Compounds containing s-n-valeryl-n--valine and (2r,4s)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester moieties and cations

Abstract

A method for treatment of a cardiovascular or renal condition or disease with a specific combination, linked pro-drug or a compound of an angiotensin receptor antagonist and a NEPi.

What is claimed is: 
     
         1 . A method of preparing a dual-acting compound comprising
 (a) an the angiotensin receptor antagonist valsartan;   (b) a the neutral endopeptidase inhibitor (NEPi) 2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester of formula   
       
         
           
           
               
               
           
         
       
       and
 (c) a pharmaceutically acceptable cation; 
 said method comprising the steps of: 
 (i) dissolving an the angiotensin receptor antagonist and a the neutral endopeptidase inhibitor (NEPi) in a suitable solvent; 
 (ii) dissolving a basic compound of Cat in a suitable solvent, wherein Cat is a cation; 
 (iii) combining the solutions obtained in steps (i) and (ii); 
 (iv) precipitating the solid, and drying same to obtain the dual-acting compound; or alternatively 
 obtaining the dual-acting compound by exchanging the solvent(s) employed in steps (i) and (ii) by 
 (iva) evaporating the resulting solution to dryness; 
 (va) re-dissolving the solid in a suitable solvent; 
 (via) precipitation of the solid and drying same to obtain the dual-acting compound. 
 
     
     
         2 . The method of  claim 1  wherein the suitable solvent in steps (i) and/or (iva) is acetone. 
     
     
         3 . The method of  claim 1 , wherein the basic compound of (Cat) is (Cat)OH, (Cat) 2 CO 3 , (Cat)HCO 3 , CatOMe, CatOAc or CatOCHO. 
     
     
         4 . The method of  claim 1 , wherein the cation (c) and Cat in step (ii) is selected from the group consisting of Na, K and NH 4 . 
     
     
         5 . The method of  claim 4 , wherein Cat in step (ii) is Na. 
     
     
         6 . A method of preparing a compound comprising the sum formula R(S)—N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine) ((2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester]Na 3 .xH2O, wherein x is 0 to 3, and being in the solid form said method comprising the steps of:
 (i) dissolving (S)—N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester in a suitable solvent; 
 (ii) dissolving a basic compound of Na in a suitable solvent; 
 (iii) combining the solutions obtained in steps (i) and (ii); 
 (iv) precipitating the solid, and drying same to obtain the dual-acting compound. 
 
     
     
         7 . The process according to  claim 6 , wherein the suitable solvent in step (i) is selected from the group consisting of water, methanol, ethanol, 2-propanol, acetone, ethyl acetate, isopropyl acetate, methyl-t-butylether, acetonitrile, toluene, DMF, NMF and methylene chloride and mixtures of such solvents. 
     
     
         8 . The process according to  claim 7  wherein the mixtures of solvents are selected from ethanol-water, methanol-water, 2-propanol-water, acetonitrile-water, acetone-water, 2-propanol-toluene, ethyl acetate-heptane, isopropyl acetate-acetone, methyl-t-butyl ether-heptane, methyl-t-butyl ether-ethanol, ethanol-heptane, acetone-ethyl acetate, acetone-cyclohexane, and toluene-heptane. 
     
     
         9 . The process according to  claim 6 , wherein the suitable solvent in step (i) is acetone. 
     
     
         10 . The process according to  claim 6 , wherein the basic compound of Na is NaOH, Na2CO3, NaHCO3, NaOMe, NaOAc or NaOCHO. 
     
     
         11 . The process according to  claim 6 , wherein the suitable solvent in step (ii) is water. 
     
     
         12 . The process according to  claim 6 , wherein the precipitation in step (iv) is effected by stirring the solutions for an appropriate amount of time from 20 min to 6 h. 
     
     
         13 . The process according to  claim 6 , wherein in step (iv) a co-solvent is added. 
     
     
         14 . The process according to  claim 13 , wherein the co-solvent is selected from the group consisting of ethanol, 2-propanol, acetone, ethylacetate, isopropyl acetate, methyl-t-butylether, acetonitrile, toluene, and methylene chloride and mixtures of such solvents. 
     
     
         15 . The process according to  claim 14 , wherein the co-solvent is isopropyl acetate. 
     
     
         16 . The process according to  claim 6 , wherein the compound comprises the sum formula [((S)—N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine) ((2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester]Na 3 .xH2O, wherein x is 2.5. 
     
     
         17 . The process according to  claim 16 , wherein the compound comprising the sum formula [((S)—N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine) ((2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester]Na 3 .xH2O, wherein x is 2.5, is termed Trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate] hemipentahydrate and is in the crystalline form. 
     
     
         18 . A process for preparing a compound comprising the sum formula [((S)—N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine) ((2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester]Na 3 .xH2O, wherein x is 0 to 3 in the solid form, said method comprising the steps of:
 (i) dissolving (S)—N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine and (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester in a suitable solvent; 
 (ii) dissolving a basic compound of Na in a suitable solvent; 
 (iii) combining the solutions obtained in steps (i) and (ii); 
 (iv) evaporating the resulting solution to dryness; 
 (v) re-dissolving the solid in a suitable solvent; 
 (vi) precipitating the solid and drying the same to obtain the compound. 
 
     
     
         19 . The process according to  claim 18 , wherein the suitable solvent in step (i) is selected from the group consisting of water, methanol, ethanol, 2-propanol, acetone, ethyl acetate, isopropyl acetate, methyl-t-butylether, acetonitrile, toluene, DMF, NMF and methylene chloride and mixtures of such solvents. 
     
     
         20 . The process according to  claim 19 , wherein the mixtures of solvents are selected from ethanol-water, methanol-water, 2-propanol-water, acetonitrile-water, acetone-water, 2-propanol-toluene, ethyl acetate-heptane, isopropyl acetate-acetone, methyl-t-butyl ether-heptane, methyl-t-butyl ether-ethanol, ethanol-heptane, acetone-ethyl acetate, actetone-cyclohexane, and toluene-heptane. 
     
     
         21 . The process according to  claim 20  wherein the suitable solvent in step (i) is acetone. 
     
     
         22 . The process according to  claim 18 , wherein the basic compound of Na is NaOH, Na2CO3, NaHCO3, NaOMe, NaOAc or NaOCHO. 
     
     
         23 . The process according to  claim 18 , wherein the suitable solvent in step (ii) is water. 
     
     
         24 . The process according to  claim 18 , wherein the solution is evaporated to dryness at elevated temperatures from room temperature to 50° C. 
     
     
         25 . The process according to  claim 18 , wherein the suitable solvent in step (v) is selected from the group consisting of water, ethanol, 2-propanol, acetone ethylacetate, isopropyl acetate, methyl-t-butylether, acetonitrile, toluene, and methylene chloride and mixtures of such solvents. 
     
     
         26 . The process according to  claim 25 , wherein the suitable solvent in step (v) is isopropyl acetate or acetone. 
     
     
         27 . The process according to  claim 18 , wherein the precipitation in step (vi) is effected by stirring and/or sonicating the solution. 
     
     
         28 . The process according to  claim 18 , wherein the compound comprises the sum formula [((S)—N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine) ((2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester]Na 3 . xH2O, wherein x is 2.5. 
     
     
         29 . The process according to  claim 28 , wherein the compound comprising the sum formula [((S)—N-valeryl-N-{[2′-(1H-tetrazole-5-yl)-biphenyl-4-yl]-methyl}-valine) ((2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester]Na 3 .xH2O, wherein x is 2.5, is termed Trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate] hemipentahydrate and is in the crystalline form. 
     
     
         30 . The process according to  claim 17  or  29 , wherein the compound Trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate] hemipentahydrate in the crystalline form has the sum formula C 48 H 55 N 6 O 8 Na 3 .2.5H 2 O and is in the form of an asymmetric unit comprising six C 48 H 55 N 6 O 8 Na 3 .2.5H 2 O formula units. 
     
     
         31 . The process according to  claim 17  or  29 , wherein the compound trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate] hemipentahydrate is characterized by an Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) spectrum having the following absorption bands expressed in reciprocal wave numbers (cm −1 )(±2 cm −1 ): 1711 (st), 1637 (st), 1597 (st) and 1401 (st). 
     
     
         32 . The process according to  claim 17  or  29 , wherein the compound trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate] hemipentahydrate is characterized by an Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) spectrum having the following absorption bands expressed in reciprocal wave numbers (cm −1 )(±2 cm −1 ):
 2956 (w), 1711 (st), 1637 (st), 1597 (st), 1488 (w), 1459 (m), 1401 (st), 1357 (w), 1295 (m), 1266 (m), 1176 (w), 1085 (m), 1010 (w), 942 (w), 907 (w), 862 (w), 763 (st), 742 (m), 698 (m), 533 (st). 
 
     
     
         33 . The process according to  claim 17  or  29 , wherein the compound trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionate-(S)-3′-methyl-2′-(pentanoyl{2″-(tetrazol-5-ylate)biphenyl-4′-ylmethyl}amino)butyrate] hemipentahydrate is characterized by an X-ray powder diffraction pattern taken with a Scintag XDS2000 powder diffractometer comprising the following interlattice plane intervals:
 d in [Å] (±0.1 Å): 21.2 (s), 17.0 (w), 7.1 (s), 5.2 (w), 4.7 (w), 4.6 (w), 4.2 (w), 3.5 (w), 3.3 (w).