Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-10-15
1994-05-03
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514529, 549292, 560 84, 560181, A61K 3135, A61K 31215, A61K 31225, C07D30930
Patent
active
053088646
DESCRIPTION:
BRIEF SUMMARY
This invention relates to pharmaceutically active compounds, which are substituted decalins. The compounds of the present invention are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the rate limiting enzyme in the biosynthesis of cholesterol in mammals including man, and as such are useful in the treatment of hypercholesterolaemia and hyperlipidaemia. Clinical evidence shows that reduction of serum cholesterol levels lead to a decreased risk of heat disease.
The natural fermentation products compactin (disclosed by A. Endo, et al. in Journal of Antibiotics, 29, 1346-1348 (1976) and mevinolin (disclosed by A. W. Alberts, et al. in J. Proc. Natl. Acad. Sci. U.S.A., 77, 3957 (1980)) are very active antihypercholesterolaemic agents which limit cholesterol biosynthesis by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme and natural point of cholesterolgenesis regulation in mammals, including man. Compactin (R=H, a=double bond) and mevinolin (R=.alpha.-CH.sub.3, a=double bond; also known as lovastatin) have the structures shown below: ##STR1##
Also known in the art are the natural products dihydrocompactin (R=H, a=single bond) disclosed by Y. K. T. Lam et al., Journal of Antibiotics, 34, 614-616 (1981), dihydromevinolin (R=.alpha.-CH.sub.3, a=single bond) disclosed by G. Albers-Schonberg et al., Journal of Antibiotics, 34, 507-512 (1981), and eptastatin (R=.beta.-OH, a=double bond) disclosed by N. Serizawa et al., in Journal of Antibiotics, 36, 604-607 (1983).
U.S. Pat. No. 4,293,496 (Willard) disclosed a number of semisynthetic analogues of mevinolin having the structure ##STR2## where the dotted lines represent single or double bonds and R is C.sub.1-8 straight chain alkyl, C.sub.3-10 branched chain alkyl except (S)-2-butyl, C.sub.3-10 cycloalkyl, C.sub.2-10 alkenyl, C.sub.1-10 CF.sub.3 substituted alkyl, halophenyl, phenyl C.sub.1-3 alkyl and substituted phenyl C.sub.1-3 alkyl.
U.S. Pat Nos. 4,444,784, 4,661,483, 4,668,699 and 4,771,071 (Hoffman) disclose compounds of similar structure where the R group contains extra functional groups, for example ether, amide and ester groups. In J. Med. Chem., 29, 849-852 (1986), W. F. Hoffman et al. report the synthesis and testing of a number of the analogues referred to above, the preferred compound (now known as simvastatin) have the structure ##STR3## EP-A-0251625 (Inamine) discloses compounds of structure ##STR4## where R is similar to the corresponding group in the compounds described above, R.sup.1 is a group of formula CH.sub.2 OH, CH.sub.2 OCO.R.sup.3, CO.sub.2 R.sup.4 or CO.NR.sup.6 R.sup.7 wherein R.sup.3, R.sup.4, R.sup.6, and R.sup.7 can cover a range of alkyl, alkoxy, or aryl groups, and the dotted lines represent single or double bonds. Only one of these compounds, in which R.sup.1 is CH.sub.2 OCO.NHPh, R is 1,1-dimethylpropyl and a and c are double bonds has a disclosed activity better than that of mevinolin. In general, the above patent publications also cover compounds in which the delta lactone has been hydrolysed to a delta hydroxy acid or a salt of that acid.
EP-A-0142146 disclosed compounds of structure ##STR5## where E is --CH.sub.2 --CH.sub.2 --, --CH.dbd.CH-- or --(CH.sub.2).sub.3 -- and Z is (amongst others) a substituted decalin system of the same form as in those compounds referred to above.
None of the cited patents and articles disclose or suggest the possibility of preparing the compounds of the present invention. The unique pattern of substituents on the decalin ring system differs from the cited art, whilst the compounds exhibit potent HMG-CoA activity.
The present invention provides novel decalin based compounds which are potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and, therefore, are useful in the treatment or prevention of hypercholesterolaemia, hyperlipoproteinaemia and atherosclerosis.
According to a first aspect of the invention, there is provided a compound of either of general formul
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A. Endo et al., J. Antibiotics, 29:1346-1348, Dec. 1976.
A. W. Alberts et al., J. Proc. Nat'l. Acad. Sci. USA, 77:3957, Jul. 1980.
Y. K. Tong Lam et al., J. Antibiotics, 34:614-616, May 1981.
G. Albers-Schonberg et al., J. Antibiotics, 34:507-512, May 1981.
N. Serizawa et al., J. Antibiotics, 36:604-607, May 1983.
W. F. Hoffman et al., J. Med. Chem., 29:849-852 (1986).
K. Chen et al., Chemistry Letters, 1923-1926 (1987).
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Kleinsek et al., Proc. Nat'l. Acad. Sci. USA, 74(4):1431-1435, Apr. 1977.
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Davidson Alan H.
Dickens Jonathan P.
Floyd Christopher D.
Lewis Christopher N.
British Bio-technology Limited
Ivy C. Warren
Owens A. A.
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