ACYLSULFAMIDE INHIBITORS OF FACTOR VIIa

a technology of acylsulfamide and inhibitors, applied in the direction of biocide, drug composition, extracellular fluid disorder, etc., can solve the problems of pulmonary embolism, reduced blood flow to the affected area, and reduced blood flow, so as to improve the pharmacokinetic

Inactive Publication Date: 2007-02-15
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0046] Prodrug forms of Formula I compounds, e.g. where Pr1 and / or Pr2 forms a prodrug moiety, may possess improved pharmacokinetic, e.g. oral bioavailability, properties.

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.
Also, typically the cost of monitoring blood levels far exceeds the cost of coumarin and heparin type anticoagulant therapy.
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
Comparison scheme
Effect test

example 1

[0199]

[0200] 4-Benzyloxy-5-methoxy-2-nitrobenzaldehyde (12.2 g 42 mmoles) and 4-aminobenzonitrile (5 g, 42 mmoles) were dissolved in methanol (165 ml) and stirred for two hours and then heated to 60° C. for 30 minutes. The reaction was allowed to cool to room temperature and benzyl isonitrile (5 g. 42 mmoles) added. The reaction was cooled to 0° C. and boron trifluoroetherate (16 ml, 126 mmoles) added dropwise over five minutes. The reaction was stirred at 0° C. for 20 minutes and then allowed to come to room temperature and then stirred at ambient temperature for two hours. Water (4 ml) was added and the mixture stirred at room temperature overnight. A yellow precipitate was evident the next morning and the solid filtered off. The solid was washed with methanol and air dried to yield 8 grams of the desired product. The solvent from the filtrate was removed in vacuo and replaced with ethyl acetate. The solution was washed with water and saturated sodium bicarbonate, dried over anhyd...

example 2

[0201]

[0202] The methyl ester of the acid above (920 mg 2.85 mmoles) was suspended in 3 / 1 THF / water (40 ml) and cooled to 0° C. The solution was treated with 1 N LiOH (7.1 ml, 7.1 mmoles) and allowed to stir overnight. The reaction was acidified with trifluoroacetic acid until pH=4.0 was obtained. The solvent was removed in vacuo and the crude material purified by flash chromatography (ethyl acetate with 0.5% acetic acid) to yield Ig of carboxylic acid.

example 3

[0203]

[0204] 4,5-diethoxy-2-nitrobenzaldehyde (55.5 gm, 206 mmoles) and 4-aminobenzonitrile (23 g, 195 mmoles) were dissolved in methanol (700 ml) and stirred at 60° C. for 2 hours. The reaction was allowed to cool to 0° C. and tosylmethylisonitrile (45 g. 230 mmoles) added. Boron trifluoroetherate (78 ml, 620 mmoles) was added dropwise over 10 minutes. The reaction was stirred at 0° C. for 30 minutes, allowed to come to room temperature and then stirred at ambient temperature for 1.5 hours. Water (18 ml) was added and the mixture stirred at room temperature overnight. The following day the methanol was removed in vacuo and the residue taken up in ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The sodium sulfate was filtered off and the ethyl acetate removed in vacuo. The crude material was submitted to flash chromatography (hexanes:ethyl acetate, 2:1 then 1:1) to yield 46 g of the desired product (4-ethoxy-5-ethoxy-2-nitro-pheny...

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PUM

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Abstract

Compounds having the general formula I are useful for inhibiting serine protease enzymes, such as Tissue Factor VIIa, factor Xa, thrombin and kallikrein and have improved permeability properties. These compounds may be used in methods of preventing and/or treating clotting disorders.

Description

[0001] This non-provisional application filed under 37 CFR §1.53(b), claims the benefit under 35 USC § 19(e) of U.S. Provisional Application Ser. No. 60 / 471,804 filed on May 20, 2003.FIELD OF THE INVENTION [0002] 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 mediated thereby. For example, the compounds are useful for preventing thrombosis or treating abnormal thrombosis in a mammal by inhibiting TF / factor VIIa, factor Xa, thrombin and / or kallikrein. BACKGROUND OF THE INVENTION [0003] Normal haemeostasis is the result of a complex balance between the processes of clot initiation, formation and clot dissolution. The complex interactions between blood cells, specific plasma proteins and the vascular surface, maintain the fluidity of blood ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/501A61K31/50A61K31/4439A61K31/44C07D403/02A61P7/02C07C307/06C07C311/51C07D307/79C07D307/80C07D307/81C07D307/82C07D307/86
CPCC07C307/06C07C311/51C07D307/79C07D307/86C07D307/81C07D307/82C07D307/80A61P7/02A61P43/00
Inventor RAWSON, THOMAS E.GAZZARD, LEWIS J.
Owner GENENTECH INC
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