Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-02-06
1997-06-03
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514 58, 514212, 514300, 514301, 514302, 514320, 514323, 514324, 514333, 514337, 514339, 514415, 514418, 514419, 514422, 514443, 514444, 514445, 514447, 514448, 514469, 514470, 536103, 540602, 546113, 546114, 546115, 546116, 546196, 546201, 546202, 546256, 5462777, 5462781, 5462811, 5462841, 5462844, 5462847, 548467, 548483, 548484, 548486, 548492, 548525, 548527, 549 54, 549 55, 549 56, 549 57, 549466, 549467, 549468, 549471, A61K 31715, A61K 3155, A61K 3144, A61K 31445, A61K 31405, A61K 3140, A61K 3138, A6
Patent
active
056355270
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 PCT/JP95/01119 filed Jun. 6, 1995.
TECHNICAL FIELD
The present invention relates to novel carboxylic acid compounds having a condensed ring, pharmacologically acceptable salts thereof, pharmaceutical compositions thereof and pharmaceutical use thereof. More particularly, the present invention relates to novel carboxylic acid compounds having a condensed ring, which are useful for the prophylaxis and treatment of thrombotic diseases and the prophylaxis and treatment of the formation of thrombus during operation and extracorporeal circulation, pharmacologically acceptable salts thereof, pharmaceutical compositions thereof and pharmaceutical use thereof.
BACKGROUND ART
A platelet membrane glycoprotein GPIIb/IIIa (hereinafter abbreviated sa GPIIb/IIIa) belongs to the integrin family which is one of the receptor groups concerned with the adhesion between cells or between cell substrates, and forms a heterodimer on the platelet surface in the presence of Ca.sup.++. It is also called .alpha..sub.IIb .beta..sub.3. By the adhesion of platelets to the injured site of a blood vessel and on stimulation by adenosine 5'-diphosphate (ADP) or thrombin, GPIIb/IIIa undergoes stereostructural changes and binds to a ligand having an RGD (arginine-glycine-aspartic acid) sequence, such as fibrinogen and von Willebrand's factor (GPIIb/IIIa does not bind to these ligands when it is not stimulated), as a result of which the final stage of the transmission of stimulation, namely, platelet aggregation, is induced. Therefore, a pharmaceutical agent (GPIIb/IIIa antagonist) which inhibits the binding of GPIIb/IIIa to these ligands can be a superior antiplatelet agent.
From this viewpoint, there have been already known [[4-[(p-amidino-N-methylbenzamide)acetyl]-o-phenylene]dioxy]diacetic acid (Ro 43-8857), [[1-[N-(p-amidinobenzoyl)-L-tyrosyl]-4-piperidinyl]oxy]-acetic acid (Ro 44-9883) (see Leo Alig et al., Journal of Medicinal Chemistry 1992, Vol. 35 (No.23), 4393-4407), N-(n-butanesulfonyl)-O-(4-(4-piperidinyl)-butyl-(S)-tyrosine (L-700,462; MK-383) (see G. D. Hartmans et al., Journal of Medicinal Chemistry 1992, Vol. 35 (No.24), 4640-4642), (3S, 5S)-5-(4'-amidino-4-biphenyl) oxymethyl-3-[(methoxycarbonyl)methyl]-2-pyrrolidinone (BIBU-52) (see Japanese Patent Unexamined Publication No. 264068/1992) and 4-amidino-4'-[(4-carboxycyclohexyl)aminocarbonyl]biphenyl hydrochloride (see Japanese Patent Unexamined Publication No. 334351/1992).
Yet, none of these are necessarily satisfactory in terms of, for example, efficacy, duration of efficacy, side-effects and possibility of oral administration.
Accordingly, an object of the present invention is to provide a novel compound having more superior GPIIb/IIIa-antagonistic action, a pharmaceutical composition thereof and a GPIIb/IIIa antagonist.
DISCLOSURE OF THE INVENTION
The present inventors have conducted various studies with the aim of achieving the above-mentioned objects and found that a carboxylic acid compound having a condensed ring, which has a specific structure, has superior GPIIb/IIIa-antagonistic action and low toxicity, which resulted in the completion of the present invention.
Accordingly, the present invention relates to a carboxylic acid compound having a condensed ring, which is represented by the formula (I) ##STR2## wherein A is a group of the formula (1) ##STR3## wherein E is hydrogen, alkyl or a protecting group for amidino, guanidino or amino, or a group of the formula (2) ##STR4## wherein E is as defined above; B is a group of the formula (3) ##STR5## wherein D is a group of the formula (i) ##STR6## wherein R.sup.5 is hydrogen, alkyl, cycloalkyl or aralkyl, Q is --O--, --S-- or --NR.sup.6 -- wherein R.sup.6 is hydrogen, alkyl, cycloalkyl, aralkyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, acyl or --(CH.sub.2).sub.d --COOR.sup.7 wherein R.sup.7 is hydrogen, alkyl, cycloalkyl or aralkyl and d is 1, 2 or 3, G is hydrogen, hydroxy, alkyl, cycloalkyl, phenyl, biphenylyl, pyridyl, aralkyl or E.sup.1 --NR.sup.8 -- wherein E.sup.1 is hydroge
REFERENCES:
patent: 4800211 (1989-01-01), Tischler et al.
patent: 5068226 (1991-11-01), Weinshenker et al.
patent: 5118680 (1992-06-01), Muller et al.
patent: 5576343 (1996-11-01), Nagahara et al.
Journal of Medicinal Chemistry, vol. 35, No. 23, Nov. 13, 1992.
Ashimori Atsuyuki
Ebisu Hajime
Eda Masahiro
Ikegawa Ruriko
Imada Teruaki
Coleman Brenda
Grumbling Matthew V.
The Green Cross Corporation
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