CN1334797A - 3,4-diamino-3-cyclobutene-1,2-dione derivs. which inhibit leukocyte adhesion mediated by VLA-4 - Google Patents
3,4-diamino-3-cyclobutene-1,2-dione derivs. which inhibit leukocyte adhesion mediated by VLA-4 Download PDFInfo
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- CN1334797A CN1334797A CN99816064A CN99816064A CN1334797A CN 1334797 A CN1334797 A CN 1334797A CN 99816064 A CN99816064 A CN 99816064A CN 99816064 A CN99816064 A CN 99816064A CN 1334797 A CN1334797 A CN 1334797A
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- 210000005003 heart tissue Anatomy 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- VEEIFXWJNCAVEQ-RGMNGODLSA-N methyl (2s)-2-amino-3-(1h-imidazol-5-yl)propanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CNC=N1 VEEIFXWJNCAVEQ-RGMNGODLSA-N 0.000 description 1
- VXYFARNRGZWHTJ-FVGYRXGTSA-N methyl (2s)-2-amino-3-(4-hydroxyphenyl)propanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VXYFARNRGZWHTJ-FVGYRXGTSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- VFZWCTYGZWDQGK-UHFFFAOYSA-N n-benzylhexan-1-amine Chemical compound CCCCCCNCC1=CC=CC=C1 VFZWCTYGZWDQGK-UHFFFAOYSA-N 0.000 description 1
- DYFFAVRFJWYYQO-UHFFFAOYSA-N n-methyl-n-phenylaniline Chemical compound C=1C=CC=CC=1N(C)C1=CC=CC=C1 DYFFAVRFJWYYQO-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007830 nerve conduction Effects 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Chemical compound OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000000954 titration curve Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
Classifications
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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Abstract
Compounds of formula (I) which inhibit leukocyte adhesion mediated by interaction of the alpha 4 beta 1 integrin (VLA-4) with its counterreceptor VCAM-1, and their use for the treatment of inflammatory and autoimmune diseases.
Description
Invention field
The present invention relates to 3 of new N-replacement, 4-diamino-3-cyclobutene-1, the 2-derovatives, it suppresses through α
4β
1The leukocyte adhesion effect that integrin (VLA-4) and its counter receptor VCAM-1 interact and mediate, and the purposes of their treatment inflammatories and autoimmune disorder.
Background of invention
The VLA-4 that is at first identified by Hemler and Takada (on August 30th, 1989 is open, Hemler and Takada, european patent application, publication No. 330,506) (is also referred to as α
4β
1Integrin and CD49d/CD29) be the β of cell surface receptor
1A member in the integrin family, wherein each acceptor comprises two kinds of subunit: α
4Chain and β
1Chain.There are at least 9 kinds of β
1Integrin, all acceptors have identical β
1Chain and each acceptor have unique α chain.These 9 kinds of acceptors are all in conjunction with the different complements of various kinds of cell substrate molecule, again for example fibronectin, ln and collagen protein.For example, VLA-4 is incorporated into fibronectin.VLA-4 is at β
1Be single in the integrin, wherein it is also in conjunction with the non-substrate molecule through endotheliocyte and other cell expressing.These non-substrate molecules comprise VCAM-1, express on the cytokine activatory Human umbilical vein endothelial cells of VCAM-1 in substratum.The epitope of VLA-4 uniqueness is responsible for fibronectin and VCAM-1 in conjunction with active and shown each active independently be suppressed (Elices etc., Cell, 60:577-584 (1990)).
In the cell of VLA-4 and the mediation of other cell surface receptor, adhere to relevant with multiple inflammatory response.Damage or other inflammatory stimulus position, the activatory vascular endothelial cell is expressed and is adhered to leukocytic molecule.Leukocyte adhesion relates to cell surface receptor in the identification on the white corpuscle be bonded to corresponding cell surface molecule on the endotheliocyte in the mechanism part of endotheliocyte.In case combination, leucocyte migration are passed vessel wall and are entered into damage location and discharge chemical mediator with to anti-infective.To the summary of immune adhesion receptor, referring to for example Springer (Springer, Nature, 346:425-434 (1990)) and Osborn (Osborn, Cell, 62:3-6 (1990)).
Inflammatory disease of brain for example multiple sclerosis (MS) and meningitis is the example of central nervous system disease, and wherein endotheliocyte/leukocyte adhesion mechanism causes the infringement to the cerebral tissue of health.A large amount of leucocyte migrations passes the hemato encephalic barrier (BBB) of the patient with these inflammatory diseasess.White corpuscle discharges the toxicity medium that can cause extensive tissue injury, and such tissue injury causes injuring nerve conduction and paralysis.
In other tract, by the mechanism of adhering to, tissue injury also takes place, it causes leukocytic migration or activation.For example, shown, can make the initial damage further complicated (Vedder etc., Surgery, 106:509 (1989)) after the myocardial ischaemia of heart tissue because white corpuscle enters into injured tissues and causes further invasion and attack.By other the inflammatory diseases that adheres to the mechanism mediation comprise asthma (Pretolani, etc., J.Exp.Med., 180:795 (1994); Abraham, etc., Clin.Invest., 93:776 (1994); Mulligan, etc., Immunology, 150:2407 (1993)), Alzheimer, atherosclerosis (Cybulsky, etc., Science, 251:788 (1991); Li, etc., Atherosclerosis Thromb., 13:197 (1993)), (Sasseville is etc., Am.J.Path. for the AIDS dementia, 144:27 (1994)), (Yang is etc., Proc.Nat.Acad.Science (USA) for diabetes, 90:10494 (1993), Burkly, etc., Diabetes, 43:526 (1994), Baron, etc., J.Clin.Invest., 93:1700 (1994)), (Hamann is etc., Immunology for inflammatory bowel disease, 152:3238 (1994)), multiple sclerosis (Yednock, Deng, Nature, 356:63 (1992); Baron, etc., J.Exp.Med., 177:57 (1993)), rheumatoid arthritis (Van Dinther-Janssen, etc., Annals.Rheumatic Dis., 52:672 (1993); Elices, etc., J.Clin.Invest., 93:405 (1994); Postigo, etc., J.Clin.Invest., 89:1445 (1991)), tissue transplantation (Paul, etc., Transpl.Proceed., 25:813 (1993) and metastases (Okahara, etc., Can.Res., 54:3233 (1994); Paavonen etc., Int.J.Can., 58:298 (1994); Schadendorf, etc., J.Path., 170:429 (1993)).
Because the meaning of VLA-4 in inflammatory and autoimmune disease presses for to the existence of VLA-4 in biological sample and to the compound that suppresses cell adhesion and tests.
It is respectively rapid reversible that each receptor/ligand interacts; Yet, during cell adhesion, the multiple α on a cell
4β
1Integrin receptor relates to the multiple VCAM-1 part on another cell, and strong and stable associative key is provided together.For stoping cell adhesion, α
4β
1The acceptor that the micromolecular inhibitor of integrin must obtain high level occupies rate to be used to disturbing these adhesions of significant amounts to interact.In addition, owing to adhere to interactional polyvalency, inhibitor compound presents very steep titration curve because restraining effect begin to have the acceptor of 85-90% occupies rate and when the acceptor of 95-100% is occupied restraining effect be completely.Follow narrow like this dynamics range, such test that is worthy of consideration, it is used for measuring the variant based in the cellular adhesion studies.Press for the existence that can detect single VCAM-1 molecule and therefore stop the assay method of measuring variant with single receptor.
3 of N-replacement has been described, 4-diamino-3-cyclobutene-1,2-derovatives.Japanese Patent JP 05229999 A2 930907 open cyclobutenediones, it is replaced by the a-amino acid symmetric double.
The wherein A that 5,168, No. 103 descriptions of U.S. patent that issue and that transfer American Home Products Corp. on December 1st, 1992 have formula (2) is the cyclobutenedione derivatives of alkylidene group or alkylene group.
It is said that these compounds are as the N-methyl-D-aspartate antagonist.
Invention is described
The invention provides new formula I compound or its salt pharmaceutically
R wherein
1Be alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
R
2Be H, alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; Or
R
1And R
2Can form saturated or unsaturated Heterocyclylalkyl together;
R
3Be H, alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
A is aryl or heteroaryl; With
X, y and z independently are 0,1,2,3.
In certain preferred embodiments of the present invention, R
1Be the aralkyl of the alkyl of 1 to 10 carbon atom, 7 to 11 carbon atoms or have 1 to 3 heteroatomic heteroaralkyl of 7 to 11 yuan.In the still preferred embodiment of the present invention, R
1Be straight chained alkyl, benzyl, diphenyl-methyl, styroyl, pyridylmethyl or the pyridyl ethyl of 4 to 8 carbon atoms.
R
2Be preferably the alkyl of hydrogen, 1 to 10 carbon atom or the aralkyl of 7 to 11 carbon atoms.R
2More preferably alkyl, benzyl or the menaphthyl of hydrogen, 1 to 6 carbon atom.
Perhaps, work as R
1And R
2One time-out, they are preferably formed has 1 to 3 Heterocyclylalkyl of 5 to 7 yuan that is selected from the heteroatomic replacement of N, O and S.
A is preferably aryl replacement or unsubstituted.When A was substituted, substituting group was preferably selected from-NR
4COR
5,-OCONR
6R
7Or-O (CH
2) mNR
6R
7, R wherein
4Alkyl for hydrogen or 1 to 3 carbon atom.R for replace or unsubstituted aryl, heteroaryl or Heterocyclylalkyl.R
6And R
7Independent is the alkyl of hydrogen or 1 to 3 carbon atom, or R
6And R
7Can form the Heterocyclylalkyl of replacement together, and m is 1 to 6 integer.
In some embodiments of the present invention, x and y be 0 and z be 1 for preferred.In the present invention is aspect some, R
3Be preferably hydrogen.
Be the purpose of the Heterocyclylalkyl that defines preferred replacement, preferred substituted be 1 to 3 carbon atom alkyl, aryl ,-COR
8Or-COOR
9, R wherein
8Be the aryl of the alkyl of 1 to 3 carbon atom, 5 to 6 carbon atoms or the aralkyl of 6 to 7 carbon atoms, and R
9Be the aryl of the alkyl of hydrogen, 1 to 3 carbon atom, 5 to 6 carbon atoms or the aralkyl of 6 to 7 carbon atoms.
In some embodiments of the present invention, R
1Be alkyl, aralkyl or heteroaralkyl, A is a phenyl, x and y be 0 and z be 1.
The preferred compound of the present invention is following compound: [2-(benzylamino)-3,4-dioxo-ring but-1-ene base]-L-phenylalanine; [2-(diphenyl-methyl amino)-3,4-dioxo-ring but-1-ene base]-L-phenylalanine; 2-{2-[2-(1H-indol-3-yl)-ethylamino]-3,4-dioxo-ring but-1-ene base amino }-the L-phenylalanine; 3,4-dioxo-2-[(pyridin-3-yl methyl)-amino]-ring but-1-ene base }-the L-phenylalanine; [2-(benzyl-hexyl-amino)-3,4-dioxo-ring but-1-ene base]-L-phenylalanine; (2-dibenzyl amino-3,4-dioxo-ring but-1-ene base amino)-L-phenylalanine; (S)-2-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-3-phenyl-propionic acid; (S)-and 2-[2-(hexyl-naphthalene-2-ylmethyl-amino)-3,4-dioxo-ring but-1-ene base amino]-3-phenyl-propionic acid; (S)-2-{2-[(4-dimethylamino-benzyl)-hexyl-amino]-3,4-dioxo-ring but-1-ene base amino }-3-phenyl-propionic acid; N-[3,4-dioxo-2-(4-phenyl-Piperazine-1-yl)-ring but-1-ene-1-yl }-the L-phenylalanine; (S)-and 2-[2-(4-ethanoyl-piperazine-1-yl)-3,4-dioxo-ring but-1-ene base amino]-3-phenyl-propionic acid; (S)-3-(4-benzoyl-amido-phenyl)-2-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-propionic acid; (S)-3-(1-benzyl-1H-imidazol-4 yl)-2-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-propionic acid; N-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-O-(3-dimethylamino-propyl group)-L-tyrosine; N-[2-[methyl [2-(4-pyridyl) ethyl] amino]-3,4-dioxo-1-cyclobutene-1-yl]-4-[(4-pyridyl carbonyl) amino]-the L-phenylalanine; N-[2-[methyl (2-phenylethyl) amino]-3,4-dioxo-1-cyclobutene-1-yl]-4-[(4-pyridyl carbonyl) amino]-the L-phenylalanine; N-[2-(dihexyl amino)-3,4-dioxo-1-cyclobutene-1-yl]-4-[(4-pyridyl carbonyl)-amino]-the L-phenylalanine; N-[2-(methyl-pyridin-3-yl methyl-amino)-3,4-dioxo-ring but-1-ene base]-4-[(pyridine-4-carbonyl)-amino]-the L-phenylalanine; N-[2-(dihexyl amino)-3,4-dioxo-1-cyclobutene-1-yl]-4-[(3-pyridyl carbonyl)-amino]-the L-phenylalanine; N-[2-[methyl [2-(4-pyridyl) ethyl] amino]-3,4-dioxo-1-cyclobutene-1-yl]-4-[(3-pyridyl carbonyl) amino]-the L-phenylalanine; N-[2-(methyl-pyridin-3-yl methyl-amino)-3,4-dioxo-ring but-1-ene base]-4-[(pyridine-3-carbonyl)-amino]-the L-phenylalanine; N-{2-[methyl-(2-pyridin-4-yl-ethyl)-amino]-3,4-dioxo-ring but-1-ene base }-the L-phenylalanine; N-[2-(dihexyl amino)-3,4-dioxo-1-cyclobutene-1-yl]-4-[4-(N-carboxyl-benzoyl) piperidino carbonyl] amino }-the L-phenylalanine methyl ester; (2S)-and 3-(4-dimethylamino methanoyl-phenyl)-2-[2-(methyl-styroyl-amino)-3,4-dioxo-ring but-1-ene base amino]-propionic acid; (2S)-2-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-3-(4-dimethyl-carbamoyloxy-phenyl)-propionic acid; (2S)-and 3-(4-dimethylamino methanoyl-phenyl)-2-[2-(methyl-pyridin-3-yl methyl-amino)-3,4-dioxo-ring but-1-ene base amino]-propionic acid; (2S)-and 3-(4-dimethylamino methanoyl-phenyl)-2-{2-[methyl-(2-pyridin-4-yl-ethyl)-amino]-3,4-dioxo-ring but-1-ene base amino }-propionic acid; (2S)-3-[4-(4-methylpiperazine base) carbamoyloxy-phenyl]-2-[2-(methyl-styroyl-amino)-3,4-dioxo-ring but-1-ene base amino]-propionic acid; (2S)-3-[4-(4-methylpiperazine base) carbamoyloxy-phenyl)-2-{2-[methyl-(2-pyridin-4-yl-ethyl)-amino]-3,4-dioxo-ring but-1-ene base amino }-propionic acid; (2S)-3-[4-(4-methylpiperazine base) carbamoyloxy-phenyl)-2-{2-dihexyl amino]-3,4-dioxo-ring but-1-ene base amino }-propionic acid; Or its salt pharmaceutically.
Term as used herein " alkyl " means has 1 to 10 carbon atom and the more preferably side chain or the straight chain of 1 to 8 carbon atom.Illustrational alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group and hexyl.Alkyl can be replacement with unsubstituted.
Term as used herein " aryl " means monocycle or the bicyclic aromatic ring with 5 to 12 carbon atoms.Monocycle preferably has 5 to 6 yuan and dicyclo and preferably has 8,9 or 10 ring structures.Illustrational aryl comprises phenyl and naphthyl.Aryl can be replacement or unsubstituted.
Term as used herein " aralkyl " means the wherein aryl-alkyl of aryl and alkyl such as previous definition.Illustrational aralkyl comprises benzyl and styroyl.Aralkyl can be replacement or unsubstituted.
" halogen " is chlorine, fluorine, iodine or bromine.
No matter " heteroaryl " use separately or mean as the part of " heteroaralkyl " as group has 1 to 3 heteroatomic 5 to 10 yuan of monocycles or bicyclic aromatic ring that is selected from N, O and S.Illustrational heteroaryl comprises pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, indyl, imidazolyl, pyrazolyl and pyrryl.Preferred heteroaryl comprises 1H-indol-3-yl, pyridin-3-yl, pyridin-4-yl and 1H-imidazol-4 yl.Heteroaryl can be replacement or unsubstituted.
" heteroaralkyl " means wherein heteroaryl and alkyl heteroaryl-alkyl as previously described.Illustrational heteroaralkyl comprises pyridylmethyl, pyridyl ethyl, thiophene ethyl, thenyl, indole methyl and furfuryl.Heteroaralkyl can be replacement or unsubstituted.
Heterocyclylalkyl refers to have heteroatomic 5 to the 10 yuan of monocycle alkyl that comprise one or more N of being selected from, O or S.Heterocyclylalkyl can be saturated or unsaturated and can be replacement or unsubstituted.
Except as otherwise noted, Shi Yi substituting group be unsubstituted and include but is not limited to 1 to 3 carbon atom alkyl, halogen ,-CN ,-NO
2, 1 to 3 carbon atom perhaloalkyl radical, aryl, aralkyl ,-NR
4COR
5,-CO
2R
4,-OR
4,-OCONR
6R
7Or-O (CH
2) mNR
6R
7, R wherein
4Be the alkyl of hydrogen, 1 to 3 carbon atom or the aralkyl of 7 to 10 carbon atoms, R
5Be aryl, heteroaryl or Heterocyclylalkyl.R
6And R
7Independent is the alkyl of hydrogen or 1 to 3 carbon atom, or R
6And R
7Can form Heterocyclylalkyl together, and m is 1 to 6 integer.
Carbon number refers to the number of carbon on the carbon skeleton and does not comprise the carbon atom that appears on its substituting group.
When term is used in combination, except as otherwise noted, adopt the definition of each unitary part in this combination.
Pharmacy acceptable salt is an acid salt, and it can be from formation such as the compound of above general formula and pharmaceutically acceptable acid such as phosphoric acid, sulfuric acid, hydrochloric acid, Hydrogen bromide, Citric Acid, toxilic acid, succsinic acid, fumaric acid, acetate, lactic acid, nitric acid, sulfonic acid, tosic acid, methylsulfonic acids
The compounds of this invention contains a chiral centre, and the multiple stereoisomer form that compound is provided is racemic mixture and optical isomer separately for example.Can be directly or through asymmetric or stereospecificity synthetic or prepare separately isomer from racemic mixture through conventional separating optical isomeric body.
As showing in the following reaction process, by in alcoholic solvent suitable amine nucleophilic reagent being added to 3 continuously, 4-diethoxy-3-cyclobutene-1 is on the 2-diketone, make the precursor carboxylic acid ester be hydrolyzed to parent acid by handling subsequently, prepare new formula I compound with alkali aqueous solution.
Flow process 1
Product in method 1 comprises under the situation of X=OH, can be as the corresponding carbamate of flow process 2 preparations.
By above method 2, further process carbamate ester products then.
In the following specific embodiment illustrated method of preparation I compound as described above.These embodiment are for illustrating and not meaning and limit the disclosure by any way.The method of other of preparation The compounds of this invention is obvious to those skilled in the art.Employed reactant and reagent are available on the market or can prepare according to the normative document method.
Embodiment 1 (method 1) [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-phenylalanine methyl ester
(2.0mmol 431mg) adds triethylamine (2.2mmol, 202mg in the solution in absolute ethanol (20mL) to the L-phenylalanine methyl ester HCl that is stirring; 278 μ L) and at room temperature the solution stirring that generates 15 minutes.Subsequently, drip pure 3,4-diethoxy-3-cyclobutene-1,2-diketone (2mmol, 340mg; 296 μ L) and at room temperature the solution stirring that generates is spent the night, during from solution, be settled out white solid.Vacuum is removed volatile matter and is handled resistates and distribute between EtOAc and water with EtOAc.Dry (Na
2SO
4) organism and through flash chromatography method purifying (SiO
21) 20%EtOAc/ hexane; 2) 30%EtOAc/ hexane; 3) 40%EtOAc/ hexane), obtain title compound (551mg into water white oil; 85%).
1H?NMR(DMSO-d
6，300MHz)δ9.1(br?d，1H)，7.24(m，6H)，4.88(m，1H)，4.55(m，3H)，4.16(m，2H)，3.23(dd，1H)，2.96(m，1H)，1.30(m，2H)。
Embodiment 2 (method 2) [2-(benzylamino)-3,4-dioxo-ring but-1-ene base]-L-phenylalanine methyl ester
At room temperature, (0.33mmol 100mg) drips pure benzyl amine (0.36mmol, 39mg in the solution in absolute ethanol (3mL) to [2-oxyethyl group-3,4-dioxo-ring but-1-ene the base]-L-phenylalanine methyl ester that is stirring; 40 μ L).At room temperature, the solution stirring that generates is spent the night, during from solution, be settled out white solid.Vacuum is removed volatile matter and is handled resistates and distribute between EtOAc and water with EtOAc.Dry (Na
2SO
4) organism, vacuum concentration and through flash chromatography method purifying (SiO
2The EtOAc/ hexane), obtain title compound (113mg into white solid; 94%).
1H?NMR(DMSO-d
6，400MHz)δ?7.85(br?s，1H)，7.66(br?s，1H)，7.37(m，2H)，7.26(m，6H)，7.13(m，2H)，5.1(m，1H)，4.68(m，2H)，3.68(s，3H)，3.16(dd，1H，J＝13.9，5.4Hz)，3.03(m，1H)。
Embodiment 3 (method 3) [2-(benzylamino)-3,4-dioxo-ring but-1-ene base]-L-phenylalanine
To [2-(benzylamino)-3,4-dioxo-ring but-1-ene the base]-L-phenylalanine methyl ester that is stirring (0.16mmol, 60mg) add in the solution in THF (5mL) the LiOH aqueous solution (1.0M; 0.16mmol; 160 μ L) and at room temperature the solution stirring that generates 3 hours.Vacuum is removed volatile matter and resistates is distributed between 0.1M acetate and EtOAc.Dry (Na
2SO
4) organism and vacuum concentration, obtain title compound, mp=215-216 ℃ of (33mg into white solid; 59%).
1H?NMR(DMSO-d
6，400MHz)δ13.1(br?s，1H)，7.89(br?s，1H)，7.59(br?s，1H)，7.37(m，2H)，7.26(m，6H)，7.14(m，2H)，4.91(m，1H)，4.68(m，2H)，3.17(m，1H)，3.01(m，1H)。MS(EI.m/e(％))350(17，M
-)，259(16)，91(100)。
Embodiment 4 (method 2) [2-(diphenyl-methyl amino)-3,4-dioxo-ring but-1-ene base]-L-phenylalanine methyl ester
According to the method for above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-phenylalanine methyl ester and diphenyl methyl amine, the yield with 88% obtains title compound.
1H?NMR(DMSO-d
6，400MHz)δ8.38(br?s，1H)，7.68(br?s，1H)，7.39(m，4H)，7.26(m，9H)，7.12(m，2H)，6.33(m，1H)，5.01(m，1H)，3.69(s，3H)，3.16(dd，1H，J＝13.4；5.6Hz)，3.05(dd，1H，J＝13.4；5.6Hz)。Embodiment 5 (method 3) [2-(diphenyl-methyl amino)-3,4-dioxo-ring but-1-ene base]-L-phenylalanine
According to the method for above method 3, obtaining with 76% yield is the title compound of white solid, mp=187-188 ℃.
1H?NMR(DMSO-d
6，400MHz)δ13.2(br?s，1H)，8.41(br?s，1H)，7.62(be?s，1H)，7.38(m，4H)，7.30(m，2H)，7.24(m，7H)，7.13(d，2H，J＝7.02Hz)，6.34(m，1H)，4.90(M，1H)，3.16(dd，1H，J＝13.7；4.9Hz)，3.05(m，1H)。MS((+)FAB.m/e(％))449(14，(M＋Na)
+)，427(45，(M＋H)
+)，217(33)，167(100)。IR(KBr，cm
-1)3200，1790，1730，1640，1575，1530，1440，710。C
26H
22N
2O
40.25H
2The analytical calculation value of O: C, 72.45; H, 5.26; N, 6.50.Measured value: C, 72.69; H, 5.22; N, 6.67.
Embodiment 6 (method 2) 2-{2-[2-(1H-indol-3-yl)-ethylamino]-3,4-dioxo-ring but-1-ene base amino }-the L-phenylalanine methyl ester
According to the method for above method 2,, obtain title compound with 86% yield from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-phenylalanine methyl ester and tryptamines.
1H?NMR(DMSO-d
6，400MHz)δ10.88(s，1H)，7.68(br?s，1H)，7.57(d，2H，J＝7.8Hz)，7.33(d，1H，J＝7.8Hz)，7.23(m，3H)，7.12(m，3H)，7.07(dt，1H，J＝7.03；1.1Hz)，6.96(dt，1H，J＝7.03；1.1Hz)，5.0(m，1H)，3.79(m，2H)，3.67(s，3H)，3.13(M，1H)，3.02(m，1H)，2.91(m，2H)。Embodiment 7 (method 3) 2-{2-[2-(1H-indol-3-yl)-ethylamino]-3,4-dioxo-ring but-1-ene base amino }-the L-phenylalanine
According to the method for above method 3, obtaining with 61% yield is the title compound of white solid.
1H?NMR(DMSO-d
6，400MHz)δ13.3(br?s，1H)，10.8(s，1H)，7.58(d，2H，J＝7.8Hz)，7.32(d，1H，J＝8.1Hz)，7.10-7.30(m，6H)，7.06(m，1H)，6.97(m，1H)，4.90(m，1H)，3.79(m，2H)，3.38(q，1H，J＝7.0Hz)，3.14(dd，1H，J＝13.9；4.7Hz)，3.01(dd，1H，J＝13.9；4.7Hz)，2.92(m，2H)。
MS(EI，m/e(％))403(4，M
+)，385(16)，294(60)，143(100)。C
23H
21N
3O
40.4H
2The analytical calculation value of O: C, 67.27; H, 5.35; N, 10.23.Measured value: C, 67.58; H, 5.82; N, 9.78.
Embodiment 8 (method 2) 2-{3,4-dioxo-2-[(pyridin-3-yl methyl)-amino]-ring but-1-ene base amino }-3-phenyl-methyl propionate
According to the method for above method 2,, obtain title compound with 81% yield, mp=191-192 ℃ from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-phenylalanine methyl ester and 3-pyridylmethyl amine.
1H?NMR(DMSO-d
6，400MHz)δ8.51(d，2H，J＝5.1Hz)，7.87(br?s，1H)，7.68(br?s，2H)，7.40(dd，1H，J＝4.7，7.6Hz)，7.24(m，3H)，7.13(d，2H，J＝7.2Hz)，5.01(br?s，1H)，4.72(d，2H，5.7Hz)，3.68(s，3H)，3.17(dd，1H，J＝5.2，13.7Hz)，3.03(m，1H)。MS(EI，m/e(％))365(6，M
-)，337(7)，274(15)，242(40)，214(18)，186(13)，146(44)，44(100)。IR(KBr，cm
-1)3175，2960，1800，1745，1650，1570，1480，1430，1310，1280。C
20H
19N
3O
4The analytical calculation value: C, 65.74; H, 5.24; N, 11.50.Measured value: C, 65.22; H, 5.15; N, 11.27.
Embodiment 9 (method 3) 3,4-dioxo-2-[(pyridin-3-yl methyl)-amino]-ring but-1-ene base }-the L-phenylalanine
According to the method for above method 3, obtaining with 9% yield is the title compound of white solid, mp=259-261 ℃.
1H?NMR(DMSO-d
6，300MHz)δ13.25(br?s，1H)，8.53(br?d，2H)，7.93(br?s，1H)，7.69(br?d，2H)，7.41(m，1H)，7.20(m，5H)，4.91(m，1H)，4.73(m，2H)，3.18(dd，1H)，3.03(m，1H)。MS((+)FAB，m/e(％))352(10，(M＋H)
+)，232(17)，179(23)，157(100)。
Embodiment 10 (method 2) [2-(benzyl-hexyl-amino)-3,4-dioxo-ring but-1-ene base]-L-phenylalanine methyl ester
According to the method for above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-phenylalanine methyl ester and benzyl (hexyl)-amine, obtaining with 57% yield is the title compound of light yellow oil, and it can carry out subsequent reaction immediately.Embodiment 11 (method 3) [2-(benzyl-hexyl-amino)-3,4-dioxo-ring but-1-ene base]-L-phenylalanine
According to the method for above method 3, obtain being yellow foamy title compound, mp=61-65 ℃ with 41% yield.
1H?NMR(DMSO-d
6，400MHz)δ13.1(s，1H)，7.79(br?s，1H)，7.35(dd，3H，J＝10.6，6.9Hz)，7.21(m，6H)，5.14(m，1H)，4.67(br?s，2H)，3.38(brm，2H)，3.26(dd，2H，J＝14，4.0Hz)，2?98(dd，1H，J＝14.1，11.2Hz)，1.38(br?s，2H)，1.15(m，6H)，0.82(t，3H，J＝6.8Hz)。MS((+)FAB，m/e(％))457(76，(M＋Na)
+)，435(100，(M＋H)
+)，389(13)，192(35)。IR(KBr，cm
-1)3290，2940，1800，1740，1675，1570，1520，700。C
26H
30N
2O
40.25H
2The analytical calculation value of O: C, 71.13; H, 7.00; N, 6.38.Measured value: C, 71.31; H, 7.00; N, 6.20.
Embodiment 12 (method 2) (2-dibenzyl amino-3,4-dioxo-ring but-1-ene base amino)-L-phenylalanine methyl ester
According to the method for above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-phenylalanine methyl ester and dibenzyl-amine, obtaining with 44% yield is the title compound of faint yellow solid, and it can carry out subsequent reaction immediately.Embodiment 13 (method 3) (2-dibenzyl amino-3,4-dioxo-ring but-1-ene base amino)-L-phenylalanine
According to the method for above method 3, obtaining with 79% yield is the title compound of yellow solid.
1H?NMR(DMSO-d
6，400MHz)δ13.13(s，1H)，8.01(d，1H，J＝9.0Hz)，7.35(m，6H)，7.20(m，8H)，5.19(m，1H)，4.55(br?s，4H)，3.26(dd，2H，J＝3.9，14.0Hz)，2.97(m，1H)。MS(EI，m/e(％))440(20，M
+)，349(16)，91(100)。IR(KBr，cm
-1)3450-3250(br)，2925，1800，1740，1680，1570，1520，1445，1265，700。C
27H
24N
2O
4The analytical calculation value: C, 73.62; H, 5.49; N, 6.36.Measured value: C, 72.48; H, 5.41; N, 6.01.
Embodiment 14 (method 2) (S)-2-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-3-phenyl-methyl propionate
According to the method for above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-phenylalanine methyl ester and dihexyl amine, obtaining with 62% yield is the title compound of faint yellow solid, and it can carry out subsequent reaction immediately.Embodiment 15 (method 3) (S)-2-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-3-phenyl-propionic acid
According to the method for above method 3, obtaining with 86% yield is the title compound of water white oil.
1H?NMR(DMSO-d
6，400MHz)δ13.1(br?s，1H)，7.58(d，1H，J＝9.2Hz)，7.2(m，5H)，5.09(m，1H)，3.44(br?s，4H)，3.24(dd，1H，J＝4.0，13.8Hz)，3.0(dd，1H，J＝11.3，14.1Hz)，1.43(br?s，4H)，1.20(m，12H)，0.84(t，6H，J＝7.0Hz)。MS(EI，m/e(％))428(100，M
+)，372(36)，337(55)，224(30)。
Embodiment 16 (method 2) (S)-2-[2-(hexyl-naphthalene-2-ylmethyl-amino)-3,4-dioxo-ring but-1-ene base amino]-3-phenyl-methyl propionate
According to the method for above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-phenylalanine methyl ester and (2-naphthyl-methyl) hexyl amine, obtaining with 63% yield is the title compound of water white oil, and it can carry out subsequent reaction immediately.Embodiment 17 (method 3) (S)-2-[2-(hexyl-naphthalene-2-ylmethyl-amino)-3,4-dioxo-ring but-1-ene base amino-3-phenyl-propionic acid
According to the method for above method 3, obtaining with 80% yield is the title compound of faint yellow solid, mp=62-70 ℃.
1H?NMR(DMSO-d
6，400MHz)δ13.15(br?s，1H)，7.91(m，2H)，7.80(s，1H)，7.52(m，2H)，7.29(m，2H)，7.21(m，6H)，5.17(m，1H)，4.84(br?s，2H)，3.24(dd，2H，J＝3.7，14.3Hz)，2.99(m，1H)，1.48-1.2(m，3H)，1.13(s，6H)，0.78(t，3H，J＝6.7Hz)。MS(EI，m/e(％))484(5，M
+)，439(4)，219(28)，44(100)。
Embodiment 18 (method 2) (S)-2-{2-[(4-dimethylamino-benzyl)-hexyl-amino]-3,4-dioxo-ring but-1-ene base amino }-3-phenyl-methyl propionate
According to the method for above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-phenylalanine methyl ester and (4-dimethyl-aminobenzyl) hexyl amine, obtaining with 59% yield is the title compound of water white oil, and it can carry out subsequent reaction immediately.Embodiment 19 (method 3) (S)-2-{2-[(4-dimethylamino-benzyl)-hexyl-amino]-3,4-dioxo-ring but-1-ene base amino }-3-phenyl-propionic acid
According to the method for above method 3, obtaining with 97% yield is the title compound of white solid, mp=77-80 ℃.
1H?NMR(DMSO-d
6，400MHz)δ13.07(s，1H)，7.78(br?s，1H)，7.23(m，5H)，7.02(br?s，2H)，6.65(d，2H，J＝7.9Hz)，5.16(br?s，1H)，4.49(br?s，2H)，3.26(dd，1H，J＝3.7，13.8Hz)，3.0(m，1H)，2.87(s，6H)，1.48(br?s，3H)，1.15(m，7H)，0.82(t，3H，J＝6.8Hz)。MS((+)FAB，m/e(％))500(100，[M＋Na]
+)，478(34，[M＋H]
+)，455(17)，357(32)。
Embodiment 20 (method 2) N-[3,4-dioxo-2-(4-phenyl-Piperazine-1-yl)-ring but-1-ene-1-yl]-the L-phenylalanine methyl ester
According to the method for above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-phenylalanine methyl ester and 1-phenyl-Piperazine, obtaining with 63% yield is the title compound of white solid, and it can carry out subsequent reaction immediately.Embodiment 21 (method 3) N-[3,4-dioxo-2-(4-phenyl-Piperazine-1-yl)-ring but-1-ene-1-yl]-the L-phenylalanine
According to the method for above method 3, obtaining with 65% yield is the title compound of white solid, mp=165-167 ℃.
1H?NMR(DMSO-d
6，400MHz)δ13.1(br?s，1H)，8.01(d，1H，J＝9.0Hz)，7.29-7.16(m，7H)，6.98(d，2H，J＝8.1Hz)，6.82(t，1H，J＝7.2Hz)，5.08(m，1H)，3.77(br?s，4H)，3?24(dd，2H，J＝4.0，14.0Hz)，3.19(t，3H，J＝5.0Hz)，2.98(dd，1H，J＝11.0，13.8Hz)。MS(EI，m/e(％))405(48，M
+)，361(6)，304(5)，44(100)。
Embodiment 22 (method 2) (S)-2-[2-(4-ethanoyl-piperazine-1-yl)-3,4-dioxo-ring but-1-ene base amino]-3-phenyl-methyl propionate
According to the method for above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-phenylalanine methyl ester and 1-ethanoyl piperazine, obtaining with 71% yield is the title compound of white solid, and it can carry out subsequent reaction immediately.Embodiment 23 (method 3) (S)-2-[2-(4-ethanoyl-piperazine-1-yl)-3,4-dioxo-ring but-1-ene base amino]-3-phenyl-propionic acid
According to the method for above method 3, obtaining with 39% yield is the title compound of white solid, mp=155-158 ℃.
1H?NMR(DMSO-d
6，400MHz)δ13.1(br?s，1H)，7.96(d，1H，J＝9.2Hz)，7.24(m，5H)，5.07(m，1H)，3.66(br?s，2H)，3.57(br?s，3H)，3.50(d，3H，J＝4.2Hz)，3.23(dd，1H，J＝4.2，13.8Hz)，2.97(dd，1H，J＝11.0，13.8Hz)，2.03(s，3H)。MS(EI，m/e(％))371(21，M
+)，270(10)。
Embodiment 24 (method 1) [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-(4-benzoyl-amido) phenylalanine methyl ester
According to the method for above method 1, from L-(4-benzoyl-amido) phenylalanine methyl ester hydrochloride and 3,4-diethoxy-3-cyclobutene-1, the 2-diketone obtains title compound with 64% yield.
1H?NMR(DMSO-d
6，300MHz)δ10.2(s，1H)，9.1(br?dd，1H)，7.93(dd，2H)，7.69(d，2H)，7.53(m，3H)，7.2(d，2H)，4.59(m，3H)，3.7(s，3H)，3.21(dd，1H)，2.93(br?m，1H)，1.31(m，3H)。Embodiment 25 (method 2) (S)-3-(4-benzoyl-amido-phenyl)-2-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-methyl propionate
According to the method for above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-(4-benzoyl-amido) phenylalanine methyl ester and dihexyl amine, obtaining with 70% yield is the title compound of white solid, and it can carry out subsequent reaction immediately.
Embodiment 26 (method 3) (S)-3-(4-benzoyl-amido-phenyl)-2-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-propionic acid
According to the method for above method 3, obtaining with 61% yield is the title compound of white solid, mp=95-100 ℃.
1H?NMR(DMSO-d
6，400MHz)δ13.1(br?s，1H)，10.17(s，1H)，7.91(m，2H)，7.68(d，2H，J＝8.6Hz)，7.6-7.48(m，4H)，7.19(d，2H，J＝8.6Hz)，5.09(m，1H)，3.45(br?m，4H)，3.22(dd，1H，J＝3.8，13.9Hz)，2.98(dd，1H，J＝11.2，13.8Hz)，1.43(br?s，4H)，1.20(s，12H)，0.80(t，6H，J＝6.7Hz)。MS((+)FAB，m/e(％))570(51，[M＋Na]
+)，548(25，[M＋H]
+)，210(10)，105(100)。C
32H
41N
3O
50.4H
2The analytical calculation value of O: C, 69.26; H, 7.59; N, 7.57.Measured value: C, 69 14; H, 7.55; N, 7.52.
Embodiment 27 (method 1) [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-(im-benzyl) histidine methyl esters
According to the method for above method 1, from L-(im-benzyl) histidine methyl ester hydrochloride and 3,4-diethoxy-3-cyclobutene-1, the 2-diketone obtains title compound with 58% yield.
1H?NMR(DMSO-d
6，300MHz)δ9.0(br?dd，1H)，7.67(s，1H)，7.31(m，3H)，7.16(d，2H)，6.91(br?s，1H)，5.12(s，2H)，4.6(m，3H)，3.62(d，3H)，3.05(dd，1H)，2.9(m，1H)，1.3(m，3H)。
Embodiment 28 (method 2) (S)-3-(1-benzyl-1H-imidazol-4 yl)-2-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-methyl propionate
According to the method for above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-(im-benzyl) histidine methyl esters and dihexyl amine, obtaining with 94% yield is the title compound of white solid, and it can carry out subsequent reaction immediately.
Embodiment 29 (method 3) (S)-3-(1-benzyl-1H-imidazol-4 yl)-2-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-propionic acid
According to the method for above method 3, obtaining with 45% yield is the title compound of white solid, mp=75-80 ℃.
1H?NMR(DMSO-d
6，400MHz)δ7.87(d，J＝8.8Hz，1H)，7.66(s，1H)，7.29(m，3H)，7.16(dd，J＝6.4，1.8Hz，2H)，6.92(s，1H)，5.13(s，2H)，5.04(q，J＝8.3，5.8Hz，1H)，3.55(br，4H)，3.01(m，2H)，1.49(br?s，4H)，1.21(s，13H)，0.82(s，6H)。MS((+)FAB，m/e(％))509(100，[M＋H]
+)，185(30)，172(40)。C
29H
40N
4O
40.5H
2The analytical calculation value of O: C, 67.28; H, 7.98; N, 10.82.Measured value: C, 67.53; H, 8.10; N, 10.47.
Embodiment 30 (method 1) [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-O-(3-dimethylaminopropyl)-L-L-Tyrosine methyl ester
According to the method for above method 1, from O-(3-dimethylaminopropyl)-L-tyrosine methyl ester hydrochloride and 3,4-diethoxy-3-cyclobutene-1, the 2-diketone obtains title compound with 71% yield.
1H?NMR(DMSO-d
6，300MHz)δ9.1(br?d，1H)，7.12(d，2H)，6.82(d，2H)，4.89(m，1H)，4.6(m，2H)，3.93(t，2H)，3.69(s，3H)，3.1(m，1H)，2.88(m，1H)，2.31(t，2H)，2.12(s，6H)，1.8(m，2H)，1.3(m，3H)。
Embodiment 31 (method 2) N-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-O-(3-dimethylamino-propyl group)-L-L-Tyrosine methyl ester
Method according to above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-O-(3-dimethylaminopropyl)-L-L-Tyrosine methyl ester and dihexyl amine, obtaining with 23% yield is the title compound of white solid, it can carry out subsequent reaction immediately.Embodiment 32 (method 3 (improved)) N-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-O-(3-dimethylamino-propyl group)-L-tyrosine
According to improving one's methods of above method 3, obtaining with 66% yield is the lithium salts of title compound of faint yellow solid.The requirement of improving one's methods (is generally at room temperature 3 hours) after finishing the ester hydrolysis vacuum is removed volatile matter from reaction mixture, distributes reaction mixture subsequently between EtOAc and water.With the water freeze-drying, obtain lithium salts then into amorphous powder.
1H?NMR(DMSO-d
6，400MHz)δ7.08(d，1H，J＝6.6Hz)，6.95(d，2H，J＝8.6Hz)，6.68(d，2H，J＝8.6Hz)，4.28(m，1H)，3.87(t，2H，J＝6.4Hz)，3.3(br?s，4H)，3.05(d，2H，J＝5.1Hz)，2.31(t，2H，J＝7.1Hz)，2.11(s，6H)，1.78(t，2H，J＝6.9Hz)，1.43(br?s，4H)，1.19(br?m，12H)，0.82(t，6H，J＝7.0Hz)。MS((+)FAB，m/e(％))536(100，[M＋Li]
+)，530(50，[M＋H]
+)。IR(KBr，cm
-1)3400，2960，2930，2880，1800，1575，1520，1240。
Embodiment 33 (method 1) [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-4-[(4-pyridyl carbonyl) amino]-the L-phenylalanine methyl ester
According to the method for above method 1, from 4-[(4-pyridyl carbonyl) amino]-L-phenylalanine methyl ester hydrochloride and 3,4-diethoxy-3-cyclobutene-1, the 2-diketone obtains title compound with 71% yield.
1H?NMR(DMSO-d
6，300MHz)δ10.47(s，1H)，9.12(br?dd，1H)，8.78(dd，2H)，7.83(d，2H)，7.69(d，2H)，7.23(d，2H)，4.9(br?m，1H)，4.59(m，2H)，3.7(s，3H)，3.22(dd，1H)，2.94(m，1H)，1.31(m，3H)。
Embodiment 34 (method 2) N-[2-[methyl [2-(4-pyridyl) ethyl] amino]-3,4-dioxo-1-cyclobutene-1-yl]-4-[(4-pyridyl carbonyl) amino]-the L-phenylalanine methyl ester
Method according to above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-4-[(4-pyridyl carbonyl) amino]-L-phenylalanine methyl ester and methyl-[2-(4-pyridyl) ethyl] amine, obtain being yellow foamy title compound with 41% yield, it can carry out subsequent reaction immediately.Embodiment 35 (method 3 (improved)) N-[2-[methyl [2-(4-pyridyl) ethyl] amino]-3,4-dioxo-1-cyclobutene-1-yl]-4-[(4-pyridyl carbonyl) amino]-the L-phenylalanine
According to above method 3 (improved) method, obtaining with 73% yield is the title compound as its corresponding lithium salts of yellow solid.
1H?NMR(DMSO-d
6，400MHz)δ10.45(s，1H)，8.74(dd，J＝1.5，4.6Hz，2H)，8.40(d，J＝4.8Hz，2H)，7.81(d，J＝6.1Hz，2H)，7.59(d，J＝8.3Hz，2H)，7.40(br?m，1H)，7.20(d，J＝5.3Hz，2H)，7.10(d，J＝8.3Hz，2H)，4.40(m，1H)，3.70(br?s，2H)，3.10(m，6H)，2.81(m，2H)。MS((+)FAB，m/e(％))506(100，[M＋Li]
+)，500(50，[M＋H]
+)。IR(KBr，cm
-1)3400，1575，1530，1410，1320。C
27H
24N
5O
5Li3.5H
2The analytical calculation value of O: C, 56.98; H, 5.49; N, 12.31.Measured value: C, 56.96; H, 5.34; N, 11.82.
Embodiment 36 (method 2) N-[2-[methyl (2-phenylethyl) amino]-3,4-dioxo-1-cyclobutene-1-yl]-4-[(4-pyridyl carbonyl) amino]-the L-phenylalanine methyl ester
Method according to above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-4-[(4-pyridyl carbonyl) amino]-L-phenylalanine methyl ester and methyl-(2-styroyl) amine, obtaining with 93% yield is the title compound of colourless foam, it can carry out subsequent reaction immediately.Embodiment 37 (method 3 (improved)) N-[2-[methyl (2-phenylethyl) amino]-3,4-dioxo-1-cyclobutene-1-yl]-4-[(4-pyridyl carbonyl) amino]-the L-phenylalanine
According to above method 3 (improved) method, obtaining with 90% yield is the title compound as its corresponding lithium salts of white solid.
1H?NMR(DMSO-d
6，400MHz)δ10.45(s，1H)，8.73(m，2H)，7.80(d，J＝5.7Hz，2H)，7.60(d，J＝8.6Hz，2H)，7.32-7.08(m，8H)，4.38(d，J＝4.6Hz，1H)，3.67(br?s，2H)，3.08(m，5H)，2.79(m，2H)。MS((+)FAB，m/e(％))521(100，[M＋Na]
+)，505(85，[M＋Li]
+)，499(60，[M＋H]
+)。IR(KBr，cm
-1)3400，1810，1660，1580，1530，1410，1330。
Embodiment 38 (method 2) N-[2-(dihexyl amino)-3,4-dioxo-1-cyclobutene-1-yl]-4-[(4-pyridyl carbonyl) amino]-the L-phenylalanine methyl ester
Method according to above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-4-[(4-pyridyl carbonyl) amino]-L-phenylalanine methyl ester and dihexyl amine, obtaining with 87% yield is the title compound of weak yellow foam, it can carry out subsequent reaction immediately.Embodiment 39 (method 3 (improved)) N-[2-(dihexyl amino)-3,4-dioxo-1-cyclobutene-1-yl]-4-[(4-pyridyl carbonyl) amino]-the L-phenylalanine
According to above method 3 (improved) method, obtaining with 92% yield is the title compound as its corresponding lithium salts of white solid.
1H?NMR(DMSO-d
6，400MHz)δ10.46(s，1H)，8.75(dd，J＝4.4，1.8Hz，2H)，7.83(dd，J＝4.4，1.8Hz，2H)，7.61(d，J＝8.6Hz，2H)，7.11(d，J＝6.2Hz，1H)，7.05(d，J＝8.6Hz，2H)，4.33(q，J＝5.5Hz，1H)，3?65(br?s，2H)，3.25(br?s，2H)，3.11(d，J＝5.7Hz，3H)，1.43(br?s，4H)，1.15(br?s，11Hz)，0.78(s，6H)。MS((+)FAB，m/e(％))555(100，[M＋Li]
+)，549(97，[M＋H]
+)。IR(KBr，cm
-1)3330，2910，1800，1660，1580，1520，1410，1300。C
31H
39N
4O
5Li2H
2The analytical calculation value of O: C, 62.99; H, 7.33; N, 9.48.Measured value: C, 62.65; H, 7.23; N, 9.31.
Embodiment 40 (method 2) N-[2-(methyl-pyridin-3-yl methyl-amino)-3,4-dioxo-ring but-1-ene base]-4-[(pyridine-4-carbonyl)-amino]-the L-phenylalanine methyl ester
Method according to above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-4-[(4-pyridyl carbonyl) amino]-L-phenylalanine methyl ester and methyl-(3-pyridylmethyl) amine, obtaining with 88% yield is the title compound of colourless foam, and it can carry out subsequent reaction immediately.Embodiment 41 (method 3 (improved)) N-[2-(methyl-pyridin-3-yl methyl-amino)-3,4-dioxo-ring but-1-ene base]-4-[(pyridine-4-carbonyl)-amino]-the L-phenylalanine
According to above method 3 (improved) method, obtaining with 85% yield is the title compound as its corresponding lithium salts of yellow solid.
1H?NMR(DMSO-d
6，400MHz)δ10.47(s，1H)，8.77(dd，J＝4.4，1.8Hz，2H)，8.50(m，2H)，7?84(m，2H)，7.70(br?m，1H)，7.58(d，J＝8.6Hz，3H)，7.39(dd，J＝7.6，4.9Hz，1H)，7.11(d，J＝8.3Hz，2H)，4.7(d，J＝15.2Hz，1H)，4.68(br?m，1H)，4.54(br?s，1H)，3.18(dd，J＝13.6，4.3Hz，1H)，3.01(s，3H)，2.94(dd，J＝13.6，8.3Hz，1H)。MS((+)，(-)ESI，m/e(％))486(82，[M＋H]
+)，484(58，[M－H]
-)。IR(KBr，cm
-1)3400，1800，1620，1580，1530，1410，1325。
Embodiment 42 (method 1) [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-4-[(3-pyridyl carbonyl) amino]-the L-phenylalanine methyl ester
According to the method for above method 1, from 4-[(3-pyridyl carbonyl) amino]-L-phenylalanine methyl ester hydrochloride and 3,4-diethoxy-3-cyclobutene-1, the 2-diketone obtains title compound with 74% yield.
1H?NMR(DMSO-d
6，300MHz)δ10.4(s，1H)，9.1(br?dd，1H)，9.08(d，1H)，8.75(dd，1H)，8?27(dt，1H)，7.68(d，2H)，7.56(dd，1H)，7.23(d，2H)，4.9(m，1H)，4.58(m，2H)，3.68(s，3H)，3.23(dd，1H)，2.96(m，1H)，1.32(m，3H)。Embodiment 43 (method 2) N-[2-(dihexyl amino)-3,4-dioxo-1-cyclobutene-1-yl]-4-[(3-pyridyl carbonyl) amino]-the L-phenylalanine methyl ester
Method according to above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-4-[(3-pyridyl carbonyl) amino]-L-phenylalanine methyl ester and dihexyl amine, obtain being yellow foamy title compound with 95% yield, it can carry out subsequent reaction immediately.Embodiment 44 (method 3 (improved)) N-[2-(dihexyl amino)-3,4-dioxo-1-cyclobutene-1-yl]-4-[(3-pyridyl carbonyl) amino]-L-phenylpropyl alcohol hydracid
According to above method 3 (improved) method, obtaining with 53% yield is the title compound as its corresponding lithium salts of white solid.
1H?NMR(DMSO-d
6，400MHz)δ10.38(s，1H)，9.06(dd，J＝2.4，1.8Hz，1H)，8.72(dd，J＝4.7，1.7Hz，1H)，8.25(dt，J＝2.0Hz，1H)，7.60(d，J＝8.6Hz，2H)，7.54(m，1H)，7.09(d，J＝6.4Hz，1H)，7.04(d，J＝8.6Hz，2H)，4.45(m，1H)，3.28(br?s，4H)，3.11(dd，J＝13.6，4.8Hz，1H)，2.99(dd，J＝13.8，7.2Hz，1H)，1.40(br?s，4H)，1.16(br?s，12H)，0.74(s，6H)。MS((+)FAB，m/e(％))555(43，[M＋Li]
+)，549(100，[M＋H]
+)。IR(KBr，cm
-1)3375(br)，2900，1800，1660，1575，1530，1410，1325。
Embodiment 45 (method 2) N-[2-[methyl [2-(4-pyridyl) ethyl] amino]-3,4-dioxo-1-cyclobutene-1-yl]-4-[(3-pyridyl carbonyl) amino]-the L-phenylalanine methyl ester
Method according to above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-4-[(3-pyridyl carbonyl) amino]-L-phenylalanine methyl ester and methyl-[2-(4-pyridyl) ethyl] amine, obtain being yellow foamy title compound with 54% yield, it can carry out subsequent reaction immediately.Embodiment 46 (method 3 (improved)) N-[2-[methyl [2-(4-pyridyl) ethyl] amino]-3,4-dioxo-1-cyclobutene-1-yl]-4-[(3-pyridyl carbonyl) amino]-the L-phenylalanine
According to above method 3 (improved) method, obtaining with 81% yield is the title compound as its corresponding lithium salts of light yellow solid.
1H?NMR(DMSO-d
6，400MHz)δ10.39(s，1H)，9.04(d，J＝1.8Hz，1H)，8.71(dd，J＝4.8，1.8Hz，1H)，8.39(d，J＝4.6Hz，2H)，8.24(d，J＝8.1Hz，1H)，7.58(d，J＝8.3Hz，2H)，7.52(m，1H)，7.43(br?s，1H)，7.19(d，J＝5.3Hz，2H)，7.10(d，J＝8.6Hz，2H)，4.42(d，J＝4.4Hz，1H)，3.70(br?s，2H)，3.10(m，5H)，2.81(m，2H)。MS((+)ESI，m/e(％))506(25，[M＋Li]
+)，500(100，[M＋H]
+)。IR(KBr，cm
-1)3400(br)，1810，1660，1580，1535，1410，1320。C
27H
24N
5O
5Li2.5H
2The analytical calculation value of O: C, 58.90; H, 5.49; N, 12.72.Measured value: C, 58.68; H, 5.25; N, 12.46.
Embodiment 47 (method 2) N-[2-(methyl-pyridin-3-yl methyl-amino)-3,4-dioxo-ring but-1-ene base]-4-[(pyridine-3-carbonyl)-amino]-L-phenylalanine methyl ester
Method according to above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-4-[(3-pyridyl carbonyl) amino]-L-phenylalanine methyl ester and methyl-(3-pyridylmethyl) amine, obtaining with 66% yield is the title compound of colourless foam, and it can carry out subsequent reaction immediately.Embodiment 48 (method 3 (improved)) N-[2-(methyl-pyridin-3-yl methyl-amino)-3,4-dioxo-ring but-1-ene base]-4-[(pyridine-3-carbonyl)-amino]-the L-phenylalanine
According to above method 3 (improved) method, obtaining with 73% yield is the title compound as its corresponding lithium salts of white solid.
1H?NMR(DMSO-d
6，400MHz)δ10.4(s，1H)，9.08(d，J＝2.2Hz，1H)，8.73(dd，J＝4.8，1.8Hz，1H)，8.5(m，2H)，8.28(dt，J＝2.0Hz，1H)，7.72(brm，1H)，7.57(m，4H)，7.39(dd，J＝7.7，4.8Hz，1H)，7.12(d，J＝8.6Hz，2H)，4.76(d，J＝14.9Hz，1H)，4.66(br?m，1H)，4.55(br?s，1H)，3.18(dd，J＝13.6，4.3Hz，1H)，3.01(s，3H)，2.94(dd，J＝13.8，8.2Hz，1H)。MS((-)，(+)ESI，m/e(％))486(18，[M＋H]
+)，484(100，[M－H]
-)。IR(KBr，cm
-1)3275(br)，1800，1660，1580，1530，1410，1315。C
26H
22N
5O
5Li2.8H
2The analytical calculation value of O: C, 57.62; H, 5.13; N, 12.92.Measured value: C, 57.56; H, 4.74; N, 12.73.
Embodiment 49 (method 2) N-{2-[methyl-(2-pyridin-4-yl-ethyl)-amino]-3,4-dioxo-ring but-1-ene base]-the L-phenylalanine methyl ester
Method according to above method 2, from [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]--L-phenylalanine methyl ester and methyl-[2-(4-pyridyl) ethyl] amine obtains being clarification buttery title compound that it can carry out subsequent reaction immediately with 55% yield.Embodiment 50 (method 3 (improved)) N-{2-[methyl-(2-pyridin-4-yl-ethyl)-amino]-3,4-dioxo-ring but-1-ene base]-the L-phenylalanine
According to above method 3 (improved) method, obtaining with 87% yield is the title compound as its corresponding lithium salts of white solid.
1H?NMR(DMSO-d
6，400MHz)δ8.4(d，J＝5.7Hz，2H)，7.42(br?m，1H)，7.2(d，J＝5.7Hz，2H)，7.11(m，5H)，4.39(d，J＝4.6Hz，1H)，3.68(br?s，2H)，3.18(m，5H)，2.78(m，2H)。MS((+)FAB，m/e(％))402(45，[M＋Na]
+)，380(100，[M＋H]
+)。IR(KBr，cm
-1)3375，1800，1580，1530，1410。C
21H
20N
3O
4Li1.5H
2The analytical calculation value of O: C, 61.21; H, 5.63; N, 10.20.Measured value: C, 61.00; H, 5.44; N, 10.05.
Embodiment 51 (method 1) [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-and 4-[4-(N-carboxylbenzoyl) piperidino carbonyl] amino }-the L-phenylalanine methyl ester
According to the method for above method 1, from 4-[4-(N-carboxylbenzoyl) piperidino carbonyl] amino }-L-phenylalanine methyl ester hydrochloride and 3,4-diethoxy-3-cyclobutene-1, the 2-diketone obtains title compound with 37% yield.
Embodiment 52 (method 2) N-[2-(dihexyl amino)-3,4-dioxo-1-cyclobutene-1-yl]-4-[4-(N-carboxylbenzoyl) piperidino carbonyl] amino }-the L-phenylalanine methyl ester
Method according to above method 2; from [2-oxyethyl group-3; 4-dioxo-ring but-1-ene base]-4-[4-(N-carboxylbenzoyl) piperidino carbonyl]-amino }-L-phenylalanine methyl ester and dihexyl amine; obtain title compound into clear and bright oil with 50% yield, it can carry out subsequent reaction immediately.
Embodiment 53 (method 3) N-[2-(dihexyl amino)-3,4-dioxo-1-cyclobutene-1-yl]-4-[4-(N-carboxylbenzoyl)-piperidino carbonyl] amino }-L-phenylalanine methyl ester
According to the method for above method 3, obtaining with 75% yield is the title compound of faint yellow solid, mp=75-80 ℃.
1H NMR (DMSO-d
6, 400MHz) δ 13.01 (br s, 1H), 9.83 (s, 1H), 7.57 (d, 1H, J=9.0Hz), 7.47 (d, 2H, J=8.3Hz), 7.33 (m, 4H), 7.12 (d, 2H, J=8.6Hz), 5.07 (s, 2H), 5.03 (m, 1H), 4.04 (d, 2H, J=13.2Hz), 3.5 (br m, 4H), 3.28 (br s, under H2O, 1H), 3.16 (dd, 1H, J=3.8Hz), 2.93 (dd, 1H, J=11.0Hz), 2.85 (br m, 2H), 1.76 (m, 2H), 1.48 (m, 6H), 1.20 (br s, 13H), 0.82 (t, 6H, J=6.7Hz).MS([M＋H]
+，m/e(％))689(30)，555(25)，186(65)，91(100)。IR(KBr，cm
-1)3320，2930，1810，1675，1580，1520，1235。C
39H
52N
4O
7The analytical calculation value: C, 68.00; H, 7.61; N, 8.13.Measured value: C, 67.60; H, 7.79; N, 7.95.
Embodiment 54 (method 1) [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-L-Tyrosine methyl ester
According to the method for above method 1, from L-tyrosine methyl ester hydrochloride and 3,4-diethoxy-3-cyclobutene-1, the 2-diketone obtains title compound with 95% yield.
Embodiment 55 (method 4) (2S)-3-(4-formyl-dimethylamino oxygen base-phenyl)-2-oxyethyl group-3,4-dioxo-ring but-1-ene base amino]-the propionic acid methyl ester
(1.6mmol 500mg) drips pure dimethylcarbamyl chloride (4.7mmol, 505mg in the solution in pyridine (15mL) to [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-L-Tyrosine methyl ester; 433 μ L) and at 40 ℃ following solution that generates heated 18 hours.Vacuum is removed volatile matter and resistates is distributed between EtOAc and 1N HCl.With other 1N HCl, water and salt water washing organism and dry (Na
2SO
4).Through flash chromatography method purifying (SiO
2The 60%EtOAc/ hexane), obtain being yellow foamy title compound (282mg; 45%).
Embodiment 56 (method 2) (2S)-3-(4-formyl-dimethylamino oxygen base-phenyl)-2-[2-(methyl-styroyl-amino)-3,4-dioxo-ring but-1-ene base amino]-methyl propionate
Method according to above method 2; from (2S)-3-(4-formyl-dimethylamino oxygen base-phenyl)-2-oxyethyl group-3; 4-dioxo-ring but-1-ene base amino]-methyl propionate and methyl-(2-styroyl) amine; obtaining with 75% yield is the title compound of colourless foam, and it can carry out subsequent reaction immediately.
1H?NMR(DMSO-d
6，400MHz)δ7.85(d，1H，J＝9.0Hz)，7.22(m，8H)，7.01(d，2H，J＝8.6Hz)，5.12(m，1H)，3.72(br?m，1H)，3.68(s，3H)，3.21(dd，1H，J＝4.5Hz)，3.09(s，3H)，2.99(s，4H)，2.88(s，3H)，2.81(m，2H)。Embodiment 57 (method 3 (improved)) (2S)-3-(4-formyl-dimethylamino oxygen base-phenyl)-2-[2-(methyl-styroyl-amino)-3,4-dioxo-ring but-1-ene base amino]-propionic acid
According to above method 3 (improved) method, obtain being the title compound of white solid as its corresponding lithium salts with 82% yield.
1H?NMR(DMSO-d
6，400MHz)δ7.33(br?m，1H)，7.26(m，5H)，7.1(d，2H，J＝8.6Hz)，6.88(d，2H，J＝8.6Hz)，4.36(d，1H，J＝4.8Hz)，3.65(br?m，2H)，3.12(dd，2H，J＝5.1Hz)，3.07(s，3H)，2.98(s，3H)，2.86(s，3H)，2.79(m，2H)。MS((+)FAB，m/e(％))488(55，[M＋Na]
+)，472(60，[M＋Li]
+)，466(100，[M＋H]
+)。IR(KBr，cm
-1)3410，2910，1810，1725，1580，1530，1410，1210。C
25H
26N
3O
6Li1.5H
2The analytical calculation value of O: C, 60.24; H, 5.86; N, 8.43.Measured value: C, 60.40; H, 5.65; N, 8.27.
Embodiment 58 (method 2) (2S)-2-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-3-(4-formyl-dimethylamino oxygen base-phenyl)-methyl propionate
Method according to above method 2; from (2S)-3-(4-formyl-dimethylamino oxygen base-phenyl)-2-oxyethyl group-3; 4-dioxo-ring but-1-ene base amino]-methyl propionate and dihexyl amine, obtaining with 40% yield is the title compound of yellow oil, it can carry out subsequent reaction immediately.Embodiment 59 (method 3) (2S)-2-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-3-(4-formyl-dimethylamino oxygen base-phenyl)-propionic acid
According to above method 3 (improved) method, obtain being the title compound of faint yellow solid as its corresponding lithium salts with 70% yield.
1H?NMR(DMSO-d
6，400MHz)δ7.11(d，1H，J＝6.4Hz)，7.045(m，2H)，6.87(m，2H)，4.28(m，1H)，3.5(br?m，4H)，3.12(d，2H，J＝5.3Hz)，2.99(s，3H)，2.87(s，3H)，1.43(br?m，4H)，1.18(br?m，12H)，0.82(t，6H，J＝6.9Hz)。MS((+)ESI，m/e(％))533(30，(M＋NH4
+)
+)，516(100，(M＋H)
+)。IR(KBr，cm
-1)3400，2910，1800，1730，1580，1520，1380，1220。C
28H
40N
3O
6Li1.25H
2The analytical calculation value of O: C, 61.77; H, 7.87; N, 7.72.Measured value: C, 61.67; H, 7.42; N, 7.45.
Embodiment 60 (method 2) (2S)-3-(4-formyl-dimethylamino oxygen base-phenyl)-2-[2-(methyl-pyridin-3-yl methyl-amino)-3,4-dioxo-ring but-1-ene base amino]-methyl propionate
Method according to above method 2; from (2S)-3-(4-formyl-dimethylamino oxygen base-phenyl)-2-oxyethyl group-3; 4-dioxo-ring but-1-ene base amino]-methyl propionate and methyl-(3-pyridylmethyl) amine; obtaining with 82% yield is the title compound of colourless foam, and it can carry out subsequent reaction immediately.Embodiment 61 (method 3 (improved)) (2S)-3-(4-formyl-dimethylamino oxygen base-phenyl)-2-[2-(methyl-pyridin-3-yl methyl-amino)-3,4-dioxo-ring but-1-ene base amino]-propionic acid
According to above method 3 (improved) method, obtain being the title compound of faint yellow solid as its corresponding lithium salts with 88% yield.
1H?NMR(DMSO-d
6，400MHz)δ8.50(m，2H)，7.67(br?m，1H)，7.61(d，1H，J＝7.7Hz)，7.38(dd，1H，J＝4.7Hz)，7.12(d，2H，J＝8.6Hz)，6.88(d，2H，J＝8.3Hz)，4.0(m，2H)，4.51(br?s，1H)，3.18(dd，1H，J＝4.3Hz)，3.02(s，3H)，2.99(s，3H)，2.94(m，1H)，2.88(s，3H)。MS((+)ESI，m/e(％))459(19，[M＋Li]
+)，453(100，[M＋H]
+)。IR(KBr，cm
-1)3410，2920，1810，1730，1580，1530，1410，1220。C
23H
23N
4O
6Li1.5H
2The analytical calculation value of O: C, 56.90; H, 5.40; N, 11.54.Measured value: C, 56.63; H, 5.17; N, 11.41.
Embodiment 62 (method 2) (2S)-3-(4-formyl-dimethylamino oxygen base-phenyl)-2-{2-[methyl-(2-pyridin-4-yl-ethyl)-amino]-3,4-dioxo-ring but-1-ene base amino }-methyl propionate
Method according to above method 2; from (2S)-3-(4-formyl-dimethylamino oxygen base-phenyl)-2-oxyethyl group-3; 4-dioxo-ring but-1-ene base amino]-methyl propionate and methyl-[2-(4-pyridyl) ethyl] amine; obtaining with 77% yield is the title compound of colourless foam, and it can carry out subsequent reaction immediately.Embodiment 63 (method 3 (improved)) (2S)-3-(4-formyl-dimethylamino oxygen base-phenyl)-2-{2-[methyl-(2-pyridin-4-yl-ethyl)-amino]-3,4-dioxo-ring but-1-ene base amino }-propionic acid
According to above method 3 (improved) method, obtaining with 88% yield is the title compound as its corresponding lithium salts of yellow solid.
1H?NMR(DMSO-d
6，400MHz)δ8.41(d，2H，J＝5.5Hz)，7.41(m，1H)，7.21(d，2H，J＝5.7Hz)，7.09(d，2H，J＝8.6Hz)，6.88(d，2H，J＝8.6Hz)，4.37(m，1H)，3.70(br?m，2H)，3.09(m，5H)，2.98(s，3H)，2.86(s，3H)，2.80(br?m，2H)。MS((+)ESI，m/e(％))473(20，[M＋Li]
+)，467(100，[M＋H]
+)。IR(KBr，cm
-1)3410，2930，1800，1770，1580，1530，1410，1210，1160。C
24H
25N
4O
6Li2.0H
2The theoretical value of O: C, 56.69; H, 5.75; N, 11.02.Measured value: C, 56.82; H, 5.43; N, 10.89.
Embodiment 64 (method 5) (2S)-3-[4-(4-methylpiperazine base) formamyl oxygen base-phenyl]-2-oxyethyl group-3,4-dioxo-ring but-1-ene base amino]-methyl propionate
Under 0 ℃, in 15 minutes, (1.9M solution is in toluene to phosgene; 7.8mmol; 4.1mL) at CH
2Cl
2Drip in the solution (80mL) [2-oxyethyl group-3,4-dioxo-ring but-1-ene base]-L-L-Tyrosine methyl ester (7.8mmol, 2.5g) and pyridine (8.0mmol, 633mg; 647 μ L) at CH
2Cl
2In the solution (10mL).Under 0 ℃, the solution stirring that generates was also dripped N methyl piperazine (11.7mmol, 1.2g in 30 minutes then in 30 minutes; 1.3mL) and pyridine (11.7mmol, 929mg; 950 μ L) at CH
2Cl
2In the solution (10mL).The solution that generates is warmed to room temperature and stirs and spend the night.The vacuum concentration reaction mixture also distributes resistates between EtOAc and water.Dry (Na
2SO
4) organism, concentrate and through flash chromatography method purifying (SiO
25%Et
3N/EtOAc), obtain title compound (1.3g into colourless foam; 37%).
Embodiment 65 (method 2) (2S)-3-[4-(4-methylpiperazine base) formamyl oxygen base-phenyl]-2-[2-(methyl-styroyl-amino)-3,4-dioxo-ring but-1-ene base amino]-methyl propionate
Method according to above method 2; from (2S)-3-[4-(4-methylpiperazine base) formamyl oxygen base-phenyl]-2-oxyethyl group-3; 4-dioxo-ring but-1-ene base amino]-methyl propionate and methyl-(2-styroyl) amine; obtaining with 95% yield is the title compound of colourless foam, and it can carry out subsequent reaction immediately.
Embodiment 66 (method 3) (2S)-3-[4-(4-methylpiperazine base) formamyl oxygen base-phenyl]-2-[2-(methyl-styroyl-amino)-3,4-dioxo-ring but-1-ene base amino]-propionic acid
According to above method 3 (improved) method, obtaining with 90% yield is the title compound as its corresponding lithium salts of white solid.
1H?NMR(DMSO-d
6，400MHz)δ7.32-7.16(m，6H)，7.09(d，2H，J＝8.6Hz)，6.90(d，2H，J＝8.6Hz)，4.32(m，1H)，3.65(br?m，2H)，3.51(br?s，2H)，3.38(br?s，2H)，3.08(m，5H)，2.79(br?m，2H)，2.31(m，4H)，2.19(s，3H)。MS(FAB，m/e(％))543(35，(M＋Na)
+)，527(40，(M＋Li))，521(100)。IR(KBr，cm
-1)3410，2930，1810，1725，1580，1530，1410，1210。C
28H
31N
4O
6Li2.0H
2The analytical calculation value of O: C, 59.78; H, 6.27; N, 9.96.Measured value: C, 60.04; H, 6.07; N, 9.77.
Embodiment 67 (method 2) (2S)-3-[4-(4-methylpiperazine base) formamyl oxygen base-phenyl]-2-{2-[methyl-(2-pyridin-4-yl-ethyl)-amino]-3,4-dioxo-ring but-1-ene base amino }-methyl propionate
Method according to above method 2; from (2S)-3-[4-(4-methylpiperazine base) formamyl oxygen base-phenyl]-2-oxyethyl group-3; 4-dioxo-ring but-1-ene base amino]-methyl propionate and methyl-[2-(4-pyridyl) ethyl] amine; obtain being yellow foamy title compound with 62% yield, it can carry out subsequent reaction immediately.Embodiment 68 (method 3 (improved)) (2S)-3-[4-(4-methylpiperazine base) formamyl oxygen base-phenyl]-2-{2-[methyl-(2-pyridin-4-yl-ethyl)-amino]-3,4-dioxo-ring but-1-ene base amino }-propionic acid
According to above method 3 (improved) method, obtaining with 80% yield is the title compound as its corresponding lithium salts of pale solid.
1H NMR (DMSO-d
6, 400MHz) δ 8.41 (d, 2H, J=5.9Hz), 7.39 (m, 1H), 7.21 (d, 2H, J=5.7Hz), 7.09 (d, 2H, J=8.6Hz), 6.90 (d, 2H, J=8.6Hz), 4.38 (m, 1H), 3.69 (br m, 2H), 3.51 (br s, 2H), 3.35 (br s, 4H is at H
2Under the O peak), 3.09 (m, 4H), 2.82 (m, 2H), 2.30 (m, 4H), 2.19 (s, 3H).MS((+)FAB，m/e(％))534(100，[M＋2Li]
+)，528(50，[M＋Li]
+)。IR(KBr，cm
-1)3400(br)，2920，1810，1720，1580，1530，1410。Embodiment 69 (method 2) (2S)-3-[4-(4-methylpiperazine base) formamyl oxygen base-phenyl]-2-{2-dihexyl amino]-3,4-dioxo-ring but-1-ene base amino }-methyl propionate
Method according to above method 2; from (2S)-3-[4-(4-methylpiperazine base) formamyl oxygen base-phenyl]-2-oxyethyl group-3; 4-dioxo-ring but-1-ene base amino]-methyl propionate and dihexyl amine; obtaining with 85% yield is the title compound of colourless foam, and it can carry out subsequent reaction immediately.Embodiment 70 (method 3 (improved)) (2S)-3-[4-(4-methylpiperazine base) formamyl oxygen base-phenyl]-2-{2-dihexyl amino]-3,4-dioxo-ring but-1-ene base amino }-propionic acid
According to above method 3 (improved) method, obtaining with 84% yield is the title compound as its corresponding lithium salts of white solid.
1H NMR (DMSO-d
6, 400MHz) (J=6.4Hz), 7.05 (m, 2H), 6.88 (m, 2H), 4.29 (m, 1H), 3.65 (br m, 2H), 3.55 (br s, 3H), 3.34 (br s, 4H is at H for d, 1H for δ 7.11
2Under the O peak), 3.12 (d, 2H, J=5.3Hz), 2.31 (m, 4H), 2.19 (s, 3H), 1.43 (brm, 4H), 1.18 (br m, 11H), 0.82 (t, 6H, J=6.9Hz).MS((+)FAB，m/e(％))577(100，[M＋Li]
+)，531(20)，186(45)，127(80)。IR(KBr，cm
-1)3410，2920，1810，1580，1520，1410。C
31H
45N
4O
6Li1.5H
2The analytical calculation value of O: C, 61.68; H, 8.02; N, 9.28.Measured value: C, 61.43; H, 7.78; N, 9.04.
Use following unit price FACS test, aforesaid compound is measured VLA-4 in conjunction with activity.The IC of compound
50Reflect that 50% acceptor occupies rate.The activity of compound, Compound I C can be accurately measured in this test
50In 0.5nM to 1mM scope.Be used for α
4β
1Integrin/VCAM-1 bonded unit price FACS test
Use is by Yednock, etc., J.Biol.Chem, and 1995, the improving one's methods of fluorescent activation cell sorter (FACS) test that 270:28740 describes is by measuring VCAM-1 and the high-caliber α of its expression to solubility
4β
1The interactional restraining effect of the Jurkat cell (ATCC#TIB-153) of integrin (VLA-4), the VLA-4 that measures the embodiment compound is in conjunction with activity.VACM-1 and cell surface are with α
4β
1Integrin dependence mode interacts.
As by as described in the above-mentioned Yednock, the Jurkat cell is growth in the RPMI 1640 that replenishes with 10% calf serum, penicillin, Streptomycin sulphate and glutamine.
As by as described in the above-mentioned Yednock, the VCAM-1 (rsVCAM-1) that in baculovirus expression system, produces recombinant soluble as seven kinds of immunoglobulin (Ig) territories that comprise VCAM-1 on the N-end and on the C-end human IgG
1The chimeric fusion protein of heavy chain constant area.Collecting supernatant liquor and not purified being used for of the rsVCAM-1 that contains about 10ug/ml after 72 hours tests.
On ice, use 1.5mM MnCl
2Handle Jurkat cell (about 10 with 5 μ g/ml 15/7
-7Cell/ml) 30 minutes is with activation β
1Integrin.Mn
2+Activated receptor to be strengthening the part combination, and 15/7 be monoclonal antibody, and it discerns α
4β
1The conformation that the activatory/part of integrin occupies also stops molecule to enter this conformation, stablizes VCAM-1/ α thus
4β
1Integrin interacts.Yednock etc., as mentioned above.Prepared the antibody similar and can be used for this test to 15/7.For example referring to Luque, etc., 1996.J.Bio.Chem., 271:11067.
At room temperature, use the 5-point serial dilutions of standard, the separatory that waits of 25 μ l cells was hatched 30 minutes with compound.As above-mentioned by Yednock etc., the rsVCAM-Fc that 15 μ l are contained the baculovirus supernatant liquor joins in the cell and hatched 30 minutes on ice.
Twice of cell washing and be resuspended in the anti-human IgG of FITC bonded goat of dilution in 1: 100 of 100 μ l detecting the people Ig-VCAM-1 structure of in the test medium that contains 2.5% mice serum, diluting, blocking-up and the potential cross reactivity that combines 15/7 cell surface.In the dark, in cell being hatched 30 minutes on ice.Twice of cell washing and as Yednock etc. above-mentioned like that, the FACS flow cytometer (Becton Dickinson, Mountain View, CA) on, the analysis of usefulness standard facs analysis method.
Data presentation is in table 1.
Table 1
| Embodiment | ?IC50(FACS)μM |
| ????3 | ????58μM |
| ????5 | ????101μM |
| ????7 | ????52μM |
| ????9 | ????116μM |
| ????11 | ????4.4μM |
| ????13 | ????4.4μM |
| ????15 | ????1.5μM |
| ????17 | ????36μM |
| ????19 | ????13μM |
| ????21 | ????86μM |
| ????23 | ????40μM |
| ????26 | ????150nM |
| ????29 | ????631nM |
| ????32 | ????12nM |
| ????35 | ????15nM |
| ????37 | ????2.2nM |
| ????39 | ????1.3nM |
| ????41 | ????26nM |
| ????44 | ????6.5nM |
| Embodiment | ?IC50(FACS)μM |
| ????46 | ????40nM |
| ????48 | ????160nM |
| ????50 | ????9μM |
| ????53 | ????71nM |
| ????57 | ????0.9nM |
| ????59 | ????0.6nM |
| ????61 | ????8.3nM |
| ????63 | ????1.6nM |
| ????66 | ????0.5nM |
| ????68 | ????1.3nM |
| ????70 | ????0.2nM |
Therefore, The compounds of this invention presents high-affinity to VLA-4, and can effectively suppress the interaction of VLA-4 and VCAM.Compound is used for the treatment of following inflammatory and autoimmune disease, includes but is not limited to multiple sclerosis, meningitis, asthma, Alzheimer, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel syndrome, rheumatoid arthritis, metastases, tissue transplantation and myocardial ischaemia.
The compounds of this invention can be to use from acceptable acid pharmaceutically or on the physiology or alkali deutero-salt form.These salt include but is not limited to salt that forms with mineral acid example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the salt that forms with organic acid such as acetate, oxalic acid, succsinic acid and toxilic acid.Other salt comprises and basic metal or the alkaline-earth metal salt that forms of sodium, potassium, calcium or magnesium for example.The compounds of this invention also can use forms such as the carbamate, acid amides of ester with the C-end, N-end or use other routine " prodrug " form, and when administration, prodrug is converted into active part in vivo.
The compounds of this invention can with one or more pharmaceutically acceptable carriers Combined Preparation such as solvent, thinner for example.Solid carrier comprises starch, lactose, Lin Suanergai, Microcrystalline Cellulose, sucrose and kaolin, and liquid vehicle comprises aqua sterilisa, polyoxyethylene glycol, nonionogenic tenside and edible oil for example Semen Maydis oil, peanut oil and sesame oil.The auxiliary that routine is used to prepare medicinal compositions can favourablely comprise for example correctives, tinting material, sanitas and oxidation inhibitor, for example vitamin-E, xitix, BHT and BHA.These compound Orally-administrables and give through vein, intramuscular or subcutaneous route.But when with the such form oral administration of tablet, capsule dispersion powder, granule or suspensoid, preparation can comprise for example about 0.05 to 5% suspension agent, contain the syrup of for example about 10 to 50% sugar or contain the elixir of for example about 20 to 50% ethanol etc.When parenterai administration, preparation for example can be sterilizing injecting solution or oozes the suspension that contains about 0.05 to 5% suspension agent in the medium waiting.Such medicinal preparations can comprise and carrier blended for example about 25 to the activeconstituents of about 90% (weight) and more preferably comprise activeconstituents between about 5% to 60% (weight).
From the viewpoint of preparation and administration situation, preferred medicinal compositions is the capsule of solids composition, particularly tablet and hard filling or liquid filling.The orally give compound is preferred.
Dosage requires and can be determined and it will change with the seriousness of employed concrete composition, route of administration, the symptom that presented and the concrete patient who is treated by those skilled in the art.
Claims (39)
1. a following formula: compound or its salt pharmaceutically:
R wherein
1Be alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
R
2Be H, alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; Or
R
1And R
2Can form saturated or unsaturated heterocycle together;
R
3Be H, alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
A is aryl or heteroaryl; With
X, y and z independently are 0,1,2,3.
2. the compound of claim 1, wherein A is a phenyl, R
1Be alkyl, R
2And R
3Be H, x and y be 0 and z be 1.
3. the compound of claim 2, the wherein phenyl of A for replacing.
4. the compound of claim 1, wherein A is a phenyl, R
1Be heteroaralkyl, R
2And R
3Be H, x and y be 0 and z be 1.
5. the compound of claim 1, wherein A is OCONR for aryl and the substituting group that replaces
6R
7
6. the compound of claim 1, it is [2-(benzylamino)-3,4-dioxo-ring but-1-ene base]-L-phenylalanine or its salt pharmaceutically.
7. the compound of claim 1, it is [2-(diphenyl-methyl amino)-3,4-dioxo-ring but-1-ene base]-L-phenylalanine or its salt pharmaceutically.
8. the compound of claim 1, it is 2-{2-[2-(1H-draws diindyl-3-yl)-ethylamino]-3,4-dioxo-ring but-1-ene base amino }-L-phenylalanine or its salt pharmaceutically.
9. the compound of claim 1, its be 3,4-dioxo-2-[(pyridin-3-yl methyl)-amino]-ring but-1-ene base-L-phenylalanine or its salt pharmaceutically.
10. the compound of claim 1, it is [2-(benzyl-hexyl-amino)-3,4-dioxo-ring but-1-ene base]-L-phenylalanine or its salt pharmaceutically.
11. the compound of claim 1, it is (2-dibenzyl amino-3,4-dioxo-ring but-1-ene base amino)-L-phenylalanine or its salt pharmaceutically.
12. the compound of claim 1, it is (S)-2-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-3-phenyl-propionic acid or its salt pharmaceutically.
13. the compound of claim 1, it is (S)-2-[2-(hexyl-naphthalene-2-ylmethyl-amino)-3,4-dioxo-ring but-1-ene base amino]-3-phenyl-propionic acid or its salt pharmaceutically.
14. the compound of claim 1, it is (S)-2-{2-[(4-dimethylamino-benzyl)-hexyl-amino]-3,4-dioxo-ring but-1-ene base amino }-3-phenyl-propionic acid or its salt pharmaceutically.
15. the compound of claim 1, it is N-[3,4-dioxo-2-(4-phenyl-Piperazine-1-yl)-ring but-1-ene-1-yl }-L-phenylalanine or its salt pharmaceutically.
16. the compound of claim 1, it is (S)-2-[2-(4-ethanoyl-piperazine-1-yl)-3,4-dioxo-ring but-1-ene base amino]-3-phenyl-propionic acid or its salt pharmaceutically.
17. the compound of claim 1, it is (S)-3-(4-benzoyl-amido-phenyl)-2-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-propionic acid or its salt pharmaceutically.
18. the compound of claim 1, it is (S)-3-(1-benzyl-1H-imidazol-4 yl)-2-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-propionic acid or its salt pharmaceutically.
19. the compound of claim 1, it is N-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-O-(3-dimethylamino-propyl group)-L-tyrosine or its salt pharmaceutically.
20. the compound of claim 1, it is N-[2-[methyl [2-(4-pyridyl) ethyl] amino]-3,4-dioxo-1-cyclobutene-1-yl]-4-[(4-pyridyl carbonyl) amino]-L-phenylalanine or its salt pharmaceutically.
21. the compound of claim 1, it is N-[2-[methyl (2-phenylethyl) amino]-3,4-dioxo-1-cyclobutene-1-yl]-4-[(4-pyridyl carbonyl) amino]-L-phenylalanine or its salt pharmaceutically.
22. the compound of claim 1, it is N-[2-(dihexyl amino)-3,4-dioxo-1-cyclobutene-1-yl]-4-[(4-pyridyl carbonyl) amino]-L-phenylalanine or its salt pharmaceutically.
23. the compound of claim 1, it is N-[2-(methyl-pyridin-3-yl methyl-amino)-3,4-dioxo-ring but-1-ene base] 4-[(pyridine-4-carbonyl)-amino]-L-phenylalanine or its salt pharmaceutically.
24. the compound of claim 1, it is N-[2-(dihexyl amino)-3,4-dioxo-1-cyclobutene-1-yl]-4-[(3-pyridyl carbonyl)-amino]-L-phenylalanine or its salt pharmaceutically.
25. the compound of claim 1, it is N-[2-[methyl [2-(4-pyridyl) ethyl] amino]-3,4-dioxo-1-cyclobutene-1-yl]-4-[(3-pyridyl carbonyl) amino]-L-phenylalanine or its salt pharmaceutically.
26. the compound of claim 1, it is N-[2-(methyl-pyridin-3-yl methyl-amino)-3,4-dioxo-ring but-1-ene base]-4-[(pyridine-3-carbonyl)-amino]-L-phenylalanine or its salt pharmaceutically.
27. the compound of claim 1, it is N-{2-[methyl-(2-pyridin-4-yl-ethyl)-amino]-3,4-dioxo-ring but-1-ene base }-L-phenylalanine or its salt pharmaceutically.
28. the compound of claim 1, it is N-[2-(dihexyl amino)-3,4-dioxo-1-cyclobutene-1-yl]-4-[4-(N-carboxylbenzoyl) piperidino carbonyl] amino }-L-phenylalanine methyl ester or its salt pharmaceutically.
29. the compound of claim 1, it is (2S)-3-(4-dimethylamino methanoyl-phenyl)-2-[2-(methyl-styroyl-amino)-3,4-dioxo-ring but-1-ene base amino]-propionic acid or its salt pharmaceutically.
30. the compound of claim 1, it is (2S)-2-(2-dihexyl amino-3,4-dioxo-ring but-1-ene base amino)-3-(4-dimethyl-carbamoyloxy-phenyl)-propionic acid or its salt pharmaceutically.
31. the compound of claim 1, it is (2S)-3-(4-dimethylamino methanoyl-phenyl)-2-[2-(methyl-pyridin-3-yl methyl-amino)-3,4-dioxo-ring but-1-ene base amino]-propionic acid or its salt pharmaceutically.
32. the compound of claim 1, it is (2S)-3-(4-dimethylamino methanoyl-phenyl)-2-{2-[methyl-(2-pyridin-4-yl-ethyl)-amino]-3,4-dioxo-ring but-1-ene base amino }-propionic acid or its salt pharmaceutically.
33. the compound of claim 1, it is (2S)-3-[4-(4-methylpiperazine base) carbamoyloxy-phenyl]-2-[2-(methyl-styroyl-amino)-3,4-dioxo-ring but-1-ene base amino]-propionic acid or its salt pharmaceutically.
34. the compound of claim 1, it is (2S)-3-[4-(4-methylpiperazine base) carbamoyloxy-phenyl)-2-{2-[methyl-(2-pyridin-4-yl-ethyl)-amino]-3,4-dioxo-ring but-1-ene base amino }-propionic acid or its salt pharmaceutically.
35. the compound of claim 1, it is (2S)-3-[4-(4-methylpiperazine base) carbamoyloxy-phenyl)-2-{2-dihexyl amino]-3,4-dioxo-ring but-1-ene base amino }-propionic acid or its salt pharmaceutically.
36. one kind is used for the method that suppresses leukocyte adhesion with the patient of leukocyte adhesion diseases associated suffering from, it comprises following formula: compound or its salt pharmaceutically that gives described patient treatment significant quantity,
R wherein
1Be alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
R
2Be H, alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; Or
R
1And R
2Can form saturated or unsaturated heterocycle together;
R
3Be H, alkyl, aryl, heteroaryl, aralkyl or assorted virtue;
A is aryl or heteroaryl; With
X, y and z independently are 0,1,2,3.
37. a treatment suffers from the patient's of inflammatory diseases method, it comprises following formula: compound or its salt pharmaceutically that gives described patient treatment significant quantity,
R wherein
1Be alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
R
2Be H, alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; Or
R
1And R
2Can form saturated or unsaturated heterocycle together;
R
3Be H, alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
A is aryl or heteroaryl; With
X, y and z independently are 0,1,2,3.
38. the method for claim 36, wherein said inflammatory diseases are selected from multiple sclerosis, meningitis, asthma, Alzheimer, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel syndrome, rheumatoid arthritis, metastases, tissue transplantation and myocardial ischaemia.
39. a medicinal compositions, it comprises following formula: compound or pharmaceutically acceptable carrier,
R wherein
1Be alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
R
2Be H, alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; Or
R
1And R
2Can form saturated or unsaturated heterocycle together;
R
3Be H, alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
A is aryl or heteroaryl; With
X, y and z independently are 0,1,2,3.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US21118398A | 1998-12-14 | 1998-12-14 | |
| US09/211,183 | 1998-12-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1334797A true CN1334797A (en) | 2002-02-06 |
Family
ID=22785877
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99816064A Pending CN1334797A (en) | 1998-12-14 | 1999-12-10 | 3,4-diamino-3-cyclobutene-1,2-dione derivs. which inhibit leukocyte adhesion mediated by VLA-4 |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1140792A1 (en) |
| JP (1) | JP2002532457A (en) |
| CN (1) | CN1334797A (en) |
| AU (1) | AU2357600A (en) |
| BR (1) | BR9916211A (en) |
| CA (1) | CA2351464A1 (en) |
| WO (1) | WO2000035855A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100338032C (en) * | 2002-07-30 | 2007-09-19 | 先灵公司 | 3,4-di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands |
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| US6329372B1 (en) | 1998-01-27 | 2001-12-11 | Celltech Therapeutics Limited | Phenylalanine derivatives |
| ATE273273T1 (en) | 1998-02-26 | 2004-08-15 | Celltech Therapeutics Ltd | PHENYLALANINE DERIVATIVES AS INHIBITORS OF ALPHA4 INTEGRINS |
| GB9805655D0 (en) | 1998-03-16 | 1998-05-13 | Celltech Therapeutics Ltd | Chemical compounds |
| GB9811159D0 (en) | 1998-05-22 | 1998-07-22 | Celltech Therapeutics Ltd | Chemical compounds |
| GB9811969D0 (en) | 1998-06-03 | 1998-07-29 | Celltech Therapeutics Ltd | Chemical compounds |
| GB9812088D0 (en) | 1998-06-05 | 1998-08-05 | Celltech Therapeutics Ltd | Chemical compounds |
| US6518283B1 (en) * | 1999-05-28 | 2003-02-11 | Celltech R&D Limited | Squaric acid derivatives |
| US6534513B1 (en) | 1999-09-29 | 2003-03-18 | Celltech R&D Limited | Phenylalkanoic acid derivatives |
| BR0016818A (en) | 1999-12-28 | 2002-10-01 | Pfizer Prod Inc | Non-peptidyl inhibitors of vla-4-dependent cell adhesion useful in the treatment of inflammatory, autoimmune and respiratory diseases |
| JP2003531141A (en) | 2000-04-17 | 2003-10-21 | セルテック アール アンド ディ リミテッド | Enamine derivatives |
| US6403608B1 (en) * | 2000-05-30 | 2002-06-11 | Celltech R&D, Ltd. | 3-Substituted isoquinolin-1-yl derivatives |
| US6545013B2 (en) * | 2000-05-30 | 2003-04-08 | Celltech R&D Limited | 2,7-naphthyridine derivatives |
| US6740654B2 (en) * | 2000-07-07 | 2004-05-25 | Celltech R & D Limited | Squaric acid derivatives |
| JP2004505110A (en) * | 2000-08-02 | 2004-02-19 | セルテック アール アンド ディ リミテッド | 3-position substituted isoquinolin-1-yl derivative |
| FR2815345B1 (en) * | 2000-10-12 | 2002-12-13 | Servier Lab | NOVEL CYCLOBUTENE-DIONE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| GB0028844D0 (en) * | 2000-11-27 | 2001-01-10 | Celltech Chiroscience Ltd | Chemical compounds |
| WO2002051396A1 (en) * | 2000-12-26 | 2002-07-04 | Sankyo Company, Limited | Pharmaceutical compositions containing cyclobutene derivatives |
| US20040106794A1 (en) * | 2001-04-16 | 2004-06-03 | Schering Corporation | 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands |
| NZ543869A (en) * | 2001-04-16 | 2007-09-28 | Schering Corp | 3,4-di-substituted cyclobutene-1,2-diones as cxc-chemokine repcetor ligands |
| US7132445B2 (en) | 2001-04-16 | 2006-11-07 | Schering Corporation | 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands |
| CA2462862A1 (en) | 2001-10-12 | 2003-04-17 | Schering Corporation | 3,4-di-substituted maleimide compounds as cxc-chemokine receptor antagonists |
| US6878709B2 (en) | 2002-01-04 | 2005-04-12 | Schering Corporation | 3,4-di-substituted pyridazinediones as CXC chemokine receptor antagonists |
| US7446109B2 (en) | 2002-03-13 | 2008-11-04 | Janssen Pharmaceutica N.V. | Carbonylamino-derivatives as novel inhibitors of histone deacetylase |
| PL213783B1 (en) | 2002-03-13 | 2013-05-31 | Janssen Pharmaceutica Nv | Inhibitors of histone deacetylase |
| MXPA04008795A (en) | 2002-03-13 | 2004-11-26 | Janssen Pharmaceutica Nv | Piperazinyl-, piperidinyl- and morpholinyl-derivatives as novel inhibitors of histone deacetylase. |
| EP1485089B1 (en) | 2002-03-18 | 2013-04-17 | Merck Sharp & Dohme Corp. | Combination treatments for chemokine-mediated diseases |
| GB0216574D0 (en) * | 2002-07-17 | 2002-08-28 | Celltech R&D Ltd | Chemical compounds |
| WO2004033440A1 (en) | 2002-10-09 | 2004-04-22 | Schering Corporation | Thiadiazoledioxides and thiadiazoleoxides as cxc- and cc-chemokine receptor ligands |
| ATE406356T1 (en) | 2003-12-19 | 2008-09-15 | Schering Corp | THIADIAZOLES AS CXC AND CC CHEMOKINE RECEPTOR LIGANDS |
| MXPA06007205A (en) | 2003-12-22 | 2006-08-31 | Schering Corp | Isothiazole dioxides as cxc- and cc- chemokine receptor ligands. |
| PL1781639T3 (en) | 2004-07-28 | 2012-07-31 | Janssen Pharmaceutica Nv | Substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylase |
| ES2327840T3 (en) | 2004-12-23 | 2009-11-04 | Gpc Biotech Ag | DERIVATIVES OF ESCUARIC ACID WITH ANTIPROLIFERATIVE ACTIVITY. |
| CN101253165A (en) | 2005-06-29 | 2008-08-27 | 先灵公司 | Di-substituted oxadiazoles as CXC-chemokine receptor ligands |
| DE602006017849D1 (en) | 2005-06-29 | 2010-12-09 | Schering Corp | 5,6-DISUBSTITUTED OXADIAZOLO PYRAZINES AND THIADIAZOLOPYRACINES AS LIGANDS OF THE CXC CHEMOKIN RECEPTOR |
| CA2623360C (en) * | 2005-10-27 | 2014-04-22 | Janssen Pharmaceutica N.V. | Squaric acid derivatives as inhibitors of histone deacetylase |
| DK1979326T3 (en) | 2006-01-19 | 2013-01-07 | Janssen Pharmaceutica Nv | PYRIDINE AND PYRIMIDINE DERIVATIVES AS INHIBITORS OF HISTONDEACETYLASE |
| US8450348B2 (en) | 2007-02-21 | 2013-05-28 | Forma Tm, Llc | Derivatives of squaric acid with anti-proliferative activity |
| FR2918665B1 (en) * | 2007-07-13 | 2009-10-02 | Sod Conseils Rech Applic | TRI-AMINO-PYRIMIDINE CYCLOBUTENEDIONE DERIVATIVES AS CDC25 PHOSPHATASE INHIBITORS |
| CN112969504B (en) | 2018-10-30 | 2024-04-09 | 吉利德科学公司 | Compounds for inhibiting alpha 4 beta 7 integrin |
| CN112969700B (en) | 2018-10-30 | 2024-08-20 | 吉利德科学公司 | Imidazopyridine derivatives as alpha 4 beta 7 integrin inhibitors |
| CN112996786B (en) | 2018-10-30 | 2024-08-20 | 吉利德科学公司 | Compounds for inhibiting alpha 4 beta 7 integrin |
| US11116760B2 (en) | 2018-10-30 | 2021-09-14 | Gilead Sciences, Inc. | Quinoline derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9311282D0 (en) * | 1993-06-01 | 1993-07-21 | Rhone Poulenc Rorer Ltd | New compositions of matter |
| AU7273598A (en) * | 1997-05-05 | 1998-11-27 | Regents Of The University Of California, The | Naphthols useful in antiviral methods |
-
1999
- 1999-12-10 AU AU23576/00A patent/AU2357600A/en not_active Abandoned
- 1999-12-10 JP JP2000588117A patent/JP2002532457A/en active Pending
- 1999-12-10 WO PCT/US1999/029369 patent/WO2000035855A1/en not_active Application Discontinuation
- 1999-12-10 EP EP99967265A patent/EP1140792A1/en not_active Withdrawn
- 1999-12-10 CN CN99816064A patent/CN1334797A/en active Pending
- 1999-12-10 CA CA002351464A patent/CA2351464A1/en not_active Abandoned
- 1999-12-10 BR BR9916211-3A patent/BR9916211A/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100338032C (en) * | 2002-07-30 | 2007-09-19 | 先灵公司 | 3,4-di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2357600A (en) | 2000-07-03 |
| EP1140792A1 (en) | 2001-10-10 |
| CA2351464A1 (en) | 2000-06-22 |
| BR9916211A (en) | 2001-09-11 |
| JP2002532457A (en) | 2002-10-02 |
| WO2000035855A1 (en) | 2000-06-22 |
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