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Aryl and heteroaryl compounds, compositions, and methods of use

A technology for heteroaryl groups and compounds, which can be used in drug combinations, chemical instruments and methods, preparation of organic compounds, etc., and can solve problems such as no effective drug treatment.

Inactive Publication Date: 2006-09-13
TRANSTECH PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Likewise, for arterial thrombosis, there are currently no effective medical treatments for the prevention of restenosis after mechanical recanalization

Method used

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  • Aryl and heteroaryl compounds, compositions, and methods of use
  • Aryl and heteroaryl compounds, compositions, and methods of use
  • Aryl and heteroaryl compounds, compositions, and methods of use

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Experimental program
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preparation example Construction

[0450] Scheme III describes the preparation of compounds of formula (4).

[0451] Ar 5 , Ar 6 are mutually independent groups such as, but not limited to, heteroaryl, heteroarylene, arylene, or aromatic ring systems.

[0452] As shown in Scheme III, in another embodiment, amino acid methyl esters (or other Esterified amino acids attached to Wang resin) (8) to form amides (9). The resulting amide is then coupled with an arylboronic acid or a heteroarylboronic acid in the presence of a catalyst such as but not limited to tetrakis(triphenylphosphine)palladium(0) and a base such as but not limited to sodium carbonate to form Compound (10). Hydrolysis of the methyl ester (10) with a base such as but not limited to LiOH yields the free carboxylic acid (4), where Ar 1 and Ar 2 The definition of the same formula (I).

[0453] Process III

[0454]

[0455] Scheme IV describes the preparation of compounds of formula (4).

[0456] Ar 3 , Ar 7 , Ar 5 and Ar 6 are mutually ...

Embodiment 1

[0688] (2S)-[5-Bromo-2-(4-trifluoromethylbenzyloxy)-benzamide]-3-(2′-phenoxybiphenyl-4-yl)-propionic acid

[0689] 5-Bromo-salicylic acid (2.16 g, 10 mmol) was first converted to 2-acetyl-5-bromo-salicylic acid ( 252g). The above acid (1.29 g, 5.0 mmol) was converted to the acid chloride with oxychloride (1.97 g, 15 mmol) and a catalytic amount of DMF in DCM, then 2-phenoxy-biphenylalanine was added to the acid chloride acid (1.45g, 5.0mmol) and DIEA (0.77g, 6.0mmol) to form (2S)-[5-bromo-2-hydroxybenzoylamine]-3-(2'-phenoxybiphenyl-4 -yl)-methyl propionate (1.92 g). Reaction of the above methyl ester (50 mg, 0.092 mmol) with 4-trifluoromethylbenzyl bromide (44 mg, 0.18 mmol) as described in General Procedure H affords (2S)-[5-bromo-2-(4- Trifluoromethylbenzyloxy)-benzoylamino]-3-(2'-phenoxybiphenyl-4-substituted)-propionic acid methyl ester (55 mg). The ester was hydrolyzed as in General Procedure C to give the title compound (52 mg).

[0690] 1 H-NMR (400MHz, CDCl 3 )...

Embodiment 2

[0692] (2S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-[2′-(4-trifluoromethyl-phenoxy)-biphenyl-4-yl]-propionic acid

[0693] 5-Bromo-2-hydroxy-benzoic acid methyl ester (1.0 g, 4.32 mmol) was reacted with iodoheptane (1.46 g, 6.49 mmol) following general procedure H by addition of potassium carbonate (1.5 g, 10.8 mmol) to prepare 5- Bromo-2-heptyloxy-benzoic acid. The ester thus obtained was hydrolyzed following General Procedure C to give 5-bromo-2-heptyloxy-benzoic acid (0.950 g).

[0694] From 4-bromophenylalanine (5.g, 20.48mmol), 2-hydroxyphenylboronic acid (4.23g, 30.72mmol) and Pd (PPh 3 ) 4 (2.36g, 2.038mmol) according to process D to produce the corresponding amino acid, further esterified with anhydrous methanol containing 2-3ml HCl to produce the corresponding HCl salt (2S)-amino-3-(2'-hydroxy-biphenyl -4-yl)-propionic acid methyl ester (5.0 g) to prepare (2S)-amino-3-(2'-hydroxybiphenyl-4-yl)-propionic acid.

[0695] 5-Bromo-2-heptyloxy-benzoic acid (0.231 g, 0.738 ...

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Abstract

This invention provides aryl and heteroaryl compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, and their use in treating human or animal disorders. The compounds of the invention may be useful as antagonists, or partial antagonist of factor IX and / or factor XI and thus, may be used to inhibit the intrinsic pathway of blood coagulation. The compounds may be useful in a variety of applications including the management, treatment and / or control of diseases caused in part by the intrinsic clotting pathway.

Description

[0001] Related application statement [0002] This application claims priority under 35 USC 119 to the following U.S. Provisional Patent Application: Serial Application No. 60 / 493,879, filed August 8, 2003, entitled "Aryl and Heteroaryl Compounds as Antiviral Agents"; 2003 Serial Application No. 60 / 493,878, filed August 8, 2003, entitled "Aryl and Heteroaryl Compounds and Methods of Modulating Erythrocyte Production"; Serial Application No. 60 / 493,903, filed August 8, 2003, entitled is "Aryl and Heteroaryl Compounds and Methods of Modulating Blood Coagulation," which is hereby incorporated by reference in its entirety. field of invention [0003] The present invention relates to aryl and heteroaryl compounds and compositions capable of antagonizing the intrinsic blood coagulation pathway by binding to and inhibiting the function of Factor XI or Factors XI and IX, and methods of using such compounds and compositions. Background of the invention [0004] Hemostasis to stop bl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/20C07C233/29C07C233/87C07C235/42C07C235/52C07C235/60C07C235/66C07D207/09C07D207/26C07D211/66C07D213/71C07D217/02C07D231/14A61K31/166A61P31/12C07C237/36C07C237/42C07C311/08C07C311/09C07C311/21C07C311/44C07C317/32C07C323/36C07D295/155
CPCC07C237/36C07C271/20C07C2101/08C07C237/42C07C235/60C07C235/52C07C311/21C07C311/08C07C235/42C07C323/36C07C311/09C07C311/44C07C317/32C07D295/155C07C233/87C07C235/66C07C2601/08A61P13/12A61P29/00A61P31/12A61P37/02A61P43/00A61P7/02A61P9/00A61P9/06A61P9/10
Inventor 阿德南·M·M·米亚利罗伯特·C·安德鲁斯郭晓川丹尼尔·彼得·克里森黛维·雷迪·戈穆库拉黄国响罗伯特·勒特莱因萨梅尔·泰亚吉特里普拉·亚拉马舒克里斯多佛·贝梅
Owner TRANSTECH PHARMA INC
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