Benzamidine derivatives

Details Benzamidine derivatives Benzamidine derivatives

2002-04-25

2003-04-29

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S221000, C546S216000, C548S541000, C514S424000

Reexamination Certificate

active

06555556

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to benzamidine derivatives and their pharmaceutically acceptable salts having excellent inhibitory activity against factor Xa. This invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient for prevention or treatment of a blood coagulation disorder. In another aspect, this invention relates to the use of said compounds in the preparation of a medicament for the prevention or treatment of a blood coagulation disorder. In another aspect, this invention relates to a method for the prevention or treatment of a blood coagulation disorder, which method comprises administering a pharmaceutically effective amount of said compounds to a warm-blooded animal in need of such treatment. In yet another aspect, this invention relates to a process for the preparation of said compounds.
Recently the number of patients with cardiovascular diseases is increasing in accordance with the increase in the elderly population. Among these diseases, thrombotic diseases such as cerebral infarction, myocardial infarction and peripheral occlusive diseases not only lead to death, but also cause a significant limitation in the individual and social lives of patients which have a poor prognosis. Thus, it is suggested that anticoagulant therapy against thrombotic diseases is becoming increasingly important.
Blood coagulation involves a complex cascade of enzymatic reactions that can be triggered by an initial stimulus, and amplified to terminate in the thrombin-catalyzed conversion of the soluble fibrinogen to the insoluble plasma protein fibrin. This process is known as the blood coagulation cascade and comprises the intrinsic and the extrinsic pathways. The activated factor X (factor Xa) is a key enzyme at the point of convergence of both coagulation pathways. It forms a complex with bivalent calcium ions, phospholipids and factor Va to efficiently convert prothrombin to thrombin, and thereby accelerates blood coagulation [e.g., E. L. Smith, A. White et al., ‘Principles of Biochemistry’: Mammalian Biochemistry, 7
th
edition, McGraw-Hill, Inc. (1983), etc.].
Warfarin and thrombin inhibitors are currently used as anti-coagulants. Although warfarin is a widely used as an orally active anti-thrombotic agent, it has significant clinical limitations. The anti-coagulant activity of warfarin is antagonized by vitamin K, and is often affected by interactions with the diet or commonly used drugs [e.g.,
Clin. Pharmacokinet
., 30, 416 (1996)]. In addition, currently available thrombin inhibitors carry a hemorrhage risk as adverse events associated with their pharmacological actions, and thus novel anti-coagulants need to be developed. Since factor Xa affects thrombin formation and factor Xa inhibitors are known to exert anti-coagulant activities, factor Xa inhibitors are suggested to become a novel type of anti-coagulant [e.g.,
Drugs
, 49, 856 (1995)].
Aromatic amidine derivatives or amidinonaphthyl derivatives are described as competitive factor Xa inhibitors in Japanese Patent Application Publication No. Hei 5-208946 (EP 540051), WO 96/16940 (EP 798295) or WO 00/47553. Further, benzamidine derivatives such as N-[4-[1-acetimidoyl-4-piperidyloxy]phenyl]-N-[2-(3-amidinophenoxy)ethyl]sulfamoylacetic acid bis(trifluoroacetate) are described in WO 98/31661 (EP 976722).
DISCLOSURE OF THE INVENTION
The inventors studied the pharmacological actions of various benzamidine derivatives for many years to develop compounds with excellent anti-factor Xa activity. Our study resulted in the finding that benzamidine derivatives with specific substituents exhibit excellent anti-factor Xa activity, but do not exhibit anti-trypsin activity which is associated with adverse events. Furthermore, these derivatives are useful for the prophylaxis and therapy (particularly therapy) of blood coagulation disorders. These results led to the present invention.
The present invention relates to benzamidine derivatives and their pharmaceutically acceptable salts having excellent inhibitory activity against factor Xa. This invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient for the prevention or treatment of a blood coagulation disorder. In another aspect, this invention relates to the use of said compounds in the preparation of a medicament for the prevention or treatment of a blood coagulation disorder. In another aspect, this invention relates to a method for the prevention or treatment of a blood coagulation disorder, which method comprises administering a pharmaceutically effective amount of said compounds to a warm-blooded animal in need of such treatment. In yet another aspect, this invention relates to a process for the preparation of said compounds.
Benzamidine derivatives of the present invention have the following formula (I):
wherein:
R
1
represents a hydrogen atom, a halogen atom, a C
1
-C
6
alkyl group or a hydroxyl group;
R
2
represents a hydrogen atom, a halogen atom or a C
1
-C
6
alkyl group;
R
3
represents a hydrogen atom; a C
1
-C
6
alkyl group; a C
1
-C
6
alkyl group which is substituted with a hydroxyl group, a carboxyl group or a (C
1
-C
6
alkoxy)carbonyl group; a group of formula (II)
 (wherein R
7
represents a C
1
-C
6
alkyl group, m and n are the same as or different from each other and each represent an integer from 1 to 6); a C
7
-C
15
aralkyl group; a C
1
-C
6
alkanoyl group; a hydroxy C
2
-C
6
alkanoyl group; a C
1
-C
6
alkylsulfonyl group; or a C
1
-C
6
alkylsulfonyl group which is substituted with a carboxyl group or a (C
1
-C
6
alkoxy)carbonyl group; and
R
4
and R
5
are the same as or different from each other and each represent a hydrogen atom, a halogen atom, a C
1
-C
6
alkyl group, a halogeno-C
1
-C
6
alkyl group, a C
1
-C
6
alkoxy group, a carboxyl group, a (C
1
-C
6
alkoxy)carbonyl group, a carbamoyl group, a (C
1
-C
6
alkyl)carbamoyl group or a di(C
1
-C
6
alkyl)carbamoyl group; and
R
6
represents a 1-acetimidoylpyrrolidin-3-yl group or 1-acetimidoylpiperidin-4-yl group.
The active ingredients of the pharmaceutical composition for prevention or treatment of a blood coagulation disorder of the present invention are the benzamidine derivatives of formula (I) or their pharmaceutically acceptable salts.
The “halogen atom” in the definition of R
1
may be, for example, a fluorine, chlorine, bromine or iodine atom; preferably a fluorine, chlorine or bromine atom; more preferably a fluorine or chlorine atom; and most preferably a fluorine atom.
The “C
1
-C
6
alkyl group” in the definition of R
1
is, for example, a straight or branched chain alkyl group having from one to six carbon atoms such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl group; preferably a C
1
-C
4
alkyl group; more preferably a methyl or ethyl group; and most preferably a methyl group.
The “halogen atom” in the definition of R
2
may be, for example, as described in the definition of R
1
; preferably a fluorine or chlorine atom; and most preferably a fluorine atom.
The “C
1
-C
6
alkyl group” in the definition of R
2
may be, for example, as described in the definition of R
1
; preferably a C
1
-C
4
alkyl group; more preferably a methyl or ethyl group; and most preferably a methyl group.
The C
1
-C
6
alkyl moiety of the “C
1
-C
6
alkyl group” and the “C
1
-C
6
alkyl group which is substituted with a hydroxyl group, a carboxyl group or a (C
1
-C
6
alkoxy)carbonyl group” in the definition of R
3
may be, for example, as described in the definition of R
1
. Preferably the “C
1
-C
6
alkyl group” is a C
1
-C
4
alkyl group; more preferably a methyl, ethyl or isopropyl group; and most preferably an isopropyl group.

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