Banyu Pharmaceutical Co. Ltd

Mitsuo Yano

Kiyofumi Ishikawa

Masaki Ihara

Takashi Hayama

Takehiro Fukami

Toshio Nagase

Toshiaki Mase

Kenji Niiyama

Masaru Nishikibe

Kagari Fujita

Fumihiko Ikemoto

Junji Yoshizawa

Kenji Matsuyama

Ikuo Matsumoto

Yoshimi Tsuchiya

Kazuhito Noguchi

Nobuo Harada

Kyoko Nakamichi

Yukio Hirayama

Takeshi Hayama

Endothelin antagonistic heteroaromatic ring-fused cyclopentene

The invention relates to compounds which are antagonists of endothelin, to processes for their preparation, and to their use as pharmaceuticals. The compounds of the invention are Useful in the treatment of hypertension, pulmonary hypertension, Reynaud's disease, myocardial infarction, angina pectoris, acute renal failure, cerebral infarction, cerebral vasospasm, arteriosclerosis, asthma, endotoxin shock, endotoxin-induced multiple organ failure or disseminated intravascular coagulation, and/or cyclosporin-induced renal failure or hypertension.

Endothelin antagonistic peptide derivatives

Peptides having the formula: ##STR1## inhibit the binding of endothelin to its ET.sub.B receptor and are useful in treating diseases associated with excess production or secretion of endothelin.

Endothelin antagonistic substance

Peptides having the formula: ##STR1## inhibit the binding of endothelin and are useful in treating diseases associated with excess production or secretion of endothelin.

A peptide derivative of the formula: ##STR1## is a novel compound having antagonism against three endothelin isopeptides. A 2-cyanotryptophan or a protected compound thereof, is an intermediate for the preparation of the endothelin antagonist.

Endothelin antagonistic peptide

Peptides having the formula: ##STR1## inhibit the binding of endothelin to its receptor and are useful in treating diseases associated with excess production or secretion of endothelin.

Peptides having the formula ##STR1## inhibit the binding of endothelin to its receptor and are useful in treating diseases associated with excess production or secretion of endothelin.

A heteroaromatic ring-fused cyclopentene derivative of the formula: ##STR1## wherein the variables are as defined in the specification; or a pharmaceutically acceptable salt thereof.

There are provided novel aminophosphonic acid derivatives of the general formula [I]: ##STR1## wherein n is an integer of 2 or 3; R.sup.1 is a phenyl, naphthyl, indolyl, benzothienyl, benzofuryl or benzoxazolyl group which may have 1 to 3 substituents selected from the group consisting of hydroxyl and lower alkyloxy groups, or a hydrogen atom; R.sup.2 is a lower alkyl group, a benzyl group, a 4-hydroxybenzyl group, a 3-indolylmethyl group or a .beta.-phenethyl group; and A is an optional residue of an amino acid selected from the group consisting of tryptophane, tyrosine, phenylalanine, homophenylalanine, naphthylalanine or N.sup..omega. -nitroarginine, and their pharmaceutically acceptable salts. The compounds according to the present invention and their pharmaceutically acceptable salts exhibit an inhibitory activity against endothelin-converting enzyme, and are expected to be useful as a drug treating various diseases with which endothelin is concerned.

Aminophosponic acid derivative

Novel isoquinoline derivatives represented by formula (I): ##STR1## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, X.sup.1 and X.sup.2 are as defined in the specification, have an anti-arrhythmic activity and bradycardiac activity and are effective for the treatment of arrhythmia, myocardiac infarction or angina pectoris.

Isoquinoline derivatives

Endothelin antagonistic cyclic pentapeptides

A 1,3-dithiole derivative having the formula: ##STR1## wherein each of R.sup.1 and R.sup.2 is a substituted or unsubstituted alkyl, cycloalkyl, lower alkenyl, lower alkynyl, aryl or aralkyl group or R.sup.1 and R.sup.2 together form a substituted or unsubstituted alkylene or alkenylene group having from 3 to 6 carbon atoms, which may contain a cycloalkylene group, an o-phenylene group or a hetero atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom which may have a substituent, and Q is an acid residue useful for the treatment of liver diseases.

1,3-dithiole derivatives and pharmaceutical compositions

An .alpha.-tocopheryl 5-substituted picolinate of the formula ##STR1## wherein R represents an alkyl group which may have a substituent, a lower alkenyl group, a phenyl(lower alkyl) group, or a phenyl group which may have a substituent, and Q represents a methylene group or an oxygen or sulfur atom, or a pharmaceutically acceptable acid addition salt thereof. This compound can be produced by reacting a substituted picolinic acid of the formula ##STR2## wherein R and Q are as defined above, or its reactive derivative with .alpha.-tocopherol of the formula ##STR3## and as required, contacting the resulting compound with a pharmaceuticlly acceptable acid. A pharmaceutical composition comprising said compound as an active ingredient is useful for the treatment of hypertension.

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Tokyo, Japan

Mitsuo Yano