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Details for Patent: 5,185,328

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Details for Patent: 5,185,328

Title: Quinoline type mevalonolactones useful for treating hyperlipidemia, hyperlipoproteinemia or atherosclerosis
Abstract: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).
Inventor(s): Fukikawa; Yoshihiro (Funabashi, JP), Suzuki; Mikio (Funabashi, JP), Iwasaki; Hiroshi (Funabashi, JP), Sakashita; Mitsuaki (Shiraoka, JP), Kitahara; Masaki (Shiraoka, JP)
Assignee: Nissan Chemical Industries Ltd. (Tokyo, JP)
Filing Date:Feb 23, 1990
Application Number:07/483,829
Claims:1. A compound of the formula: ##STR17## 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.1-3 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; 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 ##STR18## (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.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, ##STR19## (wherein R.sup.9 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 provided that at least one of R.sup.1, R.sup.2 and R.sup.6 is trimethylsilyloxy or diphenyl-t-butylsilyloxy.

2. The compound according to claim 1, wherein in the formula I, R.sup.1, R.sup.2 and R.sup.6 are independently hydrogen, fluoro, chloro, bromo, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, dimethylamino, hydroxy, hydroxymethyl, hydroxyethyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, phenoxy or benzyloxy; trimethylsilyloxy or diphenyl-t-butylsilyloxy; when R.sup.4 is hydrogen, R.sup.3 is hydrogen, 3'-fluoro, 3'-chloro, R.sup.11 is hydrogen or C.sub.1-3 alkyl 3'-methyl, 4'-methyl, 4'-chloro or 4'-fluoro; or R.sup.3 and R.sup.4 together represent 3'-methyl-4'-chloro, 3',5'-dichloro, 3',5'-difluoro, 3',5'-dimethyl or 3'-methyl-4'-fluoro; R.sup.5 is primary or secondary C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl; and Y is --CH.sub.2 --CH.sub.2 or --CH.dbd.CH--; and Z is ##STR20## provided that at least one of R.sup.1, R.sup.2 and R.sup.6 is trimethylsilyloxy or diphenyl-t-butylsilyloxy.

3. Compound according to claim 2, wherein R.sup.1, R.sup.2 and R.sup.6 are independently trimethylsilyloxy or diphenyl-t-butylsilyloxy; when R.sup.3 is hydrogen, R.sup.4 is hydrogen, 4'-methyl, 4'-chloro or 4'-fluoro; or when both R.sup.3 and R.sup.4 are not hydrogen, they represent 3',5'-dimethyl or 3'-methyl-4'-fluoro; and Y is --CH.sub.2 --CH.sub.2 -- or (E)----CH.dbd.CH--.

4. The compound according to claim 3, wherein R.sup.3 is hydrogen, R.sup.4 is hydrogen, 4'-fluoro or 4'-chloro; or R.sup.3 and R.sup.4 together represent 3'-methyl-4'-fluoro; R.sup.5 is ethyl, n-propyl, i-propyl or cyclopropyl; and Y is (E)----CH.dbd.CH--.

5. The compound according to claim 3, wherein when both R.sup.2 and R.sup.6 are hydrogen, R.sup.1 is trimethylsilyloxy or diphenyl-t-butylsilyloxy; when R.sup.3 is hydrogen, R.sup.4 is hydrogen, 4'-chloro or 4'-fluoro; R.sup.5 is i-propyl or cyclopropyl; and Y is (E)----CH.dbd.CH--.

6. The compound according to claim 1, which is (E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-(1"-methylethyl)6'-trimethyls ilyloxy-quinolin-3'-yl]-hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or C.sub.1-3 alkyl ester of the carboxylic acid.

7. The compound according to claim 1, which is (E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-(1"-methylethyl)7'-trimethyls ilyloxy-6'-chloro-quinolin-3'-yl]-hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or C.sub.1-3 alkyl ester of the carboxylic acid.

8. The compound according to claim 1, which is (E)-3,5-dihydroxy-7-[4'-(4"-fluorophenyl)-2'-(1"-methylethyl)8'-trimethyls ilyloxy-6'-methyl-quinolin-3'-yl]-hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or C.sub.1-3 alkyl ester of the carboxylic acid.

9. The compound according to claim 1, which is (E)-3,5-dihydroxy-7-2'-cyclopropyl[4'-(4"-fluorophenyl)6'-trimethylsilylox y-quinolin-3'-yl]-hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or C.sub.1-3 alkyl ester of the carboxylic acid.

10. The compound according to claim 1, which is (E)-3,5-dihydroxy-7-[2-cyclopropyl4'-(4"-fluorophenyl)7'-trimethylsilyloxy -2'-cyclopropyl-quinolin-3'-yl]-hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or C.sub.1-3 alkyl ester of the carboxylic acid.

11. The compound according to claim 1, which is (E)-3,5-dihydroxy-7-[2'-cyclopropyl4'-(4"-fluorophenyl)7'-trimethylsilylox y-2'-cyclopropyl-6'-chloro-quinolin-3'-yl]-hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or C.sub.1-3 alkyl ester of the carboxylic acid.

12. A method for treating hyperlipidemia, which comprises administering an effective amount of the compound of the formula I as defined in claim 1 to a host in need of treatment for hyperlipidemia.

13. A method for treating hyperlipoproteinemia which comprises administering an effective amount of the compound of the formula I as defined in claim 1 to a host in need of treatment for hyperlipoproteinemia.

14. A method for treating atherosclerosis which comprises administering an effective amount of the compound of the formula I as defined in claim 1 to a host in need of treatment for atherosclerosis.
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