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Crystalline forms of a known pyrrolidine factor Xa inhibitor

A pyrrolidinedicarboxamide and crystallization technology, applied in 1 field, can solve problems such as unpredictable results

Inactive Publication Date: 2008-03-19
WARNER LAMBERT CO LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Finding the most stable form and such other forms is arduous and the results are unpredictable

Method used

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  • Crystalline forms of a known pyrrolidine factor Xa inhibitor
  • Crystalline forms of a known pyrrolidine factor Xa inhibitor
  • Crystalline forms of a known pyrrolidine factor Xa inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] (2R,4R)-4-Methoxy-pyrrolidine-2-carboxylic acid [2-fluoro-4-(2-oxo-pyridin-1-yl)phenyl]-amide

[0103] Step 1 Preparation of (2R, 4R)-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

[0104] To a nitrogen purged, 500ml 3-neck flask equipped with a mechanical stirrer and thermocouple was added 60% (w / w) NaH (8g, 200mmol) and hexane (250ml). The mixture was stirred for 1 min, after which time agitation was stopped and a solid was allowed to settle. Hexane was removed using a candle filter. THF (250ml) and CH were then added to the flask 3 I (6.51ml, 105mmol) and the resulting mixture was cooled to 0°C in an ice bath. Then, (R,R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (22 g, 95 mmol) was added in portions while maintaining the reaction temperature at 5°C or lower. The reaction was allowed to warm to room temperature overnight. Add H to the reaction mixture 2 O (100ml), 1N HCl (100ml) and NaCl (42g). The reaction was stirred for...

Embodiment 2

[0112] From amorphous 1,2-pyrrolidinedicarboxamide, N1-(4-chlorophenyl)-N2-[2-fluoro-4-(2-oxo-1(2H)-pyridyl)phenyl]- 4-Methoxy, (2R,4R)-(9C1) Synthesis Form A.

[0113] 1.8g of amorphous 1,2-pyrrolidinedicarboxamide, N1-(4-chlorophenyl)-N2-[2-fluoro-4-(2-oxo-1(2H)-pyridyl)phenyl ]-4-Methoxy-, (2R,4R)-(9C1 ) (prepared as described by Bigge et al. in Example 150 of US2003 / 016272787) was slurried in 100 ml of water at room temperature for three days. The solid was filtered off, washed with 50 ml of water and dried under vacuum overnight to give 1.44 g of 1,2-pyrrolidinedicarboxamide, N1-(4-chlorophenyl)-N2-[2-fluoro-4-(2-oxo Substitute-1(2H)-pyridyl)phenyl]-4-methoxy-, (2R,4R)-(9C1). PXRD and DSC confirmed that the crystalline form was Form A.

Embodiment 3

[0115] Synthesis of Form A from Form B

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Abstract

Disclosed are crystalline forms A, B and C of 1 ,2-Pyrrolidinedicarboxamide, N1 -(4- chlorophenyl)-N2-[2-fluoro-4-(2-oxo-1 (2H)-pyridinyl)phenye]-4-methoxy-, (2R,4R)- (9Cl). These crystalline forms a re characterized by their powder X-ray diffraction, solid-state NMR, as well as methods for the preparation and pharmaceutical compositions of the same which are useful for the treatment of acute, subacute, or chronic thrombotic disorders including treatment of venous thrombosis, arterial thrombosis, pulmonary embolism, myocardial infarction, cerebral infarction, restenosis, atherosclerosis, angina, primary and secondary deep vein thrombosis, thromboembolism associated with cardiovascular disease, including, but not limited to, acute coronary syndrome, atrial fibrillation, cardiac valve replacement and deep vein thrombosis. The crystalline forms of the present invention are also useful for the treatment of cancer, sepsis and diabetes.

Description

technical field [0001] The present invention relates to 1,2-pyrrolidinedicarboxamide, N1-(4-chlorophenyl)-N2-[2-fluoro-4-(2-oxo-1(2H)-pyridyl)phenyl]- 4-Methoxy-, a crystalline form of (2R,4R)-(9C1), which exhibits inhibitory effect on the serine protease Factor Xa. In particular, the invention relates to 1,2-pyrrolidinedicarboxamide, N1-(4-chlorophenyl)-N2-[2-fluoro-4-(2-oxo-1(2H)-pyridyl)benzene ]-4-methoxy-, crystalline forms A, B and C of (2R,4R)-(9C1) and methods of using them as therapeutic agents to treat diseases in mammals characterized by abnormal thrombosis. Background technique [0002] Ischemic heart disease and cerebrovascular disease are the leading causes of death in the world. Abnormal coagulation and inappropriate thrombus formation within blood vessels contribute to many acute cardiovascular diseases. [0003] Thrombin can be considered a key or major regulatory enzyme in the coagulation cascade; it has multiple roles as a positive and negative feedback...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61P7/02
CPCC07D401/12A61P11/00A61P31/04A61P35/00A61P43/00A61P7/00A61P7/02A61P9/00A61P9/08A61P9/10A61P3/10A61K31/4439
Inventor B·M·萨马斯D·C·弗里泽
Owner WARNER LAMBERT CO LLC
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