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New 5,6-dihydropyrin-2-one compounds useful as inhibitors of thrombin

A compound and derivative technology, applied in the field of new pharmaceutically acceptable compounds, can solve problems such as not disclosed or implied

Inactive Publication Date: 2007-01-10
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] None of the above documents disclose or suggest (at the P2 position) compounds with a 1-amino-2-oxo-1,2,5,6-triazinepyridine structural unit

Method used

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  • New 5,6-dihydropyrin-2-one compounds useful as inhibitors of thrombin
  • New 5,6-dihydropyrin-2-one compounds useful as inhibitors of thrombin
  • New 5,6-dihydropyrin-2-one compounds useful as inhibitors of thrombin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0905] Compounds (i)-(ix) listed below were prepared starting from the corresponding compound of Preparation 2 by hydrolysis in step (i), followed by amide coupling as described in step (ii), Method A.

[0906] Unless otherwise stated, the compounds (x)-(xxiii) listed below are starting from the corresponding compound of Preparation 2 by hydrolysis in step (i), followed by the amido-isolysis as described in step (ii), method B. made in conjunction.

[0907] Unless otherwise stated, compounds (xxiv)-(l) listed below are hydrolyzed as described in Example 1(xxvi) starting from the corresponding compound of Preparation 2, followed by hydrolysis as described in Example 1(xxiii) Prepared by amide coupling.

[0908] step (i)

[0909] To the indicated ester (0.041 mmol; see Preparation 2 above) dissolved in THF (1 mL) and water (3 drops) was added lithium hydroxide (1.5 molar equivalents). The reaction mixture was stirred at room temperature for 11 hours, then quenched with water ...

Embodiment 2

[1058] Compounds (i)-(ix) listed below were prepared starting from the corresponding compound of Example 1 according to Method A below, unless otherwise stated. Compounds (x)-(xxxiv) listed below are prepared from the corresponding compound of Example 1 according to the following method B

[1059] Method A

[1060] To a solution of the indicated benzyloxycarbonyl-protected compound (0.03 mmol; see Example 1 above) in methanol (3 mL) was added palladium-carbon (10%, 1 mass equivalent) and HCl (cone, 2-3 drops ). The suspension was hydrogenated at room temperature and pressure for 90 minutes. Pass the suspension through Celite  Filter, wash with methanol (3 x 5 mL), and remove the solvent under reduced pressure. The residue was dissolved in a minimum amount of methanol and the deprotected product was precipitated with ethyl acetate. The yield is close to quantitative.

[1061] Method B

[1062] The indicated amide (0.04 mmol; see Example 1 above) was dissolved in HCl sat...

Embodiment 3

[1181] [4-chloro-2-({2-[4-methyl-1-(naphthalene-1-sulfonylamino)-2-oxo-1,2,5,6-tetrahydropyridin-3-yl] Acetylamino}methyl)benzyl]carbamate tert-butyl

[1182] [4-Methyl-1-(naphthalene-1-sulfonylamino)-2-oxo-1,2,5,6-tetrahydropyridin-3-yl] was hydrolyzed following the general procedure described in Example 1 above Ethyl acetate (0.12 mmol; see Preparation 2(iii) above), except that the solvent volume was 3 mL and the reaction time was 16 hours. The crude acid thus obtained was dissolved in DCM (2 mL) and amide coupling was carried out as described in Example 1 above (coupling with (2-aminomethyl-4-chlorobenzyl)-1-carbamic acid tert-butyl ester) , and just stirred the reaction mixture for two nights. The crude product was chromatographed (SiO 2 , 5% methanol / DCM) and preparative HPLC to afford the title compound (41%).

[1183] 1 H NMR (500MHz, CDCl 3 )δ1.50(s, 9H), 2.01(s, 3H), 2.48-2.63(m, 2H), 3.02(s, 2H), 3.72-3.79(m, 2H), 4.07(d, 2H), 4.19 -4.29(m, 2H), 5.10(br s, 1H...

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PUM

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Abstract

There is provided a compound of formula (I) wherein R<1>, R<2a>, R<2b>, R<3a>, R<3b>, R<4>, R<5>, R<6>, A, G and L have meanings given in the description, which compounds are useful as, or are useful as prodrugs of, competetive inhibitors of trypsin-like proteases, such as trombin, and thus, in particular, in the treatment of conditions where inhibition of thrombin is beneficial (e,g. conditions, such as thrombo-embolisms, where inhibition of trombin is required or desired, and / or conditions wherea anticoagulant thererapy is indicated).

Description

technical field [0001] The present invention relates to new pharmaceutically acceptable compounds, in particular those compounds which are themselves and / or are capable of being metabolized to competitive inhibitors of trypsin-like serine proteases, especially thrombin, their use as medicaments, their pharmaceutical compositions and their synthetic methods. Background technique [0002] Blood coagulation is a key process involved in both hemostasis (ie, preventing blood loss from damaged blood vessels) and thrombosis (ie, the formation of blood clots in blood vessels, sometimes leading to blockage). [0003] Blood coagulation is the result of a series of complex enzymatic reactions. One of the final steps in this series of reactions is the conversion of prothrombin to active thrombin. [0004] Thrombin is known to play an important role in blood coagulation. It activates platelets, causing platelet aggregation, converting fibrinogen to fibrin monomers (which polymerize sp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/98A61K31/4412A61P7/02C07D
Inventor K·伯格伦O·戴维森O·菲杰尔斯特罗姆D·古斯塔夫森S·黑尼斯安T·英哈特M·纳加德I·尼尔森E·塞里恩W·范奥特洛
Owner ASTRAZENECA AB
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