Taisho Pharmaceutical Co., Ltd.

Kiyoshi Oguma

Kazunori Hanada

Takashi Adachi

Sadafumi Omura

Masaharu Tamai

Shigeo Morimoto

Kazuya Kameo

Jiro Sawada

Masami Goi

Nobuhiko Katunuma

Masahuru Tamai

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 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.

Epoxysuccinic acid derivatives

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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Saitama, Japan

Kiyoshi Oguma