New salts of HMG-CoA reductase inhibitors

Abstract

Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, and derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic agents. The majority of them are produced by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus, some are obtained by treating the fermentation products using the methods of chemical synthesis or they are the products of total chemical synthesis. The present invention relates to the new amine salts of HMG-CoA reductase inhibitors, the preparation thereof, the preparation of pure HMG-CoA reductase inhibitors via amine salts thereof, use of the amine salts of HMG-CoA reductase inhibitors in the process for semisynthetic preparation of HMG-CoA reductase inhibitors, use of the amine salts of HMG-CoA reductase inhibitors in the process for biotechnological modification of HMG-CoA reductase inhibitors as well as the conversion of the amine salts of HMG-CoA reductase inhibitors into the pharmaceutically acceptable salts of the HMG-CoA reductase inhibitors and the conversion of the amine sails of HMG-CoA reductase inhibitors into the HMG-CoA reductase inhibitors in the lactone form.

1 - 48 . (canceled) 
     
     
         49 . The sodium salt of pravastatin in a crystalline form. 
     
     
         50 . The sodium salt of pravastatin in solid form made by a process comprising the steps of:
 (a) dissolving an amine salt of pravastatin in an alkaline solution containing sodium cations;   (b) adding ethyl acetate to said alkaline solution;   (c) cooling of said alkaline solution; and   (d) forming and isolating the solid salt of pravastatin sodium;   
       wherein the amine salt of pravastatin comprises 
       an amine selected from the group consisting of amines of formulae I and II: 
       
         
           
           
               
               
           
         
       
       wherein
 a1) R 1 , R 2 , R 3  and R 4  independently denote: 
 a hydrogen atom; 
 a straight or a branched alkyl group having 1 to 8 carbon atoms; 
 a cycloalkyl group having 3 to 8 carbon atoms; 
 an arylalkyl group wherein the alkyl group is methyl or ethyl and the aryl group is phenyl, which is optionally substituted by an N-alkyl or N,N-dialkyl group wherein the alkyl group is alkyl having 1 to 4 carbon atoms; 
 an arylalkyl group which is optionally substituted by one or more substituents; 
 a hydroxyalkyl group having 2 to 4 carbon atoms; or 
 an aminoalkyl group having 2 to 4 carbon atoms, which are optionally substituted by an N-alkyl or N,N-dialkyl group wherein the alkyl group is alkyl having 1 to 4 carbon atoms; 
 X denotes a hydrogen atom, a hydroxyl group, a halogen or a methyl group; 
 m and n independently denote an integer from 0 to 5; or 
 a2) NR 1 R 2  or NR 3 R 4  denote a heterocyclic ring having 3 to 7 methylene groups attached to a hydrogen atom, one of these groups being optionally substituted by an oxygen or a sulphur atom or an imine group; and X, m and n are the same as defined above; 
 
       
         
           
           
               
               
           
         
       
       wherein:
 b1) R′ 1 , R′ 2 , and R′ 3  are the same or different and denote hydrogen, alkyl, alkenyl, amino- or hydroxy- or alkoxy-substituted alkyl or alkenyl, or substituted ammo-substituted alkyl or alkenyl, provided that R′ 1 , R′ 2  and R′ 3  are not hydrogen at the same time; or 
 b2) R′ 1 , and R′ 2 , and optionally R′ 3 , together with the nitrogen atom form an optionally substituted heterocyclic ring system including the nitrogen atom as a ring member, and optionally including an additional hetero atom, and if R′ 3  is not part of the ring system it is independently selected from hydrogen, alkyl, alkenyl, amino- or hydroxyl- or alkoxy-substituted alkyl, or substituted amino-substituted alkyl; or 
 b3) R′ 1  is an optionally substituted cyclic group of formula III,
   R′(CHR′ 4 ) m —  III 
 
 wherein m is zero or an integer from 1 to 5, R′ is optionally substituted aliphatic hydrocarbon cyclic system having 3 to 8 carbon atoms in the ring, R′ 4  is hydrogen, alkyl, amino- or hydroxy- or alkoxy-substituted alkyl, substituted amino-substituted alkyl, or a group of the same formula as R′ 1  as defined herein above; R′ 2  and R′ 3  are the same as R′ 1  or hydrogen, alkyl, alkenyl, amino- or hydroxy- or alkoxy-substituted alkyl, or substituted amino-substituted alkyl or alkenyl; or 
 b4) R′ 1  is an optionally substituted aryl group of formula IV: 
 
       
         
           
           
               
               
           
         
         wherein R′ 5  is hydrogen or one or more substituents, and m is zero or an integer from 1 to 5; and R′ 2  and R′ 3  may be independently hydrogen, alkyl, amino- or hydroxyl or alkoxy-substituted alkyl, or substituted amino-substituted alkyl, or groups of the same general formula R′ 1 . 
       
     
     
         51 . The sodium salt of pravastatin according to  claim 49 , wherein the amine salt of pravastatin is the tertiarybutyl amine salt of pravastatin. 
     
     
         52 . The sodium salt of pravastatin according to  claim 50 , wherein the amine salt of pravastatin is dissolved in an alkaline ethanol/water mixture in step (a). 
     
     
         53 . The sodium salt of pravastatin according to  claim 50 , wherein the amine salt of pravastatin is dissolved in an ethanolic solution and/or aqueous solution of NaOH or Na 2 CO 3 . 
     
     
         54 . The sodium salt of pravastatin according to  claim 50 , wherein the amine salt of pravastatin sodium dissolved in step a) is prepared by
 dissolving pravastatin in the free acid form in ethyl acetate and   adding the respective amine into said solution, thereby crystallizing said amine salt of pravastatin.   
     
     
         55 . A pharmaceutical composition containing the sodium salt of pravastatin according to  claim 49 . 
     
     
         56 . A method of treating hypercholesteremia in humans, comprising administering to a patient in need of such treatment an antihypercholesterolemic effective amount of the sodium salt of pravastatin according to  claim 49 . 
     
     
         57 . The sodium salt of pravastatin according to  claim 50 , wherein the amine salt of pravastatin is the tertiarybutyl amine salt of pravastatin. 
     
     
         58 . The sodium salt of pravastatin according to  claim 51 , wherein the amine salt of pravastatin is dissolved in an alkaline ethanol/water mixture in step (a). 
     
     
         59 . The sodium salt of pravastatin according to  claim 51 , wherein the amine salt of pravastatin is dissolved in an ethanolic solution and/or aqueous solution of NaOH or Na 2 CO 3 . 
     
     
         60 . The sodium salt of pravastatin according to  claim 52 , wherein the amine salt of pravastatin is dissolved in an ethanolic solution and/or aqueous solution of NaOH or Na 2 CO 3 . 
     
     
         61 . The sodium salt of pravastatin according to  claim 51 , wherein the amine salt of pravastatin sodium dissolved in step a) is prepared by
 dissolving pravastatin in the free acid form in ethyl acetate and   adding the respective amine into said solution, thereby crystallizing said amine salt of pravastatin.   
     
     
         62 . The sodium salt of pravastatin according to  claim 52 , wherein the amine salt of pravastatin sodium dissolved in step a) is prepared by
 dissolving pravastatin in the free acid form in ethyl acetate and   adding the respective amine into said solution, thereby crystallizing said amine salt of pravastatin.   
     
     
         63 . The sodium salt of pravastatin according to  claim 53 , wherein the amine salt of pravastatin sodium dissolved in step a) is prepared by
 dissolving pravastatin in the free acid form in ethyl acetate and   adding the respective amine into said solution, thereby crystallizing said amine salt of pravastatin.   
     
     
         64 . A method of treating hypercholesteremia in humans, comprising administering to a patient in need of such treatment an antihypercholesterolemic effective amount of the sodium salt of pravastatin according to  claim 50 . 
     
     
         65 . A method of treating hypercholesteremia in humans, comprising administering to a patient in need of such treatment an antihypercholesterolemic effective amount of the sodium salt of pravastatin according to  claim 51 . 
     
     
         66 . A method of treating hypercholesteremia in humans, comprising administering to a patient in need of such treatment an antihypercholesterolemic effective amount of the sodium salt of pravastatin according to  claim 52 . 
     
     
         67 . A method of treating hypercholesteremia in humans, comprising administering to a patient in need of such treatment an antihypercholesterolemic effective amount of the sodium salt of pravastatin according to  claim 53 . 
     
     
         68 . A method of treating hypercholesteremia in humans, comprising administering to a patient in need of such treatment an antihypercholesterolemic effective amount of the sodium salt of pravastatin according to  claim 54 .