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Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade

Inactive Publication Date: 2005-03-10
PHARMACIA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

It is another object of the present invention to provide methods for preventing and treating thrombotic conditions, such as coronary artery disease, cerebrovascular disease, and other coagulation related disorders. Such thrombotic conditions are prevented and treated by administering to a patient in need thereof an effective amount of compounds of Formula (I).

Problems solved by technology

Arterial thrombosis may result in ischemic necrosis of the tissue supplied by the artery.
When the thrombosis occurs in a coronary artery, a myocardial infarction or heart attack can result.
A thrombosis occurring in a vein may cause tissues drained by the vein to become edematous and inflamed.
Thrombosis of a deep vein may be complicated by a pulmonary embolism.

Method used

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  • Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
  • Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
  • Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade

Examples

Experimental program
Comparison scheme
Effect test

example 1

(EX-1A) A solution of ethyl benzimidate hydrochloride (92.25 g, 496.9 mmol) in 300.0 mL dry methanol (1.68 M) was cooled to ca 0° C. and added a solution of aminoacetaldehyde dimethyl acetal (73.10 mL, 670.9 mmol) in dry methanol (75.0 mL, 9.0 M) drop wise at such a rate the temperature was kept below 5° C. The resulting solution was allowed to stir for 3 days with the temperature being maintained below 5° C. The reaction mixture was then concentrated under reduced pressure to give a yellow oil. The residue was dissolved in 1 N NaOH (750 mL) and extracted with dichloromethane (4×250 mL). The organic solutions were combined, dried (MgSO4), and concentrated to give 108.13 g crude N-(2,2-dimethoxyethyl)benzamidine as a yellow oil. The crude N-(2,2-dimethoxyethyl)benzamidine (108.13 g, 519.2 mmol) in dry methanol (125.0 mL, 4.2 M) was added dimethyl methoxymethylenemalonate (94.13 g, 540.5 mmol) in one portion at room temperature. The resulting mixture was heated to approximately 100° ...

example 2

By following the method of Example 1, the title compound was prepared: 1H NMR (300 MHz, d-DMSO) δ 9.40-9.33 (m, 4H), 8.86 (s, 1H), 7.82 (s, 2H), 7.72-7.37 (m, 15H), 4.65-4.59 (m, 4H), 4.41-4.40 (m, 2H); HRMS (EI) calcd for C27H27N6O4S 531.1815, found 531.1794.

example 3

(EX-3A) A solution of [5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetic acid t-butyl ester (EX-1F) (613.7 mg, 2.037 mmol) in 7.0 mL tetrahydrofuran and dichloromethane (1:1, 0.3 M) was added 25.0 mL acetic acid and phenylacetaldehyde (0.475 mL, 4.060 mmol). The solution was cooled to 0° C. in an ice bath and added sodium triacetoxyborohydride (1.9131 g, 9.027 mmol) in one portion. After stirring for 5 minutes, the ice bath was removed and the reaction mixture was allowed to stir at room temperature for 2 hours. The reaction was quenched by the addition of 1 N NaOH (5 mL), and the mixture was stirred for 5 minutes. The reaction mixture was diluted 0.5 N NaOH (100 mL). The aqueous solution was extracted with ethyl acetate (3×25 mL). The combined organic solutions were washed with 0.5 N NaOH (1×25 mL) and brine (1×25 mL). The solution was dried (MgSO4), filtered and concentrated under reduced pressure. Purification by MPLC (25% ethyl acetate / hexanes) afforded EX-3A as a yellow ...

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Abstract

The invention relates to substituted polycyclic aryl and heteroaryl pyrimidinone compounds useful as inhibitors of serine proteases of the coagulation cascade and compounds, compositions and methods for anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular diseases.

Description

FIELD OF THE INVENTION This invention is in the field of anticoagulant therapy, and specifically relates to compounds, compositions and methods for preventing and treating thrombotic conditions such as coronary artery and cerebrovascular disease. More particularly, the invention relates to substituted polycyclic aryl and heteroaryl pyrimidinone compounds that inhibit serine proteases of the coagulation cascade. BACKGROUND OF THE INVENTION Physiological systems control the fluidity of blood in mammals [Majerus, P. W. et al: Anticoagulant, Thrombolytic, and Antiplplatelet Drugs. In Hardman, J. G. and Limbird, L. E., editors: Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th edition. New York, McGraw-Hill Book Co., 1996, pp. 1341-1343]. Blood must remain fluid within the vascular systems and yet be able to undergo hemostasis, cessation of blood loss from a damaged vessel, quickly. Hemostasis or clotting begins when platelets first adhere to macromolecules in subendoth...

Claims

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Application Information

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IPC IPC(8): C07D239/46C07D239/47C07D253/07C07D401/04C07D417/12
CPCC07D239/47C07D417/12C07D401/04C07D253/07
Inventor SOUTH, MICHAEL S.HAMME, ASHTON T. IINEUMANN, WILLIAM L.JONES, DARIN E.RUEPPEL, MELVIN L.
Owner PHARMACIA CORP
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