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Cyclic amide derivative, and its production and use

a technology of cyclic amide and derivative, applied in the field of new cyclic amide derivative, can solve problems such as safety problems, and achieve the effects of improving drug efficacy, oral absorption and duration of action, and fewer side effects

Inactive Publication Date: 2008-10-16
TAKEDA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The cyclic amide derivative effectively inhibits FXa, offering improved safety and efficacy in preventing and treating thrombotic diseases, inflammation, and cancer by providing sustained anticoagulant activity with minimal bleeding risks.

Problems solved by technology

However, since not only platelet aggregation inhibitors, but also anti-thrombin agents suppress the aggregation of platelets in addition to their anticoagulant activity, these medicaments tend to cause bleeding and the like as adverse side-effects.
Therefore, there is a problem in their safety.

Method used

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  • Cyclic amide derivative, and its production and use
  • Cyclic amide derivative, and its production and use
  • Cyclic amide derivative, and its production and use

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

(2S)-3-[(6-Chloronaphthalen-2-yl)thio]-2-hydroxypropionic acid

[0200]

1a) Methyl (2S)-3-[(6-chloronaphthalen-2-yl)thio]-2-hydroxypropionate

[0201]Under an argon atmosphere, a solution of 3M ethyl magnesium bromide in diethyl ether was added dropwise to THF (25 mL) under ice-cooling. To this solution was added dropwise a solution of 6-chloronaphthalene-2-thiol (5.0 g) in THF (50 mL) at 0° C. and the mixture was stirred at room temperature for 30 minutes. To the resulting solution was added dropwise a solution of methyl (2R)-oxylane-2-carboxylate (2.3 mL) in THF (15 mL) and the mixture was stirred at room temperature for 3 hours. An aqueous ammonium chloride solution (50 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane / ethyl acetate (3:1) to obtain the title compoun...

example 1

1′-{(2S)-3-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropanoyl}-1,4′-bipiperidin-2-one

[0205]

[0206]WSC (0.19 g) was added to a mixture of (2S)-3-[(6-chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropinoic acid (0.31 g), 1,4′-piperidin-2-one (JP 2001-524466 A) (0.18 g) and HOBt (0.15 g) in DMF (15 mL) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and diluted with dichloromethane and an aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate to ethyl acetate / methanol=10 / 1) to obtain the title compound (0.26 g, 54%) as a colorless powder.

[0207]NMR (CDCl3) δ: 1.62-1.79 (9H, m), 2.41-2.45 (2H, m), 2.68-2.82 (1H, m), 3.14-3.26 (3H, m), 3.40-3.48 (2H, m), 3.97-4.01 (1H, m), 4.60-4.68 (1H, m), 4.80-4.84 (1H, m), 4.96-5.04 (1H, m), 7.59 (1H, dd, J...

example 2

1-(1-{(2S)-3-[(6-Chloronaphthalen-2-yl)sulfonyl]-2-hydroxypropanoyl}piperidin-4-yl)pyrrolidin-2-one

[0211]

[0212]According to the manner similar to that in Example 1, the title compound (0.19 g, 41%) was obtained as a colorless powder from 1-(4-piperidinyl)-2-pyrrolidinone (JP 08-502511 A).

[0213]NMR (CDCl3) δ: 1.62-1.87 (3H, m), 2.01-2.08 (3H, m), 2.39-2.44 (2H, m), 2.66-2.81 (1H, m), 3.13-3.48 (5H, m), 3.75-4.24 (3H, m), 4.61-4.65 (1H, m), 5.02-5.03 (1H, m), 7.59 (1H, dd, J=2.1, 8.7), 7.94-7.97 (4H, m), 8.51 (1H, s).

[0214]Elemental analysis for C22H25ClN2O5S.0.5H2O

[0215]Calcd (%): C, 55.75; H, 5.53; N, 5.91.

[0216]Found (%): C, 55.63; H, 5.74; N, 5.71.

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Abstract

The present invention provides a cyclic amide derivative useful as a drug for treating thrombosis, which is represented by the formula (I):wherein R1 represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, W represents a bond or an optionally substituted divalent chain hydrocarbon group, a represents 0, 1, or 2, X1 represents an optionally substituted lower alkylene or an optionally substituted lower alkenylene, Y1 represents —C(O)—, —S(O)— or —S(O)2—, A represents a piperazine ring which may be further substituted or a piperidine ring which may be further substituted, X2 represents a bond or an optionally substituted lower alkylene, Y2 represents —C(O)—, —S(O)—, —S(O)2— or —C(═NR7)—, X3 represents an optionally substituted C1-4 alkylene or an optionally substituted C2-4 alkenylene, Z3 represents —N(R4)—, —O— or a bond, Z1 represents —C(R2)(R2′)—, —N(R2)—, etc., and Z2 represents —C(R3)(R3′)—, —N(R3)—, etc., or a salt thereof.

Description

TECHNICAL FIELD[0001]The present invention relates to a novel cyclic amide derivative which inhibits activated blood coagulation factor X (FXa) to exhibit anticoagulant activity and antithrombotic activity, and therefore is useful for preventing and treating arterial and venous thrombotic obstructive diseases, inflammation, cancer and the like; and its production process and use.BACKGROUND ART[0002]It is important to suppress the formation of thrombi for preventing and treating myocardial infarction, cerebral thrombosis and the like, and various antithrombin agents, platelet aggregation inhibitors and the like have been studied and developed as thrombosis inhibitors. However, since not only platelet aggregation inhibitors, but also anti-thrombin agents suppress the aggregation of platelets in addition to their anticoagulant activity, these medicaments tend to cause bleeding and the like as adverse side-effects. Therefore, there is a problem in their safety. On the other hand, it is ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D413/04C07D211/76C07D401/04C07D403/04C07D417/04
CPCC07D211/76C07D401/04C07D417/04C07D413/04C07D403/04A61P29/00A61P35/00A61P43/00A61P7/00A61P7/02A61P9/10
Inventor KUBO, KEIJIIMAEDA, YASUHIRO
Owner TAKEDA PHARMA CO LTD