4 × 10−9
    74 5.1 × 10−8
    75 8.5 × 10−7
    76  2.3 × 10−10
    77 7.2 × 10−9
    78 4.3 × 10−9
    79 1.7 × 10−6
    80 6.7 × 10−8
    81 1.3 × 10−7
    82 1.1 × 10−8
    83 1.3 × 10−7
    84 1.2 × 10−6
    85 9.5 × 10−6
    90  9.3 × 10−10
    91  8.3 × 10−10
    92 1.5 × 10−6
    93 1.8 × 10−6
    94 3.0 × 10−6
    95 1.1 × 10−8
    96 1.7 × 10−9
    97 3.2 × 10−8
    98 6.0 × 10−9
    99 3.8 × 10−6
    100 2.3 × 10−6
    101 2.1 × 10−6
    102 1.2 × 10−7
    103 1.1 × 10−7
    104 3.5 × 10−6
    105 1.8 × 10−8
    106 9.7 × 10−8
    108 7.1 × 10−6
    • In Vivo Methodology
  • Compounds of this invention may be further tested in any of the various preclinical assays for in vivo activity which are indicative of clinical utility. Such assays are conducted with nude mice into which tumor tissue, preferably of human origin, has been transplanted (“xenografted”), as is well known in this field. Test compounds are evaluated for their anti-tumor efficacy following administration to the xenograft-bearing mice.
  • More specifically, human tumors grown in athymic nude mice can be transplanted into new recipient animals, using tumor fragments which are about 50 mg in size. The day of transplantation is designated as day O, Six to ten days later, the mice are treated with the test compounds given as an intravenous or intraperitoneal injection, in groups of 5-10 mice at each dose. Compounds are given daily for 5 days, 10 days or days, at doses from 10-100 mg/kg body weight. Tumor diameters and body weights are measured twice weekly. Tumor masses are calculated using the diameters measured with Vernier calipers, and the formula:

  • (length×width2)/2=mg of tumor weight
  • Mean tumor weights are then calculated for each treatment group, and T/C values are determined for each group relative to the untreated control tumors.
  • Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims (3)

1-39. (canceled)
40. A compound of the formula

A-B-D-E-F-(G)r-(K)s-L
wherein
r and s are 0;
A is
a proline derivative of Formula IIa,
Figure US20130046077A1-20130221-C00037
wherein na is 0 to 2; Ra is hydrogen or unsubstituted normal or branched C1-C3-alkyl; R1 a is hydrogen; or Ra and R1 a together form a propylene bridge; and R2 a, R3 a, R4 a, and R5 a are each hydrogen;
B is valyl, isoleucyl, or 2-tert-butylglycyl;
D is N-methylvalyl or N-methylisoleucyl;
E is prolyl, thiazolidinyl-4-carbonyl or 3,4-didehydroprolyl;
F is prolyl; and
L is N-benzylamide, N-methoxy-N-benzylamide, tert-butylamide, tert-butyl ester, N-methoxy-N-methylamide, isopropylamide, 5-phenyl isoxasolidinyl, isoxazolidinyl, pentylamide, (R) or (S) phenethylamide, —O-tert-butyl, isoxazolidinyl, 5-phenyl isoxazolidinyl,
Figure US20130046077A1-20130221-C00038
or a pharmaceutically acceptable salt thereof.
41. A compound of claim 40 selected from the group consisting of:
Xad Ile Xaa Pro Xbx
Xad Ile Xaa Pro Xch
Xad Val Xaa Pro Xap
Xad Val Xaa Pro Xbr
Xad Val Xaa Pro Xbx
Xad Val Xaa Pro Xch
Xad Val Xaa Pro Xci
Xad Val Xaa Pro Xck
Xad Val Xaa Pro Xcl
Xad Val Xaa Pro Xcm
Xad Val Xaa Pro Xcn
Xad Val Xaa Pro Xco
Xad Val Xaa Pro Xcp
Xad Val Xaa Pro Xcq
Xad Val Xaa Pro Xcr
Xad Val Xaa Xal Xbx
Xad Val Xaa Xal Xch
Xad Val Xaa Xal Xcr
Xad Val Xaa Xan Xbx
Xad Val Xaa Xan Xch
Xad Val Xaa Xan Xcr
Xad Val Xct Pro Xbx
Xad Val Xct Pro Xch
Xad Xcs Xaa Pro Xbx
Xad Xcs Xaa Pro Xch
Xae Val Xaa Pro Xab
Xah Val Xaa Pro Xab
Xai Val Xaa Pro Xab
Xam Val Xaa Pro Xab
Xao Val Xaa Pro Xab
Xaq Val Xaa Pro Xab
Xas Val Xaa Pro Xab
Xav Val Xaa Pro Xab
Xaw Ile Xaa Pro Xbx
Xaw Ile Xaa Pro Xch
Xaw Val Xaa Pro Xbn
Xaw Val Xaa Pro Xbp
Xaw Val Xaa Pro Xbq
Xaw Val Xaa Pro Xbr
Xaw Val Xaa Pro Xbx
Xaw Val Xaa Pro Xch
Xaw Val Xaa Pro Xci
Xaw Val Xaa Pro Xck
Xaw Val Xaa Pro Xcl
Xaw Val Xaa Pro Xcm
Xaw Val Xaa Pro Xcn
Xaw Val Xaa Pro Xco
Xaw Val Xaa Pro Xcp
Xaw Val Xaa Pro Xcq
Xaw Val Xaa Pro Xcr
Xaw Val Xaa Xal Xbx
Xaw Val Xaa Xal Xch
Xaw Val Xaa Xal Xcr
Xaw Val Xaa Xan Xbx
Xaw Val Xaa Xan Xch
Xaw Val Xaa Xan Xcr
Xaw Val Xct Pro Xbx
Xaw Val Xct Pro Xch
Xaw Xcs Xaa Pro Xbx
Xaw Xcs Xaa Pro Xch
Xbo Val Xaa Pro Xbn isomer 1
Xbo Val Xaa Pro Xbn isomer 2
Xbo Val Xaa Pro Xbp isomer 1
Xbo Val Xaa Pro Xbp isomer 1
Xbo Val Xaa Pro Xbp isomer 2
Xbo Val Xaa Pro Xbp isomer 2
Xbo Val Xaa Pro Xbq isomer 1
Xbo Val Xaa Pro Xbq isomer 2
Xbo Val Xaa Pro Xbr isomer 1
Xbo Val Xaa Pro Xbr isomer 2
Xbo Val Xaa Pro Xbx isomer 1
Xbo Val Xaa Pro Xbx isomer 2
Xbs Val Xaa Pro Xbt isomer 1 and
Xbs Val Xaa Pro Xbt isomer 2
or a pharmaceutically acceptable salt thereof,
wherein:
Xaa is N-methyl-valine, Xab is Prolyl N-benzylamide, Xad is D-N-methyl-piperidine-2-carboxylic acid, Xae is N-methyl-L-proline, Xah is L-proline, Xai is L-piperidine-2-carboxylic acid, Xak is 2-[N,N-dimethylamino]-isobutyric acid, Xal is L-thiazolidine-4-carboxylic acid, Xam is N-propyl-D-piperidine-2-carboxylic acid, Xan is L-3,4-didehydroproline, Xao is D-piperidine-2-carboxylic acid, Xap is proline tertbutylester, Xaq is N-ethyl-D-piperidine-2-carboxylic acid, Xar is N-methyl-[2,2,5,5-tetramethyl]-L-thiazolidine-2-carboxylic acid, Xas is N-isopropyl-D-piperidine-2-carboxylic acid, Xav is D-proline, Xaw is N-methyl-D-proline, Xax is N,N-dimethyl-2-[2-fluoro]phenyl-glycine, Xbn is proline-N-methoxy-N-methyl-amide, Xbo is N-methyl-piperidine-2-carboxylic acid, Xbp is proline-isopropylamide, Xbq is proline-isoxazolidinyl, Xbr is proline-N-methoxy-N-benzylamide, Xbs is N-methyl-D,L-proline, Xbt is proline-[5-phenyl]isoxazolidinyl, Xbx is proline-tert-butylamide,
Xch is
Figure US20130046077A1-20130221-C00039
Xci is
Figure US20130046077A1-20130221-C00040
Xck is
Figure US20130046077A1-20130221-C00041
Xcl is
Figure US20130046077A1-20130221-C00042
Xcm is
Figure US20130046077A1-20130221-C00043
Xcn is
Figure US20130046077A1-20130221-C00044
Xco is
Figure US20130046077A1-20130221-C00045
Xcp is
Figure US20130046077A1-20130221-C00046
Xcq is
Figure US20130046077A1-20130221-C00047
Xcr
Figure US20130046077A1-20130221-C00048
Xcs is L-2-tert-butyl-glycine, and
Xct is N-methyl-L-isoleucine.
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