Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method

Abstract

Dipeptidyl peptidase IV (DP 4) inhibiting compounds are provided having the formula where x is 0 or 1 and y is 0 or 1 (provided that x=1 when y=0 and x=0 when y=1); n is 0 or 1; X is H or CN; and wherein R 1 , R 2 , R 3 and R 4 are as described herein. A method is also provided for treating diabetes and related diseases, especially Type II diabetes, and other diseases as set out herein, employing such DP 4 inhibitor *or a combination of such DP 4 inhibitor and one or more of another antidiabetic agent such as metformin, glyburide, troglitazone, pioglitazone, rosiglitazone and/or insulin and/or one or more of a hypolipidemic agent and/or anti-obesity agent and/or other therapeutic agent.

What is claimed is: 
     
       1. A compound having the structure 
       
         
           
           
               
               
           
         
       
       wherein x is 0 or 1 and y is 0 or 1, provided that
 x=1 when y=0 and 
 x=0 when y=1; and wherein 
 n is 0 or 1; 
 X is H or CN; 
 R 1 , R 2 , R 3  and R 4  are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, tricycloalkyl, alkylcycloalkyl, hydroxyalkyl, hydroxyalkylcycloalkyl, hydroxycycloalkyl, hydroxybicycloalkyl, hydroxytricycloalkyl, bicycloalkylalkyl, alkylthioalkyl, arylalkylthioalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl or cycloheteroalkylalkyl; all optionally substituted through available carbon atoms with 1, 2, 3, 4 or 5 groups selected from hydrogen, halo, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonylamino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; 
 and R 1  and R 3  may optionally be taken together to form —(CR 5 R 6 ) m — where m is 2 to 6, and R 5  and R 6  are the same or different and are independently selected from hydroxy, alkoxy, H, alkyl, alkenyl, alkynyl, cycloalkyl, halo, amino, substituted amino, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, alkoxycarbonyl, aryloxycarbonyl, or alkylaminocarbonylamino, or R 1  and R4 may optionally be taken together to form —(CR 7 R 8 ) p — wherein p is 2 to 6, and R 7  and R 8  are the same or different and are independently selected from hydroxy, alkoxy, cyano, H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, halo, amino, substituted amino, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, alkoxycarbonyl, aryloxycarbonyl, or alkylaminocarbonylamino, or optionally R 1  and R 3  together with 
 
       
         
           
           
               
               
           
         
          form a 5 to 7 membered ring containing a total of 2 to 4 heteroatoms selected from N, O, S, SO, or SO 2 ; 
         or optionally R 1  and R 3  together with 
       
       
         
           
           
               
               
           
         
          form a 4 to 8 membered cycloheteroalkyl ring wherein the cycloheteroalkyl ring has an optional aryl ring fused thereto or an optional 3 to 7 membered cycloalkyl ring fused thereto; 
         with the proviso that where x is 1 and y is 0, X is H, n is o, and one of R 1  and R 2  is H and the other is alkyl, then R 3  is other than pyridyl or substituted pyridyl; 
         including all stereoisomers thereof; 
         andor a pharmaceutically acceptable salt thereof, or a prodrug ester thereof, and all stereoisomers thereof. 
       
     
     
       2. The compound as defined in  claim 1  having the structure: 
       
         
           
           
               
               
           
         
       
     
     
       3. The compound as defined in  claim 1  having the structure: 
       
         
           
           
               
               
           
         
       
     
     
       4. The compound as defined in  claim 1  having the structure: 
       
         
           
           
               
               
           
         
       
     
     
       5. The compound as defined in  claim 1  having the structure: 
       
         
           
           
               
               
           
         
       
     
     
       6. The compound as defined in  claim 1  wherein:
 R 3  is H, R 1  is H, alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, alkylcycloalkyl, hydroxyalkyl, hydroxyalkylcycloalkyl, hydroxycycloalkyl hydroxybicycloalkyl, or hydroxytricycloalkyl, 
 R 2  is H or alkyl, n is 0, 
 X is CN. 
 
     
     
       7. The compound as defined in  claim 1  wherein the cyclopropyl fused to the pyrrolidine has the configuration: 
       
         
           
           
               
               
           
         
       
     
     
       8. A compound having the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       9. The compound as defined in  claim 8  wherein the pharmaceutically acceptable salt is the hydrochloride salt or the trifluoroacetic acid salt. 
     
     
       10. A compound which is 
       
         
           
           
               
               
           
         
       
       wherein R 1  is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, alkylcycloalkyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylcycloalkyl, hydroxybicycloalkyl, or hydroxytricycloalkyl,
 or 
 
       
         
           
           
               
               
           
         
       
       wherein R 1  is alkyl, cycloalkyl, bicycloalkyl, tricycloalkyl, alkylcycloalkyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylcycloalkyl, hydroxybicycloalkyl, or hydroxytricycloalkyl. 
     
     
       11. A pharmaceutical composition comprising a compound as defined in  claim 1  and a pharmaceutically acceptable carrier therefor. 
     
     
       12. A pharmaceutical combination comprising a DP4 inhibitor compound as defined in  claim 1  and an antidiabetic agent other than a DP4 inhibitor for treating diabetes and related diseases, an anti-obesity agent and/or a lipid-modulating agent. 
     
     
       13. The pharmaceutical combination as defined in  claim 12  comprising said DP4 inhibitor compound as defined in claim 1 and an the antidiabetic agent other than a DP4 inhibitor. 
     
     
       14. The combination as defined in  claim 13  wherein the antidiabetic agent is 1, 2, 3 or more of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ agonist, a PPAR α/γ dual agonist, an SGLT2 inhibitor, an aP2 inhibitor, a glycogen phosphorylase inhibitor, an AGE inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1) or mimetic thereof, insulin and/or a meglitinide. 
     
     
       15. The combination as defined in  claim 14  wherein the antidiabetic agent is 1, 2, 3 or more of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, G1 -262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, AR-HO39242, GW-409544, KRP297, AC2993, Exendin-4, LY307161, NN2211, and/or LY315902. 
     
     
       16. The combination as defined in  claim 13  wherein the compound as defined in claim 1 is present in a weight ratio to the antidiabetic agent within the range from about 0.01 to about 100:1. 
     
     
       17. The combination as defined in  claim 12  wherein the anti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound, an anorectic agent, and/or a fatty acid oxidation upregulator. 
     
     
       18. The combination as defined in  claim 17  wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and/or mazindol. 
     
     
       19. The combination as defined in  claim 12  wherein the lipid modulating agent is an MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, an ACAT inhibitor, a cholesteryl ester transfer protein inhibitor, or an ATP citrate lyase inhibitor. 
     
     
       20. The combination as defined in  claim 19  wherein the lipid modulating agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, implitapide, CP-529, 414, avasimibe, TS-962, MD-700, and/or LY295427. 
     
     
       21. The combination as defined in  claim 19  wherein the DP4 inhibitor compound as defined in claim 1 is present in a weight ratio to the lipid-modulating agent within the range from about 0.01 to about 100:1. 
     
     
       22. A pharmaceutical combination comprising a DP4 inhibitor compound as defined in  claim 1  and an agent for treating infertility, an agent for treating polycystic ovary syndrome, an agent for treating a growth disorder and/or frailty, an anti-arthritis agent, an agent for preventing or inhibiting allograft rejection in transplantation, an agent for treating autoimmune disease, an anti-AIDS agent, an agent for treating inflammatory bowel disease/syndrome, an agent for treating anorexia nervosa, an anti-osteoporosis agent and/or an anti-obesity agent. 
     
     
       23. A method for treating diabetes, insulin resistance, hyperglycemia, hyperisulinemia, or elevated blood levels of free fatty acids or glycerol, obesity, Syndrome X, dysmetabolic syndrome, diabetic complications, hypertriglyceridemia, hyperinsulinemia, atherosclerosis, impaired glucose homeostasis, impaired glucose tolerance, infertility, polycystic ovary syndrome, growth disorders, frailty, arthritis, allograft rejection in transplantation, autoimmune diseases, AIDS, intestinal diseases, inflammatory bowel syndrome, nervosa, osteoporosis, or an immunomodulatory disease or a chronic inflammatory bowel disease, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound as defined in  claim 1 . 
     
     
       24. The method as defined in  claim 23  for treating type II diabetes and/or obesity. 
     
     
       25. A compound that is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       26. The compound as defined in claim 25, wherein the pharmaceutically acceptable salt is the hydrochloride salt. 
     
     
       27. A pharmaceutical composition comprising the compound of claim 25 and a pharmaceutically acceptable carrier therefor. 
     
     
       28. A pharmaceutical composition comprising the compound of claim 26 and a pharmaceutically acceptable carrier therefor. 
     
     
       29. The composition of claim 27 or 28 further comprising an antidiabetic agent other than a DP4 inhibitor. 
     
     
       30. The composition of claim 29 wherein the antidiabetic agent is metformin. 
     
     
       31. The composition of claim 29, wherein the antidiabetic agent is a SGLT2 inhibitor. 
     
     
       32. A method for treating diabetes, insulin resistance, hyperglycemia, hyperinsulinemia, impaired glucose homeostasis, or impaired glucose tolerance in a mammal comprising administering to the mammal a pharmaceutical composition comprising a compound that is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor. 
     
     
       33. The method of claim 32, wherein the pharmaceutically acceptable salt is the hydrochloride salt. 
     
     
       34. The method of claim 32, for treating diabetes. 
     
     
       35. The method of claim 33, for treating diabetes. 
     
     
       36. The method of any one of claim 32, 33, 34, or 35 wherein the pharmaceutical composition further comprises an antidiabetic agent other than a DP4 inhibitor. 
     
     
       37. The method of claim 36, wherein the antidiabetic agent is metformin. 
     
     
       38. The method of claim 36, wherein the antidiabetic agent is a SGLT2 inhibitor. 
     
     
       39. A method for treating type II diabetes in a mammal comprising administering to the mammal a pharmaceutical composition comprising a compound that is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor. 
     
     
       40. The method of claim 39, wherein the pharmaceutically acceptable salt is the hydrochloride salt. 
     
     
       41. The method of any one of claims 39 or 40, wherein the pharmaceutical composition further comprises an antidiabetic agent other than a DP4 inhibitor. 
     
     
       42. The method of claim 41, wherein the antidiabetic agent is metformin. 
     
     
       43. The method of claim 41, wherein the antidiabetic agent is a SGLT2 inhibitor.