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Patent US6333321 - Selective factor Xa inhibitors - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsNovel compounds, their salts and compositions related thereto having activity against mammalian factor Xa are disclosed. The compounds are useful in vitro or in vivo for preventing or treating coagulation disorders....http://www.google.com/patents/US6333321?utm_source=gb-gplus-sharePatent US6333321 - Selective factor Xa inhibitorsAdvanced Patent SearchPublication numberUS6333321 B1Publication typeGrantApplication numberUS 09/132,228Publication dateDec 25, 2001Filing dateAug 11, 1998Priority dateAug 11, 1997Fee statusLapsedPublication number09132228, 132228, US 6333321 B1, US 6333321B1, US-B1-6333321, US6333321 B1, US6333321B1InventorsRobert ScarboroughOriginal AssigneeCor Therapeutics, Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (90), Non-Patent Citations (62), Referenced by (11), Classifications (10), Legal Events (5) External Links: USPTO, USPTO Assignment, EspacenetSelective factor Xa inhibitorsUS 6333321 B1Abstract Novel compounds, their salts and compositions related thereto having activity against mammalian factor Xa are disclosed. The compounds are useful in vitro or in vivo for preventing or treating coagulation disorders.
R1 and R2 are independently selected from the group consisting of H, C1-6alkyl, C3-8cycloalkyl, C1-3alkylaryl, C1-3alkyl-C3-8cycloalkyl and aryl; R3 is H, C1-6alkyl or R2 and R3 are taken together to form a carbocyclic ring; q is an integer from 0-1; r is an integer from 0-4; s is an integer from 0-1; t is an integer from 0-4; A is selected from the group consisting of R8, �NR8R9, where R8, R9, R10 and R11 are independently selected from the group consisting of H, �OH, C1-6alkyl, aryl and C1-4alkylaryl; R12 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R10 or R11 to form a 5-6 membered ring; and R13 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R11 to form a 5-6 membered ring; D is selected from the group consisting of a direct link, C3-8cycloalkyl, C1-6alkenyl, C1-4alkenylaryl, aryl and a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S; E is selected from the group consisting of a direct link, �CO�, �SO2�, �O�CO�, �NR14�SO2� and �NR14�CO�, where R14 is selected from the group consisting of H, �OH, C1-6alkyl, aryl and C1-4alkylaryl; G is selected from the group consisting of a direct link, C3-8cycloalkyl, aryl, and a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S; J is selected from the group consisting of R15, �NR15R16, where R15, R16, R17 and R18 are independently selected from the group consisting of H, �OH, C1-6alkyl, aryl and C1-4alkylaryl; R19 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R17 or R18 to form a 5-6 membered ring; and R20 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R18 to form a 5-6 membered ring; with the proviso that when J is R15, then G must contain at least one N atom; L is selected from the group consisting of R33, �NR33R34, where R33, R34, R35 and R36 are independently selected from the group consisting of H, �OH, C1-6alkyl, aryl and C1-4alkylaryl; R37 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R35 or R36 to form a 5-6 membered ring; and R38 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R36 to form a 5-6 membered ring; M is selected from the group consisting of a direct link, C1-6alkyl, C3-8cycloalkyl, C1-6alkenyl, C1-6alkenylaryl, aryl and a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S; Q is selected from the group consisting of H, where R21 and R22 are independently selected from the group consisting of H, C1-3alkyl and aryl; and T is selected from the group consisting of H, �COOR23, �CONR23R24, �CF3, �CF2CF3 and a group having the formula: where,
R23 and R24 are independently selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl; U′ and U″ are independently selected from the group consisting of �O�, �S�, �N� and �NH�; with the proviso that at least one of U′ or U″ is �N� or �NH�; R25 is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C0-6alkylaryl, C2-6alkenylaryl, C0-6alkylheterocyclo C2-6alkenylheterocyclo, �CF3 and �CF2CF3; V is selected from the group consisting of �S�, �SO�, �SO 2, �O� and �NR26�, where R26 is selected from the group consisting of H, C1-6alkyl and benzyl; and W is selected from the group consisting of: a C6-10 heterocyclic ring system substituted by R29 and R30 and containing 1-4 heteroatoms selected from N, S and O; where a is an integer from 0-2; R27 and R28 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, �COOR31, �CONR31R32, �CN and �CF3; and R29 and R30 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, C1-4alkyloxy, halogen, �NO2, �NR31R32, �NR31COR32, �OR31, �OCOR31, �COOR31, �CONR31R32, �CN, �CF3, �SO2NR31R32 and C1-6alkyl-OR31; where R31 and R32 are independently selected from the group consisting of H, C1-6alkyl, C1-3alkylaryl and aryl; or a pharmaceutically acceptable salt or an optical isomer thereof. 2. The compound of claim 1 wherein R1 is H or C1-6alkyl.
3. The compound of claim 2 wherein R1 is H or methyl.
5. The compound of claim 1 wherein R2 is H or C1-6alkyl.
6. The compound of claim 5 wherein R2 is H or methyl.
13. The compound of claim 1 wherein R8, R9, R10 and R11 are independently selected from the group consisting of H and methyl.
20. The compound of claim 1 wherein E is a direct link.
23. The compound of claim 1 wherein R33, R34, R35 and R36 are independently selected from the group consisting of H and C1-6alkyl.
24. The compound of claim 23 wherein R33, R34, R35 and R36 are independently selected from the group consisting of H and methyl.
25. The compound of claim 1 wherein R37 is H, C1-6alkyl or taken together with R35 or R36 to form a 5-6 membered ring.
26. The compound of claim 25 wherein R37 is H or methyl.
27. The compound of claim 1 wherein R38 is H, C1-6alkyl or taken together with R36 to form a 5-6 membered ring.
28. The compound of claim 27 wherein R38 is H or methyl.
29. The compound of claim 1 wherein M is a direct link, C1-6alkyl, C3-8cycloalkyl, aryl or a five to ten membered heterocyclic ring system.
30. The compound of claim 29 wherein M is C1-4alkyl, aryl or a five to ten membered heterocyclic ring system.
31. The compound of claim 1 wherein the integer q is 0.
32. The compound of claim 1 wherein Q is: 33. The compound of claim 32 wherein R21 is H.
34. The compound of claim 33 wherein R22 is H.
35. The compound of claim 32 wherein T is H, �COOR23, �CONR23R24 or a group having the formula: 36. The compound of claim 35 wherein R23 is H.
37. The compound of claim 35 wherein R24 is C1-4alkylaryl.
38. The compound of claim 35 wherein V is �S�, �O� or �NR26�.
39. The compound of claim 38 wherein R26 is H or methyl.
40. The compound of claim 39 wherein R26 is H.
41. The compound of claim 35 wherein W is selected from the group consisting of: 42. The compound of claim 41 wherein W is: 43. The compound of claim 41 wherein R29 is selected from the group consisting of H, �OR31, �COOR31, �CONR31R32 or �CF3.
44. The compound of claim 43 wherein R29 is H.
45. The compound of claim 41 wherein R30 is selected from the group consisting of H, �OR31, �COOR31, �CONR31R32 or �CF3.
46. The compound of claim 45 wherein R30 is H.
47. The compound of claim 35 wherein W is: and R27 is H.
48. The compound of claim 47 wherein R28 is H.
49. The compound of claim 32 wherein T is: U′ is O, U″ is N and R25 is �CF3 or �CF2CF3.
50. A compound having the formula: wherein:
R1 and R2 are independently selected from the group consisting of H, C1-6alkyl, C3-8cycloalkyl, C1-3alkylaryl, C1-3alkyl-C3-8cycloalkyl and aryl; q is an integer from 0-1; r is an integer from 0-4; t is an integer from 0-4; A is selected from the group consisting of R8, �NR8R9, where R8, R9, R10 and R11 are independently selected from the group consisting of H, �OH, C1-6alkyl, aryl and C1-4alkylaryl; R12 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R10 or R11 to form a 5-6 membered ring; and R13 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R11 to form a 5-6 membered ring; D is selected from the group consisting of a direct link, C3-8cycloalkyl, C1-6alkenyl, C1-4alkenylaryl, aryl and a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S; E is selected from the group consisting of a direct link, �CO�, �SO2�, �O�CO�, �NR14�SO2� and �NR14�CO�, where R14 is selected from the group consisting of H, �OH, C1-6alkyl, aryl and C1-4alkylary; G is selected from the group consisting of a direct link, C3-8cycloalkyl, aryl, and a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S; J is selected from the group consisting of R15, �NR15R16, where R15, R16, R17 and R18 are independently selected from the group consisting of H, �OH, C1-6alkyl, aryl and C1-4alkylaryl; R19 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R17 or R18 to form a 5-6 membered ring; and R20 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R18 to form a 5-6 membered ring; with the proviso that when J is R15, then G must contain at least one N atom; L is selected from the group consisting of R33, �NR33R34, where R33, R34, R35 and R36 are independently selected from the group consisting of H, �OH, C1-6alkyl, aryl and C1-4alkylaryl; R37 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R35 or R36 to form a 5-6 membered ring; and R38 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R36 to form a 5-6 membered ring; M is selected from the group consisting of a direct link, C1-6alkyl, C3-8cycloalkyl, C1-6alkenyl, C1-6alkenylaryl, aryl and a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S; T is selected from the group consisting of H, �COOR23, �CONR23R24, �CF3, �CF2CF3 and a group having the formula: where: R23 and R24 are independently selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl; U′ and U″ are independently selected from the group consisting of �O�, �S�, �N� and �NH�; with the proviso that at least one of U′ or U″ is �N� or �NH�; R25 is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C0-6alkylaryl, C2-6alkenylaryl, C0-6alkylheterocyclo, C2-6alkenylheterocyclo, �CF3 and �CF2CF3; V is selected from the group consisting of �S�, �SO�, �SO2�, �O� and �NR26�, where R26 is selected from the group consisting of H, C1-6alkyl and benzyl; and W is selected from the group consisting of: a C6-10 heterocyclic ring system substituted by R29 and R30 and containing 1-4 heteroatoms selected from N, S and O; where a is an integer from 0-2; R27 and R28 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, �COOR31, �CONR31R32, �CN and �CF3; and R29 and R30 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, C1-4alkyloxy, halogen, �NO2, �NR31R32, �NR31COR32, �OR31, �OCOR31, �COOR31, �CONR31R32, �CN, �CF3, �SO2NR31R32 and C1-6alkyl-OR31; where R31 and R32 are independently selected from the group consisting of H, C1-6alkyl, C1-3alkylaryl and aryl; or a pharmaceutically acceptable salt or an optical isomer thereof.
51. A compound having the formula: wherein:
q is an integer from 0-1; t is an integer from 0-4; A is selected from the group consisting of R8, �NR8R9, where R8, R9, R10 and R11 are independently selected from the group consisting of H, �OH, C1-6alkyl, aryl and C1-4alkylaryl; R12 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R10 or R11 to form a 5-6 membered ring; and R13 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R11 to form a 5-6 membered ring; D is selected from the group consisting of a direct link, C3-8cycloalkyl, C1-6alkenyl, C1-4alkenylaryl, aryl and a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S; E is selected from the group consisting of a direct link, �CO�, �SO2�, �O�CO�, �NR14�SO2� and �NR14�CO�, where R14 is selected from the group consisting of H, �OH, C1-6alkyl, aryl and C1-4alkylaryl; L is selected from the group consisting of R33, �NR33R34, where R33, R34, R35 and R36 are independently selected from the group consisting of H, �OH, C1-6alkyl, aryl and C1-4alkylaryl; R37 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R35 or R36 to form a 5-6 membered ring; and R38 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R36 to form a 5-6 membered ring; M is selected from the group consisting of a direct link, C1-6alkyl, C3-8cycloalkyl, C1-6alkenyl, C1-6alkenylaryl, aryl and a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S; T is selected from the group consisting of H, �COOR23, �CONR23R24, �CF3, �CF2CF3 and a group having the formula: where: R23 and R24 are independently selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl; U′ and U″ are independently selected from the group consisting of �O�, �S�, �N� and �NH�; with the proviso that at least one of U′ or U″ is �N� or �NH�; R25 is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C0-6alkylaryl, C2-6alkenylaryl, C0-6alkylheterocyclo, C2-6alkenylheterocyclo, �CF3 and �CF2CF3; V is selected from the group consisting of �S�, �SO�, �SO2�, �O� and �NR26�, where R26 is selected from the group consisting of H, C1-6alkyl and benzyl; and W is selected from the group consisting of: a C6-10 heterocyclic ring system substituted by R29 and R30 and containing 1-4 heteroatoms selected from N, S and O; where a is an integer from 0-2; R27 and R28 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, �COOR31, �CONR31R32, �CN and �CF3; and R29 and R30 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, C1-4alkyloxy, halogen, �NO2, �NR31R32, �NR31COR32, �OR31, �OCOR31, �COOR31, �CONR31R32, �CN, �CF3, �SO2NR31R32 and C1-6alkyl-OR31; where R31 and R32 are independently selected from the group consisting of H, C1-6alkyl, C1-3alkylaryl and aryl; or a pharmaceutically acceptable salt or an optical isomer thereof.
52. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1.
53. A method for treating a condition in a mammal characterized by undesired thrombosis comprising administering to said mammal a therapeutically effective amount of the compound of claim 1.
54. The method of claim 53, wherein the condition is selected from the group consisting of: unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, thrombotic stroke, embolic stroke, disseminated intravascular coagulation, deep venous thrombosis, pulmonary embolism, and reocclusion or restenosis of reperfused coronary arteries.
�This application claims priority of copending provisional application(s) No. 60/082.316 filed on Aug. 11, 1997, which is incorporation herein by reference.�
FIELD OF THE INVENTION This invention relates to a novel class of fused aryl diazepinone compounds which are potent and highly selective inhibitors of factor Xa or factor Xa when assembled in the prothrombinase complex. These compounds show selectivity for factor Xa versus other proteases of the coagulation (e.g. thrombin, fVIIa, fIXa) or the fibrinolytic cascades (e.g. plasminogen activators, plasmin).
Other polypeptide type inhibitors of factor Xa have been reported including the following citations by: Condra, et al., �Isolation and Structural Characterization of a Potent Inhibitor of Coagulation Factor Xa from the Leech Haementetia ghilianii�, Thromb. Haemost. 61:437-441 (1989); Blankenship, et al., �Amino Acid Sequence of Ghilanten: Anti-coagulant-antimetastatic Principle of the South American Leech, Haementeria ghilianii�, Biochem. Biophys. Res. Commun. 166:1384-1389 (1990); Brankamp, et al., �Ghilantens: Anticoagulants, Antimetastatic Proteins from the South American Leech Haementeria ghilianii�, J. Lab. Clin. Med. 115:89-97 (1990); Jacobs, et al., �Isolation and Characterization of a Coagulation Factor Xa Inhibitor from Black Fly Salivary Glands�, Thromb. Haemost. 64:235-238 (1990); Rigbi, et al., �Bovine Factor Xa Inhibiting Factor and Pharmaceutical Compositions Containing the Same�, European Patent Application, 352,903 (1990); Cox, �Coagulation Factor X Inhibitor From the Hundred-pace Snake Deinagkistrodon acutus venom�, Toxicon 31:1445-1457 (1993); Cappello, et al., �Ancylostoma Factor Xa Inhibitor: Partial Purification and its Identification as a Major Hookworm-derived Anticoagulant In Vitro�, J. Infect. Dis. 167:1474-1477 (1993); Seymour, et al., �Ecotin is a Potent Anticoagulant and Reversible Tight-binding Inhibitor of Factor Xa�, Biochemistry 33:3949-3958 (1994).
Factor Xa inhibitory compounds which are not large polypeptide-type inhibitors have also been reported including: Tidwell, et al., �Strategies for Anticoagulation With Synthetic Protease Inhibitors. Xa Inhibitors Versus Thrombin Inhibitors�, Thromb. Res. 19:339-349 (1980); Turner, et al., �p-Amidino Esters as Irreversible Inhibitors of Factor IXa and Xa and Thrombin�, Biochemistry 25:4929-4935 (1986); Hitomi, et al., �Inhibitory Effect of New Synthetic Protease Inhibitor (FUT-175) on the Coagulation System�, Haemostasis 15:164-168 (1985); Sturzebecher, et al., �Synthetic Inhibitors of Bovine Factor Xa and Thrombin. Comparison of Their Anticoagulant Efficiency�, Thromb. Res. 54:245-252 (1989); Kam, et al., �Mechanism Based Isocoumarin Inhibitors for Trypsin and Blood Coagulation Serine Proteases: New Anticoagulants�, Biochemistry 27:2547-2557 (1988); Hauptmann, et al., �Comparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors�, Thromb. Haemost. 63:220-223 (1990); Miyadera, et al., Japanese Patent Application JP 6327488 (1994); Nagahara, et al., �Dibasic (Amidinoaryl)propanoic Acid Derivatives as Novel Blood Coagulation Factor Xa Inhibitors�, J. Med. Chem. 37:1200-1207 (1994); Vlasuk, et al., �Inhibitors of Thrombosis�, WO 93/15756; and Brunck, et al., �Novel Inhibitors of Factor Xa�, WO 94/13693. Al-obeidi, et al., �Factor Xa Inhibitors�, WO 95/29189, discloses pentapeptide X1�Y�I�R�X2 derivatives as factor Xa inhibitors. Said compounds are useful for inhibiting blood clotting in the treatment of thrombosis, stroke, and myocardial infarction.
q is an integer from 0-1;
A is selected from the group consisting of R8, �NR8R9, where R8, R9, R10 and R11 are independently selected from the group consisting of H, �OH, C1-6alkyl, aryl and C1-4alkylaryl; R12 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R10 or R11 to form a 5-6 membered ring; and R13 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R11 to form a 5-6 membered ring;
E is selected from the group consisting of a direct link, �CO�, �SO2�, �O��CO�, �NR 14�SO2� and �NR14�CO�, where R14 is selected from the group consisting of H, �OH, C1-6alkyl, aryl and C1-4alkylaryl;
J is selected from the group consisting of R15, �NR15R16, where R15, R16, R17 and R18 are independently selected from the group consisting of H, �OH, C1-6alkyl, aryl and C1-4alkylaryl; R19 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R17 or R18 to form a 5-6 membered ring; and R20 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R18 to form a 5-6 membered ring; with the proviso that when J is R15, then G must contain at least one N atom; K′; K″, K′″ and K″″ are independently selected from the group consisting of �CH�, �CR4�, �CR5� and �N�; with the proviso that no more than one of K′, K″, K′″ and K″″ are �CR4� and no more than one of K′, K″, K′″ and K″″ are �CR5�;
R4 and R5 are independently selected from the group consisting of C1-6alkyl, aryl, C1-6alkylaryl, C1-4alkyloxy, halogen, �NO2, �NR6R7, �NR6COR7, �OR6, �OCOR6, �COOR6, �CONR6R7, �CN, �CF3, �SO2NR6R7 and C1-6alkyl-OR6; where R6 and R7 are independently selected from the group consisting of H, C1-6alkyl, C1-3alkylaryl and aryl;
L is selected from the group consisting of R33, �NR33R34, where R33, R34, R35 and R36 are independently selected from the group consisting of H, �OH, C1-6alkyl, aryl and C1-4alkylaryl; R37 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4aikylaryl, or can be taken together with R35 or R36 to form a 5-6 membered ring; and R38 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R36 to form a 5-6 membered ring;
M is selected from the group consisting of a direct link, C1-6alkyl, C3-8cycloalkyl, C1-6alkenyl, C1-6alkenylaryl, aryl, and a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
Q is selected from the group consisting of H, where R21 and R22 are independently selected from the group consisting of H, C1-3alkyl and aryl; and T is selected from the group consisting of H, �COOR23, �CONR23R24, �CF3, �CF2CF3 and a group having the formula: where: R23 and R24 are independently selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl; U′ and U″ are independently selected from the group consisting of �O�, �S�, �N� and �NH�; with the proviso that at least one of U′ or U″ is �N� or �NH�; R25 is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C0-6alkylaryl, C2-6alkenylaryl, C0-6alkylheterocyclo, C2-6alkenylheterocyclo, �CF3 and �CF2CF3; V is selected from the group consisting of �S�, �SO�, �SO2�, �O� and �NR26�, where R26 is selected from the group consisting of H, C1-6alkyl and benzyl; and W is selected from the group consisting of: a C6-10 heterocyclic ring system substituted by R29 and R30 and containing 1-4 heteroatoms selected from N, S and O; where a: is an integer from 0-2; R27 and R28 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, �COOR31, �CONR31R32, �CN and �CF3; and R29 and R30 are independently selected from the group consisting of H, C1-6alkyl, aryl, C1-6alkylaryl, C1-4alkyloxy, halogen, �NO2, �NR31R32, �NR31COR32, �OR31, �OCOR31, �COOR31, �CONR31R32, �CN, �CF3, �SO2NR31R32 and C1-6alkyl-OR31; where R31 and R32 are independently selected from the group consisting of H, C1-6alkyl, C1-3alkylaryl and aryl;
The term �aryl� refers to an unsubstituted or substituted aromatic ring(s), substituted with one, two or three substituents such as, by way of example and not limitation, C1-6alkoxy, C1-6alkyl, C1-6alkylamino, hydroxy, halogen, cyano (�CN), mercapto, nitro (�NO2), thioalkoxy, carboxaldehyde, carboxyl, carboalkoxy, carboxamide, �NR′R″, �NR′COR″, �OR, �OCOR, �COOR, �CONR′R″, �CF3, �SO2NR′R″ and C1-6alkyl-OR; aryl, C1-6alkylaryl (where the R groups can be H, C1-6alkyl, C1-3alkylaryl and aryl), including but not limited to carbocyclic aryl, heterocyclic aryl, biaryl and triaryl groups and the like, all of which may be optionally substituted. Preferred aryl groups include phenyl, halophenyl, C1-6alkylphenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and aromatic heterocyclics or heteroaryls, the latter of which is an aryl group containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Aryl groups preferably have 5-14 carbon atoms making up the ring(s) structure, while heteroaryls preferably have 1-4 heteroatoms, with the remaining 4-10 atoms being carbon atoms.
The terms �heterocyclo� and �heterocyclic ring system� as used herein refer to any saturated or unsaturated mono- or bicyclic ring system, containing from one to four heteroatoms, selected from the group consisting of nitrogen, oxygen and sulfur. A typical heterocyclic ring system will have five to ten members, 1-4 of which are heteroatoms. Typical examples of monocyclic ring systems include piperidinyl, pyrrolidinyl, pyridinyl, piperidonyl, pyrrolidonyl and thiazolyl, while examples of bicyclic ring systems include benzimidazolyl, benzothiazolyl and benzoxazolyl, all of which may be substituted.
The term �carbocyclic ring� as used herein refers to any saturated or unsaturated ring containing from three to six carbon atoms. The terms �alkylaryl� and �alkenylaryl� as used herein refer to an alkyl group or alkenyl group, respectively, having the number of carbon atoms designated, appended to one, two, or three aryl groups. The term benzyl as used herein refers to �CH2�C6H5.
�Biological property� for the purposes herein means an in vivo effector or antigenic function or activity that is directly or indirectly performed by a compound of this invention. Effector functions include receptor or ligand binding, any enzyme activity or enzyme modulatory activity, any carrier binding activity, any hormonal activity, any activity in promoting or inhibiting adhesion of cells to an extracellular matrix or cell surface molecules, or any structural role. Antigenic functions include possession of an epitope or antigenic site that is capable of reacting with antibodies raised against it. The biological properties of the compounds of the present invention can be readily characterized by the methods described in Examples 6 and 7 and by such other methods as are well known in the art.
�BOP� refers to benzotriazol-l-yloxy-tris-(dimethylamino) phosphonium hexafluorophosphate.
�HBTU� refers to O�(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate.
In the compounds of this invention, carbon atoms bonded to four non-identical substituents are asymmnetric. Accordingly, the compounds may exist as diastereoisomers, enantiomers or mixtures thereof. The syntheses described herein may employ racemates, enantiomers or diastereomers as starting materials or intermediates. Diastereomeric products resulting from such syntheses may be separated by chromatographic or crystallization methods, or by other methods known in the art. Likewise, enantiomeric product mixtures may be separated using the same techniques or by other methods known in the art. Each of the asymmetric carbon atoms, when present in the compounds of this invention, may be in one of two configurations (R or S) and both are within the scope of the present invention. In the processes described above, the final products may, in some cases, contain a small amount of diastereomenic or enantiomeric products; however, these products do not affect their therapeutic or diagnostic application.
In all of the peptides of the invention, one or more amide linkages (�CO�NH�) may optionally be replaced with another linkage which is an isostere such as �CH2NH�, �CH2S�, �CH2�O�, �CH2CH2�, �CH═CH�(cis and trans), �COCH2�, �CH(OH)CH2�, �CH2SO�, and �CH2SO2�. This replacement can be made by methods known in the art. The following references describe preparation of peptide analogs which include these alternative-linking moieties: Spatola, �Peptide Backbone Modifications� (general review) Vega Data, Vol. 1, Issue 3, (March 1983); Spatola, �Chemistry and Biochemistry of Amino Acids, Peptides and Proteins,� (general review) B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983); Morley, Trends Pharm. Sci. (general review) pp. 463A468 (1980); Hudson, et al., Int. J. Pept. Prot. Res. 14:177-185 (1979) (�CH2NH�, �CH2CH2�); Spatola, et al., Life Sci. 38:1243-1249 (1986) (�CH2�S); Hann, J. Chem. Soc. Perkin Trans. I pp.307-314 (1982) (�CH═CH�, cis and trans); Almquist, et al. J. Med. Chem. 23:1392-1398 (1980) (�COCH2�); Jennings-White, et al., Tetrahedron Lett. 23:2533 (�COCH2�) (1982); Szelke, et al., European Application EP 45665; CA:97:39405 (1982) (�CH(OH)CH2�); Holladay, et al., Tetrahedron Lett 24:4401-4404 (1983) (�CH(OH)CH2�); and Hnuby, Life Sci. 31:189-199 (1982) (�CH2�S�).
Preferred Embodiments This invention relates to a new class of fused aryl diazepinone compounds selected from those of general formula I which are potent and specific inhibitors of Xa, their pharmaceutically acceptable compositions thereof, and the methods of using them as therapeutic agents for disease states in mammals characterized by abnormal thrombosis: Wherein:
L is selected from the group consisting of R33, �NR33R34, where R33, R34, R35 and R36 are independently selected from the group consisting of H, �OH, C1-6alkyl, aryl and C1-4alkylaryl; R37 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R35 or R36 to form a 5-6 membered ring; and R38 is selected from the group consisting of H, C1-6alkyl, aryl and C1-4alkylaryl, or can be taken together with R36 to form a 5-6 membered ring;
In the �J� substituent, it is preferred that R15 R16, R17, R18, R19 and R20 are independently selected from the group consisting of H and C1-6alkyl, more preferably H and methyl.
Preferably at least three of K′, K″, K′″ and K″″ are �CH�; more preferably K′, K″, K′″ and K″″ are all �CH�. When one of the K's are �CR4� or �CR5�, then R4 or R5 is preferably halogen.
In the various �L� substituents, it is preferred that R33, R34, R35 and R36 are independently selected from the group consisting of H and C1-6alkyl; and are more preferably independently selected from the group consisting of H and methyl. It is also preferred that R37 is H, C1-6alkyl or taken together with R35 or R36 to form a 5-6 membered ring; and is more preferably H or methyl. It is also preferred that R38 is H, C1-6alkyl or taken together with R36 to form a 5-6 membered ring; and is more preferably H or methyl. M is preferably a direct link, C1-6alkyl, C3-8cycloalkyl, aryl, or a five to ten membered heterocyclic ring system. More preferably, M is C1-4alkyl, aryl, or a five to ten membered heterocyclic ring system. The integer q is preferably 0.
When W is: then R27 is preferably H and R28 is preferably H. When T is: then U′ is preferably O, U″ is preferably N and R25 is preferably �CF3 or �CF2CF3.
In one preferred embodiment of the invention, s is 0; R2 and R3 are H; K′. K″. K′″ and K″″ are �CH�; and Q is �C(O)�T. This is also illustrated as a preferred group of compounds defined by the general structural formula II as: A preferred embodiment of compounds of general structural formula II have the following stereochemistry: In another preferred embodiment of the invention, s is 0; r is 3; R1, R2 and R3 are H; K′. K″. K′″ and K″″ are �CH�; G is a bond; J is: where R15, R17, R18 and R19 are all H; and Q is �C(O)�T. This is also illustrated as a preferred group of compounds defined by the general structural formula III as: A preferred embodiment of compounds of general structural formula III have the following stereochemistry: This invention also encompasses all pharmaceutically acceptable isomers, salts, hydrates and solvates of the compounds of formulas I, II and III. In addition, the compounds of formulas I, II and III can exist in various isomeric and tautomeric forms, and all such forms are meant to be included in the invention, along with pharmaceutically acceptable salts, hydrates and solvates of such isomers and tautomers.
This invention also encompasses prodrug derivatives of the compounds contained herein. The term �prodrug� refers to a pharmacologically inactive derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug. Prodrugs are variations or derivatives of the compounds of this invention which have groups cleavable under metabolic conditions. Prodrugs become the compounds of the invention which are pharmaceutically active in vivo, when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. Prodrug compounds of this invention may be called single, double, triple etc., depending on the number of biotransformation steps required to release the active drug within the organism, and indicating the number of functionalities present in a precursor-type form. Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, Calif., 1992). Prodrugs commonly known in the art include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, or arnides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative. Moreover, the prodrug derivatives of this invention may be combined with other features herein taught to enhance bioavailability.
The following structures are illustrative of the compounds of the present invention and are not intended to be limiting in any manner. It is to be noted that in the compounds of the invention, certain substituents are present between two other substituents. For example, D is positioned between A- and �(CH2)t�E�. Accordingly, substituents such as D are illustrated below as having two �dangling� bonds, the bond on the left representing a direct link to substituent A- and the bond on the right representing a direct link to �(CH2)t�E�. Therefore, the general formula of A�D�(CH2)t�E� where D is phenyl can be written as: D, a phenyl group, would then be written as follows in the tables below: Other substituents in the table below may also be presented as having one or two similar �dangling� bonds. It is understood that these represent direct links to the adjacent substituent(s). It is also understood that the compounds illustrated below can exist as other isomers, and the isomeric form illustrated herein is not intended to be limiting in any manner.
The invention encompasses compounds of general structural formula IV, where R1, R2 and R3 are H; r is 3; q and s are 0; G is a direct link; J is �NH�C(NH)NH2; K′, K″, K′″ and K″″ are �CH�; L is H; M is a direct link; and Q is (IV)
The invention encompasses compounds of general structural formula V, where R1, R2 and R3 are H; r is 3; q and s are 0; G is a direct link; J is �NH�C(NH)NH2; K′, K″, K′″ and K″″ are �CH�; L is H; M is and Q is (V)
The encompasses compounds of general structural formula VI, where R1, R2 and R3 are H; q is 0; t is 1; A is H; D is phenyl; E is �SO2�; K′, K″, K′″ and K″″ are �CH�; L is H; M is a direct link; and Q is (VI)
�NH2 The invention encompasses compounds of general structural formula VII, where q is 0; r is 3; s is 0; t is 1; A is H; D is phenyl; E is �SO2�; G is a direct link; J is �NH�C(NH)NH2; K′, K″, K′″ and K″″ are �CH�; L is H; M is a direct link; and Q is (VII)
The invention encompasses compounds of general structural formula VIII, where R1, R2 and R3 are H; q is 0; r is 3; s is 0; t is 1; A is H; D is phenyl; E is �SO2�; G is a direct link; J is �NH�C(NH)NH2; K′, K″, K′″ and K″″ are �CH�; L is H; and M is a direct link:
�C(O)�CF2CF3 11
The invention encompasses compounds of general structural formula IX, where R1, R2 and R3 are H; q and s are 0; r is 3; t is 1; A and L are H; D is phenyl; E is �SO2�; G and M are direct links; J is �NH�C(NH)NH2; and Q is (IX)
The invention encompasses compounds of general structural formula X, where R1, R2 and R3 are H; s is 0; r is 3; t is 1; A is H; D is phenyl; E is �SO2�; G is a direct link; K′, K″, K′″ and K″″ are �CH�, J is �NH�C(NH)NH2; and Q is (X)
The compounds of the present invention may also be used in combination with other therapeutic or diagnostic agents. In certain preferred embodiments, the compounds of this invention may be coadministered along with other compounds typically prescribed for these conditions according to generally accepted medical practice such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin. The compounds of the present invention may act in a synergistic fashion to prevent reocclusion following a successful thrombolytic therapy and/or reduce the time to reperftision. These compounds may also allow for reduced doses of the thrombolytic agents to be used and therefore minimize potential hemorrhagic side-effects. The compounds of this invention can be utilized in vivo, ordinarily in mammals such as primates, (e.g. humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
Formulations of the compounds of this invention are prepared for storage or administration by mixing the compound having a desired degree of-purity with physiologically acceptable carriers, excipients, stabilizers etc., and may be provided in sustained release or timed release formulations. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A.R. Gennaro edit. 1985). Such materials are nontoxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counterions such as sodium and/or nonionic surfactants such as Tween, Pluronics or polyethyleneglycol.
The compounds of formula (b) wherein Q is a boron containing compound can be prepared by the methods disclosed in J. Org. Chem. 60:3717-3722-(1995) and de Nanteuil, et al., EP 688,788, the disclosures of which are incorporated herein by reference.
The compounds of formula (b) wherein Q is �C(O)�T, where T is H, may be prepared by the methods disclosed in WO 93/15756, supra; Vlasuk, et al., WO 94/17817; Abelman, et al., WO 94/21673; Webb, et al., WO 94/08941; Veber, et al., WO 94/25051; Levy, etal., WO 95/35312; Semple, et al., WO 95/35313; Abelman, et al., WO 95/28420; and Abelman, et al., WO 96/19493, the disclosures of which are incorporated herein by reference.
The compounds of formula (b) wherein Q is �C(O)�T, where T is and V is �S�, �O�, �SO� or �SO2� can be readily synthesized by the methods disclosed in Costanzo, et al., U.S. Pat. No. 5,523,308; Di Maio, et al., WO 96/19483; U.S. Pat. No. 5,164,371; J. Am. Chem. Soc. 114: 1854-1863 (1992); J. Med. Chem. 38:76-85 (1995); and J. Med. Chem. 37:3492-3502 (1994). Lastly, fragments where V is �NR21�, where R21 is H, C1-6alkyl or benzyl, can be synthesized by techniques illustrated in J. Med. Chem. 37:3492-3502 (1994). All of these references are incorporated herein by reference.
The starting compound of formula (a) is either a known compound or can be produced by known methods (Heitsch, et al., Canadian Patent No. 2,071,744; Sugihara, et al., Canadian Patent No. 2,126,026; Baker, et al., EP 365,992; U.S. Pat. No. 4,251,438; Carr, etal., U.S. Pat. No. 4,341,698; Goldman, etal., U.S. Pat. No. 5,120,718; Biswanath, et al., U.S. Pat. No. 5,164,388; Duggan, etal., U.S. Pat. No. 5,281,585; Sugihara, etal., U.S. Pat. No. 5,294,713; Bovy, et al., WO 95/06038; WO 95/35308; J. Chem. Soc. Perkin Trans. I 1687-1689 (1989); and Int. J. Peptide Protein Res. 37:468475 (1991)) or can be prepared by the methods shown in the following reaction formulae.
EXAMPLE 1 To a suspension of Boc-Arg(Tos)-OH (2 g, 4.7 mmol) in DMF (20 mL) at 0� C. was added MeNHOMe.HCl (1 g, 10.3 mmol), DIEA (6 mL) and BOP (2.5 g, 5.6 mmol). The solution was stirred at 0� C. for 10 hours. DMF was evaporated by vacuum. The oily residue was dissolved in EtOAc (200 mL) and water (20 mL). The organic layer was washed with sat. NaHCO3, water (20 mL), 1 M HCl (10 mL) and sat. NaCl (2�20 mL). The organic layer was dried over MgSO4, filtered and evaporated to give a suspension. The suspension was filtered, and the solid was washed with cold EtOAc (10 mL) and dried to give Boc-Arg(Tos)-N(Me)OMe, shown above, (1.5 g, 70% yield). FAB-MS (M+H)+=472
EXAMPLE 2 To a solution of thiazole (2.5 g, 29 mmol) in THF (25 mL) at −78� C. was added n-BuLi (1.6 M in hexane, 19 mnL) dropwise. The mixture was stirred for 30 minutes. Then a solution of Boc-Arg(Tos)-N(Me)OMe, from Example 1, (1.7 g, 3.6 mmol) in THF (50 mL) was added to the lithiothiazole mixture at −78� C. The solution was stirred for 2 hours. 1M HCl (30 mL) was added to the reaction mixture and warmed to room temperature. The mixture was extracted with EtOAc (100 mL). The organic layer was washed with sat. NaCl (30 mL), dried over MgSO4, filtered and evaporated. The crude oily residue was purified by flash column chromatography over SiO2 (50% EtOAc in CH2Cl2) to give Boc-Arg(Tos)-thiazole, shown above, (1.5 g, 84% yield) as a powder. DCI-MS (M+H)+=496
EXAMPLE 3 To a solution of Boc-Arg(Tos)-thiazole from Example 2, (300 mg, 0.6 mmol) in CH2Cl2 (10 mL) at 0� C., was added TFA (10 mL). The solution was stirred at 0� C. for 2 hours. The solvent and excess TFA were evaporated to give an oily residue which was then used directly without further purification.
EXAMPLE 4 Part 1 Preparation of methyl 2-(3-(((9H-9-fluorenylmethoxy)carbonyl)amino)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)acetate: A solution of (R,S)Fmoc-3-amino-N-1-carboxymethyl-2-oxo-5-phenyl-1,4-benzodiazepine from Neosystem Laboratorie (Strasbourg, France) (212 mg, 0.4 mmol) in MeOH at 0� C., was treated with excess amount of thionyl chloride (20 eq). The mixture was stirred at room temperature overnight and evaporated to give the title compound (100% yield). ES-MS (M+H)+=546.2.
Part 2 Preparation of methyl 2-(3-amino-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)acetate: A solution of the compound of Part 1 (226 mg, 0.4 mmol) in DMF (2 mL) was treated with piperidine (0.5 mL, 5 mmol) to make a final solution of 20% piperidine/DMF and stirred at room temperature overnight. The reaction mixture was evaporated in vacuo then acidified with 10% HCl and extracted with CH2Cl2. The aqueous layer was then neutralized with 1N NaOH and extracted with EtOAc. The organic layer was dried over Na2SO4 and evaporated in vacuo to give title compound (99% yield). ES-MS (M+H)+=324.2.
Part 3 Preparation of methyl 2-(3-((benzylsulfonyl)amino)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)acetate: To a solution of the compound of Part 2 (128 mg, 0. 4 mmol) and DIEA (0.092 mL, 0.5 mmol) in CH2Cl2 (2 mL) at −78� C., was added α-toluenesulfonyl chloride (92 mg, 0.48 mmol). The mixture was stirred at −78� C. for three hours and evaporated in vacuo. The residue was dissolved in EtOAc and washed with H2O, sat. NaHCO3, sat. NaCl, dried over Na2SO4 and evaporated to give the title compound as a solid (67% yield). ES-MS (M+H)+=478.3.
Part 4 Preparation of 2-(3-((benzylsulfonyl)amino)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)acetic acid: A solution of the compound of Part 3 (128 mg, 0.27 mmol) in THF (2 mL) was treated with 2 N LiOH (0.54 mL, 1.08 mmol). The mixture was stirred at room temperature overnight. The organic solvent was evaporated in vacuo. The aqueous layer was acidified to pH 2-3 with 1N aq HCl, extracted with EtOAc and the organic layer was dried over Na2SO4 and evaporated to give the title compound (100% yield). ES-MS (M+H)+=464.0.
Part 5 Preparation of N1-(1R)-4-((imino(((4-methylphenyl)sulfonyl)amino)methyl) amino)-1-(1,3-thiazol-2-ylcarbonyl)butyl)-2-(3-((benzylsulfonyl)amino)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)acetamide: The compound of Part 4 (0.3 mmol) was dissolved in DMF (2 mL) and cooled to 0� C. The solution was neutralized with DIEA followed by addition of the compound of Example 3 (142 mg, 0.36 mmol) and coupling reagent HBTU (136 mg, 0.36 mmol). The solution was stirred at room temperature overnight. The reaction mixture was diluted in a mixture of EtOAc/H2O. The organic layer was washed with sat. NaHCO3, sat. NaCl, dried over Na2SO4, and solvent evaporated to give the title compound (82% yield). ES-MS (M+H)+=841.4.
Part 6 Preparation of N1-((1R)-4-((amino(imino)methyl)amino)-1-(1,3-thiazol-2-ylcarbonyl)butyl)-2-(3-((benzylsulfonyl)amino)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)acetamide (Compound X(8)): The compound of Part 5 (206 mg, 0.25 mmol), anisole (1 mL) and ethyl methyl sulfide (two drops) were placed in HF-cleavage vessel and cooled under liquid N2. HF (10 mL) was then condensed and the mixture was stirred at −10� C. for half hour and 0� C. for half hour. HF was removed under vacuum to give a gum-like residue. The residue was triturated with 50% Et2O in hexane (20 mL) and the solvent removed by filtration. The gum residue was dissolved in 0.1% aq. TFA (15 mnL) and filtered through the above sintered funnel. The filtrate was lyophilized to give a powder which was purified by RP-HPLC to give the title compound as inseparable diastereoisomers as a white powder (85% yield). ES-MS (M+H)+=686.8.
EXAMPLE 5 Part 1 Preparation of 9H-9-fluorenylmethyl N-(1-(2-(((1R)4-((imino(((4-methylphenyl)sulfonyl)amino)methyl)amino)-1-(1,3-thiazol-2-ylcarbonyl)butyl)amino)-2-oxoethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)carbamate: (R,S)Fmoc-3-amino-N-1-carboxymethyl-2-oxo-5-phenyl-1,4-benzodiazepine from Neosystem Laboratorie (134 mg, 0.25 mmol) was dissolved in DMF (2 mL) and cooled to 0� C. The solution was neutralized with DIEA followed by addition of the compound of Example 3 (118 mg, 0.3 mmol) and coupling reagent HBTU (114 mg, 0.3 mmol). The solution was stirred overnight at room temperature. The reaction mixture was diluted in a mixture of EtOAc/H2O. The organic layer was washed with sat. NaHCO3, sat. NaCl, dried over Na2SO4, filtered and solvent evaporated to give the title compound (93% yield). ES-MS (M+H)+=909.3.
Part 2 Preparation of N1-((1R)4-((imino(((4-methylphenyl)sulfonyl)amino)methyl) amino)-1-(1,3-thiazol-2-ylcarbonyl)butyl)-2-(3-amino-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)acetamide: A solution of the compound of Part 1 (211 mg, 0.232 mmol) in DMF (2 mL) was treated with piperidine (0.5 mL, 5 mmol) to make a final solution of 20% piperidine/DMF and stirred at room temperature overnight. The reaction mixture was evaporated in vacuo then acidified with 10% HCl and extracted with CH2Cl2. The aqueous layer was then neutralized with IN NaOH and extracted with EtOAc. The organic layer was dried over Na2SO4 and evaporated in vacuo to give title compound (100% yield). ES-MS (M+H)+=687.1.
Part 3 Preparation of N1-((1R)4-((amnino(imino)methyl)amino)-1-(1,3-thiazol-2-ylcarbonyl)butyl)-2-(3-amino-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-1-yl)acetamide (Compound V(1)): The compound of Part 2 (0.232 mrnmol), anisole (1 mL) and ethyl methyl sulfide (two drops) were placed in HF-cleavage vessel and cooled under liquid N2. HF (10 mL) was then condensed and the mixture was stirred at −10� C. for half hour and 0� C. for half hour. HF was removed under vacuum to give a gum-like residue. The residue was triturated with 50% Et2O in hexane (20 mL) and the solvent removed by filtration. The gum residue was dissolved in 0.1% aq. TFA (15 mL) and filtered through the above sintered funnel. The filtrate was lyophilized to give a powder which was purified by RP-HPLC to give the title compound as inseparable diastereoisomers as a white powder (88% yield). ES-MS (M+H)+=533.1.
EXAMPLE 6 Determination of IC50 The compounds of the present invention are first dissolved in a buffer to give solutions containing concentrations such that assay concentrations range from 0-100 μM. In assays for thrombin, prothrombinase and factor Xa, a synthetic chromogenic substrate would be added to a solution containing a test compound and the enzyme of interest and the residual catalytic activity of that enzyme would then be determined spectrophotometrically.
EXAMPLE 7 The antithrombotic efficacy of the compounds of this invention can readily be evaluated using a series of studies in rabbits, as described below. These studies are also useful in evaluating a compounds effects on hemostasis and its the hematological parameters.
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OlsonCyclic malonamides as inhibitors of aβ protein productionUS6794381Feb 17, 2000Sep 21, 2004Bristol-Myers Squibb CompanySuccinoylamino lactams as inhibitors of aβ proteinUS6962913Nov 1, 2002Nov 8, 2005Bristol-Myers Squibb CompanyBenzo-1,4-diazepin-2-ones as inhibitors of Aβ protein productionUS7053081Dec 24, 2003May 30, 2006Bristol-Myers Squibb Pharma CompanyCyclic malonamides as inhibitors of A-β protein productionUS7101870Jul 6, 2005Sep 5, 2006Bristol-Myers Squibb Pharma CompanySuccinoylamino lactams as inhibitors of A-β protein productionUS7276496Jan 6, 2006Oct 2, 2007Bristol-Myers Squibb Pharma CompanyCyclic malonamides as inhibitors of Aβ protein protectionUS7304055Jul 25, 2006Dec 4, 2007Bristol-Myers Squibb Pharma CompanySuccinoylamino lactams as inhibitors of Aβ protein productionUS7304056Jul 26, 2006Dec 4, 2007Bristol-Myers Squibb Pharma CompanySuccinoylamino lactams as inhibitors of Aβ protein productionUS7390896Aug 20, 2007Jun 24, 2008Bristol-Myers Squibb Pharma CorporationCyclic malonamides as inhibitors of Aβ protein productionUS7507815Dec 4, 2007Mar 24, 2009Bristol-Myers Squibb Pharma CompanySuccinoylamino lactams as inhibitors of a-β protein productionUS7528249Jun 19, 2008May 5, 2009Bristol-Myers Squibb Pharma CompanyCyclic malonamides as inhibitors of aβ protein productionClassifications U.S. Classification514/221, 540/509International ClassificationA61K38/00, C07K5/078, C07K5/06Cooperative ClassificationC07K5/06191, C07K5/06139, A61K38/00European ClassificationC07K5/06H, C07K5/06TLegal EventsDateCodeEventDescriptionFeb 21, 2006FPExpired due to failure to pay maintenance feeEffective date: 20051225Dec 27, 2005LAPSLapse for failure to pay maintenance feesJul 13, 2005REMIMaintenance fee reminder mailedMay 24, 2002ASAssignmentOwner name: MILLENNIUM PHARMACEUTICALS, INC., MASSACHUSETTSFree format text: MERGER;ASSIGNOR:COR THERAPEUTICS, INC.;REEL/FRAME:012928/0446Effective date: 20020212Owner name: MILLENNIUM PHARMACEUTICALS, INC. 75 SIDNEY STREETOwner name: MILLENNIUM PHARMACEUTICALS, INC. 75 SIDNEY STREETCFree format text: MERGER;ASSIGNOR:COR THERAPEUTICS, INC. /AR;REEL/FRAME:012928/0446Nov 10, 1998ASAssignmentOwner name: COR THERAPEUTICS, INC., CALIFORNIAFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:SCARBOROUGH, ROBERT M.;REEL/FRAME:009585/0074Effective date: 19981008RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google