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Ethylenediamine derivatives

a technology of ethylenediamine and derivatives, applied in the field of ethylenediamine derivatives, can solve the problems of high molecular weight peptides, inability to exhibit oral administration effectiveness, and inability to produce thrombin, and achieve strong anticoagulant effect and anticoagulant effect, strong anticoagulant effect and antithrombotic effect, and inhibit fxa

Inactive Publication Date: 2006-01-05
DAIICHI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides a new compound that can inhibit FXa and prevent blood clots, which can be used as a prophylactic or remedy for various diseases caused by thromboembolism. The compound has strong anticoagulant and anti-thrombotic effects, and can be easily synthesized."

Problems solved by technology

As described above, since the coagulation system in the upper stream of FXa is divided into the endogenous system and the exogenous system, production of FXa cannot be sufficiently inhibited by inhibiting enzymes 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 unavailable in oral administration.

Method used

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  • Ethylenediamine derivatives
  • Ethylenediamine derivatives
  • Ethylenediamine derivatives

Examples

Experimental program
Comparison scheme
Effect test

preparation process 1

[Preparation Process 1]

[0127] An ethylenediamine derivative 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.

[0128] 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 can be prepared. 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 ...

preparation process 2

[Preparation Process 2]

[0131] 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 a 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile.

[0132] 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 under the following conditions. The reaction is conducted at −10° C. to 40° C. in the presence of triethylamine in a solvent such as dichloromethane. Reacti...

preparation process 3

[Preparation Process 3]

[0134] Compound (1) according to the present invention can be prepared by reacting diamine (2) with sulfonyl halide (10).

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.

[0135] 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 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

The invention relates a compound represented by the formula (1): Q1-Q2-C(═O)—N(R1)-Q3-N(R2)-T1-Q4  (1) wherein R1 and R2 represent H or the like; Q1 represents an aromatic ring, heterocyclic ring or the like; Q2 represents a single bond, aromatic ring, heterocyclic ring or the like; Q3 represents a group or the like, Q4 represents an aromatic ring, heterocyclic ring or the like; and T1 represents —CO— or —SO2—, and a medicine which comprises the compound and is useful for thrombosis and embolism.

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 strong 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] In 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 valve replacement, reocclusion after angioplasty and thrombus formation during extracorporeal circulation, hypercoagulable state is a pivotal factor. 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 fast onset of sufficient effec...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/519C07D498/02C07D491/02A61K31/50C07D209/12C07D209/42C07D401/12C07D409/12C07D417/12C07D417/14C07D487/04C07D495/04C07D498/04C07D513/04C07D513/14
CPCC07D213/56C07D487/04C07D495/04C07D498/04C07D513/04A61P11/00A61P29/00A61P43/00A61P7/02A61P7/04A61P9/00A61P9/10
Inventor YOSHINO, TOSHIHARUNAGATA, TSUTOMUHAGINOYA, NORIYASUYOSHIKAWA, KENJIKANNO, HIDEYUKINAGAMOCHI, MASATOSHI
Owner DAIICHI PHARMA CO LTD
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