Method of treating diabetes and related disease states

A method for treating obesity which comprises administering to a patient in need thereof an effective amount of a compound of formula XI or XII:

• ##STR22## or a pharmaceutically acceptable salt or acid addition salt thereof, wherein:
• each R is independently H, OH, alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• alkenyl of 2 to 6 carbon atoms which may be straight chain or branched;
• trifluoromethyl;
• alkoxy of 1 to 6 carbon atoms which may be straight chain or branched;
• SH;
• thioalkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• phenyl;
• phenyl substituted by alkyl of 1 to 3 carbon atoms or by halogen;
• benzyl;
• phenethyl;
• halogen, amino;
• N(R.sub.4).sub.2 wherein R.sub.4 is H or alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• COOR.sub.4 ;
• CH.sub.2 OR.sub.4 ;
• formyl;
• CN;
• trifluoromethylthio;
• or nitro;
• each R' is independently R.sub.4 ;
• OR.sub.4 ;
• COOR.sub.4 ;
• N(R.sub.4).sub.2 ;
• SR.sub.4 ;
• CH.sub.2 OR.sub.4 ;
• CHO;
• or together R' and R' are O;
• CH.sub.2 ;
• or ##STR23## Y' is sulfur, sulfoxide,sulfone;
• ##STR24## R.sub.11 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched;
• alkanoyl of 1-4 carbon atoms which may be straight chain or branched;
• phenylsulfonyl;
• tosyl;
• NR.sub.12 wherein R.sub.12 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched;
• or ##STR25## wherein R.sub.13 is alkyl of 1-4 carbon atoms which may be straight chain or branched, alkoxy of 1-4 carbon atoms which may be straight chain or branched;
• N--CN, CH.sub.2, or C.dbd.O;
• Y is Y' and oxygen;
• each R.sub.1 is independently hydrogen or alkyl of 1-3 carbon atoms;
• each m is independently an integer from 0-6;
• R.sub.2 is ##STR26## each R.sub.6 is independently H or alkyl of 1-4 carbons;
• each R.sub.7 is independently H, OH, or alkyl of 1-4 carbons;
• each R.sub.8 is independently H, or alkyl of 1-4 carbons, and is absent when a triple bond is present;
• R.sub.5 is COOR.sub.4 ;
• CH.sub.2 OH;
• CHO;
• tetrazole;
• NHSO.sub.2 R.sub.14 ;
• hydroxymethylketone;
• CN;
• CON(R.sub.7).sub.2 ;
• a monocyclic or bicyclic heterocyclic ring containing an acidic hydroxyl group;
• or COOR.sub.15 where R.sub.15 is ##STR27## wherein each s is independently 0-3;
• R.sub.16 is
• A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N and S with at least one being N, and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or
• B) the radical W--R.sub.17 wherein W is O, S or NH and R.sub.17 contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;
• R.sub.14 is OH, alkyl or alkoxy of 1 to 6 carbon atoms, phenyl or phenyl substituted by alkyl or alkoxy groups of I to 3 carbon atoms, halogen, hydroxy, haloalkyl, COOH, CN, formyl, acyl of I to 6 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms;
• r an q are each independently 0-20 provided that the total of r and q does not exceed 20;
• p is 0 or 1;
• R.sub.3 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• or alkenyl of 3 to 6 carbon atoms which may be straight chain or branched as illustrated in formulas IV and V;
• R.sub.9 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• alkoxy of 1 to 6 carbon atoms which may be straight chain or branched;
• or (CH.sub.2).sub.r R.sub.5 ;
• and
• R.sub.10 is H;
• alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• ##STR28## or R.sub.4 OCH.sub.2 --.

A method for lowering triglyceride levels which comprises administering to a patient needing lower triglyceride an effective amount of a compound of formula XI or XII:

• ##STR29## or a pharmaceutically acceptable salt or acid addition salt thereof, wherein:
• each R is independently H, OH, alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• alkenyl of 2 to 6 carbon atoms which may be straight chain or branched;
• trifluoromethyl;
• alkoxy of 1 to 6 carbon atoms which may be straight chain or branched;
• SH;
• thioalkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• phenyl;
• phenyl substituted by alkyl of 1 to 3 carbon atoms or by halogen;
• benzyl;
• phenethyl;
• halogen, amino;
• N(R.sub.4).sub.2 wherein R.sub.4 is H or alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• COOR.sub.4 ;
• CH.sub.2 OR.sub.4 ;
• formyl;
• CN;
• trifluoromethylthio;
• or nitro;
• each R' is independently R.sub.4 ;
• OR.sub.4 ;
• COOR.sub.4 ;
• N(R.sub.4).sub.2 ;
• SR.sub.4 ;
• CH.sub.2 OR.sub.4 ;
• CHO;
• or together R' and R' are O;
• CH.sub.2 ;
• or ##STR30## Y' is sulfur, sulfoxide,sulfone;
• ##STR31## R.sub.11 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched;
• alkanoyl of 1-4 carbon atoms which may be straight chain or branched;
• phenylsulfonyl;
• tosyl;
• NR.sub.12 wherein R.sub.12 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched;
• or ##STR32## wherein R .sub.13 is alkyl of 1-4 carbon atoms which may be straight chain or branched, alkoxy of 1-4 carbon atoms which may be straight chain or branched;
• N--CN, CH.sub.2, or C.dbd.O;
• Y is Y' and oxygen;
• each R.sub.1 is independently hydrogen or alkyl of 1-3 carbon atoms;
• each m is independently an integer from 0-6;
• R.sub.2 is ##STR33## each R.sub.6 is independently H or alkyl of 1-4 carbons;
• each R.sub.7 is independently H, OH, or alkyl of 1-4 carbons;
• each R.sub.8 is independently H, or alkyl of 1-4 carbons, and is absent when a triple bond is present;
• R.sub.5 is COOR.sub.4 ;
• CH.sub.2 OH;
• CHO;
• tetrazole;
• NHSO.sub.2 R.sub.14 ;
• hydroxymethylketone;
• CN;
• CON(R.sub.7).sub.2 ;
• a monocyclic or bicyclic heterocyclic ring containing an acidic hydroxyl group;
• or COOR.sub.15 where R.sub.15 is ##STR34## wherein each s is independently 0-3;
• R.sub.16 is
• A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N and S with at least one being N, and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or
• B) the radical W--R.sub.17 wherein W is O, S or NH and R.sub.17 contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;
• R14 is OH, alkyl or alkoxy of 1 to 6 carbon atoms, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbon atoms, halogen, hydroxy, haloalkyl, COOH, CN, formyl, acyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms;
• r an q are each independently 0-20 provided that the total of r and q does not exceed 20;
• p is 0 or 1;
• R.sub.3 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• or alkenyl of 3 to 6 carbon atoms which may be straight chain or branched as illustrated in formulas IV and V;
• R.sub.9 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• alkoxy of 1 to 6 carbon atoms which may be straight chain or branched;
• or (CH.sub.2).sub.r R.sub.5 ;
• and
• R.sub.10 is H;
• alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• ##STR35## or R.sub.4 OCH.sub.2 --.

A method for halting, preventing or reducing the risk of developing atherosclerosis and related diseae events in a patient in need of such treatment, comprising the administration of a pharmaceutically effective amount of a compound of formula XI or XII:

• ##STR36## or a pharmaceutically acceptable salt or acid addition salt thereof, wherein:
• each R is independently H, OH, alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• alkenyl of 2 to 6 carbon atoms which may be straight chain or branched;
• trifluoromethyl;
• alkoxy of 1 to 6 carbon atoms which may be straight chain or branched;
• SH;
• thioalkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• phenyl;
• phenyl substituted by alkyl of 1 to 3 carbon atoms or by halogen;
• benzyl;
• phenethyl;
• halogen, amino;
• N(R.sub.4).sub.2 wherein R.sub.4 is H or alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• COOR.sub.4 ;
• CH.sub.2 OR.sub.4 ;
• formyl;
• CN;
• trifluoromethylthio;
• or nitro;
• each R' is independently R.sub.4 ;
• OR.sub.4 ;
• COOR.sub.4 ;
• N(R.sub.4).sub.2 ;
• SR.sub.4 ;
• CH.sub.2 OR.sub.4 ;
• CHO;
• or together R' and R' are O;
• CH.sub.2 ;
• or ##STR37## Y' is sulfur, sulfoxide,sulfone;
• ##STR38## R.sub.1 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched;
• alkanoyl of 1-4 carbon atoms which may be straight chain or branched;
• phenylsulfonyl;
• tosyl;
• NR.sub.12 wherein R.sub.12 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched;
• or ##STR39## wherein R.sub.13 is alkyl of 1-4 carbon atoms which may be straight chain or branched, alkoxy of 1-4 carbon atoms which may be straight chain or branched;
• N--CN, CH.sub.2, or C.dbd.O;
• Y is Y' and oxygen;
• each R.sub.1 is independently hydrogen or alkyl of 1-3 carbon atoms;
• each m is independently an integer from 0-6;
• R.sub.2 is ##STR40## each R.sub.6 is independently H or atkyl of 1-4 carbons;
• each R.sub.7 is independently H, OH, or alkyl of 1-4 carbons;
• each R.sub.8 is independently H, or alkyl of 1-4 carbons, and is absent when a triple bond is present;
• R.sub.5 is COOR.sub.4 ;
• CH.sub.2 OH;
• CHO;
• tetrazole;
• NHSO.sub.2 R.sub.14 ;
• hydroxymethylketone;
• CN;
• CON(R.sub.7).sub.2 ;
• a monocyclic or bicyclic heterocyclic ring containing an acidic hydroxyl group;
• or COOR.sub.15 where R.sub.15 is ##STR41## wherein each s is independently 0-3;
• R.sub.16 is
• A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N and S with at least one being N, and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or
• B) the radical W--R.sub.17 wherein W is O, S or NH and R.sub.17 contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;
• R.sub.14 is OH, alkyl or alkoxy of 1 to 6 carbon atoms, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbon atoms, halogen, hydroxy, haloalkyl, COOH, CN, formyl, acyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms;
• r an q are each independently 0-20 provided that the total of r and q does not exceed 20;
• p is 0 or 1;
• R.sub.3 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• or alkenyl of 3 to 6 carbon atoms which may be straight chain or branched as illustrated in formulas IV and V;
• R.sub.9 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• alkoxy of 1 to 6 carbon atoms which may be straight chain or branched;
• or (CH.sub.2).sub.r R.sub.5 ;
• and
• R.sub.10 is H;
• alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• ##STR42## or R.sub.4 OCH.sub.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 XI or XII:

• ##STR43## or a pharmaceutically acceptable salt or acid addition salt thereof, wherein:
• each R is independently H, OH, alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• alkenyl of 2 to 6 carbon atoms which may be straight chain or branched;
• trifluoromethyl;
• alkoxy of 1 to 6 carbon atoms which may be straight chain or branched;
• SH;
• thioalkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• phenyl;
• phenyl substituted by alkyl of 1 to 3 carbon atoms or by halogen;
• benzyl;
• phenethyl;
• halogen, amino;
• N(R.sub.4).sub.2 wherein R.sub.4 is H or alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• COOR.sub.4 ;
• CH.sub.2 OR.sub.4 ;
• formyl;
• CN;
• trifluoromethylthio;
• or nitro;
• each R' is independently R.sub.4 ;
• OR.sub.4 ;
• COOR.sub.4 ;
• N(R.sub.4).sub.2 ;
• SR.sub.4 ;
• CH.sub.2 OR.sub.4 ;
• CHO;
• or together R' and R' are O;
• CH.sub.2 ;
• or ##STR44## Y' is sulfur, sulfoxide,sulfone;
• ##STR45## R.sub.11 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched;
• alkanoyl of 1-4 carbon atoms which may be straight chain or branched;
• phenylsulfonyl;
• tosyl;
• NR.sub.12 wherein R.sub.12 is H, alkyl of 1-4 carbon atoms which may be straight chain or branched;
• or ##STR46## wherein R.sub.13 is alkyl of 1-4 carbon atoms which may be straight chain or branched, alkoxy of 1-4 carbon atoms which may be straight chain or branched;
• N--CN, CH.sub.2, or C.dbd.O;
• Y is Y' and oxygen;
• each R.sub.1 is independently hydrogen or alkyl of 1-3 carbon atoms;
• each m is independently an integer from 0-6;
• R.sub.2 is ##STR47## each R.sub.6 is independently H or alkyl of 1-4 carbons;
• each R.sub.7 is independently H, OH, or alkyl of 1-4 carbons;
• each R.sub.8 is independently H, or alkyl of 1-4 carbons, and is absent when a triple bond is present;
• R.sub.5 is COOR.sub.4 ;
• CH.sub.2 OH;
• CHO;
• tetrazole;
• NHSO.sub.2 R.sub.14 ;
• hydroxymethylketone;
• CN;
• CON(R.sub.7).sub.2 ;
• a monocyclic or bicyclic heterocyclic ring containing an acidic hydroxyl group;
• or COOR.sub.15 where R.sub.15 is ##STR48## wherein each s is independently 0-3;
• R.sub.16 is
• A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N and S with at least one being N, and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or
• B) the radical W--R.sub.17 wherein W is O, S or NH and R.sub.17 contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;
• R14 is OH, alkyl or alkoxy of 1 to 6 carbon atoms, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbon atoms, halogen, hydroxy, haloalkyl, COOH, CN, formyl, acyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 4 carbon atoms;
• r an q are each independently 0-20 provided that the total of r and q does not exceed 20;
• p is 0 or 1;
• R.sub.3 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• or alkenyl of 3 to 6 carbon atoms which may be straight chain or branched as illustrated in formulas IV and V;
• R.sub.9 is alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• alkoxy of 1 to 6 carbon atoms which may be straight chain or branched;
• or (CH.sub.2).sub.r R.sub.5 ;
• and
• R.sub.10 is H;
• alkyl of 1 to 6 carbon atoms which may be straight chain or branched;
• ##STR49## or R.sub.4 OCH.sub.2 --.