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Combination therapy with a compound acting as a platelet adp receptor inhibitor

a technology of platelet adp receptor and compound, which is applied in the direction of drug compositions, peptides, cardiovascular disorders, etc., can solve the problems of thrombotic complications and vascular occlusion, and achieve the effect of improving safety, improving therapeutic results, and reducing the amount to achieve equivalent

Inactive Publication Date: 2008-11-13
ALEXION PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]It is contemplated based on experimental results that a combination of Compound A with an anticoagulant agent, such as a factor Xa inhibitor, and / or another antiplatelet agent, such as a cyclooxygenase inhibitor, will produce improved antithrombotic effect over any of the agents alone.
[0020]The compositions of this invention are contemplated to provide for a synergistic effect in one or more of the following areas: improved therapeutic results, improved safety, reduced amount to achieve equivalent efficacy of one or more of the combination drugs as compared to the amount of that drug required to achieve the same level of efficacy when used alone.

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 with 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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  • Combination therapy with a compound acting as a platelet adp receptor inhibitor
  • Combination therapy with a compound acting as a platelet adp receptor inhibitor
  • Combination therapy with a compound acting as a platelet adp receptor inhibitor

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Compound A and Its Potassium Salt Formula I

[0214]

Step 1:

[0215]Methyl 2-amino-4,5-difluorobenzoate (1) (38 kg, 1.0 eq.) and dichloromethane (560 kg, 8×, ACS>99.5%) were charged to a 2000 L GL reactor. The reaction mixture was agitated for mins. 4-Nitrophenylchloroformate (49.1 kg, 1.2 eq.) was charged into the 200 L reactor followed by dichloromethane (185 kg) and the contents were agitated for 5 mins. After pressurizing the 200 L reactor, the 4-nitrophenylchloroformate solution was transferred into a 2000 L reactor containing dichloromethane solution of compound 1. The reaction mixture was heated to 40±5° C. (reflux) under nitrogen gas purge for 3 hrs. Representative TLC analysis confirmed completion of reaction (in-process TLC, no compound 1 remaining; 99:1 CHCl3-MeOH). The solution was cooled to 30° C. and 460 kg of dichloromethane was distilled off under vacuum. The 2000 L reactor was charged with 520 kg of hexanes and the contents of the reactor were cooled to 0±5...

example 2

Preparation of Betrixaban

[0223]

Step 1:

[0224]5-Methoxy-2-nitrobenzoic acid (5) (25.0 kg, 1.0 eq.), 2-amino-5-chloropyridine (6) (16.3 kg, 1.0 eq.), and acetonitrile (87.5 kg, 3.5 parts) were charged to a 380 L GLMS reactor. The reaction mixture was adjusted to 22° C. (19 to 25° C.) and anhydrous pyridine (30.0 kg, 3.0 eq.) was added. The pump and lines were rinsed forward with acetonitrile (22.5 kg, 0.9 parts), and the reactor contents were adjusted to a temperature of 19-22° C. Phosphorous oxychloride (23.3 kg, 1.20 eq.) was charged to the contents of the reactor via a metering pump, while maintaining a temperature of 25° C. (22-28° C.). The metering pump and lines were rinsed forward with acetonitrile (12.5 kg, 0.5 parts), while keeping the temperature at 25° C. (22-28° C.). The reaction mixture normally turned from a slurry to a clear solution after the addition of about ⅓ of the POCl3. At the end of the addition, it became turbid. After complete addition, the reaction mixture was...

example 3

Combination of Compound A and Betrixaban in a Perfusion Chamber Thrombosis Assay (I)

[0228]The real time perfusion chamber assay couples the features of animal thrombosis models that use intravital microscopy to those of perfusion chamber technology in order to produce an assay suited to monitoring drug activity in clinical trials. This assay perfuses whole blood through capillaries at arterial rates of shear, exposing the blood to thrombogenic type III collagen. Platelets are labeled with a fluorescent dye (rhodamine 6 G) prior to perfusion such that analysis of the thrombus deposition can be performed by measurement of fluorescence intensity inside the perfusion chamber. Quantification is performed by analysis of the thrombus height (fluorescence intensity (number of pixels) / total area (μm2)).

[0229]Compound A was tested in this assay at a concentration capable of generating equivalent levels of inhibition of ADP induced platelet aggregation in human platelet rich plasma as targeted...

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Abstract

The present invention is directed to pharmaceutical compositions and methods of using combination therapies containing [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea, or a pharmaceutically acceptable salt thereof, for the treatment of thrombosis diseases.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application Nos. 60 / 915,649, filed on May 2, 2007, 60 / 915,911, filed on May 3, 2007, 60 / 947,921, filed on Jul. 3, 2007, and 60 / 978,700, filed on Oct. 9, 2007, all of which are hereby incorporated by reference in their entirety.FIELD OF INVENTION[0002]The present invention relates generally to novel compositions and methods of using a combination of a platelet ADP receptor inhibitor, [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea (Compound A), and an anticoagulant agent or another antiplatelet agent for the treatment of thrombotic diseases. The present invention also relates to novel compositions and methods using a combination of Compound A with an anticoagulant and another antiplatelet agent for the treatment of thrombotic diseases.BACKGROUND OF THE INVENTION[0003]Thrombotic complicatio...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/517A61K31/5377A61K31/496A61P7/00A61K31/397A61K31/715A61K31/727A61K39/395A61K31/616A61K38/12A61K31/519
CPCA61K31/235A61K31/422A61K31/435A61K31/517A61K31/4545A61K45/06A61K38/4846A61K2300/00A61P15/00A61P43/00A61P7/00A61P7/02A61P9/00A61P9/10A61K31/496A61K31/5377
Inventor CONLEY, PAMELA B.ANDRE, PATRICKSINHA, UMA
Owner ALEXION PHARMA INC
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