Sankyo Company, Limited

Yoshio Tsujita

Masao Kuroda

Akira Terahara

Kiyoshi Hamano

Seigo Iwado

Kouhei Furuya

Akira Endo

Minoru Tanaka

Hiroyuki Koike

Hiroyoshi Horikoshi

Takao Okazaki

Yukio Sugimura

Shigeki Muramatsu

Tomowo Kobayashi

Kimio Iino

Takeshi Kagasaki

Junya Ide

Kunio Nakano

Toshiaki Iwai

Yoko Shimada

Chihiro Tamura

Takashi Ito

Naoki Tanaka

Hiroaki Yanagisawa

Toshihiko Fujiwara

Koichi Fujimoto

Mitsuo Yamazaki

Sadao Ishihara

Fumitoshi Asai

Teiichiro Koga

Akiko Ando

Toshio Sada

Fumio Nakagawa

Takuro Kanazaki

Kazuhiko Tanzawa

Taketoshi Ogawa

Tatsuo Tanimoto

Masashi Shiomi

Naoyuki Maeda

Msao Kuroda

A pharmaceutical composition comprising as its active ingredients one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and one or more insulin resistance improving agents exhibits excellent arteriosclerotic progress inhibitory effects, and is useful as a drug, particularly as a drug for the prevention or treatment of arteriosclerosis. The invention also provides a method for the treatment or prophylaxis of arteriosclerosis by administering in combination (i) at least one of said angiotensin II receptor antagonists or angiotensin converting enzyme inhibitors and (ii) one or more insulin resistance improving agents to a mammal suffering from or susceptible to arteriosclerosis. The invention also provides kits containing at least a first container which comprises at least one angiotensin II receptor antagonists and/or angiotensin converting enzyme inhibitor and a second container which contains at least one insulin resistance improving agent.

Pharmaceutical compositions and methods for the treatment of arteriosclerosis

A combination of one or more HMG-CoA reductase inhibitors (for example pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin or atorvastatin) with one or more insulin sensitizers (for example troglitazone, pioglitazone, englitazone, BRL-49653, 5-(4-{2-[1-(4-2'-pyridylphenyl)ethylideneaminooxy]ethoxy}benzyl)thiazolidi ne-2,4-dione, 5-{4-(5-methoxy-3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}thiazolid ine-2,4-dione or its hydrochloride, 5-[4-(6-methoxy-1-methylbenzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-d ione, 5-[4-(1-methylbenzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione and 5-[4-(5-hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy)benzyl]thiazol idine-2,4-dione) exhibits a synergistic effect and is significantly better at preventing and/or treating arteriosclerosis and/or xanthoma than is either of the components of the combination alone.

Treatment of arteriosclerosis and xanthoma

Compounds of formula (I): ##STR1## wherein: R.sup.1 represents a saturated heterocyclic group attached to the bond or group represented by A through a ring carbon atom; R.sup.2a, R.sup.2b, R.sup.2c, R.sup.3a, R.sup.3b, R.sup.3c and R.sup.3d are hydrogen or various other groups or atoms; and A represents a single bond or an alkylene group having from 1 to 6 carbon atoms are serotonin 2 receptor antagonists and have the ability to inhibit the activity of squalene synthase. They can not only prevent and inhibit the development and progression of arteriosclerosis but can also inhibit thrombosis in arteriosclerotic lesions and can improve hemodynamics.

Diphenylethane compounds containing a saturated heterocyclic group,

A combination of one or more HMG-CoA reductase inhibitors (for example pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin or atorvastatin) with one or more insulin sensitizers (for example troglitazone, pioglitazone, englitazone, BRL-49653, 5-(4-{2-�1-(4-2'-pyridylphenyl)ethylideneaminooxy!-ethoxy}benzyl)thiazolid ine-2,4-dione, 5-{4-(5-methoxy-3-methylimidazo�5,4-b!pyridin-2-yl-methoxy)benzyl}thiazoli dine-2,4-dione or its hydrochloride, 5-�4-(6-methoxy-l-methylbenzimidazol-2-ylmethoxy)benzyl!thiazolidine-2,4-d ione, 5-�4-(l-methylbenzimidazol-2-ylmethoxy)benzyl!-thiazolidine-2,4-dione and 5-�4-(5-hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyllthiazolidine-2,4-dione) exhibits a synergistic effect and is significantly better at preventing and/or treating arteriosclerosis and/or xanthoma than is either of the components of the combination alone.

Radicicol derivatives in which one or both hydroxy groups are acylated have valuable anti-tumor activity or may be used as chemical intermediates.

Radicicol derivatives, their preparation and their anti-tumor activity

A compound of the formula ##STR1## in which: R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen atoms and groups of formula R.sup.3 --CO--, wherein R.sup.3 represents a group selected from the group consisting of unsubstituted alkyl groups having from 9 to 20 carbon atoms; substituted alkyl groups having from 10 to 20 carbon atoms; unsubstituted alkenyl groups having from 9 to 20 carbon atoms; substituted alkenyl group having from 10 to 20 carbon atoms; unsubstituted alkynyl groups having from 8 to 10 carbon atoms; and substituted alkynyl groups having from 8 to 10 carbon atoms wherein R.sup.1 and R.sup.2 are not both hydrogen atoms or acetyl groups. The compounds have antitumor activity.

Derivatives of ML-236B carboxylic acid, its salts and esters and corresponding lactone have a hydroxy group at the 3'-position and optionally also at the 6'-position. These derivatives may be prepared by the enzymatic hydroxylation of a corresponding ML-236B compound employing an enzyme produced by a microorganism of the genus Streptomyces or Amycolata, especially Streptomyces sp. SANK 62285, Streptomyces sp. SANK 62385, Streptomyces sp. SANK 62485, Streptomyces sp. SANK 62585, Amycolata autotrophica SANK 62781. Amycolata autotrophica subsp. canberrica SANK 62882 or Amycolata autotrophica subsp. amethystina SANK 62981. These derivatives have the ability to inhibit cholesterol biosynthesis.

Hydroxy-ML-236B derivatives, their preparation and use

Derivatives of ML-236B carboxylic acid, its salts and esters and corresponding lactone have a hydroxy group at the 3'-position and optionally also at the 6'-position. These derivatives may be prepared by the enzymatic hydroxylation of a corresponding ML-236B compound employing an enzyme produced by a microorganism of the genus Streptomyces or Amycolata, especially Streptomyces sp. SANK 62285, Streptomyces sp. SANK 62385, Streptomyces sp. SANK 62485, Streptomyces sp. SANK 62585, Amycolata autotrophica SANK 62781, Amycolata autotrophica subsp. canberrica SANK 62882 or Amycolata autotrophica subsp. amethystina SANK 62981. These derivatives have the ability to inhibit cholesterol biosynthesis.

Hydroxyl-ML-236B derivatives, their preparation and use

Dihydrodesoxygriseolic acid, which has the formula ##STR1## and salts and esters thereof may be prepared by cultivating a suitable strain of Streptomyces, e.g. Streptomyces griseoaurantiacus No. 43894, and, if necessary, salifying or esterifying the free acid. These compounds inhibit the activity of various cyclic nucleotide phosphodiesterases, particularly cAMP PDE, and, as a result of this, have a variety of physiological activities and uses.

Enzyme-inhibitory griseolic acid derivatives, and their use

Compounds of formula (I): ##STR1## [wherein X represents a hydrogen atom or a 2-methylbutyryl group, Y represents a hydrogen atom or a methyl group and R.sup.1 and R.sup.2 are the same or different and each represents an oxygen atom or a group of formula .dbd.N--OR.sup.3 (wherein R.sup.3 represents a hydrogen atom or an alkyl group)], the free hydroxy-carboxylic acids corresponding thereto and salts and esters of said acids may be prepared by oxidizing and, if necessary, oximating a corresponding ML-236A, ML-236B, MB-530A or MB-530B compound, and these compounds have valuable antihypercholesteraemic activity.

Octahydronaphthalene derivatives and their preparation

Compounds of formula (I): ##STR1## (wherein: R.sup.1 represents an optionally substituted alkyl, cycloalkyl, aryl, partially hydrogenated aryl or heterocyclic group; R.sup.2, R.sup.3, R.sup.4 and R.sup.5 represent hydrogen or an optionally substituted alkyl, cycloalkyl, aralkyl, aryl, heterocyclic or heterocyclic-alkyl group or any adjacent pair thereof form a cyclic structure, at least one not being hydrogen; A represents a bond, or a methylene, ethylene, oxymethyl or thiomethyl group; B represents an alkylene, alkylidene, cycloalkylene or cycloalkylidene group; and n is 0, 1 or 2) and salts and esters thereof are hypotensive agents.

Perhydrothiazepine derivatives, their preparation and their therapeutic

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

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

Monacolin K, which is an antihypercholesteraemic agent of molecular formula C.sub.24 H.sub.36 O.sub.5, is prepared by cultivating one or more of the microorganisms Monascus anka SANK 10171 (IFO 6540), Monascus purpureus SANK 10271 (IFO 4513), Monascus ruber SANK 10671 (FERM 4958), Monascus vitreus SANK 10960 (FERM 4960), Monascus paxii SANK 11172 (IFO 8201), Monascus ruber SANK 13778 (FERM 4959), Monascus ruber SANK 15177 (FERM 4956) or Monascus ruber SANK 18174 (FERM 4957) in a suitable culture medium and then isolating the Monacolin K from the resulting culture broth.

Preparation of Monacolin K

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Tokyo, Japan

Yoshio Tsujita