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Drug compositions and methods for preventing and treating thrombosis or embolism

a technology of compositions and drugs, applied in drug compositions, biocides, extracellular fluid disorders, etc., can solve the problems of high-molecular weight peptide compounds, ineffective oral administration, and inability to produce thrombin, so as to prevent and/or treat thrombosis, the effect of potent inhibitory effect of activated blood coagulation factor

Inactive Publication Date: 2009-11-12
DAIICHI SANKYO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a novel compound with potent FXa-inhibiting effect and anti-thrombotic effect that can be quickly and persistently inhibited by oral administration. The compound has the formula (I) and can be used as a prophylactic or remedy for various diseases based on thromboembolism. The invention also provides a method for synthesizing the compound and its salts, solvates, and N-oxides. The compound exhibits a strong FXa-inhibiting effect and can quickly and persistently inhibit FXa and thrombin. It can also inhibit platelet aggregation and has a long-lasting anti-thrombotic effect.

Problems solved by technology

As described above, the coagulation system in the upper stream of FXa is divided into the endogenous system and the exogenous system, thus production of FXa cannot be sufficiently suppressed by inhibiting the enzymes involved in the coagulation system in the upper stream of FXa, leading to production of thrombin.
In addition, they do not exhibit effectiveness by oral administration.
However, these compounds are high-molecular weight peptides and are not effective by oral administration.

Method used

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  • Drug compositions and methods for preventing and treating thrombosis or embolism
  • Drug compositions and methods for preventing and treating thrombosis or embolism
  • Drug compositions and methods for preventing and treating thrombosis or embolism

Examples

Experimental program
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Effect test

preparation process 1

[Preparation Process 1]

[0193]A compound represented by the general formula (1), a salt thereof, a solvate thereof, or an N-oxide thereof can be prepared in accordance with, for example, the following process:

wherein Q1, Q2, Q3, Q4, R1 and R2 have the same meanings as defined above, and T1 represents a carbonyl group.

[0194]A mixed acid anhydride, acid halide, activated ester or the like, which is derived from carboxylic acid (3), may react with diamine (2), giving compound (4). The resultant compound (4) may react with carboxylic acid (5) under the same conditions, giving compound (1) according to the present invention. In the above reaction steps, reagents and conditions, which are generally used in peptide synthesis, may be applied. The mixed acid anhydride can be prepared by, for example, reaction of a chloroformate such as ethyl chloroformate or isobutyl chloroformate with carboxylic acid (3) in the presence of a base. The acid halide can be prepared by treating carboxylic acid (...

preparation process 2

[Preparation Process 2]

[0197]Compound (1) according to the present invention can also be prepared in accordance with the following process:

wherein Q1, Q2, Q3, Q4, R1 and R2 have the same meanings as defined above, T1 represents a carbonyl group, Boc represents a tert-butoxycarbonyl group, and Boc-ON represents 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile.

[0198]As described above, diamine (2) is treated with Boc-ON (6) to prepare compound (7) in which one of 2 amino groups has been protected with tert-butoxycarbonyl group. The resultant compound (7) reacts with carboxylic acid (5) and affords compound (8). Compound (8) is successively treated with an acid to give compound (9). Compound (9) then reacts with the carboxylic acid (3), giving compound (1) according to the present invention. Compound (7) can be prepared by a reaction at −10° C. to 40° C. in the presence of triethylamine in a solvent such as dichloromethane. Reaction of compound (7) with the mixed acid anhydride, ac...

preparation process 3

[Preparation Process 3]

[0200]Compound (1) according to the present invention can be prepared by reacting diamine (2) with sulfonyl halide (10) and then condensing the reaction product with carboxylic acid (5).

wherein Q1, Q2, Q3, Q4, R1 and R2 have the same meanings as defined above, T1 represents a sulfonyl group, and X represents a halogen atom.

[0201]Diamine (2) reacts with sulfonyl halide (10) at −10° C. to 30° C. in the presence of a base such as triethylamine in an inert solvent, giving compound (4). The inert solvent and base may be suitably chosen for use from those described in Preparation Process 1. The resultant compound (4) is condensed with carboxylic acid (5) using the reagents and conditions described in Preparation Process 1, whereby compound (1) according to the present invention can be prepared. Sulfonyl halide (10) may be synthesized in the presence of a proper base in accordance with the publicly known process (WO96 / 10022, WO00 / 09480) or a process according to it.

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Abstract

Drug compositions containing a substituted diamine compound represented by formula (1):Q1-Q2-r-N(R1)-Q3-N(R2)  (1)wherein Q3 represents the following groupwherein Q5 represents an alkylene group having 4 carbon atoms, R3 represents a hydrogen atom, and R4 represents a 3-6 membered heterocyclic group which may be substituted; are useful for preventing and / or treating cerebral infarction, cerebral embolism, myocardial infarction, angina pectoris, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after artificial valve or joint replacement, thrombus formation and reocclusion after angioplasty, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), thrombus formation during extracorporeal circulation, or blood clotting upon blood drawing.

Description

TECHNICAL FIELD[0001]The present invention relates to novel compounds which inhibit activated blood coagulation factor X (hereinafter abbreviated as “FXa”) to exhibit a potent anticoagulant effect and can be orally administered, and anticoagulants or agents for preventing and / or treating thrombosis or embolism, which comprise such a novel compound as an active ingredient.BACKGROUND ART[0002]Hypercoagulable state is one of the pivotal factors that account for unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Buerger's disease, deep venous thrombosis, disseminated intravascular coagulation syndrome, thrombus formation after artificial valve replacement, reocclusion after angioplasty and thrombus formation during extracorporeal circulation. Therefore, there is a demand for development of excellent anticoagulants which have good dose responsiveness, long duration, low risk of hemorrhage and little side effects and f...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/397A61K31/437A61K31/502A61K31/5377A61K31/55C07D513/04
CPCC07D213/75C07D401/12C07D401/14C07D409/04C07D409/12C07D413/12C07D413/14C07D417/14C07D471/04C07D487/04C07D498/04C07D513/14C07D519/00A61P43/00A61P7/02A61P7/04A61P9/00A61P9/04A61P9/10A61K31/429A61K31/403
Inventor OHTA, TOSHIHARUKOMORIYA, SATOSHIYOSHINO, TOSHIHARUOUTO, KOUICHINAKAMOTO, YUMINAITO, HIROYUKIMOCHIZUKI, AKIYOSHINAGATA, TSUTOMUKANNO, HIDEYUKIHAGINOYA, NORIYASUYOSHIKAWA, KENJINAGAMOCHI, MASATOSHIKOBAYASHI, SYOZOONO, MAKOTO
Owner DAIICHI SANKYO CO LTD
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