Antihypercholesterolemic compounds and related pharmaceutical compositions and methods of use

A compound having the structural formula (II) ##STR47## wherein:

• R is selected from the group consisting of CH.sub.3, CH.sub.2 OH, CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 --OH, CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 --F, and CH.dbd.CH--CH(CH.sub.3)--CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH(CH.sub.2 CH.sub.3)CH(CH.sub.3).sub.2, and CH.dbd.CH--CH(CH.sub.2 CH.sub.3)CH(CH.sub.3).sub.2 ;
• R.sup.1 is selected from the group consisting of --OH, .dbd.O, --OR.sup.8, --O(CO)R.sup.9, --O(CO)--(CH.sub.2).sub.n --COOH, a sulfate group, or an Mg, Na, or K salt of a sulfate group, where R.sup.8 is lower alkyl, R.sup.9 is a C.sub.1 -C.sub.20 aliphatic group or phenyl, and n is an integer in the range of 2 to 6 inclusive;
• X.sup.1 and Y.sup.1 are independently selected from the group consisting of NR.sup.2, CR.sup.2, O and S where the R.sup.2 may be the same or different and are selected from the group consisting of H, lower alkyl and --COOR.sup.3 where R.sup.3 is lower alkyl, or wherein the R.sup.2 are linked together to form a --(CO)--Z--(CO)--bridge, where Z is alkylene, alkenylene, phenylene having up to four ring substituents, --S--, or --NR.sup.10 -- where R.sup.10 is H, lower alkyl or phenyl having up to 5 ring substituents, and wherein the ring substituents are selected from the group consisting of --NH.sub.2, --COOH, --NO.sub.2, halogen and lower alkyl, with the proviso that X.sup.1 and Y.sup.1 are not both CR.sup.2 ;
• R.sup.2 is selected from the group consisting of H, lower alkyl and --COOR.sup.3 where R.sup.3 is lower alkyl;
• and
• a represents either a single bond or a double bond.

A pharmaceutical composition for lowering serum cholesterol, comprising, in combination with a pharmaceutically acceptable carrier, an effective serum cholesterol lowering amount of a compound having the structural formula (I) ##STR48## wherein:

• R is selected from the group consisting of CH.sub.3, CH.sub.2 OH, CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 --OH, CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 --F, CH.dbd.CH--CH(CH.sub.3)--CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH(CH.sub.2 CH.sub.3)CH(CH.sub.3).sub.2, and CH.dbd.CH--CH(CH.sub.2 CH.sub.3)CH(CH.sub.3).sub.2 ;
• R.sup.1 is selected from the group consisting of --OH, .dbd.O, --OR.sup.8, --O(CO)R.sup.9, --O(CO)--(CH.sub.2).sub.n --COOH, a sulfate group, or an Mg, Na, or K salt of a sulfate group, where R.sup.8 is lower alkyl, R.sup.9 is a C.sub.1 -C.sub.20 aliphatic group or phenyl, and n is an integer in the range of 2 to 6 inclusive;
• X and Y may be the same or different, and are selected from the group consisting of N, N.fwdarw.O, CH, C--OH, C--OCH.sub.3 and C--Z where Z is halogen, with the proviso that at least one of X and Y is N or N.fwdarw.O;
• and
• a represents either a single bond or a double bond.

A pharmaceutical composition for lowering serum cholesterol, comprising, in combination with a pharmaceutically acceptable carrier, an effective serum cholesterol lowering amount of a compound having the structural formula (II) ##STR49## wherein:

• R is selected from the group consisting of CH.sub.3, CH.sub.2 OH, CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 --OH, CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 --F, and CH.dbd.CH--CH(CH.sub.3)--CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH(CH.sub.2 CH.sub.3)CH(CH.sub.3).sub.2, and CH.dbd.CH--CH(CH.sub.2 CH.sub.3)CH(CH.sub.3).sub.2 ;
• R.sup.1 is selected from the group consisting of --OH, .dbd.O, --OR.sup.8, --O(CO)R.sup.9, --O(CO)--(CH.sub.2).sub.n --COOH, a sulfate group, or an Mg, Na, or K salt of a sulfate group, where R.sup.8 is lower alkyl, R.sup.9 is a C.sub.1 -C.sub.20 aliphatic group or phenyl, and n is an integer in the range of 2 to 6 inclusive;
• X.sup.1 and y.sup.1 are independently selected from the group consisting of NR.sup.2, CR.sup.2, O and S, where the R.sup.2 may be the same or different and are selected from the group consisting of H, lower alkyl and --COOR.sup.3 where R.sup.3 is lower alkyl, or wherein the R.sup.2 are linked together to form a --(CO)--Z--(CO)--bridge, where Z is alkylene, alkenylene, phenylene having up to four ring substituents, --S--, or --NR.sup.10 -- where R.sup.10 is H, lower alkyl or phenyl having up to 5 ring substituents, and wherein the ring substituents are selected from the group consisting of --NH.sub.2, --COOH, --NO.sub.2, halogen and lower alkyl, with the proviso that X.sup.1 and Y.sup.1 are not both CR.sup.2 ;
• R.sup.2 is selected from the group consisting of H, lower alkyl and --COOR.sup.3 where R.sup.3 is lower alkyl;
• and
• a represents either a single bond or a double bond.

A method for lowering serum cholesterol level in a warm-blooded mammal, comprising administering to such mammal an effective serum cholesterol lowering amount of a compound having the structural formula (I) ##STR50## wherein:

• R is selected from the group consisting of CH.sub.3, CH.sub.2 OH, CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 --OH, , CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 --F, CH.dbd.CH--CH(CH.sub.3)--CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH(CH.sub.2 CH.sub.3)CH(CH.sub.3).sub.2, and CH.dbd.CH--CH(CH.sub.2 CH.sub.3)CH(CH.sub.3).sub.2 ;
• R.sup.1 is selected from the group consisting of --OH, .dbd.O, --OR.sup.8, --O(CO) R.sup.9, --O(CO)--(CH.sub.2).sub.n --COOH, a sulfate group, or an Mg, Na, or K salt of a sulfate group, where R.sup.8 is lower alkyl, R.sup.9 is a C.sub.1 -C.sub.20 aliphatic group or phenyl, and n is an integer in the range of 2 to 6 inclusive;
• X and Y may be the same or different, and are selected from the group consisting of N, N.fwdarw.O, CH, C--OH, C--OCH.sub.3 and C--Z where Z is halogen, with the proviso that at least one of X and Y is N or N.fwdarw.O;
• and
• a represents either a single bond or a double bond.

A method for lowering serum cholesterol level in a warm-blooded mammal, comprising administering to such mammal an effective serum cholesterol lowering amount of a compound having the structural formula (II) ##STR51## wherein:

• R is selected from the group consisting of CH.sub.3, CH.sub.2 OH, CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 --OH, CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.2 --F, and CH.dbd.CH--CH(CH.sub.3)--CH(CH.sub.3).sub.2, CH.sub.2 CH.sub.2 CH(CH.sub.2 CH.sub.3)CH(CH.sub.3).sub.2, and CH.dbd.CH--CH(CH.sub.2 CH.sub.3)CH(CH.sub.3).sub.2 ;
• R.sup.1 is selected from the group consisting of --OH, .dbd.O, --OR.sup.8, --O(CO)R.sup.9, --O(CO)--(CH.sub.2).sub.n --COOH a sulfate group, or an Mg, Na, or K salt of a sulfate group, where R.sup.8 is lower alkyl R.sup.9 is a C.sub.1 -C.sub.20 aliphatic group or phenyl, and n is an integer in the range of 2 to 6 inclusive;
• X.sup.1 and y.sup.1 are independently selected from the group consisting of NR.sup.2, CR.sup.2, O and S where the R.sup.2 may be the same or different and are selected from the group consisting of H, lower alkyl and --COOR.sup.3 where R.sup.3 is lower alkyl, or wherein the R.sup.2 are linked together to form a --(CO)--Z--(CO)--bridge, where Z is alkylene, alkenylene, phenylene having up to four ring substituents, --S--, or --NR.sup.10 -- where R.sup.10 is H, lower alkyl or having up to 5 ring substituents, and wherein the ring substituents are selected from the group consisting of --NH.sub.2, --COOH, --NO.sub.2, halogen and lower alkyl, with the proviso that X.sup.1 and Y.sup.1 are not both CR.sup.2 ;
• R.sup.2 is selected from the group consisting of H, lower alkyl and --COOR.sup.3 where R.sup.3 is lower alkyl;
• and
• a represents either a single bond or a double bond.