Antidiabetic agents

A method for the treatment or prevention of diabetes which comprises administering to a diabetic patient a pharmaceutically effective amount of a compound of formula I ##STR44## or a pharmaceutically acceptable salt thereof, wherein:

• R is selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.5-10 aryl, and C.sub.5-10 heteroaryl, said alkyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of R.sup.a ;
• R.sup.1 is selected from a group consisting of:
• H, C.sub.1-15 alkyl, C.sub.2-15 alkenyl, C.sub.2-15 alkynyl and C.sub.3-10 cycloalkyl, said alkyl, alkenyl, alkynyl, and cycloalkyl optionally substituted with 1 to 3 groups of R.sup.a ;
• R.sup.3 is selected from a group consisting of:
• H, NHR.sup.1, NHacyl, C.sub.1-15 alkyl, C.sub.3-10 cycloalkyl, C.sub.2-15 alkenyl, C-.sub.1-15 alkoxy, CO.sub.2 alkyl, OH, C.sub.2-15 alkynyl, C.sub.5-10 aryl, C.sub.5-10 heteroaryl said alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of R.sup.a ;
• (Z--W--) is Z--CR.sup.6 R.sup.7 --, Z--CH.dbd.CH--, or ##STR45## R.sup.8 is selected from the group consisting of CR.sup.6 R.sup.7, O, NR.sup.6, and S(O).sub.P ;
• R.sup.6 and R.sup.7 are independently selected from the group consisting of H, C.sub.1-6 alkyl;
• B is selected from the group consisting of:
• 1) a 5 or 6 membered heterocycle containing 0 to 2 double bonds, and 1 heteroatom selected from the group consisting of O, S and N, heteroatom being substituted at any position on the five or six membered heterocycle, the heterocycle being optionally unsubstituted or substituted with 1 to 3 groups of R.sup.a ;
• 2) a 5 or 6 membered carbocycle containing 0 to 2 double bonds, the carbocycle optionally unsubstituted or substituted with 1 to 3 groups of R.sup.a at any position on the five or six membered carbocycle;
• and
• 3) a 5 or 6 membered heterocycle containing 0 to 2 double bonds, and 3 heteroatoms selected from the group consisting of O, N, and S, which are substituted at any position on the five or six membered heterocycle, the heterocycle being optionally unsubstituted or substituted with 1 to 3 groups of R.sup.a ;
• X.sup.1 and X.sup.2 are independently selected from a group consisting of:
• H, OH, C.sub.1-15 alkyl, C.sub.2-15 alkenyl, C.sub.2-15 alkynyl, halo, OR.sup.3, ORCF.sub.3, C.sub.5-10 aryl, C.sub.5-10 aralkyl, C.sub.5-10 heteroaryl and C.sub.1-10 acyl, said alkyl, alkenyl, alkynyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of R.sup.a ;
• R.sup.a represents a member selected from the group consisting of:
• halo, acyl, aryl, heteroaryl, CF.sub.3, OCF.sub.3, --O--, CN, NO.sub.2, R.sup.3, OR.sup.3 ;
• SR.sup.3, .dbd.N(OR), S(O)R.sup.3, SO.sub.2 R.sup.3, NR.sup.3 R.sup.3, NR.sup.3 COR.sup.3, NR.sup.3 CO.sub.2 R.sup.3, NR.sup.3 CON(R.sup.3).sub.2, NR.sup.3 SO.sub.2 R.sup.3, COR.sup.3, CO.sub.2 R.sup.3, CON(R.sup.3).sub.2, SO.sub.2 N(R.sup.3).sub.2, OCON(R.sup.3).sub.2 said aryl and heteroaryl optionally substituted with 1 to 3 groups of halo or C1-6 alkyl;
• Y is selected from the group consisting of:
• S(O).sub.p, --CH.sub.2 --, --C(O)--, --C(O)NH--, --NR--, --O--, --SO.sub.2 NH--, --NHSO.sub.2 ;
• Y.sup.1 is selected from the group consisting of:
• O and C;
• Z is selected from the group consisting of:
• CO.sub.2 R.sup.3, R.sup.3 CO.sub.2 R.sup.3, CONHSO.sub.2 Me, CONH.sub.2 and 5-(1H-tetrazole);
• t and v are independently 0 or 1 such that t+v=1
• Q is a saturated or unsaturated straight chain hydrocarbon containing 2-4 carbon atoms and
• p is 0-2.

A method for lowering triglyceride levels which comprises administering to a patient needing lower triglyceride levels a pharmaceutically effective amount of a compound of formula I ##STR46## or a pharmaceutically acceptable salt thereof, wherein:

• R is selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.5-10 aryl, and C.sub.5-10 heteroaryl, said alkyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of R.sup.a ;
• R.sup.1 is selected from a group consisting of:
• H, C.sub.1-15 alkyl, C.sub.2-15 alkenyl, C.sub.2-15 alkynyl and C.sub.3-10 cycloalkyl, said alkyl, alkenyl, alkynyl, and cycloalkyl optionally substituted with 1 to 3 groups of R.sup.a ;
• R.sup.3 is selected from a group consisting of:
• H, NHR.sup.1, NHacyl, C.sub.1-15 alkyl, C.sub.3-10 cycloalkyl, C.sub.2-15 alkenyl, C.sub.1-15 alkoxy, CO.sub.2 alkyl, OH, C.sub.2-15 alkynyl, C.sub.5-10 aryl, C.sub.5-10 heteroaryl said alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of R.sup.a ;
• (Z--W--) is Z--CR.sup.6 R.sup.7 --, Z--CH.dbd.CH--, or ##STR47## R.sup.8 is selected from the group consisting of CR.sup.6 R.sup.7, O, NR.sup.6, and S(O).sub.P ;
• R.sup.6 and R.sup.7 are independently selected from the group consisting of H, C.sub.1-6 alkyl;
• B is selected from the group consisting of:
• 1) a 5 or 6 membered heterocycle containing 0 to 2 double bonds, and 1 heteroatom selected from the group consisting of O, S and N, heteroatom being substituted at any position on the five or six membered heterocycle, the heterocycle being optionally unsubstituted or substituted with 1 to 3 groups of R.sup.a ;
• 2) a 5 or 6 membered carbocycle containing 0 to 2 double bonds, the carbocycle optionally unsubstituted or substituted with 1 to 3 groups of R.sup.a at any position on the five or six membered carbocycle;
• and
• 3) a 5 or 6 membered heterocycle containing 0 to 2 double bonds, and 3 heteroatoms selected from the group consisting of O, N, and S, which are substituted at any position on the five or six membered heterocycle, the heterocycle being optionally unsubstituted or substituted with 1 to 3 groups of R.sup.a ;
• X.sup.1 and X.sup.2 are independently selected from a group consisting of:
• H, OH, C.sub.1-5 alkyl, C.sub.2-15 alkenyl, C.sub.2-15 alkynyl, halo, OR.sup.3, ORCF.sub.3, C.sub.5-10 aryl, C.sub.5-10 aralkyl, C.sub.5-10 heteroaryl and C.sub.1-10 acyl, said alkyl, alkenyl, alkynyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of R.sup.a ;
• R.sup.a represents a member selected from the group consisting of:
• halo, acyl, aryl, heteroaryl, CF.sub.3, OCF.sub.3, --O--, CN, NO.sub.2, R.sup.3, OR.sup.3 ;
• SR.sup.3, .dbd.N(OR), S(O)R.sup.3, SO.sub.2 R.sup.3, NR.sup.3 R.sup.3, NR.sup.3 COR.sup.3, NR.sup.3 CO.sub.2 R.sup.3, NR.sup.3 CON(R.sup.3).sub.2, NR.sup.3 SO.sub.2 R.sup.3, COR.sup.3, CO.sub.2 R.sup.3, CON(R.sup.3).sub.2, SO.sub.2 N(R.sup.3).sub.2, OCON(R.sup.3).sub.2 said aryl and heteroaryl optionally substituted with 1 to 3 groups of halo or C1-6 alkyl;
• Y is selected from the group consisting of:
• S(O).sub.p, --CH.sub.2 --, --C(O)--, --C(O)NH--, --NR--, --O--, --SO.sub.2 NH, --NHSO.sub.2 ;
• Y.sup.1 is selected from the group consisting of:
• O and C;
• Z is selected from the group consisting of:
• CO.sub.2 R.sup.3, R.sup.3 CO.sub.2 R.sup.3, CONHSO.sub.2 Me, CONH.sub.2 and 5-(1H-tetrazole);
• t and v are independently 0 or 1 such that t+v=1
• Q is a saturated or unsaturated straight chain hydrocarbon containing 2-4 carbon atoms and
• p is 0-2.

A method for treating obesity which comprises administering to a patient in need thereof a pharmaceutically effective amount of a compound of formula I ##STR48## or a pharmaceutically acceptable salt thereof, wherein:

• R is selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.5-10 aryl, and C.sub.5-10 heteroaryl, said alkyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of R.sup.a ;
• R.sup.1 is selected from a group consisting of:
• H, C.sub.1-15 alkyl, C.sub.2-15 alkenyl, C.sub.2-15 alkynyl and C.sub.3-10 cycloalkyl, said alkyl, alkenyl, alkynyl, and cycloalkyl optionally substituted with 1 to 3 groups of R.sup.a ;
• R.sup.3 is selected from a group consisting of:
• H, NHR.sup.1, NHacyl, C.sub.1-15 alkyl, C.sub.3-10 cycloalkyl, C.sub.2-15 alkenyl, C.sub.1-15 alkoxy, CO.sub.2 alkyl, OH, C.sub.2-15 alkynyl, C.sub.5-10 aryl, C.sub.5-10 heteroaryl said alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of R.sup.a ;
• (Z--W--) is Z--CR.sup.6 R.sup.7 --, Z--CH.dbd.CH--, or ##STR49## R.sup.8 is selected from the group consisting of CR.sup.6 R.sup.7, O, NR.sup.6, and S(O).sub.P ;
• R.sup.6 and R.sup.7 are independently selected from the group consisting of H, C.sub.1-6 alkyl;
• B is selected from the group consisting of:
• 1) a 5 or 6 membered heterocycle containing 0 to 2 double bonds, and 1 heteroatom selected from the group consisting of O, S and N, heteroatom being substituted at any position on the five or six membered heterocycle, the heterocycle being optionally unsubstituted or substituted with 1 to 3 groups of R.sup.a ;
• 2) a 5 or 6 membered carbocycle containing 0 to 2 double bonds, the carbocycle optionally unsubstituted or substituted with 1 to 3 groups of R.sup.a at any position on the five or six membered carbocycle;
• and
• 3) a 5 or 6 membered heterocycle containing 0 to 2 double bonds, and 3 heteroatoms selected from the group consisting of O, N, and S, which are substituted at any position on the five or six membered heterocycle, the heterocycle being optionally unsubstituted or substituted with 1 to 3 groups of R.sup.a ;
• X.sup.1 and X.sup.2 are independently selected from a group consisting of:
• H, OH, C.sub.1-15 alkyl, C.sub.2-15 alkenyl, C.sub.2-15 alkynyl, halo, OR.sup.3, ORCF.sub.3, C.sub.5-10 aryl, C.sub.5-10 aralkyl, C.sub.5-10 heteroaryl and C.sub.1-10 acyl, said alkyl, alkenyl, alkynyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of R.sup.a ;
• R.sup.a represents a member selected from the group consisting of:
• halo, acyl, aryl, heteroaryl, CF.sub.3, OCF.sub.3, --O--, CN, NO.sub.2, R.sup.3, OR.sup.3 ;
• SR.sup.3, .dbd.N(OR), S(O)R.sup.3, SO.sub.2 R.sup.3, NR.sup.3 R.sup.3, NR.sup.3 COR.sup.3, NR.sup.3 CO.sub.2 R.sup.3, NR.sup.3 CON(R.sup.3).sub.2, NR.sup.3 SO.sub.2 R.sup.3, COR.sup.3, CO.sub.2 R.sup.3, CON(R.sup.3).sub.2, SO.sub.2 N(R.sup.3).sub.2, OCON(R.sup.3).sub.2 said aryl and heteroaryl optionally substituted with 1 to 3 groups of halo or C.sub.1-6 alkyl;
• Y is selected from the group consisting of:
• S(O).sub.p, --CH.sub.2 --, --C(O)--, --C(O)NH--, --NR--, --O--, --SO.sub.2 NH, --NHSO.sub.2 ;
• Y.sup.1 is selected from the group consisting of:
• O and C;
• Z is selected from the group consisting of:
• CO.sub.2 R.sup.3, R.sup.3 CO.sub.2 R.sup.3, CONHSO.sub.2 Me, CONH.sub.2 and 5-(1H-tetrazole);
• t and v are independently 0 or 1 such that t+v=1
• Q is a saturated or unsaturated straight chain hydrocarbon containing 2-4 carbon atoms and
• p is 0-2.

A method for halting, preventing or reducing the risk of developing atherosclerosis and related disease events in a patient in need of such treatment, comprising the administration of a pharmaceutically effective amount of a compound of formula I ##STR50## or a pharmaceutically acceptable salt thereof, wherein:

• R is selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.5-10 aryl, and C.sub.5-10 heteroaryl, said alkyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of R.sup.a ;
• R.sup.1 is selected from a group consisting of:
• H, C.sub.1-15 alkyl, C.sub.2-15 alkenyl, C.sub.2-15 alkynyl and C.sub.3-10 cycloalkyl, said alkyl, alkenyl, alkynyl, and cycloalkyl optionally substituted with 1 to 3 groups of R.sup.a ;
• R.sup.3 is selected from a group consisting of:
• H, NHR.sup.1, NHacyl, C.sub.1-15 alkyl, C.sub.3-10 cycloalkyl, C.sub.2-15 alkenyl, C.sub.1-15 alkoxy, CO.sub.2 alkyl, OH, C.sub.2-15 alkynyl, C.sub.5-10 aryl, C.sub.5-10 heteroaryl said alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of R.sup.a ;
• (Z--W--) is Z--CR.sup.6 R.sup.7 --, Z--CH.dbd.CH--, or ##STR51## R.sup.8 is selected from the group consisting of CR.sup.6 R.sup.7, O, NR.sup.6, and S(O).sub.P ;
• R.sup.6 and R.sup.7 are independently selected from the group consisting of H, C.sub.1-6 alkyl;
• B is selected from the group consisting of:
• 1) a 5 or 6 membered heterocycle containing 0 to 2 double bonds, and 1 heteroatom selected from the group consisting of O, S and N, heteroatom being substituted at any position on the five or six membered heterocycle, the heterocycle being optionally unsubstituted or substituted with 1 to 3 groups of R.sup.a ;
• 2) a 5 or 6 membered carbocycle containing 0 to 2 double bonds, the carbocycle optionally unsubstituted or substituted with 1 to 3 groups of R.sup.a at any position on the five or six membered carbocycle;
• and
• 3) a 5 or 6 membered heterocycle containing 0 to 2 double bonds, and 3 heteroatoms selected from the group consisting of O, N, and S, which are substituted at any position on the five or six membered heterocycle, the heterocycle being optionally unsubstituted or substituted with 1 to 3 groups of R.sup.a ;
• X.sup.1 and X.sup.2 are independently selected from a group consisting of:
• H, OH, C.sub.1-15 alkyl, C.sub.2-15 alkenyl, C.sub.2-15 alkynyl, halo, OR.sup.3, ORCF.sub.3, C.sub.5-10 aryl, C.sub.5-10 aralkyl, C.sub.5-10 heteroaryl and C.sub.1-10 acyl, said alkyl, alkenyl, alkynyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of R.sup.a ;
• R.sup.a represents a member selected from the group consisting of:
• halo, acyl, aryl, heteroaryl, CF.sub.3, OCF.sub.3, --O--, CN, NO.sub.2, R.sup.3, OR.sup.3 ;
• SR.sup.3, .dbd.N(OR), S(O)R.sup.3, SO.sub.2 R.sup.3, NR.sup.3 R.sup.3, NR.sup.3 COR.sup.3, NR.sup.3 CO.sub.2 R.sup.3, NR.sup.3 CON(R.sup.3).sub.2, NR.sup.3 SO.sub.2 R.sup.3, COR.sup.3, CO.sub.2 R.sup.3, CON(R.sup.3).sub.2, SO.sub.2 N(R.sup.3).sub.2, OCON(R.sup.3).sub.2 said aryl and heteroaryl optionally substituted with 1 to 3 groups of halo or C1-6 alkyl;
• Y is selected from the group consisting of:
• S(O).sub.p, --CH.sub.2 --, --C(O)--, --C(O)NH--, --NR--, --O--, --SO.sub.2 NH, --NHSO.sub.2 ;
• Y.sup.1 is selected from the group consisting of:
• O and C;
• Z is selected from the group consisting of:
• CO.sub.2 R.sup.3, R.sup.3 CO.sub.2 R.sup.3, CONHSO.sub.2 Me, CONH.sub.2 and 5-(1H-tetrazole);
• t and v are independently 0 or 1 such that t+v=1;
• Q is a saturated or unsaturated straight chain hydrocarbon containing 2-4 carbon atoms and
• p is 0-2.

A method for raising high densisty lipoprotein plasma levels in a patient in need of such treatment, comprising the administration of a pharmaceutically effective amount of a compound of formula I. ##STR52## or a pharmaceutically acceptable salt thereof, wherein:

• R is selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.5-10 aryl, and C.sub.5-10 heteroaryl, said alkyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of R.sup.a ;
• R.sup.1 is selected from a group consisting of:
• H, C.sub.1-15 alkyl, C.sub.2-15 alkenyl, C.sub.2-15 alkynyl and C.sub.3-10 cycloalkyl, said alkyl, alkenyl, alkynyl, and cycloalkyl optionally substituted with 1 to 3 groups of R.sup.a ;
• R.sup.3 is selected from a group consisting of:
• H, NHR.sup.1, NHacyl, C.sub.1-15 alkyl, C.sub.3-10 cycloalkyl, C.sub.2-15 alkenyl, C.sub.1-15 alkoxy, CO.sub.2 alkyl, OH, C.sub.2-15 alkynyl, C.sub.5-10 aryl, C.sub.5-10 heteroaryl said alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of R.sup.a ;
• (Z--W--) is Z--CR.sup.6 R.sup.7 --, Z--CH.dbd.CH--, or ##STR53## R.sup.8 is selected from the group consisting of CR.sup.6 R.sup.7, O, NR.sup.6, and S(O).sub.P ;
• R.sup.6 and R.sup.7 are independently selected from the group consisting of H, C.sub.1-6 alkyl;
• B is selected from the group consisting of:
• 1) a 5 or 6 membered heterocycle containing 0 to 2 double bonds, and 1 heteroatom selected from the group consisting of O, S and N, heteroatom being substituted at any position on the five or six membered heterocycle, the heterocycle being optionally unsubstituted or substituted with 1 to 3 groups of R.sup.a ;
• 2) a 5 or 6 membered carbocycle containing 0 to 2 double bonds, the carbocycle optionally unsubstituted or substituted with 1 to 3 groups of R.sup.a at any position on the five or six membered carbocycle;
• and
• 3) a 5 or 6 membered heterocycle containing 0 to 2 double bonds, and 3 heteroatoms selected from the group consisting of O, N, and S, which are substituted at any position on the five or six membered heterocycle, the heterocycle being optionally unsubstituted or substituted with 1 to 3 groups of R.sup.a ;
• X.sup.1 and X.sup.2 are independently selected from a group consisting of:
• H, OH, C.sub.1-15 alkyl, C.sub.2-15 alkenyl, C.sub.2-15 alkynyl, halo, OR.sup.3, ORCF.sub.3, C.sub.5-10 aryl, C.sub.5-10 aralkyl, C.sub.5-10 heteroaryl and C.sub.1-10 acyl, said alkyl, alkenyl, alkynyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of R.sup.a ;
• R.sup.a represents a member selected from the group consisting of:
• halo, acyl, aryl, heteroaryl, CF.sub.3, OCF.sub.3, --O--, CN, NO.sub.2, R.sup.3, OR.sup.3 ;
• SR.sup.3, .dbd.N(OR), S(O)R.sup.3, SO.sub.2 R.sup.3, NR.sup.3 R.sup.3, NR.sup.3 COR.sup.3, NR.sup.3 CO.sub.2 R.sup.3, NR.sup.3 CON(R.sup.3).sub.2, NR.sup.3 SO.sub.2 R.sup.3, COR.sup.3, CO.sub.2 R.sup.3, CON(R.sup.3).sub.2, SO.sub.2 N(R.sup.3).sub.2, OCON(R.sup.3).sub.2 said aryl and heteroaryl optionally substituted with 1 to 3 groups of halo or C1-6 alkyl;
• Y is selected from the group consisting of:
• S(O).sub.p, --CH.sub.2 --, --C(O)--, --C(O)NH--, --NR--, --O--, --SO.sub.2 NH, --NHSO.sub.2 ;
• Y.sup.1 is selected from the group consisting of:
• O and C;
• Z is selected from the group consisting of:
• CO.sub.2 R.sup.3, R.sup.3 CO.sub.2 R.sup.3, CONHSO.sub.2 Me, CONH.sub.2 and 5-(1H-tetrazole);
• t and v are independently 0 or 1 such that t+v=1
• Q is a saturated or unsaturated straight chain hydrocarbon containing 2-4 carbon atoms and
• p is 0-2.