Sankyo Company, Limited

Akira Terahara

Minoru Tanaka

Akira Endo

Yoshio Tsujita

Masao Kuroda

Kiyoshi Hamano

Chihiro Tamura

Hidehiko Oka

Takao Okazaki

Mitsuo Yamazaki

Noritoshi Kitano

Akira Ogiso

Seigo Iwado

Fumio Nakagawa

Seiji Mitsui

Atsushi Naito

The dihydro-M-4 and dihydro-IsoM-4 hydroxy carboxylic acids of the formula (II): ##STR1## wherein one of R.sup.1 represents a hydrogen atom and the other represents a hydroxy group and wherein the structure shown as ##STR2## represents a structure of formula ##STR3## and the salts and esters of said acids. The invention also provides pharmaceutical compositions containing said acids, salts and/or esters which are useful for inhibiting cholesterol biosynthesis in the liver.

M-4 and iso M-4 derivatives, their preparation and compositions

MB-530B derivatives containing them

Tetrahydro-M-4 and tetrahydro-IsoM-4 hydroxy carboxylic acids of the formula (II): ##STR1## wherein one of R.sup.1 and R.sup.2 represents a hydrogen atom and the other represents a hydroxy group, and the salts and esters of said acids which are useful for inhibiting chloresterol biosynthesis in the liver. The invention also provides pharmaceutical compositions containing said acid(s).

M-4 and IsoM-4 derivatives, their preparation and compositions

Compounds of formula (I): ##STR1## (wherein OH represents OH or OH), that is to say M-4 carboxylic acid and M-4' carboxylic acid, as well as pharmaceutically acceptable salts and esters thereof and the corresponding ring-closed lactones may be prepared by contacting an ML-236B compound with a microorganism of the genus Nocardia or a cell-free, enzyme-containing extract thereof and then, if necessary, subjecting the resulting product to one or more of the following reactions: hydrolysis, salification, esterification and lactonisation. The resulting M-4 and M-4' derivatives have the ability to inhibit the biosynthesis of cholesterol and are therefore of value in the therapy and/or prophylaxis of hyperlipaemia and arteriosclerosis.

Process for preparing 3-hydroxy-ML-236B derivatives known as M-4 and M-4'

The 1-acyloxy-6-hydroxy-IsoMB-530B lactones of the formula (I): ##STR1## wherein R.sup.1 represents a group of the formula ##STR2## wherein R.sup.2 is a C.sub.1 -C.sub.10 alkyl group.

IsoMB-530B derivatives

Tetrahydro-M-4 and tetrahydro-IsoM-4 hydroxy carboxylic acids of the formula (I): ##STR1## wherein one of R.sup.1 and R.sup.2 represents a hydrogen atom and the other represents a hydroxy group which are useful for inhibiting chloresterol biosynthesis in the liver. The invention also provides pharmaceutical compositions containing said lactone(s).

M-4 and IsoM-4 derivatives their preparation and compositions containing

A new compound, named 'Griseolic acid', and its salts and can be prepared by the cultivation of Streptomyces griseoaurantiacus SANK 63479 (FERM-P 5223). Griseolic acid and its salts inhibit the activity of the enzyme cyclic adenosine monophosphate phosphodiesterase and, as a result of this, have variety of physiological activities and uses.

Enzyme inhibitor produced by cultivation of streptomyces microorganisms

Dihydro-M-4 and dihydro-IsoM-4 are new compounds which may be prepared by the catalytic hydrogenation of M-4 or IsoM-4 respectively. They, and their salts and esters (which may be prepared by conventional salification or esterification reactions with the parent dihydro-M-4 or dihydro-IsoM-4), are capable of inhibiting cholesterol biosynthesis in the liver and may be formulated, for therapeutic use, with conventional pharmaceutical carriers or diluents.

M-4 And IsoM-4 derivatives and compositions containing them

Compounds of formula (I): ##STR1## (wherein R represents a group of formula ##STR2## and the corresponding ring-closed lactones, salts (especially alkali metal salts) and esters (especially C.sub.1 -C.sub.5 alkyl esters) thereof may be prepared by subjecting ML-236B, or ML-236B carboxylic acid or a salt or ester thereof to enzymatic hydroxylation, which may be effected by means of microorganisms of the genera Mucor, Rhizopus, Zygorynchus, Circinella, Actinomucor, Gongronella, Phycomyces, Martierella, Pycnoporus, Rhizoctonia, Absidia, Cunninghamella, Syncephalastrum and Streptomyces, or cell-free, enzyme-containing extracts from said microorganisms. The compounds are capable of inhibiting biosynthesis of cholesterol and are thus useful in the treatment of hypercholesteraemia.

ML-236B Derivatives

A compound of formula (I): ##STR1## (called 6-methoxy-IsoML-236B lactone) and its corresponding free hydroxy-carboxylic acid and salts and esters of said acid may be prepared by the enzymatic alkoxylation of an ML-236B compound, preferably using a microorganism of the genus Syncephalastrum, Absidia or Cunninghamella, e.g. Absidia coerulea, or a cell-free enzyme-containing extract from said microorganism. If desired, the lactone or carboxylic acid may be converted by conventional salification or esterification techniques to the desired salt or ester. These compounds have the ability to inhibit the biosynthesis of cholesterol and are thus of value in the treatment of hypercholesteraemia, for which purpose they may be formulated as compositions in admixture with conventional pharmaceutical carriers or diluents.

Compounds of formula (I): ##STR1## (in which: Z represents a group of formula ##STR2## A represents a group of formula ##STR3## B represents a group of formula ##STR4## R.sup.1 represents a hydrogen atom or a methyl group; R.sup.2, R.sup.3, R.sup.4 and R.sup.6 are the same or different and each represents a hydrogen atom or an acyl group;

Hydronaphthalene derivatives

Compounds of formula (I): ##STR1## (wherein R represents a group of formula ##STR2## and the corresponding ring-closed lactones, salts (especially alkali metal salts) and esters (especially C.sub.1 -C.sub.5 alkyl esters) thereof may be prepared by subjecting ML-236B, or ML-236B carboxylic acid or a salt or ester thereof to enzymatic hydroxylation, which may be effected by means of microorganisms of the genera Mucor, Rhizopus, Zygorynchus, Circinella, Actinomucor, Gongornella, Phycomyces, Martierella, Pycnoporus, Rhizoctonia, Absidia, Cunninghamella, Syncephalastrum and Streptomyces, or cell-free, enzyme-containing extracts from said microorganisms. The compounds are capable of inhibiting biosynthesis of cholesterol and are thus useful in the treatment of hypercholesteraemia.

ML-236B Derivatives and their preparation

Antihyperlipemic dihydro-ML-236B derivatives, their preparation and use

4-Hydroxy-2-pyrone derivatives of formula (I): ##STR1## (wherein A represents an alkylene group which is optionally alkyl-substituted or an alkenylene group, and Z represents a substituted or unsubstituted aryl or aryloxy group) may be prepared by cyclizing an ester of formula (II): ##STR2## (wherein A and Z are as defined above and R represents an organic group) and have valuable antilipaemic activities.

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Hiromachi, Japan

Akira Terahara