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Factor VóÄa inhibitor

A technology for thrombin inhibitors and factors, applied in the field of preparing these inhibitors, treating or preventing thromboembolic diseases

Inactive Publication Date: 2007-06-06
ファーマサイクリックス リミティド ライアビリティ カンパニー
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unpredictable PE formation often leads to fatal outcomes

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0132] N-[3'-(5-Carboxamidino-1H-benzimidazol-2-yl)-5'-(1-carbamoyl-1-methyl-ethyl)-6,2'-dihydroxy Synthesis of biphenyl-3-ylmethyl]-(2S)-2,3-dihydroxypropionamide dihydrochloride

[0133]

[0134] step 1

[0135] To a 3-L round bottom flask equipped with a magnetic stir bar was added methyl 2-(3-bromo-5-formyl-4-hydroxyphenyl)-2-methylpropanoate (132 g, 438 mmol), potassium carbonate (66.7 g, 483 mmol) and DMF (1 L). The solution was stirred at room temperature for 0.5 hours. Iodomethane (31.5 mL, 506 mmol) was added dropwise with vigorous stirring. The reaction was complete after 3 hours. To this solution was added methyl tert-butyl ether (MTBE) (3 L) and the solution was filtered to remove inorganic salts. The solution was washed with water, then with cold 0.5% aqueous NaOH (1 L), then with brine. The aqueous layer was back extracted with MTBE (1 L). The combined organic layers were dried over sodium sulfate and concentrated. The final product can be isolated by ...

Embodiment 2

[0154] N-[3'-(5-Carboxamidino-1H-benzimidazol-2-yl)-5'-(1-carbamoyl-1-methyl-ethyl)-6,2'-dihydroxy Synthesis of biphenyl-3-ylmethyl]-(2S,3R)-2,3-dihydroxybutanamide

[0155]

[0156] step 1

[0157] (2S,3R)-2,3-O-Isopropylidene-2,3-dihydroxybutanoic acid methyl ester (5.27 g, 30.25 mmol; Fluka catalog number 59437) was dissolved in a solution containing an equimolar amount of lithium hydroxide The monohydrate (1.27 g; 30.25 mmol) was dissolved in THF / water (1:1; 220 mL) and stirred for 90 minutes. The solution was concentrated in vacuo to afford the lithium salt of (2S,3R)-2,3-O-isopropylidene-2,3-dihydroxybutanoic acid (4.90 g, 98%) as a white solid. A portion of the lithium salt of (2S,3R)-2,3-O-isopropylidene-2,3-dihydroxybutanoic acid and HATU (0.243 g; 0.64 mmol) were mixed in DMA (10 mL), then sonicated Process for 15 minutes until dissolution is achieved.

[0158] In a separate flask, 2-[5′-aminomethyl-5-(5-carbamimidino-1H-benzimidazol-2-yl)-6,2′-dihydroxybiphen...

Embodiment 3

[0162] 2S-{2-[5-(5-Formamidino-1H-benzimidazol-2-yl)-6,2'-dihydroxy-5'-sulfamoylbiphenyl-3-yl]-2- Synthesis of Methacrylamino}succinamide

[0163]

[0164] step 1

[0165] To a solution of 2-methoxy-5-tert-butylsulfamoylphenylboronic acid (4.08 g, 14.28 mmol) dissolved in methanol (36 mL) was added 2-(3-bromo-5-formyl-4-methanol oxyphenyl)-2-methylpropionate (3.0 g, 9.50 mmol) and toluene (90 mL). Potassium carbonate solution (7.14 mL, 2M, 14.28 mmol) was added and the reaction mixture was purged with nitrogen. Tetrakis(triphenylphosphine)palladium (1.10 g, 0.95 mmol) was added and the reaction mixture was refluxed for 3 hours. After cooling, the reaction mixture was partitioned with 5% citric acid solution and the organic phase was dried and evaporated. Purification by column chromatography (40% EtOAc / hexanes) afforded 2-{5'-tert-butylsulfamoyl-5-formyl-6,2'-dimethoxybiphenyl-3-yl)- 2-Methyl-propionic acid methyl ester (3.79 g, 84%).

[0166] step 2

[0167] 2-(5'-t...

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Abstract

The present invention relates to novel inhibitors of Factors VIIa, IXa, Xa, XIa, in particular Factor VIIa, pharmaceutical compositions comprising these inhibitors, and methods for using these inhibitors for treating or preventing thromboembolic disorders, cancer or rheumatoid arthritis. Processes for preparing these inhibitors are also disclosed.

Description

technical field [0001] The present invention relates to novel factor VIIa inhibitors, pharmaceutical compositions comprising these inhibitors and methods of using these inhibitors for the treatment or prevention of thromboembolic diseases. Methods of making these inhibitors are also disclosed. Background technique [0002] Thrombosis is caused by a complex sequence of biochemical events known as the coagulation cascade. The triggering event for coagulation is the binding of the serine protease Factor Vila (FVIIa) found in circulation to tissue factor (TF) found on the surface of blood vessels following injury or inflammation. Once bound to TF, Factor Vila catalyzes the formation of the serine protease Factor Xa, which then forms the final protease in the cascade, thrombin. [0003] The clinical presentation of thrombosis varies from acute myocardial infarction (AMI or heart attack) and unstable angina (UA) in the heart's key vessels (coronary vasculature) to formation in t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/18A61P7/02A61K31/4184C07D235/00
CPCC07D235/18A61P11/00A61P25/00A61P29/00A61P31/04A61P31/12A61P35/00A61P43/00A61P7/02A61P9/06A61P9/08A61P9/10A61K31/4184
Inventor 史蒂文·M·托克尔松托马斯·沃伊克弗斯凯
Owner ファーマサイクリックス リミティド ライアビリティ カンパニー
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