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US 5,219,879 AGranted
Heterocyclic steroid compounds
AssigneeThe Du Pont Merck Pharmaceutical Company
InventorsSoo S. Ko, James M. Trzaskos
Life of this patent
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Abstract
The present invention relates to novel substituted 15-oxa-, 15-thia-, and 15-aza- dihydrolanosterols, to pharmaceutical compositions containing such compounds, and to methods of using these compounds to suppress the activity of 3-hydroxy-3- methylglutaryl coenzyme A reductase (HMGR), an enzyme which is important in cholesterol biosynthesis. The overall effect of these heterocyclic lanosterol analogs is to decrease cholesterol formation, thereby resulting in lower serum cholesterol levels in mammals, and impaired ergosterol synthesis in fungi.
Claims58
Compounds having the formula:
- ##STR57## wherein R is a side chain having either 8 or 9 carbon atoms and from 15 to 20 hydrogen atoms, optionally with one site of unsaturation;
- and
- the substituents R.sub.1, independently each of R.sub.2, and R.sub.3, are selected from the groups defined as follows:
- R.sub.1 is .dbd.O, OR.sub.7, or OCOR.sub.7 ;
- R.sub.2 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, or benzyl;
- R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, benzyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, CSR.sub.4, C(.dbd.NR.sub.4)R.sub.4, COR.sub.5, CSR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 CSR.sub.4, C(R.sub.4).sub.2 C(.dbd.NR.sub.4)R.sub.4, C(R.sub.4).sub.2 COR.sub.5, C(R.sub.4).sub.2 CRS.sub.5, C(R.sub.4).sub.2 Z, C(R.sub.4).sub.2 C(R.sub.4).sub.2 Z, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, CR.sub.4 NN(R.sub.4).sub.2, CR.sub.4 NNR.sub.4 R.sub.6, CHR.sub.4 NHOR.sub.4, CHR.sub.4 NHOR.sub.6, CHR.sub.4 NHN(R.sub.4).sub.2, CHR.sub.4 NHNR.sub.4 R.sub.6, CHR.sub.4 CR.sub.4 NOR.sub.4, CHR.sub.4 CR.sub.4 NOR.sub.6, CHR.sub.4 CR.sub.4 NN(R.sub.4).sub.2, CHR.sub.4 CR.sub.4 NNR.sub.4 R.sub.6, CHR.sub.4 CHR.sub. 4 NHOR.sub.4, CHR.sub.4 CHR.sub.4 NHOR.sub.6, CHR.sub.4 CHR.sub.4 NHN(R.sub.4).sub.2, C(O)NH.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, C(S)NR.sub.4 OR.sub.4, C(S)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, C.tbd.CR.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 Z, C.tbd.CC(R.sub.4).sub.2 Z, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, C.tbd.CC(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl;
- R.sub.4 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ;
- or benzyl;
- R.sub.5 is OR.sub.4, SR.sub.4, N(R.sub.4).sub.2, or NR.sub.4 R.sub.6 ;
- R.sub.6 is COR.sub.4, CSR.sub.4, or C(.dbd.NR.sub.4)R.sub.4 ;
- R.sub.7 is H, C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ;
- or benzyl;
- X is O or s;
- Z is halogen;
- and
- n is 1;
- and their physiologically acceptable salts.
14 more elements
A composition suitable for decreasing cholesterol formation in mammals, said composition comprising (i) an effective amount of an active compound of the formula:
- ##STR62## wherein R is a side chain having either 8 or 9 carbon atoms and from 15 to 20 hydrogen atoms, optionally with one site of unsaturation;
- and
- wherein the substituents R.sub.1, independently each of R.sub.2, and R.sub.3, are selected from the groups defined as follows:
- R.sub.1 is .dbd.O, OR.sub.7, or OCOR.sub.7 ;
- R.sub.2 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, or benzyl;
- R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, benzyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, CSR.sub.4, C(.dbd.NR.sub.4)R.sub.4, COR.sub.5, CSR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 CSR.sub.4, C(R.sub.4).sub.2 C(.dbd.NR.sub.4)R.sub.4, C(R.sub.4).sub.2 COR.sub.5, C(R.sub.4).sub.2 CRS.sub.5, C(R.sub.4).sub.2 Z, C(R.sub.4).sub.2 C(R.sub.4).sub.2 Z, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, CR.sub.4 NN(R.sub.4).sub.2, CR.sub.4 NNR.sub.4 R.sub.6, CHR.sub.4 NHOR.sub.4, CHR.sub.4 NHOR.sub.6, CHR.sub.4 NHN(R.sub.4).sub.2, CHR.sub.4 NHNR.sub.4 R.sub.6, CHR.sub.4 CR.sub.4 NOR.sub.4, CHR.sub.4 CR.sub.4 NOR.sub.6, CHR.sub.4 CR.sub.4 NN(R.sub.4).sub.2, CHR.sub.4 CR.sub.4 NNR.sub.4 R.sub.6, CHR.sub.4 CHR.sub. 4 NHOR.sub.4, CHR.sub.4 CHR.sub.4 NHOR.sub.6, CHR.sub.4 CHR.sub.4 NHN(R.sub.4).sub.2, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, C(S)NR.sub.4 OR.sub.4, C(S)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, C.tbd.CR.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 Z, C.tbd.CC(R.sub.4).sub.2 Z, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, C.tbd.CC(R.sub.4).sub.2 OR.sub.6, or poly-(OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl;
- R.sub.4 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ;
- or benzyl;
- R.sub.5 is OR.sub.4, SR.sub.4, N(R.sub.4).sub.2, or NR.sub.4 R.sub.6 ;
- R.sub.6 is COR.sub.4, CSR.sub.4, or C(.dbd.NR.sub.4)R.sub.4 ;
- R.sub.7 is H, C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ;
- or benzyl;
- X is O or S;
- Z is halogen;
- and
- n is 1;
- and their physiologically acceptable salts;
- and (ii) an acceptable pharmaceutical or veterinary carrier or diluent.
15 more elements
A method of decreasing cholesterol formation in mammals in need of such therapy, said method comprising administering an effective amount of an active compound of the formula:
- ##STR67## wherein R is a side chain having either 8 or 9 carbon atoms and from 15 to 20 hydrogen atoms, optionally with one site of unsaturation;
- and
- wherein the substituents R.sub.1, independently each of R.sub.2, and R.sub.3, are selected from the groups defined as follows:
- R.sub.1 is .dbd.O, OR.sub.7, or OCOR.sub.7 ;
- R.sub.2 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, or benzyl;
- R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, benzyl, C(R.sub.4).sub.2 R.sub.5, COR.sub.4, CSR.sub.4, C(.dbd.NR.sub.4)R.sub.4, COR.sub.5, CSR.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 COR.sub.4, C(R.sub.4).sub.2 CSR.sub.4, C(R.sub.4).sub.2 C(.dbd.NR.sub.4)R.sub.4, C(R.sub.4).sub.2 COR.sub.5, C(R.sub.4).sub.2 CRS.sub.5, C(R.sub.4).sub.2 Z, C(R.sub.4).sub.2 C(R.sub.4).sub.2 Z, CN, CR.sub.4 NOR.sub.4, CR.sub.4 NOR.sub.6, CR.sub.4 NN(R.sub.4).sub.2, CR.sub.4 NNR.sub.4 R.sub.6, CHR.sub.4 NHOR.sub.4, CHR.sub.4 NHOR.sub.6, CHR.sub.4 NHN(R.sub.4).sub.2, CHR.sub.4 NHNR.sub.4 R.sub.6, CHR.sub.4 CR.sub.4 NOR.sub.4, CHR.sub.4 CR.sub.4 NOR.sub.6, CHR.sub.4 CR.sub.4 NN(R.sub.4).sub.2, CHR.sub.4 CR.sub.4 NNR.sub.4 R.sub.6, CHR.sub.4 CHR.sub.4 NHOR.sub.4, CHR.sub.4 CHR.sub.4 NHOR.sub.6, CHR.sub.4 CHR.sub.4 NHN(R.sub.4).sub.2, C(O)NR.sub.4 OR.sub.4, C(O)NR.sub.4 OR.sub.6, C(S)NR.sub.4 OR.sub.4, C(S)NR.sub.4 OR.sub.6, CR.sub.4 .dbd.CR.sub.4 R.sub.6, C.tbd.CR.sub.6, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 Z, C.tbd.CC(R.sub.4).sub.2 Z, CR.sub.4 .dbd.CR.sub.4 C(R.sub.4).sub.2 OR.sub.6, C.tbd.CC(R.sub.4).sub.2 OR.sub.6, or poly-OR.sub.4, OR.sub.6, epoxy)-C.sub.1 -C.sub.6 alkyl;
- R.sub.4 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ;
- or benzyl;
- R.sub.5 is OR.sub.4, SR.sub.4, N(R.sub.4).sub.2, or NR.sub.4 R.sub.6 ;
- R.sub.6 is COR.sub.4, CSR.sub.4, or C(.dbd.NR.sub.4)R.sub.4 ;
- R.sub.7 is H, C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ;
- or benzyl;
- X is O or S;
- Z is halogen;
- and
- n is 1;
- and their physiologically acceptable salts in an acceptable pharmaceutical or veterinary carrier or diluent to said mammal.
14 more elements
A process for the formation of 15-thia-lanosterols having the formula:
- ##STR72## wherein R is a side chain having either 8 or 9 carbon atoms and from 15 to 20 hydrogen atoms, optionally with one site of unsaturation;
- and
- wherein the substituents R.sub.1, independently each of R.sub.2, and R.sub.3, are selected from the groups defined as follows:
- R.sub.1 is OR.sub.7 or OCOR.sub.7 ;
- R.sub.2 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, or benzyl;
- R.sub.3 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, benzyl, C(R.sub.4).sub.2 R.sub.5, C(R.sub.4).sub.2 C(R.sub.4).sub.2 R.sub.5, CR.sub.4 .dbd.CR.sub.4 R.sub.6, C.tbd.CR.sub.6 ;
- R.sub.4 is H, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ;
- or benzyl;
- R.sub.5 is OR.sub.4, SR.sub.4, N(R.sub.4).sub.2, or NR.sub.4 R.sub.6 ;
- R.sub.6 is COR.sub.4, CSR.sub.4, or C(.dbd.NR.sub.4)R.sub.4 ;
- R.sub.7 is H, C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.2 -C.sub.20 alkynyl, phenyl or phenyl substituted with C.sub.1 -C.sub.3 alkyl, OR.sub.2, Z, N(R.sub.2).sub.2, or CF.sub.3 ;
- or benzyl;
- X is S;
- Z is halogen;
- and
- n is 1;
- which process comprises treating a cyclic hemiacetal of the corresponding 15-oxa-dihydrolanosterol (X.dbd.O) with hydrogen sulfide and boron trifluoride etherate in a suitable reaction medium, under suitable reaction conditions, followed by reaction of the unisolated cyclic thioacetal intermediate with a trialkylsilane to yield the desired 15-thiadihydrolanosterol.
14 more elements
Dependencies are inferred from the claim text.