Treatment for diabetes in patients inappropriate for metformin therapy

Abstract

The present invention relates to the finding that certain DPP-4 inhibitors are particularly suitable for treating and/or preventing metabolic diseases, particularly diabetes, in patients for whom metformin therapy is inappropriate due to intolerability or contraindication against metformin.

What is claimed is: 
     
         1 . A method of treating and/or preventing metabolic diseases in a patient for whom metformin therapy is inappropriate due to intolerability or contraindication against metformin comprising orally administering to the patient a DPP-IV inhibitor. 
     
     
         2 . The method according to  claim 1  wherein the patient is ineligible for metformin therapy due to intolerability or contraindication against metformin. 
     
     
         3 . The method according to  claim 1  wherein the patient is in need of reduced dose metformin therapy due to reduced tolerability, intolerability or contraindication against metformin. 
     
     
         4 . The method according to  claim 1  wherein the metabolic disease is type 2 diabetes mellitus and wherein the patient has at least one contraindication selected from:
 renal disease, renal impairment or renal dysfunction, 
 dehydration, 
 unstable or acute congestive heart failure, 
 acute or chromic metabolic acidosis, and 
 hereditary galactose intolerance. 
 
     
     
         5 . The method according to  claim 1 , wherein the contraindication is renal disease, renal impairment or renal dysfunction. 
     
     
         6 . The method according to  claim 1 , wherein the DPP-IV inhibitor is either, in a first embodiment (embodiment A), 
       
         
           
           
               
               
           
         
         wherein R1 denotes ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyl and R2 denotes 3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino or (2-(S)-amino-propyl)-methylamino, 
         or its pharmaceutically acceptable salt; 
       
       or, in a second embodiment (embodiment B),
 selected from the group consisting of 
 sitagliptin, vildagliptin, saxagliptin, alogliptin, 
 (2S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile, 
 (2S)-1-{[1,1,-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile, 
 (S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one, 
 (3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone, 
 (1((3S,4S)-4-Amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one, 
 (2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-fluoropyrrolidine-2-carbonitrile, 
 (R)-2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile, 
 5-{(S)-2-[2-((S)-2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-dimethylamide, 
 3-{(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine, 
 [(2R)-1-{[(3R)-Pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic acid, 
 (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile, 
 2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile, and 
 6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione, 
 or its pharmaceutically acceptable salt. 
 
     
     
         7 . The method according to  claim 1 , wherein said DPP-4 inhibitor is selected from the group consisting of
 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,   1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,   1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,   2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,   1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(2-amino-2-methyl-propyl)-methylamino]-xanthine,   1-[(3-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,   1-(2-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,   1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino]-xanthine,   1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,   1-[(4-methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,   1-[(4,6-dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine and   1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,   or a pharmaceutically acceptable salt thereof.   
     
     
         8 . The method according to  claim 7 , wherein said DPP-4 inhibitor is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine. 
     
     
         9 . The method according to  claim 1 , wherein said DPP-4 inhibitor is selected from the group consisting of
 saxagliptin, alogliptin,   (2S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile,   (2S)-1-{[1,1,-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile,   (S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one,   (3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone,   (1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one,   (2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-fluoropyrrolidine-2-carbonitrile,   (R)-2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile,   5-{(S)-2-[2-((S)-2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-dimethylamide,   3-{(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine,   [(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic acid,   (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile,   2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile, and   6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione,   or a pharmaceutically acceptable salt thereof.   
     
     
         10 . The method according to  claim 1 , wherein the metabolic disorder is type 2 diabetes mellitus and wherein the contraindication is renal disease, renal impairment or renal dysfunction, and wherein said DPP-4 inhibitor is used for said patient in the same dose as for a patient with normal renal function. 
     
     
         11 . The method according to  claim 1 , characterized in that said DPP-4 inhibitor and its major active metabolite(s) have a relatively wide therapeutic window and/or are primarily eliminated via hepatic metabolism or biliary excretion. 
     
     
         12 . The method according to  claim 1 , wherein said DPP-4 inhibitor is excreted mainly via the liver. 
     
     
         13 . The method according to  claim 1 , wherein excretion via the kidney represents a minor elimination pathway. 
     
     
         14 . The method according to  claim 1 , wherein said DPP-4 inhibitor is excreted mainly unchanged. 
     
     
         15 . The method according to  claim 1 , for which elimination via metabolism represents a minor elimination pathway. 
     
     
         16 . The method according to  claim 1 , wherein said DPP-4 inhibitor has placebo-like safety/tolerability and/or is eliminated primarily as the parent drug via the liver. 
     
     
         17 . The method according  claim 1 , wherein the main metabolite of said DPP-4 inhibitor is pharmacologically inactive or has a relatively wide therapeutic window. 
     
     
         18 . The method according to  claim 1 , wherein the contraindication is mild, moderate or severe renal impairment or end-stage renal disease. 
     
     
         19 . The method according to  claim 1 , further comprising the use of the DPP-IV inhibitor in combination with one or more further active substances selected from antidiabetics, active substances that lower the blood sugar level, active substances that lower the lipid level in the blood, active substances that raise the HDL level in the blood, active substances that lower the blood pressure, active substances that are indicated in the treatment of atherosclerosis, and active substances that are indicated in the treatment of obesity. 
     
     
         20 . The method according to  claim 1 , further comprising the use of the DPP-IV inhibitor in combination with one or more further active substances selected from sulphonylureas, thiazolidinediones, glinides, alpha-glucosidase blockers, GLP-1 and GLP-1 analogues, and insulin and insulin analogues. 
     
     
         21 . The method according to  claim 1 , further comprising the use of the DPP-IV inhibitor in combination with one or more further active substances selected from repaglinide, pioglitazone, and insulin and insulin analogues. 
     
     
         22 . The method according to  claim 1 , further comprising the use of the DPP-IV inhibitor in combination with pioglitazone. 
     
     
         23 . The method according to  claim 1 , wherein the metabolic disorder is type 2 diabetes mellitus and the intolerability is at least one gastrointestinal side effect selected from:
 nausea,   vomiting,   diarrhoea,   intestinal gas, and   severe abdominal discomfort.   
     
     
         24 . A method of using a DPP-4 inhibitor to treat diabetes in a patient comprising orally administering said DPP-IV inhibitor to said patient, characterized in that <10% of the administered oral dose is excreted via the kidneys. 
     
     
         25 . The method according to  claim 24 , characterized in that the DPP-IV inhibitor is primarily excreted unchanged via the bile. 
     
     
         26 . The method according to  claim 24 , characterized in that >80% of the administered oral dose is excreted unchanged as parent drug. 
     
     
         27 . The method according to  claim 24  characterized in that its main metabolite is pharmacologically inactive.