Cyclic amide derivative

Abstract

[Problem] To provide a GPR40 activating agent having, as an active ingredient, a novel compound having a GPR40 agonist action, a salt of the compound, a solvate of the salt or the compound, or the like, particularly, an insulin secretagogues and a prophylactic and/or therapeutic agent against diabetes, obesity, or other diseases. Means of Solving the Problem A compound of Formula (I): (where n is 0 to 2; p is 0 to 4; h is 0 to 3; j is 0 to 3; k is 0 to 2; a ring B is an aryl group or a heteroaryl group; X is O, S, or —NR 7 —; J 1 is —CR 11a R 11b — or —NR 11c ; J 2 is —CR 12a R 12b — or —NR 12c —; and R 1 to R 12c are specific groups), a salt of the compound, or a solvate of the salt or the compound.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         (wherein n is an integer of 0 to 2; p is an integer of 0 to 4; h is an integer of 0 to 3; j is an integer of 0 to 3; k is an integer of 0 to 2; 
         a ring A is a C 6-14  aryl group which is optionally substituted with 1 to 5 L(s), a 3- to 14-membered heterocyclic group which is optionally substituted with 1 to 5 L(s), a C 5-7  cycloalkyl group which is optionally substituted with 1 to 5 L(s), a C 5-7  cycloalkenyl group which is optionally substituted with 1 to 5 L(s), a 6- to 14-membered spiro ring group which is optionally substituted with 1 to 5 L(s), or a 2-phenylamino-2-oxoacetyl group which is optionally substituted with 1 to 5 L(s); 
         a ring B is a C 6-14  aryl group or a 5- to 14-membered heteroaryl group; 
         X is an oxygen atom, a sulfur atom, or —NR 7 —; 
         J 1  is —CR 11a R 11b — or —NR 11c ; J 2  is —CR 12a R 12b — or —NR 12c — (with the proviso that when J 1  is —NR 11c —, h is 0); 
         R 1 s are independently a group optionally selected from a halogen atom, a C 1-6  alkyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C 2-6  alkenyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C 2-6  alkynyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C 1-6  alkoxy group which is optionally substituted with 1 to 5 substituent(s) RI, and a cyano group; 
         R 2a  and R 2b  are independently a group optionally selected from a hydrogen atom, a halogen atom, a C 1-6  alkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 1-6  alkoxy group, and a cyano group; 
         R 3 , R 4 , R 5 , R 6 , and R 7  are independently a group optionally selected from a hydrogen atom, a C 1-6  alkyl group, a halogenated C 1-6  alkyl group, a C 2-6  alkenyl group, and a C 2-6  alkynyl group; 
         R 11a  and R 11b  are independently a group optionally selected from a hydrogen atom, a halogen atom, a C 1-6  alkyl group, a halogenated C 1-6  alkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 1-6  alkoxy group, a halogenated C 1-6  alkoxy group, a C 2-7  alkanoyl group, and a carboxy group which is optionally protected; 
         R 12a  and R 12b  are independently a group optionally selected from a hydrogen atom, a halogen atom, a C 1-6  alkyl group, a halogenated C 1-6  alkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 1-6  alkoxy group, a halogenated C 1-6  alkoxy group, and a cyano group; 
         R 11C  and R 12c  are independently a group optionally selected from a hydrogen atom, a C 1-6  alkyl group, and a halogenated C 1-6  alkyl group; 
         with the proviso that in the cyclic amide structure moiety, there is not one of the substituents (R 2b , R 11b , R 11c , R 12b , or R 12c ) on an atom to which the ring B is bonded; 
         Ls are independently a group optionally selected from a halogen atom, —OH, an oxo group, a cyano group, a C 1-10  alkyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C 2-10  alkenyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C 2-10  alkynyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C 1-10  alkoxy group which is optionally substituted with 1 to 5 substituent(s) RI, a C 2-10  alkenyloxy group which is optionally substituted with 1 to 5 substituent(s) RI, a C 2-10  alkynyloxy group which is optionally substituted with 1 to 5 substituent(s) RI, an aryl group which is optionally substituted with 1 to 5 substituent(s) RII, a heterocyclic group which is optionally substituted with 1 to 5 substituent(s) RII, an aralkyl group which is optionally substituted with 1 to 5 substituent(s) RII, a heteroarylalkyl group which is optionally substituted with 1 to 5 substituent(s) RII, a non-aromatic heterocyclic alkyl group which is optionally substituted with 1 to 5 substituent(s) RII, an aryloxy group which is optionally substituted with 1 to 5 substituent(s) RII, a heteroaryloxy group which is optionally substituted with 1 to 5 substituent(s) RII, a non-aromatic heterocyclic oxy group which is optionally substituted with 1 to 5 substituent(s) RII, an aralkyloxy group which is optionally substituted with 1 to 5 substituent(s) RII, a heteroarylalkyloxy group which is optionally substituted with 1 to 5 substituent(s) RII, —SH, —SF 5 , a —S(O) i R a  (i is an integer of 0 to 2) group, a —NR b R c  group, and a substituted spiropiperidinylmethyl group; 
         R a  is a C 1-6  alkyl group or a halogenated C 1-6  alkyl group; 
         R b  and R c  are independently a group optionally selected from a hydrogen atom, a C 1-6  alkyl group, a halogenated C 1-6  alkyl group, a C 2-6  alkenyl group, a C 2-6  alkynyl group, a C 2-7  alkanoyl group (the alkanoyl group is optionally substituted with —OH or a C 1-6  alkoxy group), a C 1-6  alkylsulfonyl group, an arylcarbonyl group, and a heterocyclic carbonyl group, where R b  and R c  optionally form together with a nitrogen atom to which they are bonded, a 3- to 8-membered cyclic group, where in the cyclic group, one or two carbon atom(s) is(are) optionally substituted with an atom optionally selected from an oxygen atom, a sulfur atom, and a nitrogen atom (the nitrogen atom is optionally substituted with a C 1-6  alkyl group which is optionally substituted with 1 to 5 substituent(s) RI) or with a carbonyl group, and the cyclic group is optionally further substituted with 1 to 5 substituent(s) RII; 
         where the substituents RI are the same as or different from each other and are each a group optionally selected from a halogen atom, —OH, a cyano group, a C 1-6  alkoxy group (the C 1-6  alkoxy group is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C 1-6  alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is optionally substituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (the heterocyclic group is optionally substituted with 1 to 3 C 1-6  alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O) i R a  (i is an integer of 0 to 2) group(s), 1 to 5 —SO 2 NR d R e  group(s), 1 to 5 —CONR d R e  group(s), or 1 to 5 —NR b1 R c1  group(s)), a —NR b1 R c1  group, and a heterocyclic oxy group (the heterocyclic oxy group is optionally substituted with 1 to 3 C 1-6  alkyl group(s) or 1 to 3 oxo group(s)); 
         the substituents RII are the same as or different from each other and are each a group optionally selected from the substituents RI, a C 1-6  alkyl group (the C 1-6  alkyl group is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, 1 to 5 C 1-6  alkoxy group(s), 1 to 5 —S(O) i R a  (i is an integer of 0 to 2) group(s), 1 to 5 —NR b1 R c1  group(s), 1 to 5 —SO 2 NR d R e  group(s), or 1 to 5 —CONR d R e  group(s)), a C 2-6  alkenyl group, a C 2-7  alkanoyl group, an aralkyloxy group, a heterocyclic group (the heterocyclic group is optionally substituted with 1 to 3 C 1-6  alkyl group(s) or 1 to 3 oxo group(s)), a heterocyclic carbonyl group (the heterocyclic carbonyl group is optionally substituted with 1 to 3 C 1-6  alkyl group(s) or 1 to 3 oxo group(s)), a —S(O) i R a  (i is an integer of 0 to 2) group, a —CONR d R e  group, and a —CONR d R e  l group; 
         R d  and R e  are independently a hydrogen atom or a C 1-6  alkyl group (the C 1-6  alkyl group is optionally substituted with 1 to 5 halogen atom(s), 1 to 5 —OH, or 1 to 5 C 1-6  alkoxy group(s)); 
         R e1  is a C 1-6  alkyl group (the C 1-6  alkyl group is substituted with 1 to 5 —OH, 1 to 5 C 1-6  alkoxy group(s), 1 to 5 aryl group(s) (the aryl group is optionally substituted with 1 to 3 halogen atom(s)), 1 to 5 heterocyclic group(s) (the heterocyclic group is optionally substituted with 1 to 3 C 1-6  alkyl group(s) or 1 to 3 oxo group(s)), 1 to 5 —S(O) i R a  (i is an integer of 0 to 2) group(s), 1 to 5 —SO 2 NR d R e  group(s), 1 to 5 —CONR d R e  group(s), or 1 to 5 —NR b1 R c1  group(s)); 
         R b1  and R e1  are independently a group optionally selected from a hydrogen atom, a C 1-6  alkyl group, a C 2-7  alkanoyl group, and a C 1-6  alkylsulfonyl group, where R b1  and R c1  optionally form together with a nitrogen atom to which they are bonded, a 3- to 8-membered cyclic group, where in the cyclic group, one or two carbon atom(s) is(are) optionally substituted with an atom optionally selected from an oxygen atom, a sulfur atom, and a nitrogen atom (the nitrogen atom is optionally substituted with a C 1-6  alkyl group) or with a carbonyl group (with the proviso that there are excluded a compound which is 5-[4-[2-(2-phenyl-4-oxazolyl)ethoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; a compound in which: a saturated cyclic amide structure having —S(O) n —NH—CO— is 1,1-dioxo-1,2-thiazolidin-3-one; the ring B is a benzene ring; the ring B is bonded to J 1 ; k is 1; and in the ring B, a linker moiety containing X and the cyclic amide structure are positioned at a p-position; and a compound in which: the cyclic amide structure is 1,1-dioxo-1,2,5-thiadiazolidin-3-one; the ring B is bonded to J 1 ; and in the ring B, the cyclic amide structure is bonded to an atom adjacent to an atom to which a linker containing X is bonded), 
         a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt. 
       
     
     
         2 . The compound according to  claim 1  of Formula (I)-1: 
       
         
           
           
               
               
           
         
         (wherein n, p, h, j, k, the ring A, X, J 2 , R 1 , R 2a , R 2b , R 3 , R 4 , R 5 , and R 6  are the same as defined in Formula (I); a ring B′ is a benzene ring, a pyridine ring, or a pyrimidine ring; and J 1a  is CR 11a  or a nitrogen atom (with the proviso that a compound that is 5-[4-[2-(2-phenyl-4-oxazolyl)ethoxy]phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one; a compound in which a saturated cyclic amide structure having —S(O) n —NH—CO— is 1,1-dioxo-1,2-thiazolidin-3-one, the ring B′ is a benzene ring, k is 1, and in the ring B′, the linker moiety containing X and the cyclic amide structure are at the p-position; and a compound in which the cyclic amide structure is 1,1-dioxo-1,2,5-thiadiazolidin-3-one, and in the ring B′, the cyclic amide structure is bonded to an atom adjacent to an atom to which the linker containing X is bonded, are excluded), 
         a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt. 
       
     
     
         3 . The compound according to  claim 2  of Formula (II): 
       
         
           
           
               
               
           
         
         (wherein n, p, h, j, k, X, J 2 , R 1 , R 2a , R 2b , R 3 , R 4 , R 5 , and R 6  are the same as defined in Formula (I); the ring B′ and J 1a  are the same as defined in Formula (I)-1; 
         q and r are independently an integer of 0 to 4; s is an integer of 0 to 2 (with the proviso that q+s is an integer of 0 to 5); 
         a ring A′ is an aryl group or a heteroaryl group; 
         V is a single bond or an oxygen atom; 
         R 8 s are independently a group optionally selected from a C 1-6  alkoxy group which is substituted with 1 to 5 substituent(s) M, a C 2-6  alkenyloxy group which is substituted with 1 to 5 substituent(s) M, a C 2-6  alkynyloxy group which is substituted with 1 to 5 substituent(s) M, a —CONR d R e1  group, an aralkyloxy group, a heterocyclic oxy group (the heterocyclic oxy group is optionally substituted with 1 to 3 C 1-6  alkyl group(s) or 1 to 3 oxo group(s)), a heterocyclic group (the heterocyclic group is optionally substituted with 1 to 3 C 1-6  alkyl group(s) or 1 to 3 oxo group(s)), and a heterocyclic carbonyl group (the heterocyclic carbonyl group is optionally substituted with 1 to 3 C 1-6  alkyl group(s) or 1 to 3 oxo group(s)); 
         the substituents M are independently a group optionally selected from a halogen atom, —OH, a C 1-6  alkoxy group, an aryl group (the aryl group is optionally substituted with 1 to 3 halogen atom(s)), a heterocyclic group (the heterocyclic group is optionally substituted with 1 to 3 —OH, 1 to 3 C 1-6  alkyl group(s), or 1 to 3 oxo group(s)), a —S(O) i R a  (i is an integer of 0 to 2) group, a —NR b1 R c1  group, a —SO 2 NR d R e  group, and a —CONR d R e  group; 
         R 9 s and R 10 s are independently a group optionally selected from a halogen atom, —OH, a cyano group, a C 1-6  alkyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C 2-6  alkenyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C 2-6  alkynyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C 1-6  alkoxy group which is optionally substituted with 1 to 5 substituent(s) RI, a C 2-7  alkanoyl group, —SH, a —S(O) i R a  (i is an integer of 0 to 2) group, a —NR b1 R c1  group, and a —CONR d R e  group; 
         R a , R d , R e , R b1 , R c1 , and R e1  are the same as defined in Formula (I) (with the proviso that a compound in which the saturated cyclic amide structure having —S(O) n —NH—CO— is 1,1-dioxo-1,2-thiazolidin-3-one, the ring B′ is a benzene ring, k is 1, and in the ring B′, the linker moiety containing X and the cyclic amide structure are at the p-position, is excluded), 
         a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt. 
       
     
     
         4 . The compound according to  claim 3 , wherein X is an oxygen atom, k is 0, and any one of q and s is 1 or more,
 a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt.   
     
     
         5 . The compound according to  claim 3  of Formula (II-1)-1: 
       
         
           
           
               
               
           
         
         (wherein n, p, h, J 2 , R 1 , R 2a , and R 2b  are the same as defined in Formula (I); the ring B′ and J 1a  are the same as defined in Formula (I)-1; 
         q, r, s, R 8 , R 9 , and R 10  are the same as defined in Formula (II); 
         a ring A″ is a benzene ring, a pyridine ring, or a pyrimidine ring; 
         broken lines indicate where the ring A″ or R 8 s are bonded; 
         E is a group optionally selected from Formula (c1) to Formula (c6): 
       
       
         
           
           
               
               
           
         
         a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt. 
       
     
     
         6 . The compound according to  claim 5 , wherein E is Formula (c2), and any one of q and s is 1 or more,
 a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt.   
     
     
         7 . The compound according to  claim 3  or  5 , wherein s is 1,
 a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt. 
 
     
     
         8 . The compound according to  claim 2  of Formula (III): 
       
         
           
           
               
               
           
         
         (wherein n, p, h, j, k, J 2 , X, R 1 , R 2a , R 2b , R 3 , R 4 , R 5 , and R 6  are the same as defined in Formula (I); the ring B′ and J 1a  are the same as defined in Formula (I)-1; 
         f is an integer of 0 to 2; g is an integer of 1 to 4; q1 is an integer of 0 to 3; q2 is 0 or 1; r1 is an integer of 0 to 2 (with the proviso that q1+q2+r1 is an integer of 0 to 5); 
         a ring A″′ is a benzene ring or a pyridine ring; 
         T is —CH 2 —, an oxygen atom, —S(O) i — (i is an integer of 0 to 2), or —NR 7 — (R 7  is the same as R 7  defined in Formula (I)); 
         R 13 s are independently a group optionally selected from a halogen atom, —OH, a cyano group, a C 1-10  alkyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C 2-10  alkenyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C 2-10  alkynyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C 1-10  alkoxy group which is optionally substituted with 1 to 5 substituent(s) RI, a C 2-10  alkenyloxy group which is optionally substituted with 1 to 5 substituent(s) RI, a C 2-10  alkynyloxy group which is optionally substituted with 1 to 5 substituent(s) RI, —SH, a —S(O) i R a  (i is an integer of 0 to 2) group, and a —NR b R c  group; 
         R 13a  is a group optionally selected from an aryl group which is optionally substituted with 1 to 5 substituent(s) RII, a heterocyclic group which is optionally substituted with 1 to 5 substituent(s) RII, an aralkyl group which is optionally substituted with 1 to 5 substituent(s) RII, a heteroarylalkyl group which is optionally substituted with 1 to 5 substituent(s) RII, a non-aromatic heterocyclic alkyl group which is optionally substituted with 1 to 5 substituent(s) RII, an aryloxy group which is optionally substituted with 1 to 5 substituent(s) RII, a heteroaryloxy group which is optionally substituted with 1 to 5 substituent(s) RII, a non-aromatic heterocyclic oxy group which is optionally substituted with 1 to 5 substituent(s) RII, an aralkyloxy group which is optionally substituted with 1 to 5 substituent(s) RII, a heteroarylalkyloxy group which is optionally substituted with 1 to 5 substituent(s) RII, and a substituted spiropiperidinylmethyl group; 
         R 14 s are independently a group optionally selected from a halogen atom, —OH, a cyano group, a C 1-6  alkyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C 2-6  alkenyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C 2-6  alkynyl group which is optionally substituted with 1 to 5 substituent(s) RI, a C 1-6  alkoxy group which is optionally substituted with 1 to 5 substituent(s) RI, —SH, a —S(O) i R a  (i is an integer of 0 to 2) group, and a —NR b R c  group; 
         R a , R b , R c , the substituent RI, and the substituent RII are the same as defined in Formula (I), 
         a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt. 
       
     
     
         9 . The compound according to  claim 8  of Formula (III-1)-1: 
       
         
           
           
               
               
           
         
         (wherein n, p, h, J 2 , R 1 , R 2a , and R 2b  are the same as defined in Formula (I); J 1a  is the same as defined in Formula (I)-1; 
         q, s, the ring A′, V, R 8 , and R 9  are the same as defined in Formula (II); 
         q1, r1, T, R 13 , and R 14  are the same as defined in Formula (III); 
         Ea is Formula (c1) or Formula (c4) shown as E in Formula (II-1)-1, 
         a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt. 
       
     
     
         10 . The compound according to  claim 9 , wherein Ea is Formula (c1), and any one of q and s is 1 or more,
 a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt.   
     
     
         11 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt. 
     
     
         12 - 14 . (canceled) 
     
     
         15 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt; and
 a compound selected from the group consisting of a PPAR gamma agonist, a biguanide agent, a sulfonylurea, a rapid-acting insulin secretagogues, an alpha-glucosidase inhibitor, insulin or an insulin derivative, GLP-1 and a GLP-1 agonist, a DPP-IV inhibitor, an alpha-2 antagonist, an SGLT2 inhibitor, omega-3 fatty acids, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, a cholesterol absorption inhibitor, an acyl-CoA-cholesterol acyltransferase (ACAT) inhibitor, a CETP inhibitor, a squalene synthase inhibitor, an antioxidant, a PPAR alpha agonist, a PPAR delta agonist, an LXR agonist, an FXR agonist, an MTTP inhibitor, a squalene epoxidase inhibitor, a bile acid absorption inhibitor, a CB-1 receptor antagonist, a monoamine reuptake inhibitor, a serotonin reuptake inhibitor, a lipase inhibitor, a neuropeptide Y (NPY) receptor antagonist, a peptide YY (PYY) receptor antagonist, and an adrenergic beta-3 receptor agonist.   
     
     
         16 . The pharmaceutical composition of  claim 15  wherein the DPP-IV inhibitor is selected from sitagliptin, vildagliptin, alogliptin, and saxagliptin, or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The pharmaceutical composition of  claim 15  wherein the DPP-IV inhibitor is sitagliptin, or a pharmaceutically acceptable salt thereof. 
     
     
         18 . A method for treating or preventing diabetes comprising the administration to a patient of an effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt. 
     
     
         19 . A method for treating or preventing diabetes comprising the administration to a patient of an effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or a pharmaceutically acceptable solvate of the salt, 
       and
 a compound selected from a group consisting of a PPAR gamma agonist, a biguanide agent, a sulfonylurea, a rapid-acting insulin secretagogue, an alpha-glucosidase inhibitor, insulin or an insulin derivative, GLP-1 and a GLP-1 agonist, a DPP-IVinhibitor, an alpha-2 antagonist, an SGLT2 inhibitor, omega-3 fatty acids, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, a cholesterol absorption inhibitor, an acyl-CoA-cholesterol acyltransferase (ACAT) inhibitor, a CETP inhibitor, a squalene synthase inhibitor, an antioxidant, a PPAR alpha agonist, a PPAR delta agonist, an LXR agonist, an FXR agonist, an MTTP inhibitor, a squalene epoxidase inhibitor, a bile acid absorption inhibitor, a CB-1 receptor antagonist, a monoamine reuptake inhibitor, a serotonin reuptake inhibitor, a lipase inhibitor, a neuropeptide Y (NPY) receptor antagonist, a peptide YY (PYY) receptor antagonist, and an adrenergic beta-3 receptor agonist. 
 
     
     
         20 . The method of  claim 19  wherein the DPP-IV inhibitor is selected from sitagliptin, vildagliptin, alogliptin, saxagliptin, or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The method of  claim 19  wherein the DPP-IV inhibitor is sitagliptin, or a pharmaceutically acceptable salt thereof.