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Substituted-(quinazolinyl)phenyl thiophenyl-sulfonylureas, methods for making and intermediates thereof

a technology of phenyl thiophenyl sulfonylurea and substituted(quinazolinyl) phenyl thiophenyl sulfonylurea, which is applied in the directions of drug composition, extracellular fluid disorder, biocide, etc., can solve the problems of thrombotic complications and vascular occlusion, and achieve the effect of prevention or treatmen

Inactive Publication Date: 2007-09-06
ALEXION PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to compounds that inhibit platelet aggregation and have antithrombotic activity. The invention provides methods for making certain compounds and pharmaceutically acceptable salts thereof. These compounds are useful for the prevention or treatment of cardiovascular diseases, particularly those related to thrombosis. The invention also provides intermediate compounds that can be used to make the final compounds.

Problems solved by technology

Thrombotic complications are a major cause of death in the industrialized world.
Blood platelets, which normally circulate freely in the vasculature, become activated and aggregate to form a thrombus from disturbed blood flow caused by ruptured atherosclerotic lesions or by invasive treatments such as angioplasty, resulting in vascular occlusion.

Method used

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  • Substituted-(quinazolinyl)phenyl thiophenyl-sulfonylureas, methods for making and intermediates thereof
  • Substituted-(quinazolinyl)phenyl thiophenyl-sulfonylureas, methods for making and intermediates thereof
  • Substituted-(quinazolinyl)phenyl thiophenyl-sulfonylureas, methods for making and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of the Intermediate Sulfonylurea Carbamate (8)

[0138]

[0139] The following procedure was adapted from C. A. Hunt, et al. J. Med. Chem. 1994, 37, 240-247. In a three-necked R.B. flask, equipped with a mechanical stirrer, an air condenser, a dropping funnel, and a moisture-guard tube, was placed chlorosulfonic acid (240 mL, 3.594 mol). Under stirring, PCl5 (300 g, 1.44 mol, 0.40 equiv) was added in portions, over ca. 45 mins. During the addition, a large volume of HCl gas evolved vigorously, but the temperature of the mixture did not rise significantly (5 had been added, an almost clear, pale yellow solution resulted, with only a few solid pieces of PCl5 floating in the suspension. It was stirred until gas evolution ceased (0.5 h).

[0140] Then the reaction vessel was cooled in ice, and 2-chloro-thiophene (66.0 mL, 0.715 mol) was added via the dropping funnel, over 1.0 h. With the addition of the very first few drops of 2-Cl-thiophene, the mixture turned dark purple, and by th...

example 2

Synthesis of [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea (7a)

[0148]

Step 1

[0149] Aniline 1 (1H NMR (DMSO): δ 7.58 (dd, 1H), 6.72 (dd, 1H), 3.77 (s, 3H); 6.0 g, 32.085 mmol) was placed in a 500 mL round bottomed flask and 20% phosgene in toluene (175 mL, 332.50 mmol, 10.36 equiv) was added. The resulting somewhat sticky suspension was then magnetically stirred overnight at room temperature resulting in a clear, colorless solution. An aliquot removed, blown dry with argon, quenched with MeOH, and analyzed by RP-HPLC / MS to show no unreacted aniline 1 and clean formation of the isocyanate 2a and / or carbamoyl chloride 2b as analyzed as its methyl-carbamate. The mixture was concentrated first by rotary evaporation and then under high vacuum to yield 6.76 g (99% yield) of the isocyanate 2a and / or carbamoyl chloride 2b as a free-flowing colorless solid.

Step 2

[0150] In a 500 mL R. B. flask was placed N-Boc-1,4-phenyle...

example 3

Synthesis of [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea (7a)

[0157]

Step 1:

[0158] Methyl 2-amino-4,5-difluorobenzoate [2] (38 Kg, 1.0 eq) and dichloromethane (560 Kg, 8×, ACS>99.5%) were charged to a PP1-R1000 reactor (2000L GL reactor). The reaction mixture was agitated for 5 mins. 4-Nitrophenylchloroformate (49.1 Kg, 1.2 equiv) was charged into PP1-R2000 reactor (200L) followed by dichloromethane (185 Kg) and agitated the contents for 5 mins. After pressurizing the 200L reactor the 4-nitrophenylchloroformate solution was transferred into the 2000L reactor containing dichloromethane solution of [2]. The reaction mixture was heated to 40±5° C. (reflux) under nitrogen gas purge for 3 hrs. The representative TLC analysis confirmed reaction completion (in-process TLC, no compound 2 remaining; 99:1 CHCl3—MeOH). The solution was cooled to 30° C. and distilled off 460 Kg of dichloromethane under vacuum. The 2000L reac...

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Abstract

The present invention provides sulfonylurea compounds of formula (VIII) and pharmaceutically acceptable derivatives thereof and a process for making thereof. The compounds in their various forms are effective platelet ADP receptor inhibitors and may be used in various pharmaceutical compositions, and are particularly effective for the prevention and / or treatment of cardiovascular diseases, particularly those diseases related to thrombosis. The invention also provides intermediate compounds useful in the process, as well as final products produced by the process, and salts or prodrugs thereof. The invention also provides a method for inhibition platelet ADP receptor and preventing or treating thrombosis and thrombosis related conditions in a mammal comprising the step of administering a therapeutically effective amount of a compound of formula (VIII) or a pharmaceutically acceptable salt or forms thereof.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Patent Application No. 60 / 733,650, filed Nov. 3, 2005, the content of which are incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] Thrombotic complications are a major cause of death in the industrialized world. Examples of these complications include acute myocardial infarction, unstable angina, chronic stable angina, transient ischemic attacks, strokes, peripheral vascular disease, preeclampsia / eclampsia, deep venous thrombosis, embolism, disseminated intravascular coagulation and thrombotic cytopenic purpura. Thrombotic and restenotic complications also occur following invasive procedures, e.g., angioplasty, carotid endarterectomy, post CABG (coronary artery bypass graft) surgery, vascular graft surgery, stent placements and insertion of endovascular devices and prostheses, and hypercoagulable states related to genetic predisposition or cancers. It is generally thought tha...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/517C07D409/02
CPCC07D409/12A61P25/00A61P29/00A61P41/00A61P43/00A61P7/00A61P7/02A61P9/00A61P9/04A61P9/08A61P9/10A61P9/14C07D257/04A61K31/5513A61K31/44
Inventor SCARBOROUGH, ROBERT M.SCARBOROUGH, CARROLLPANDEY, ANJALIMEHROTRA, MUKUNDCRUSKIE, MICHAELWHITE, DAVID CHARLESYIANNIKOUROS, GEORGE PETROS
Owner ALEXION PHARMA INC
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