Substituted polycyclic aryl and heteroaryl pyrymidinones useful as anticoagulants agents

A ring carbon and alkyl technology, applied in the direction of blood diseases, antineoplastic drugs, cardiovascular system diseases, etc., can solve problems such as ischemic necrosis

Inactive Publication Date: 2002-05-29
PHARMACIA CORP
View PDF7 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Arterial thrombosis can lead to ischemic necrosis of the tissue supplied by the artery

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Substituted polycyclic aryl and heteroaryl pyrymidinones useful as anticoagulants agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0580] (EX-1A) 300.0ml of anhydrous methanol solution (1.68M) of ethyl benzimidate hydrochloride (92.25g, 496.9mmol) was cooled to about 0°C, and aminoacetaldehyde was added dropwise at such a rate Dimethyl acetal (73.10 mL, 670.9 mmol) was dissolved in anhydrous methanol (75.0 mL, 9.0 M), keeping the temperature below 5°C. The resulting solution was stirred for 3 days, keeping the temperature below 5°C. The reaction mixture was then concentrated under reduced pressure to give a yellow oil. The residue was dissolved in 1N NaOH (750ml) and extracted with dichloromethane (4 x 250ml). The organic solutions were combined and dried (MgSO 4 ), concentrated to give 108.13 g of crude N-(2,2-dimethoxyethyl)benzamidine as a yellow oil. To a solution of crude N-(2,2-dimethoxyethyl)benzamidine (108.13g, 519.2mmol) in anhydrous methanol (125.0ml, 4.2M) was added methoxysulfide in one portion at room temperature. Dimethyl methylmalonate (94.13 g, 540.5 mmol). The resulting mixture was ...

Embodiment 3

[0599] (EX-3A) to [5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl] acetate (EX-1F) (613.7mg, 2.037mmol) 25.0 ml of acetic acid and phenylacetaldehyde (0.475 ml, 4.060 mmol) were added to 7.0 ml of tetrahydrofuran and dichloromethane solution (1:1, 0.3 M). The solution was cooled to 0°C in an ice bath, and sodium triacetoxyborohydride (1.9131 g, 9.027 mmol) was added in one portion. After stirring for 5 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. 1N NaOH (5ml) was added to quench the reaction and the mixture was stirred for 5 minutes. The reaction mixture was diluted with 0.5N NaOH (100ml). The aqueous solution was extracted with ethyl acetate (3 x 25ml). The combined organic solutions were washed with 0.5N NaOH (1 x 25ml) and brine (1 x 25ml). Solution drying (MgSO 4 ), filtered and concentrated under reduced pressure. Purification by MPLC (25% ethyl acetate / hexanes) afforded EX-3A as a yellow oil in 74% yield...

preparation Embodiment 4

[0606] EX-4A) Under stirring, 1.1 N of potassium carbonate was added at one time to the solution of 5-nitro-2,4(1H,3H)pyrimidinedione in dimethyl sulfoxide (0.2M). After about 10 minutes, a solution of 1 equivalent of 2-(trimethylsilyl)ethoxymethyl chloride in dimethylsulfoxide was added dropwise. The reaction mixture was then heated to 40°C and stirred for 18 hours. Typical aqueous workup followed by chromatographic purification afforded pure product EX-4A.

[0607] EX-4B) Under stirring, add 1.1 l equivalent of potassium carbonate. After about 10 minutes, a solution of 1 equivalent of methyl bromoacetate in dimethyl sulfoxide was added dropwise. The reaction mixture was then heated to 40°C and stirred for 18 hours. Typical aqueous work-up followed by chromatographic purification affords pure product EX-4B.

[0608] EX-4C) A methanolic solution of 5-nitro-1-SEM-3-methoxycarbonylmethyl-2,4(1H,3H)pyrimidinedione (EX-4B) was degassed with hydrogen. Then 5% Pd / C was added t...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

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 invention [0001] The present invention belongs to the field of anticoagulant therapy, and in particular relates to compounds, compositions and methods for preventing and treating thrombotic diseases, such as coronary artery and cerebrovascular diseases. More specifically, the present invention relates to substituted polycyclic aryl and heteroaryl pyrimidinone compounds which inhibit serine proteases of the coagulation cascade. Background of the invention [0002] Physiological systems control the fluidity of mammalian blood [Majerus, P.W. et al. "Anticoagulant, Thrombolytic, and Antiplatelet Drugs." Hardman, J.G. and Limbird, L.E. eds. Goodman & Gilman's Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th Edition, New York, McGraw-Hill Book Co., 1996, pp. 1341-1343]. Blood must remain flowing within the vasculature and also be able to undergo rapid hemostasis, the cessation of blood loss from damaged blood vessels. Hemostasis or ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/513A61K31/53A61K45/00A61P7/02A61P9/00A61P9/10C07D253/06A61P11/00A61P43/00C07D239/46C07D239/47C07D253/07C07D401/04C07D417/12
CPCC07D239/47C07D417/12C07D253/07C07D401/04A61P11/00A61P35/00A61P43/00A61P7/00A61P7/02A61P7/04A61P9/00A61P9/02A61P9/04A61P9/10
Inventor M·S·索斯A·T·翰米二世W·纽曼D·E·琼斯M·L·鲁佩尔
Owner PHARMACIA CORP
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap