Use of 3-hydroxy-3-methylglutaryl coenzym a reductase inhibitors for the manufacture of a medicament for the treatment of diabetic neuropathy

Abstract

The present invention relates to a new use of a statin drug in the improvement of diabetic neuropathy, specifically in improving nerve conduction velocity and nerve blood flow in patients suffering diabetes, in particular to pharmaceutical combinations of the statin drug and other agents known to improve diabetic neuropathy such as an aldose reductase inhibitor (ARI), an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II (AII) antagonist which combinations are useful in the prevention and treatment of the complications of diabetes.

1 . A method for treating neuropathy in patients suffering from diabetes comprising administering to the patient a statin drug.  
     
     
         2 . A method for improving nerve conduction velocity or nerve blood flow in a patient suffering diabetic neuropathy comprising administering to the patient a statin drug.  
     
     
         3 . Use of a statin drug in the preparation of a medicament for use in the treatment of diabetic neuropathy.  
     
     
         4 . Use of a statin drug in the preparation of a medicament for use in the improvement of nerve conduction velocity or nerve blood flow in a patient having diabetic neuropathy.  
     
     
         5 . A method as claimed in either  claim 1  or  claim 2  wherein the statin drug is selected from pravastatin, simvastatin, cerivastatin, fluvastatin, atorvastatin and (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt thereof.  
     
     
         6 . Use as claimed in either  claim 3  or  claim 4  wherein the statin drug is selected from pravastatin, simvastatin, cerivastatin, fluvastatin, atorvastatin and (E)-7-[4-(4-fluoroplienyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt thereof.  
     
     
         7 . A method as claimed in  claim 1 ,  2  or  5  wherein the statin drug is used in combination with at least one other drug used for treating diabetes or the complications of diabetes.  
     
     
         8 . A method as claimed in  claim 7  wherein the drug used for treating diabetes or the complications of diabetes is selected from insulin, troglitazone, rosiglitazone, pioglitazone, MCC-555, (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid and 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-(S)-2-ethoxy propanoic acid, glimepiride, glibenclamide, gliclazide, glipizide, gliquidone and tolazamide, metformin, acarbose and repaglinide.  
     
     
         9 . Use as claimed in  claim 3 ,  4  or  6  wherein the statin drug is used in combination with at least one other drug used for treating diabetes or the complications of diabetes.  
     
     
         10 . Use as claimed in  claim 9  wherein the drug used for treating diabetes or the complications of diabetes is selected from insulin, troglitazone, rosiglitazone, pioglitazone, MCC-555, (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid and 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-(S)-2-ethoxy propanoic acid, glimepiride, glibenclamide, gliclazide, glipizide, gliquidone and tolazamide, metformin, acarbose and repaglinide.  
     
     
         11 . A method as claimed in  claim 2  or  5  wherein the statin drug is used in combination with a second drug which is also useful in improving nerve conduction velocity in a patient suffering diabetic neuropathy.  
     
     
         12 . A method as claimed in  claim 11  wherein the second drug is selected from an aldose reductase inhibitor, an ACE inhibitors and an AII antagonist.  
     
     
         13 . A method as claimed in  claim 12  wherein the second drug is selected from epalrestat, tolrestat, ponolrestat, zopolrestat, AD-5467, SNK-860, ADN-138, AS-3201, zenarestat, sorbinil, methosorbinil, imirestat and minalrestat (WAY-121509), benazepril, benazeprilat, captopril, delapril, fentiapril, fosinopril, imidopril, libenzapril, moexipril, pentopril, perindopril, pivopril, quinapril, quinaprilat, ramipril, spirapril, spiraprilat, trandolapril, zofenopril, ceronapril, enalapril, indolapril, lisinopril, alacepril, cilazapril, losartan, irbesartan, valsartan and candesartan.  
     
     
         14 . Use as claimed in either  claim 3  or  6  wherein the statin drug is used in combination with a second drug which is also useful in improving nerve conduction velocity in a patient suffering diabetic neuropathy.  
     
     
         15 . A method as claimed in  claim 14  wherein the second drug is selected from an aldose reductase inhibitor, an ACE inhibitors and an AII antagonist.  
     
     
         16 . A method as claimed in  claim 15  wherein the second drug is selected from epalrestat, tolrestat, ponolrestat, zopolrestat, AD-5467, SNK-860, ADN-138, AS-3201, zenarestat, sorbinil, methosorbinil, imirestat and minalrestat (WAY-121509), benazepril, benazeprilat, captopril, delapril, fentiapril, fosinopril, imidopril, libenzapril, moexipril, pentopril, perindopril, pivopril, quinapril, quinaprilat, ramipril, spirapril, spiraprilat, trandolapril, zofenopril, ceronapril, enalapril, indolapril, lisinopril, alacepril, cilazapril, losartan, irbesartan, valsartan and candesartan.  
     
     
         17 . A pharmaceutical combination comprising (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt thereof and lisinopril.  
     
     
         18 . A pharmaceutical combination comprising (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt thereof and candesartan.  
     
     
         19 . A pharmaceutical combination comprising (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt thereof, or atorvastatin, and (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid or 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-(S)-2-ethoxy propanoic acid  
     
     
         20 . A pharmaceutical composition comprising (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt thereof, lisinopril and a pharmaceutically acceptable diluent or carrier.  
     
     
         21 . A pharmaceutical composition comprising (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt thereon or atorvastatin, (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid, or 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-(S)-2-ethoxy propanoic acid, and a pharmaceutically acceptable carrier or diluent.