Taisho Pharmaceutical Co., Ltd.

Kazunori Hanada

Sadafumi Omura

Masaharu Tamai

Kiyoshi Oguma

Takashi Adachi

Shigeo Morimoto

Toshi Komurasaki

Hitoshi Toyoda

Jiro Sawada

Daisuke Uchida

Yuki Takahashi

Hiroshi Hara

Kazuya Kameo

Makoto Yoshimoto

Kenji Hanabusa

Chihiro Yokoo

Hirofusa Shirai

Kazutoshi Mizoue

Masami Goi

Mitsuo Murata

Nobuhiko Katunuma

Shigezo Udaka

Hiromitsu Yoshimura

Masahuru Tamai

Fumio Mizobe

Kiyoshi Nakazawa

Yumiko Matsuki

Saeko Shindo

Toshiro Amamoto

Tadayasu Okazaki

Pyridine derivative

Parenchymal hepatocyte growth factors

Human-derived tumor cell growth inhibitors

DNA fragment encoding tumor cell growth inhibitors

Novel tumor cell growth inhibitor is a protein which can be obtained from the culture supernatant of 3T3 cell-derived cell line and which has the following properties:

Tumor cell growth inhibitor

An epoxysuccinic acid derivative represented by the formula ##STR1## wherein R.sup.1 is a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, and a pharmaceutically acceptable salt are useful as cathepsin B inhibitors.

Epoxysuccinic acid derivatives

Tripeptide derivatives of the formula ##STR1## wherein R is a formyl group or a dimethoxymethyl group have antitumor and enzyme inhibition effects.

Novel tripetide derivatives

This invention is directed to novel peptide derivatives. Said peptide derivatives are useful as a substrate for the activity assay of enzymes of the group EC 3. 4. 22, for example, cathepsin L, cathepsin B and cathepsin H. Said peptide derivatives which contain L-methionine radical are prepared according to the methods conventional in peptide chemistry. As typical examples are mentioned D-leucyl-L-tyrosyl-L-methionine-.beta.-naphthylamide formate, .beta.-alanyl-L-tyrosyl-L-methionine-.beta.-naphthylamide formate and succinyl-L-tyrosyl-L-methionine-p-nitroanilide.

Peptide derivatives

An epoxysuccinyl amino acid derivative of the formula ##STR1## wherein R.sup.1 is hydrogen, alkali metal, benzyl or cycloalkyl having 5 to 6 carbon atoms, R.sup.2 is alkyl having 3 to 4 carbon atoms, R.sup.3 is hydrogen, benzyloxycarbonyl, acetyl or benzoyl, and n is an integer of 2 to 7. The subject compounds exhibit inhibitory activity towards thiol protease, especially, calcium-activated neutral thiol protease which exists in excess in muscle tissues of mammals afflicted with muscular dystrophy.

Epoxysuccinyl amino acid derivatives

An epoxysuccinyl amino acid derivative of the formula ##STR1## wherein R.sup.1 is hydrogen or alkali metal, R.sup.2 is isobutyl, R.sup.3 is hydrogen or benzyloxycarbonyl, and n is an integer of 5 to 7. The subject compounds exhibit inhibitory activity towards thiol protease, especially, calcium-activated neutral thiol protease which exists in excess in muscle tissues of mammals afflicted with muscular dystrophy.

The epoxysuccinic acid derivatives of this invention are prepared by esterification of an epoxysuccinic acid or a halide thereof, by partial hydrolysis of an epoxysuccinic acid diester, by amidation of an epoxysuccinic acid monoester, or by hydrolysis of an epoxysuccinic acid amide monoester. These epoxysuccinic acid derivatives have excellent thiol protease inhibitory activity and anti-inflammatory activity without the acceleration of vascular permeability.

The epoxysuccinamic acid compounds of the present invention are prepared by reaction of monoesters of epoxysuccinic acid or monoesters of epoxysuccinic acid chloride with amino compounds. These epoxysuccinamic acid compounds have excellent anti-inflammatory activity, thiol protease inhibitory activity, muscular dystrophy inhibitory activity and anti-hypertensive activity without acceleration of vascular permeability.

Epoxysuccinamic acid compounds

An epoxysuccinic acid derivative of the formula ##STR1## wherein R.sup.1 is hydrogen, alkali metal, alkyl having 1-2 carbon atoms, cycloalkyl having 5-6 carbon atoms or benzyl, R.sup.2 is alkyl having 3-4 carbon atoms or benzyl, R.sup.3 is hydrogen or methyl, and R.sup.4 is alkyl having 1-10 carbon atoms, phenyl, benzyl, phenethyl, cycloalkyl having 3-6 carbon atoms or a group of the formula ##STR2## wherein R.sup.5 is hydrogen, alkyl having 1-4 carbon atoms or said alkyl substituted with hydroxy, methylmercapto, phenyl, hydroxyphenyl, indolyl, an optionally protected carboxy, an optionally protected amino or an optionally protected guanidino, and R.sup.6 is hydroxy, alkalimetaloxy, alkoxy having 1-2 carbon atoms, benzyloxy, amino or dimethylamino, or R.sup.3 and R.sup.4 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring, or said heterocyclic ring substituted with a protected carboxy.

An epoxysuccinic acid derivative of the formula ##STR1## wherein R.sup.1 is hydrogen, alkali metal, alkyl having 1-2 carbon atoms, cycloalkyl having 5-6 carbon atoms or benzyl, R.sup.2 is alkyl having 3-4 carbon atoms or benzyl, R.sup.3 is hydrogen or methyl, and R.sup.4 is alkyl having 1-10 carbon atoms, phenyl, benzyl, phenethyl or cycloalkyl having 3-6 carbon atoms or R.sup.3 and R.sup.4 taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring, or said heterocyclic ring substituted with a protected carboxy.

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Tokyo, Japan

Kazunori Hanada