Claims
- 1. A compound of structural Formula I ##STR10## and the N-oxide thereof, wherein X is --CH2CH2-- or --CH.dbd.CH--;
- R.sub.1 and R.sub.4 are each independently
- alkyl of from one to six carbons;
- trifluoromethyl;
- cyclopropyl;
- cyclohexyl;
- cyclohexylmethyl;
- phenyl;
- phenyl substituted with
- fluorine,
- chlorine,
- bromine;
- hydroxy,
- trifluoromethyl,
- alkyl of from one to four carbon atoms, or
- alkoxy of from one to four carbon atoms;
- phenylmethyl;
- phenylmethyl substituted with
- fluorine,
- chlorine,
- bromine;
- hydroxy,
- trifluoromethyl,
- alkyl of from one to four carbon atoms, or
- alkoxy of from one to four carbon atoms;
- 2-pyridinyl;
- 2-pyridinyl-N-oxide;
- 3-pyridinyl;
- 3-pyridinyl-N-oxide;
- 4-pyridinyl;
- 4-pyridinyl-N-oxide;
- 2-pyrimidinyl;
- 4-pyrimidinyl;
- 5-pyrimidinyl;
- 2-thienyl;
- 3-thienyl;
- CH.sub.2 OH;
- chlorine;
- bromine;
- NR'R" wherein R' and R" are each independently hydrogen, alkyl of from one to four carbon atoms, or together with the N to which they are attached form ##STR11## wherein n' is an integer of from 0 to 5; ##STR12## wherein Y is hydrogen or an alkyl of from one to four carbon atoms; or R.sub.1 is
- CN;
- OR; or
- S(O).sub.n R
- wherein n is 0, 1, or 2 and R is lower alkyl phenyl, substituted phenyl, benzyl or substituted benzyl;
- R.sub.2 is
- hydrogen;
- alkyl of from one to six carbon atoms;
- trifluoromethyl;
- cyclopropyl;
- phenyl;
- phenyl substituted with
- fluorine,
- chlorine,
- bromine;
- hydroxy,
- trifluoromethyl,
- alkyl of from one to four carbon atoms, or
- alkoxy of from one to four carbon atoms;
- 2-pyridinyl;
- 2-pyridinyl-N-oxide;
- 3-pyridinyl;
- 4-pyridinyl;
- 2-pyrimidinyl;
- 4-pyrimidinyl;
- 5-pyrimidinyl;
- 2-thienyl;
- 3-thienyl;
- CH.sub.2 OH;
- chlorine;
- bromine; or
- NR'R" wherein R' and R" are as above;
- R.sub.3 is
- hydrogen;
- alkyl of from one to six carbon atoms;
- cyano;
- nitro;
- --NR.sub.5 R.sub.6 where R.sub.5 and R.sub.6 are independently
- hydrogen or alkyl of from one to four carbon atoms;
- phenyl;
- --NHCOR.sub.7 where R.sub.7 is alkyl of from one to four carbon atoms;
- --COR.sub.8 where R.sub.8 is
- hydroxyl,
- alkoxyl of from one to six carbon atoms,
- phenoxy,
- NR.sub.5 R.sub.6, where R.sub.5 and R.sub.6 are as defined above,
- vinyl,
- alkoxy of from one to four carbon atoms,
- hydrogen, or
- CH.sub.2 OH;
- a corresponding dihydroxy-acid compound of Formula II corresponding to the opened form of the lactone ring of a compound of Formula I above ##STR13## or the N-oxide thereof, wherein X, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are as defined above, or a lower alkyl ester or pharmaceutically acceptable salt thereof, all of the compounds being in the trans racemate of the tetrahydropyran moiety.
- 2. A compound as defined by claim 1 having structural Formula I.
- 3. A compound as defined by claim 1 wherein X is --CH.dbd.CH--.
- 4. A compound as defined by claim 1 wherein X is --CH.sub.2 CH.sub.2 --.
- 5. A compound as defined by claim 2 having the name trans-tetrahydro-4-hydroxy-6-[2-(2-methyl-4-phenyl-3-pyridinyl)ethyl]-2H-pyran-2-one.
- 6. A compound as defined by claim 2 having the name [4.alpha.,6.beta.(E)]-tetrahydro-4-hydroxy-6-[2-(2-methyl-4-phenyl-3-pyridinyl)ethenyl]-2H-pyran-2-one.
- 7. A compound as defined by claim 2 having the name [4.alpha.,6.beta.(E)]-6-[2-(2,6-dimethyl-4-phenyl-3-pyridinyl)ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
- 8. A compound as defined by claim 2 having the name [4.alpha.,6.beta.(E)]-6-[2-[4-(4-fluorophenyl)-2,6-dimethyl-3-pyridinyl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one.
- 9. A compound as defined by claim 1 having the name [2.alpha.,4.beta.(E)]-4-(4-fluorophenyl)-2,6-dimethyl-5-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethenyl]-3-pyridinecarbonitrile.
- 10. A compound as defined by claim 1 selected from the group consisting of
- [4.alpha.,6.beta.(E)]-6-[2-(4-fluorophenyl)-2,6-bis(1-methylethyl)-3-pyridinyl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-;b 2-one;
- [R*,S*(E)]-7-[4-(4-fluorophenyl)-2,6-bis(1-methylethyl)-3-pyridinyl]-3,5-dihydroxy-6-heptenoic acid, monosodium salt;
- [4.alpha.,6.beta.(E)]-6-[2-[4-(4-fluorophenyl)-6-methyl-2-(1-methylethyl)-3-pyridinyl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one;
- [R*,S*-(E)]-7-[4-(4-fluorophenyl)-6-methyl-2-(1-methylethyl)-3-pyridinyl]-3,5-dihydroxy-6-heptenoic acid, monosodium salt;
- [R*,S*-(E)]-7-[4-(4-fluorophenyl)-6-methyl-2-(1-methylethyl)-3-pyridinyl]-3,5-dihydroxy-6-heptenoic acid, hemicalcium salt;
- [4.alpha.,6.beta.(E)]-6-[2-[2,6-diethyl-4(4-fluorophenyl)-3-pyridinyl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one;
- [R*,S*-(E)]-7-[2,6-diethyl-4-(4-fluorophenyl)-3-pyridinyl]-3,5-dihydroxy-6-heptenoic acid, monosodium salt;
- [4.alpha.,6.beta.(E)]-6-[2-[4-(4-fluorophenyl)-5-methoxy-6-methyl-2-(1-methylethyl)-3-pyridinyl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one;
- [R*,S*-(E)]-7-[4-(4-fluorophenyl)-5-methoxy-6-methyl-2-(1-methylethyl)-3-pyridinyl]-3,5-dihydroxy-6-heptenoic acid, monosodium salt;
- [.alpha. . 6.beta.(E)]-6-[2-[5-ethenyl-4-(4-fluorophenyl)-6-methyl-2-(1-methylethyl)-3-pyridinyl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one;
- [R*,S*-(E)]-7-[5-ethenyl-4-(4-fluorophenyl)-6-methyl-2-(1-methylethyl)-3-pyridinyl]-3,5-dihydroxy-6-heptenoic acid, monosodium salt;
- [4.alpha.,6.beta.(E)]-6-[2-[4-(4-fluorophenyl)-6-methyl-2-(1-methylethyl)-3-pyridinyl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one, N-oxide;
- [R*,S*-(E)]-7-(4-(4-fluorophenyl)-6-methyl-2-(1-methylethyl)-3-pyridinyl]-3,5-dihydroxy-6-heptenoic acid, N-oxide, monosodium salt.
- 11. A pharmaceutical composition for inhibiting cholesterol biosynthesis comprising an effective amount of a compound as defined by claim 1 in combination with a pharmaceutically acceptable carrier.
- 12. A method of inhibiting cholesterol biosynthesis in a patient in need of said treatment comprising administering a cholesterol synthesis inhibiting amount of a compound as defined by claim 1 in combination with a pharmaceutically acceptable carrier.
CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part of copending application U.S. Ser. No. 094,198, now abandoned, filed Sept. 8, 1987.
US Referenced Citations (5)
Foreign Referenced Citations (3)
Number |
Date |
Country |
WO8600307 |
Jul 1986 |
WOX |
WO8628274 |
Jul 1986 |
WOX |
2110682 |
Jun 1983 |
GBX |
Continuation in Parts (1)
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Number |
Date |
Country |
Parent |
94198 |
Sep 1987 |
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