Compositions comprising (s)-2-amino-1-(4-chlorophenyl)-1-[4-(1h-pyrazol-4-yl)-phenyl]-ethanol as modulator of protein kinases

Abstract

The invention provides a composition comprising (S) 2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol, wherein the composition is either substantially free of (R) 2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol or the composition contains a mixture of the (S) and (R) enantiomers in which the (S) enantiomer predominates. Also provided are processes for the preparation of the (S) 2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol, novel process intermediates and methods for making the novel process intermediates.

1 - 62 . (canceled) 
   
   
       63 . A composition comprising (S) 2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]ethanol, wherein the composition is either substantially free of (R) 2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol or the composition contains a mixture of the (S) and (R) enantiomers in which the (S) enantiomer predominates. 
   
   
       64 . A composition according to  claim 63  comprising 2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol or a salt, tautomer or N-oxide thereof, wherein at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or at least 99.9% is in the S-enantiomeric form. 
   
   
       65 . A composition according to  claim 63 , wherein substantially no (R)-2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol is present in the composition. 
   
   
       66 . A composition according to  claim 63  wherein the (S)-2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol is in the form of a free base. 
   
   
       67 . A composition according to  claim 63  wherein the (S)-2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol is in the form of an acid addition salt. 
   
   
       68 . A composition according to  claim 63  consisting of (S)-2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol with less than less than 0.5% impurities, more preferably less than 0.1%, and most preferably less than 0.01% impurities. 
   
   
       69 . A composition according to  claim 63  further comprising a pharmaceutically acceptable carrier. 
   
   
       70 . A compound of the formula (I): 
     
       
         
         
             
             
         
       
     
     or a salt, tautomer or N-oxide thereof, wherein the compound is in substantially pure form. 
   
   
       71 . A compound of the formula (I) according to  claim 70  in the form of a free base or a salt, or tautomer thereof. 
   
   
       72 . A pharmaceutical composition comprising a compound according to  claim 70  and a pharmaceutically acceptable carrier. 
   
   
       73 . A method for the prophylaxis or treatment of a disease state or condition chosen from
 (a) a disease state or condition mediated by protein kinase B;   (b) a disease or condition comprising or arising from abnormal cell growth in a mammal;   (c) a disease state or condition mediated by protein kinase A;   (d) a disease or condition comprising or arising from abnormally arrested cell death in a mammal;   
     the method comprising administering a therapeutically effective amount of the composition of  claim 63 . 
   
   
       74 . A method of modulating a cellular process by inhibiting the activity of a protein kinase A comprising administering a therapeutically effective amount of the composition of  claim 63 . 
   
   
       75 . A method for modulating protein kinase B and/or protein kinase A; which method comprises bringing the protein kinase B and/or protein kinase A, in a cellular environment, into contact with the composition of  claim 63 . 
   
   
       76 . A method for the prophylaxis or treatment of a disease state or condition which is selected from a carcinoma of the bladder, breast, colon, kidney, epidermal, liver, lung, oesophagus, gall bladder, ovary, pancreas, stomach, cervix, endometrium, thyroid, prostate, or skin, a hematopoietic tumour of lymphoid lineage, a hematopoietic tumour of myeloid lineage, thyroid follicular cancer, a tumour of mesenchymal origin, a tumour of the central or peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoctanthoma, thyroid follicular cancer, or Kaposi's sarcoma; breast cancer, ovarian cancer, colon cancer, prostate cancer, oesophageal cancer, squamous cancer and non-small cell lung carcinomas, the method comprising administering to a mammal the composition of 63. 
   
   
       77 . A method of inhibiting protein kinase B or of inhibiting protein kinase A, which method comprises contacting the kinase with a kinase-inhibiting composition of  claim 63 . 
   
   
       78 . A method for the preparation of a composition as defined in  claim 63 , the method comprising partially or fully resolving a mixture of (S) and (R) enantiomers of 2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol. 
   
   
       79 . A method according to  claim 78 , wherein the (S) and (R) enantiomers are resolved using chiral chromatography. 
   
   
       80 . A compound of the formula (12): 
     
       
         
         
             
             
         
       
     
     or an acid addition salt thereof. 
   
   
       81 . A compound according to  claim 80 , wherein the acid addition salt is 4-toluenesulphonic acid salt. 
   
   
       82 . A compound of the formula (17): 
     
       
         
         
             
             
         
       
     
   
   
       83 . A process for the preparation of a compound of the formula (12) as defined in  claim 80 , which process comprises the reaction of a compound of the formula (17) as defined in  claim 82  with a tertiary phosphine such as triphenylphosphine in a polar aprotic solvent followed by treatment with aqueous acid, for example an alkyl- or arylsulphonic acid selected from methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid and camphorsulphonic acid, and most preferably 4-toluenesulphonic acid. 
   
   
       84 . A process for the preparation of a compound of the formula (17) as defined in  claim 82 , which process comprises the reaction of an epoxide compound of the formula (II): 
     
       
         
         
             
             
         
       
     
     with an azide selected from an alkali metal azide and trimethylsilyl azide in a polar solvent. 
   
   
       85 . A method for the preparation of a compound of the formula (12) as defined in  claim 80 , which method comprises the process of  claim 84  followed by the process of  claim 83 .