Kissei Pharmaceutical Co., Ltd.

Ono Pharmaceutical Co., Ltd.

Kissei Yakuhin Kogyo Kabushiki Kaisha

Kissei Yakuhin Kogyo Kabushiki Kaisha (Kissei Pharmaceutical Co. Ltd.)

Kinji Iizuka

Tetsuhide Kamijo

Kenji Akahane

Yoshiaki Kiso

Hideaki Umeyama

Tetsuhiro Kubota

Yukiyoshi Ajisawa

Hiromu Harada

Ryoji Yamamoto

Michihiro Kobayashi

Yukihiko Kinoshita

Yukio Kamijo

Denichi Momose

Kozaburo Harita

Shigeo Arikawa

Michio Toda

Tetsuhide Kamino

Keniji Akahane

Kaname Morita

Mitsuo Watanabe

Novel amino acid derivatives useful as a therapeutic agent are disclosed. These amino acid derivatives and the pharmaceutically acceptable salts thereof have a human renin inhibitory effect when administered orally and are useful for treatment of hypertension, especially renin-associated hypertension.

Novel amino acid derivatives

Dipeptides are described which are represented by the formula ##STR1## wherein the various substituents are defined hereinbelow. These compounds have a strong inhibitory efect on human renin, and are useful as a therapeutically active agent for the treatment of hypertension, especially renin-associated hypertension.

Dipeptides as renin inhibitors

New renin inhibitory amino acid derivatives represented by formula (I): ##STR1## wherein A represents an alkoxycarbonyl group having 2 to 7 carbon atoms, ##STR2## wherein R.sup.1 and R.sup.2 are defined as in the specification below or ##STR3## wherein X and Y are defined as in the specification herein below, n represents zero or one, Z represents --O-- or --NH--, and R represents a straight- or branched chain alkyl group having 1 to 7 carbon atoms, and pharmaceutically acceptable salts thereof, useful as a therapeutic agent are disclosed. The amino acid derivatives have a renin inhibitory effect when administered orally and are useful for treatment of hypertension, especially renin-associated hypertension.

Novel renin inhibitory amino acid derivatives

Amino acid derivatives

Amino acid derivatives represented by formula ##STR1## wherein His represents an L-histidyl group, X represents a straight or branched alkoxy group having 1 to 7 carbon atoms, a straight or branched alkylamino group having 1 to 7 carbon atoms, a cycloalkyloxy group having 3 to 7 carbon atoms, a morpholino group, said alkoxy group having one or more halogen atoms as substituents; or a pharmaceutically acceptable salt, are useful in the treatment of hypertension.

Morpholine containing amino acid derivatives

Histidine derivatives

The imidazole derivatives of the formula: ##STR1## wherein R is a hydrogen atom or an alkyl group, A.sub.1 and A.sub.2, which may be the same or different, each is an alkylene or an alkylene group, m is 0 or 1, and Z is ##STR2## wherein R.sub.1 and R.sub.2, which may be the same or different, each is a hydrogen atom or an alkyl group, and the terminal carbon atom bonded to the hetero atom of Z may be bonded to either A.sub.1 or A.sub.2 or COOR group (in the case of m being 0); and the pharmaceutically acceptable salts thereof. These compounds have a strong inhibitory effect on thromboxane synthetase from human or bovine platelet microsomes, and are useful as therapeutically actives for inflammation, hypertension, thrombus, cerebral apoplexy and asthma.

Imidazole derivatives and pharmaceutical use thereof

The present invention provides an improved method for producing a nuclear substituted cinnamoylanthranilic acid compound. Illustrative of the process is the reaction of 3,4-dimethoxybenzaldehyde with 2-carboxymalonanilic acid in an inert solvent medium in the presence of piperidine to provide an intermediate salt precipitate, and the salt is treated with an acidic reagent to yield N-(3,4-dimethoxycinnamoyl)anthranilic acid product.

Method for the production of nuclear substituted cinnamoylanthranilic

4-(1-Imidazolylmethyl)cinnamic acid hydrochloride monohydrate of the formula: ##STR1## and pharmaceutical compositions containing such compound. The imidazole derivative above has a strong and specific inhibitory effect on thromboxane synthetase from human or bovine platelet microsomes, and is useful as a therapeutical agent for inflammation, hypertension, thrombus, cerebral apoplexy, and asthma.

4-(1-imidazolylmethyl)cinnamic acid hydrochloride monohydrate and

The present invention provides an improved method for producing a nuclear substituted cinnamoylanthranilic acid compound. Illustrative of the process is the reaction of 3-hydroxy-4-methoxybenzaldehyde with 2-carboxymalonanilic acid in an inert solvent medium in the presence of a molar excess of piperidine to provide a high purity intermediate salt precipitate, and the salt is treated with an acidic reagent to yeild N-(3-hydroxy-4-methoxycinnamoyl)anthranilic acid product.

Process for the production of nuclear substituted cinnamoylanthranilic

1,3-Disubstituted imidazoles of the general formula (I): ##STR1## wherein A and B may be the same or different, and each is a straight- or branched-chain alkylene or alkenylene group having 1 to 8 carbon atoms, Y is an acyl group having 2 to 10 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms or an dialkoxymethyl group having 3 to 13 carbon atoms, Z is a cyano group or an alkoxycarbonyl group having 2 to 7 carbon atoms, X is a halogen atom, n is zero or 1. The said compounds are intermediates for producing the imidazole derivatives of the general formula (V) above which possess strong and specific inhibitory effects on thromboxane synthetase and thus are useful as therapeutical agents for treatment of diseases caused by thromboxane A.sub.2.

1,3-Disubstituted imidazoles

The imidazole derivatives of the general formula: ##STR1## wherein A and B may be the same or different, and each is a straight- or branched-chain alkylene or alkenylene group having 1 to 8 carbon atoms, D is an acyl group having 2 to 10 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms or a dialkoxymethyl group having 3 to 13 carbon atoms, Q is a cyano group or an alkoxycarbonyl group having 2 to 7 carbon atoms, X is a halogen atom, Z is ##STR2## (wherein E is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, Y is an oxygen atom or a sulfur atom and may be connected with either A or B), n is zero or 1, with the proviso that n is 1 when Y connects with B. These compounds are novel compounds and are useful as intermediates in producing 1-substituted imidazole derivatives which possess strong and specific inhibitory effects on thromboxane synthetase and thus are useful as therapeutically active agents for treatment of diseases caused by thromboxane A.sub.2.

Imidazole derivatives

The imidazole compounds of the general formula (I): ##STR1## wherein Y is a carboxyl group, a hydroxymethyl group, an N-di or -mono alkyl substituted or unsubstituted carbamoyl group, a cyano group, or an N-di or -mono alkyl substituted or unsubstituted aminomethyl group, and n is an integer of 3 to 20; and pharmaceutically acceptable salts thereof. These compounds have a strong inhibitory effect on thromboxane synthetase from rabbit platelet microsomes, and are useful as therapeutically active agents for inflammation, hypertension, thrombus, cerebral apoplexy and asthma.

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Nagano, Japan

Kinji Iizuka