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Serine protease inhibitors

a protease inhibitor and protease technology, applied in the direction of drug compositions, peptide/protein ingredients, extracellular fluid disorder, etc., can solve the problems of pulmonary embolism, reduced blood flow to the affected area, reduced blood flow, etc., to prevent or treat thrombosis

Inactive Publication Date: 2005-08-25
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0019] Accordingly, one object of the present invention is to provide novel compounds which inhibit factors / enzymes in the coagulation cascade and which are useful to prevent or treat thrombus formation in artertial or venous vessels. These compounds are useful as coagulation factor inhibitors and as anticoagulants in general.

Problems solved by technology

Furthermore, a high percentage of patients undergoing surgery, particularly in the lower extremities, suffer thrombus formation in the venous vascular system which results in reduced blood flow to the affected area.
In the venous vasculature, many patients undergoing surgery, particularly in the abdominal and lower body regions, experience thrombus formation which reduces blood flow and can lead to a pulmonary embolism.
Disseminated intravascular coagulopathy in both the venous and arterial systems occurs commonly during septic shock, some viral infections, and cancer and may lead to rapid and widespread thrombus formation and organ failure.
However, arterial thrombosis following these procedures remains a leading cause of failure.
Heparin, the most widely used anticoagulant, has not been shown to be entirely effective in the treatment and prevention of acute arterial thrombosis or rethrombosis.
The synthesis and development of small molecule inhibitors based on the known three-dimensional structure of proteins is a challenge of modern drug development.

Method used

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Examples

Experimental program
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Effect test

embodiments

[0086] The invention is generally directed to compounds having the structure shown below.

[0087] In this structure R2, R5, R6, A, B, N1, N2, Q, X, and Y have the meanings described above. In these meanings, alkyl is preferably unsubstituted or substituted C1-C6 alkyl; alkenyl is preferably unsubstituted or substituted C2-C6 alkenyl; alkynyl is preferably unsubstituted or substituted C2-C6 alkynyl; aryl is preferably unsubstituted or substituted naphthyl or phenyl, more preferably phenyl; aralkyl is preferably unsubstituted or substituted benzyl. The variable m is preferably 1.

[0088] The group Y is preferably S(O)n—R1 where n=1 or 2 or the group S(O)n—NR2R2 where n=1 or 2, more preferably S(O)n—R1.

[0089] In one preferred embodiment, R1, for example when Y is S(O)n—R1, is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, phenyl, naphthyl, benzyl and heteroaryl having 5-6 ring atoms selected from carbon atoms and 1-2 heteroatoms, wher...

example 1

[0155]

[0156] 4-benzyloxy-3-methoxy-styrene (10 g, 42 mmoles) was dissolved in dichloromethane (400 ml). Solid potassium bicarbonate (11 g, 110 mmoles) was added and the reaction cooled to zero degrees Celsius. Meta-chloroperbenzoic acid (12 g, ca. 42 mmoles) was added and the reaction allowed to warm to room temperature and stirred for 16 hours. The reaction was monitored by thin-layer chromatography. An additional amount of meta-chloroperbenzoic acid (4 g) was added and the reaction stirred for an additional 4 hours to completely consume starting material. The reaction was poured into a separatory funnel and washed first with water, then with sodium bicarbonate and finally with NaOH. The organic layer was separated and dried over anhydrous sodium sulfate. The solution was filtered and the solvent removed in vacuo to yield approximately 11 g of crude product.

[0157] The crude product was then dissolved in acetonitrile (60 ml) and lithium perchlorate (8.5 g, 80 mmoles) added. The sus...

examples 2a-2dd

[0163] Using an analogous procedure, other compounds of the invention were prepared, including: [0164] a) 4-[Benzenesulfonylamino-1-(4-benzyloxy-3-methoxy-phenyl)-ethylamino]-benzamidine:

[0165] MS (M+H)=531, [0166] b) N-{4-[2-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-carbamimidoyl-phenylamino)-ethylsulfamoyl]-phenyl}-acetamide: MS (M+H)=588, [0167] c) 4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-nitro-benzenesulfonylamino)-ethylamino]-benzamidine: MS (M+H)=576, [0168] d) 4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-fluoro-benzenesulfonylamino)-ethylamino]-benzamidine: MS (M+H)=549, [0169] e) 4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(4-fluoro-benzenesulfonylamino)-ethylamino]-benzamidine: MS (M+H)=565, [0170] f) 4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(3-nitro-benzenesulfonylamino)-ethylamino-benzamidine: MS (M+H)=576, [0171] g) 4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(2,5-dichloro-benzenesulfonylamino)-ethylamino]-benzamidine: MS (M+H)=599, [0172] h) 4-[1-(4-Benzyloxy-3-methoxy-phenyl)-2-(2-bromo-benze...

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Abstract

Compounds having the structure shown below are useful to inhibit serine protease enzymes, such as TF / factor VIIa, factor Xa, thrombin and kallikrein. These compounds may be used in methods of preventing and / or treating clotting disorders.

Description

[0001] This application is a continuation of U.S. application Ser. No. 10 / 224,114, filed Aug. 19, 2002, which is a continuation of U.S. application Ser. No. 09 / 509,104, filed Mar. 21, 2000, now U.S. Pat. No. 6,472,393, issued Oct. 29, 2002, which is a US national phase application of PCT / US00 / 00673, filed Jan. 11, 2000, which claims priority under 35 USC §119 to U.S. Provisional Application No. 60 / 115,772, filed Jan. 13, 1999, and U.S. Provisional Application No. 60 / 152,029, filed on Sep. 1, 1999, which applications are incorporated by reference and the benefit of the earlier filing date is claimed under 35 USC. §120.DISCUSSION OF THE BACKGROUND [0002] 1. Field of the Invention [0003] In one aspect, the invention relates to novel compounds which are inhibitors of Tissue Factor (TF) / factor VIIa, factor VIIa, factor Xa, thrombin and / or kallikrein, as well as compositions containing these compounds. The compounds are useful for inhibiting these factors and for treating disorders mediat...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/18A61K31/196A61K31/216A61K31/381A61P7/02C07D333/34A61P9/10C07C257/18C07C311/05C07C311/08C07C311/13C07C311/18C07C311/29C07C311/51
CPCC07C257/18C07C311/05C07C311/08C07C311/13C07C311/18C07C311/29C07C311/51A61P7/02A61P9/10C07D209/48
Inventor ALIAGAS-MARTIN, IGNACIOARTIS, DEANDINA, MICHAELFLYGARE, JOHNGOLDSMITH, RICHARDMUNROE, REGINAOLIVERO, ALANPASTOR, RICHARDRAWSON, THOMASROBARGE, KIRKSUTHERLIN, DANIELWEESE, KENNETHZHOU, AIHEZHU, YAN
Owner GENENTECH INC
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