Nissan Chemical Industries Limited

Hiroshi Iwasaki

Mikio Suzuki

Mitsuaki Sakashita

Masaki Kitahara

Yoshihiro Fujikawa

Yoshio Ohara

Nobuhide Miyachi

Yoshinobu Yanagawa

Masaki Kirahara

Yoshihiro Fukikawa

Described herein are mevalonolactone derivatives having a quinoline ring of formula (I) ##STR1## wherein the R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, Y and Z variables are described therein.

Quinoline type mevalonoactones

A compound of the formula ##STR1## Z=--CH(OH)--CH.sub.2 --CH(OH)--CH.sub.2 --COO.1/2Ca have HMG--CoA inhibiting effects, making them useful as inhibitors of cholesterol biosynthesis. The compound may be prepared as a pharmaceutical for reducing hyperlipidemia, hyperlipoproteinemia or atherosclerosis.

Quinoline type mevalonolactones

A diastereomer salt of optically active quinolinemevalonic acid of the formula ((-)I.multidot.(+)II): ##STR1##

Diastereomer salt of optically active quinolinemevalonic acid

A diastereomer salt of optically active quinolinemevalonic acid of the formula ((-)I.(+)II): ##STR1##

A compound of the formula: ##STR1## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.6 are independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 cycloalkyl, C.sub.1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R.sup.7 R.sup.8 N-- (wherein R.sup.7 and R.sup.8 are independently hydrogen or C.sub.1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl or --O(CH.sub.2).sub.l OR.sup.19 (wherein R.sup.19 is hydrogen or C.sub.1-3 alkyl, and l is 1,2 or 3); or when located at the ortho position to each other, R.sup.1 and R.sup.2, or R.sup.3 and R.sup.4 together form --CH.dbd.CH--CH.dbd.CH--; or when located at the ortho position to each other, R.sup.1 and R.sup.2 together form --OC(R.sup.15 l) (R.sup.16)O-- (wherein R.sup.15 and R.sup.16 are independently hydrogen or C.sub.1-3 alkyl); Y is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --CH.sub.2 --CH.dbd.CH-- or -- CH.dbd.CH--CH.sub.2 --; and Z is --Q--CH.sub.2 WCH.sub.2 --CO.sub.2 R.sup.12, ##STR2## (wherein Q is --C(O)--, --C(OR.sup.13).sub.2 -- or --CH(OH)--; W is --C(O)--, --C(OR.sup.13).sub.2 -- or --C(R.sup.11) (OH)--; R.sup.11 is hydrogen atom or C.sub.1-3 alkyl; R.sup.12 is hydrogen or R.sup.14 (wherein R.sup.14 is physiologically hydrolyzable alkyl or M (wherein M is NH.sub.4, sodium, potassium, 1/2 calcium or a hydrate of lower alkyl amine, di-lower alkyl amine or tri-lower alkyl amine)); two R.sup.13 are independently primary or secondary C.sub.1-6 alkyl; or two R.sup.13 together form --(CH.sub.2).sub.2 -- or --(CH.sub.2).sub.3 ; R.sup.17 and R.sup.18 are independently hydrogen or C.sub.1-3 alkyl; and R.sup.5 is hydrogen, C.sub.1-6 alkyl, C.sub.2-3 alkenyl, C.sub.3-6 cycloalkyl, ##STR3## wherein R.sup.9 is a hydrogen atom, C.sub.1-4 alkyl, C.sub.1-3 alkoxy, fluoro, chloro, bromo or trifluoromethyl), phenyl--(CH.sub.2).sub.m -- (wherein m is 1,2 or 3), --(CH.sub.2).sub.n CH(CH.sub.3)--phenyl or phenyl--(CH.sub.2).sub.n CH(CH.sub.3)-- (wherein n is 0,1 or 2).

Quinoline type mevalonolactones useful for treating hyperlipidemia,

The present invention provides a compound of the formula: ##STR1## process for their production, pharmaceutical compositions containing them and their pharmaceutical uses, and intermediates useful for their production and processes for the production of such intermediates.

2',3' cyclic fused pyrazolopyrimidine type mevalonolactones

A compound of the formula: ##STR1## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.6 are independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 cycloalkyl, C.sub.1-3 alkoxy, n-botoxy, i-botoxy, sec-butoxy, R.sup.7 R.sup.8 N-- (wherein R.sup.7 and R.sup.8 are independently hydrogen or C.sub.1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl or --O(CH.sub.2).sub.l OR.sup.19 (wherein R.sup.19 is hydrogen or C.sub.1-3 alkyl, and l is 1,2 or 3); or when located at the ortho position to each other, R.sup.1 and R.sup.2, or R.sup.3 and R.sup.4 together form --CH.dbd.CH--CH.dbd.CH--; or when located at the ortho position to each other, R.sup.1 and R.sup.2 together form --OC(R.sup.15) (R.sup.16)O--(wherein R.sup.15 and R.sup.16 are independently hydrogen or C.sub.1-3 alkyl); Y is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --CH.sub.2 --CH.dbd.CH-- or -- CH.dbd.CH--CH.sub.2 --; and Z is --Q--CH.sub.2 WCH.sub.2 --CO.sub.2 R.sup.12, ##STR2## (wherein Q is --C(O)--, --C(OR.sup.13).sub.2 -- or --CH(OH)--; W is --C(O)--, --C(OR.sup.13).sub.2 -- or --C(R.sup.11) (OH)--; R.sup.11 is hydrogen atom or C.sub.1-3 alkyl; R.sup.12 is hydrogen or R.sup.14 (wherein R.sup.14 is physiologically hydrolyzable alkyl or M (wherein M is NH.sub.4, sodium, potassium, 1/2 calcium or a hydrate of lower alkyl amine, di-lower alkyl amine or tri-lower alkyl amine)); two R.sup.13 are independently primary or secondary C.sub.1-6 alkyl; or two R.sup.13 together form --(CH.sub.2).sub.2 -- or --(CH.sub.2).sub.3 ; R.sup.17 and R.sup.18 are independently hydrogen or C.sub.1-3 alkyl; and R.sup.5 is hydrogen, C.sub.1-6 alkyl, C.sub.2-3 alkenyl, C.sub.3-6 cycloalkyl, ##STR3## wherein R.sup.9 is a hydrogen atom, C.sub.1-4 alkyl, C.sub.1-3 alkoxy, fluoro, chloro, bromo or trifluoromethyl), phenyl-(CH.sub.2).sub.m -- (wherein m is 1,2 or 3), --(CH.sub.2).sub.n CH(CH.sub.3)--phenyl or phenyl--(CH.sub.2).sub.n CH(CH.sub.3)-- (wherein n is 0,1 or 2).

Quinoline type mevalonolactones useful for treating hyperlipidemia and

Pyrazolopyrimidine type mevalonolactones

A compound of the formula: ##STR1## wherein R.sup.1 and R.sup.2 are independently hydrogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-3 alkoxy, n-butoxy, i-butoxy, sec-butoxy, R.sup.5 R.sup.6 N-- (wherein R.sup.5 and R.sup.6 are independently hydrogen or C.sub.1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl or --O(CH.sub.2).sub.l OR.sup.15 (wherein R.sup.15 is hydrogen or C.sub.1-3 alkyl, and l is 1, 2 or 3); or when located at the ortho position to each other, R.sup.1 and R.sup.2 together form --CH.dbd.CH--CH.dbd.CH-- or methylene dioxy; Y is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --CH.sub.2 --CH.dbd.CH-- or --CH.dbd.CH--CH.sub.2 --; Z is --Q--CH.sub.2 WCH.sub.2 --CO.sub.2 R.sup.12, ##STR2## (wherein Q is --C(O)--, --C(OR.sup.13).sub.2 -- or --CH(OH)--; W is --C(O)--, --C(OR.sup.13).sub.2 -- or --C(R.sup.11) (OH)--; R.sup.11 is hydrogen or C.sub.1-3 alkyl; R.sup.12 is hydrogen or R.sup.14 (wherein R.sup.14 is physiologically hydrolyzable alkyl or M (wherein M is NH.sub.4, sodium, potassium, 1/2 calcium or a hydrate of lower alkylamine, di-lower alkylamine or tri-lower alkylamine)); two R.sup.13 are independently primary or secondary C.sub.1-6 alkyl; or two R.sup.13 together form --(CH.sub.2).sub.2 -- or --(CH.sub.2).sub.3 --; R.sup.16 and R.sup.17 are independently hydrogen or C.sub.1-3 alkyl; R.sup.3 is hydrogen, C.sub.1-6 alkyl, C.sub.2-3 alkenyl, C.sub.3-6 cycloalkyl, ##STR3## (wherein R.sup.7 is hydrogen, C.sub.1-4 alkyl, C.sub.1-3 alkoxy, fluoro, chloro, bromo or trifluoromethyl), phenyl--(CH.sub.2).sub.m -- (wherein m is 1, 2 or 3), --(CH.sub.2).sub.n CH(CH.sub.3)--phenyl or phenyl--(CH.sub.2).sub.n CH(CH.sub.3)-- (wherein n is 0, 1 or 2): R.sup.4 is C.sub.1-8 alkyl, C.sub.3-7 cycloalkyl, .alpha.- or .beta.-naphthyl, 2--, 3-- or 4-pyridyl, ##STR4## (wherein R.sup.8, R.sup.9 and R.sup.10 are independently hydrogen, C.sub.1-4 alkyl, C.sub.1-8 alkoxy, C.sub.1-3 alkylthio, chloro, bromo, fluoro, --NR.sup.18 R.sup.19 (wherein R.sup.18 and R.sup.19 are independently C.sub.1-3 alkyl), trichloromethyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl or --O(CH.sub.2).sub.k OR.sup.20 (wherein R.sup.20 is hydrogen or C.sub.1-3 alkyl, and k is 1, 2 or 3); when R.sup.10 is hydrogen and when located at the ortho position to each other, R.sup.8 and R.sup.9 together form --OC(R.sup.23) (R.sup.24)O-- (wherein R.sup.23 and R.sup.24 are independently hydrogen or C.sub.1-3 alkyl)), ##STR5## (wherein R.sup.25 is hydrogen, C.sub.1-4 alkyl, C.sub.1-3 alkoxy, chloro, bromo, or fluoro) or C.sub.1-3 alkyl substituted by 1 member selected from the group consisting of ##STR6## (wherein R.sup.8, R.sup.9 and R.sup.10 are as defined above) and naphthyl and by 0, 1 or 2 members selected from the group consisting of C.sub.1-8 alkyl.

Pyrimidine type mevalonolactones

Thienopyridine type mevalonolactones

Pyrazolopyridine type mevalonolactones useful as pharmaeuticals

A compound of the formula: ##STR1## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.6 are independently hydrogen, C.sub.1-6 alkyl, C.sub.1-6 cycloalkyl, C.sub.1-3 alkoxy, n-botoxy, i-botoxy, sec-butoxy, R.sup.7 R.sup.8 N-- (wherein R.sup.7 and R.sup.8 are independently hydrogen or C.sub.1-3 alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl or --O(CH.sub.2).sub.l OR.sup.19 (wherein R.sup.19 is hydrogen or C.sub.1-3 alkyl, and l is 1,2 or 3); or when located at the ortho position to each other, R.sup.1 and R.sup.2, and R.sup.3 and R.sup.4 together form --CH.dbd.CH--CH.dbd.CH--; or when located at the ortho position to each other, R.sup.1 and R.sup.2 together form --OC(R.sup.15)(R.sup.16)O-- (wherein R.sup.15 and R.sup.16 are independently hydrogen or C.sub.1-3 alkyl); Y is --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, --CH.sub.2 CH.dbd.CH-- or --CH.dbd.CH-- CH.sub.2 --; and Z is --Q--CH.sub.2 WCH.sub.2 --CO.sub.2 R.sup.12, ##STR2## (wherein Q is --C(O)--, --C(OR.sup.13).sub.2 -- or --CH(OH)--; W is --C(O)--, --C(OR.sup.13).sub.2 -- or --C(R.sup.11)(OH)--; R.sup.11 is hydrogen atom or C.sub.1-3 alkyl; R.sup.12 is hydrogen or R.sup.14 (wherein R.sup.14 is physiologically hydrolyzable alkyl or M (wherein M is NH.sub.4, sodium, potassium, 1/2 calcium or a hydrate of lower alkyl amine, di-lower alkyl amine or tri-lower alkyl amine)); two R.sup.13 are independently primary or secondary C.sub.1-6 alkyl; or two R.sup.13 together form --(CH.sub.2).sub.2 -- or --(CH.sub.2).sub.3 ; R.sup.17 and R.sup.18 are independently hydrogen or C.sub.1-3 alkyl; and R.sup.5 is hydrogen, C.sub.1-6 alkyl, C.sub.2-3 alkenyl, C.sub.3-6 cycloalkyl, ##STR3## (wherein R.sup.9 is a hydrogen atom, C.sub.1-4 alkyl, C.sub.1-3 alkoxy, fluoro, chloro, bromo or trifluoromethyl), phenyl-(CH.sub.2).sub.m -- (wherein m is 1,2 or 3), --(CH.sub.2).sub.n CH(CH.sub.3)-phenyl or phenyl-(CH.sub.2).sub.n CH(CH.sub.3)-- (wherein n is 0,1 or 2).

The present invention provides a compound of the formula: ##STR1## process for their production, pharmaceutical compositions containing them and their pharmaceutical uses, and intermediates useful for their production and processes for the production of such intermediates. The compounds are used as anti-hyperlipoproteinemic agents for example.

Growing community of inventors

Funabashi, Japan

Hiroshi Iwasaki