Combination therapeutic compositions and method of use

Abstract

The present invention provides pharmaceutical compositions and methods for the treatment of diabetes mellitus using combination therapy. The compositions relate to a compound of Formula I and an antidiabetic agent such as sulfonylureas, biguanides, glitazones, α-glucosidase inhibitors, potassium channel antagonists, aldose reductase inhibitors, glucagon antagonists, activators of RXR, insulin therapy or other anti-obesity agent. The methods include the administration of the combination of compound of Formula I with antidiabetic agent where the two components are delivered in a simultaneous manner, where the compound of Formula I is administered first, followed by the antidiabetic agent, as well as wherein the antidiabetic agent is delivered first followed by the compound of Formula I.

1 - 51  (canceled).  
     
     
         52 . A method for modulating non-insulin dependent diabetes mellitus and the complications of non-insulin dependent diabetes mellitus, said method comprising administering to a host in need thereof an efficacious amount of 
 (i) a compound having the formula:                          wherein    Ar 1  is an aryl group;    X is a divalent linkage selected from the group consisting of (C 1 -C 6 )alkylene, (C 1 -C 6 )alkylenoxy, (C 1 -C 6 )alkylenamino, (C 1 -C 6 )alkylene-S(O) k —, —O—, —C(O)—, —N(R 11 )—, —N(R 11 )C(O)—, —S(O) k — and a single bond,    wherein    R 11  is a member selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )heteroalkyl and aryl(C 1 -C 4 )alkyl; and the subscript k is an integer of from 0 to 2;    Y is a divalent linkage selected from the group consisting of alkylene, —O—, —C(O)—, —N(R 12 )—S(O) m —, —N(R 12 )—S(O) m —N(R 13 )—, —N(R 12 )C(O)—, —S(O) n — and a single bond,    wherein    R 12  and R 13  are members independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )heteroalkyl and aryl(C 1 -C 4 )alkyl; and the subscripts m and n are independently integers of from 0 to 2;    R 1  is a member selected from the group consisting of hydrogen, heteroalkyl, aryl, arylalkyl, halogen, cyano, nitro, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, —C(O)R 14 , —CO 2 R 14 , —C(O)NR 15 R 16 , —S(O) p —R 14 , —S(O) q —NR 15 R 16 , —O—C(O)—OR 17 , —O—C(O)—R 17 , —O—C(O)—NR 15 R 16 , —N(R 14 )—C(O)—NR 15 R 16 , —N(R 14 )—C(O)—R 17  and —N(R 14 )—C(O)—OR 17 ; wherein    R 14  is a member selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )heteroalkyl, aryl and aryl(C 1 -C 4 )alkyl;    R 15  and R 16  are members independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )heteroalkyl, aryl, and aryl(C 1 -C 4 )alkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring;    R 17  is a member selected from the group consisting of alkyl, heteroalkyl, aryl and arylalkyl;    the subscript p is an integer of from 0 to 3; and    the subscript q is an integer of from 1 to 2; and    R 2  is a member selected from the group consisting of (C 1 -C 8 )alkyl, (C 1 -C 8 )heteroalkyl, aryl and aryl(C 1 -C 4 )alkyl; and    R 3  is a member selected from the group consisting of halogen, cyano, nitro and (C 1 -C 8 )alkoxy; and    ii) at least one therapeutically active agent or a prodrug thereof, or a pharmaceutically acceptable salt of said agent, and a pharmaceutically acceptable carrier or diluent.    
     
     
         53 . The method of  claim 52 , wherein said complication is selected from the group consisting of diabetic nephropathy and diabetic neuropathy.  
     
     
         54 . The method of  claim 52 , wherein said compound of Formula I and said at least one therapeutically active agent are formulated together.  
     
     
         55 . The method of  claim 52 , where said compound of Formula I and said at least one therapeutically active agent are formulated separately.  
     
     
         56 . The method of  claim 52 , wherein said therapeutically active agent is an antidiabetic agent.  
     
     
         57 . The method of  claim 52 , wherein said therapeutically active agent is selected from the group consisting of a sulfonylurea, a biguanide, a glitazone, a PPARγ modulator, an α-glucosidase inhibitor, a potassium channel antagonist, an aldose reductase inhibitor, a glucagon antagonist, an activator of RXR, insulin therapy, an anti-obesity agent, and mixtures thereof.  
     
     
         58 . The method of  claim 52 , wherein said compound of formula I is administered before said therapeutically active agent.  
     
     
         59 . The method of  claim 52 , wherein said therapeutically active agent is administered before said compound of formula I.  
     
     
         60 . The method of  claim 52 , wherein said compound of formula I is administered simultaneously with said therapeutically active agent.  
     
     
         61 . The method of  claim 52 , wherein said administration is parenteral.  
     
     
         62 . The method of  claim 52 , wherein said administration is oral.  
     
     
         63 . The method of  claim 52 , wherein said administration is topical.  
     
     
         64 . The method of  claim 52 , wherein said administration is local.  
     
     
         65 . The method of  claim 57 , wherein said therapeutic agent is sulfonylurea.  
     
     
         66 . The method of  claim 65 , wherein said sulfonyl urea is a member selected from the group consisting of acetohexamide, chlorpropamide, glyburide, glipizide, gliclazide, glimepiride, gliquidone, glisoxepid, glibomuride, gliamilide, glicetanile, gliflumide, glymidine, glyparamide, tolpyrramide, glyhexamide, phenbutamide, tolazamide, tolbutamide and tolcyclamide.  
     
     
         67 . The method of  claim 57 , wherein said biguanide is a member selected from the group consisting of metformin, buformin, etoformin and phenformin.  
     
     
         68 . The method of  claim 57 , wherein said glitazone is a member selected from the group consisting of troglitazone, rosiglitazone, pioglitazone, JTT-501, YM-440, ciglitazone, darglitazone, englitazone, AD-5075 and BM-131246.  
     
     
         69 . The method of  claim 57 , wherein said α-glucosidase inhibitor is a member selected from the group consisting of acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose and MDL-73,945.  
     
     
         70 . The method of  claim 57 , wherein 
 X is selected from the group consisting of —O—, —S(O) k —, —N(R 11 )—, —CH 2 —, —C(O)— and a single bond;    Y is —N(R 12 )—S(O) m —;    wherein    R 11  is hydrogen or (C 1 -C 8 ) alkyl;    R 12  is selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl; and the subscript m is an integer of from 0 to 2;    R 1  is a member selected from the group consisting of hydrogen, halogen, cyano, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkyl, —C(O)R 14 , —CO 2 R 14  and —C(O)NR 15 R 16 ;    wherein    R 14  is a member selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )heteroalkyl, aryl and aryl(C 1 -C 4 )alkyl;    R 15  and R 16  are members independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )heteroalkyl, aryl, and aryl(C 1 -C 4 )alkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring;    R 2  is a member selected from the group consisting of aryl and aryl(C 1 -C 4 )alkyl; and    R 3  is a member selected from the group consisting of halogen, cyano, (C 1 -C 8 )alkyl and (C 1 -C 8 )alkoxy.    
     
     
         71 . The method of  claim 70 , wherein Ar 1  is a substituted or unsubstituted heteroaryl group having from 1 to 3 heteroatoms as ring members.  
     
     
         72 . The method of  claim 70 , wherein Ar 1  is a phenyl, naphthyl, benzothiazole, benzimidazole, quinoline, isoquinoline or group having from 1 to 3 substituents selected from the group consisting of halogen, cyano, CF 3 , nitro, (C 1 -C 8 )alkyl and (C 1 -C 8 )alkoxy.  
     
     
         73 . The method of  claim 52 , wherein X is a divalent linkage selected from the group consisting of —O—, —C(O)—, N(R 11 )—, —CH 2 —, —S(O) k — and a single bond.  
     
     
         74 . The method of  claim 52 , wherein Y is a divalent linkage —N(R 12 )—S(O) 2 —; and R 12  is hydrogen or (C 1 -C 8 )alkyl, and R 2  is a member selected from the group consisting of aryl and arylalkyl.  
     
     
         75 . The method of  claim 52 , wherein R 1  is selected from the group consisting of hydrogen, halogen, cyano, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkyl, —C(O)R 14 , —CO 2 R 14  and —C(O)NR 15 R 16  wherein R 14  is (C 1 -C 8 )alkyl, and R 15  and R 16  are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or taken together with the nitrogen to which each is attached form a 5- or 6-membered ring.  
     
     
         76 . The method of  claim 52 , wherein Ar 1  is substituted with from one to two substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 6 )alkyl, —CF 3 , (C 1 -C 8 )alkyl and —NO 2 .