2-(pyrazol-3-yl)carbapenem derivatives

Abstract

A compound of formula (I): in which R is: wherein R α is hydrogen, optionally substituted (C 1-6 )alkyl or optionally substituted aryl; R β is hydrogen, optionally substituted (C 1-6 )alkyl or optionally substituted aryl; or R α and R β together form an optionally substituted 5 or 6 membered heterocyclic ring with or without additional heteroatoms; R 1 is (C 1-6 )alkyl which is unsubstituted or substituted by fluoro, a hydroxy group which is optionally protected by a removable hydroxy protecting group, or by an amino group which is optionally protected by a removable amino protecting group; R 2 is hydrogen or methyl; and —CO 2 R 3 is carboxy or a carboxylate anion or the group R 3 is a removable carboxy protecting group. This invention also relates to processes for its preparation, intermediates and pharmaceutical compositions comprising compounds of formula (I). Compounds of formula (I) which include pharmaceutially acceptable salts or pharmaceutially acceptable in vivo hydrolysable esters thereof have a broad spectrum of anti-bacterial activity and show good stability towards DHP-1.

We claim:  
     
         1 . A compound of formula (I):  
       
         
           
           
               
               
           
         
       
       in which R is:  
       
         
           
           
               
               
           
         
       
       wherein 
 R α  is hydrogen, optionally substituted (C 1-6 )alkyl or optionally substituted aryl;  
 R β  is hydrogen, optionally substituted (C 1-6 )alkyl or optionally substituted aryl; or  
 R α  and R β  together form an optionally substituted 5 or 6 membered heterocyclic ring with or without additional heteroatoms;  
 R 1  is (C 1-6 )alkyl which is unsubstituted or substituted by fluoro, a hydroxy group which is optionally protected by a removable hydroxy protecting group, or by an amino group which is optionally protected by a removable amino protecting group;  
 R 2  is hydrogen or methyl, and  
 —CO 2 R 3  is carboxy or a carboxylate anion or the group R 3  is a removable carboxy protecting group.  
 
     
     
         2 . A compound according to  claim 1 , having the formula (Ia):  
       
         
           
           
               
               
           
         
       
       in which R, R 1  and R 2  are as defined in  claim 1  or a pharmaceutically acceptable salt or pharmaceutically acceptable in vivo hydrolysable ester thereof.  
     
     
         3 . A compound according to  claim 1  wherein the (C 1-6 )alkyl groups for R α  and R β  are straight or branched chain alkyl groups having from 1 to 6 carbon atoms.  
     
     
         4 . A compound according to  claim 3  wherein R α  and R β  are either or both methyl, ethyl, n-propyl or isopropyl.  
     
     
         5 . A compound according to  claim 4  wherein R α  is ethyl and R β  is methyl.  
     
     
         6 . A compound according to  claim 1  wherein the aryl group includes phenyl and naphthyl, optionally substituted by up to five substituents.  
     
     
         7 . A compound according to  claim 1  wherein R 1  is (R)-1-hydroxyethyl.  
     
     
         8 . A compound according to  claim 1  wherein R 2  is hydrogen.  
     
     
         9 . A process for the preparation of a compound of formula (I) or (Ia):  
       
         
           
           
               
               
           
         
       
       in which R is:  
       
         
           
           
               
               
           
         
       
       wherein 
 R α  is hydrogen, optionally substituted (C 1-6 )alkyl or optionally substituted aryl;  
 R β  is hydrogen, optionally substituted (C 1-6 )alkyl or optionally substituted aryl; or  
 R α  and R β  together form an optionally substituted 5 or 6 membered heterocyclic ring with or without additional heteroatoms;  
 R 1  is (C 1-6 )alkyl which is unsubstituted or substituted by fluoro, a hydroxy group which is optionally protected by a removable hydroxy protecting group, or by an amino group which is optionally protected by a removable amino protecting group;  
 R 2  is hydrogen or methyl, and  
 —CO 2 R 3  is carboxy or a carboxylate anion or the group R 3  is a removable carboxy protecting group,  
 which process comprises treating a compound of formula (II):  
                     
 in which  
 R, R 1  and R 2  are as hereinbefore defined,  
 R 3  is a removable carboxy protecting group, and  
 X is oxygen or a group PR 4 R 5 R 6 ,  
 wherein R 4 , R 5  and R 6  are the same or different and is each an optionally substituted (C 1-6 )alkyl or an optionally substituted aryl group;  
 under carbapenem ring forming conditions;  
 and thereafter, and if necessary, carrying out any or all of the following steps: 
 removing any protecting group(s);  
 converting a first group R 1  which is (C 1-6 )alkyl substituted by a hydroxyl group into a further group R 1  which is (C 1-6 )alkyl substituted by fluoro or an amino group; and  
 thereafter optionally forming a pharmaceutically acceptable salt or pharmaceutically acceptable in vivo hydrolysable ester thereof.  
 
 
     
     
         10 . A process according to  claim 9 , wherein R 4 , R 5  and R 6  is each phenyl.  
     
     
         11 . A process according to  claim 9 , wherein R 4 , R 5  and R 6  is each n-butyl.  
     
     
         12 . A process for the preparation of a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       in which R is:  
       
         
           
           
               
               
           
         
       
       wherein 
 R α  is hydrogen, optionally substituted (C 1-6 )alkyl or optionally substituted aryl;  
 R β  is hydrogen, optionally substituted (C 1-6 )alkyl or optionally substituted aryl; or  
 R α  and R β  together form an optionally substituted 5 or 6 membered heterocyclic ring with or without additional heteroatoms;  
 R 1  is (C 1-6 )alkyl which is unsubstituted or substituted by fluoro, a hydroxy group which is optionally protected by a removable hydroxy protecting group, or by an amino group which is optionally protected by a removable amino protecting group;  
 R 2  is hydrogen or methyl, and  
 —CO 2 R 3  is carboxy or a carboxylate anion or the group R 3  is a removable carboxy protecting group,  
 which process comprises reacting a compound of formula (X):  
                     
 in which R 1  and R 2  are as hereinbefore defined, R 3  is a removable carboxy protecting group and X 1  is a leaving group, with a compound of formula (XI): 
 M—R  (XI) 
 in which M is a metallo group and R is as hereinbefore defined;  
 in a cross-coupling reaction in the presence of a cross-coupling reaction catalyst and  
 thereafter and if necessary removing any protecting group and/or converting the product into a salt.  
 
     
     
         13 . A process according to  claim 12 , wherein X 1  is trifluoromethanesulphonyloxy, methanesulphonyloxy, 4-toluene sulphonyloxy, fluorosulphonyloxy, chloro, bromo, iodo or diphenoxyphosphoryloxy.  
     
     
         14 . A process according to  claim 13 , wherein M is R 14 R 15 R 16 Sn, B(OR) 2  or ZnCl in which R 14 , R 15  and R 16  may the same or different and are each (C 1-6 )alkyl.  
     
     
         15 . A process according to  claim 14 , wherein M is R 14 R 15 R 16 Sn, and R 14 =R 15 =R 16 =methyl or n-butyl.  
     
     
         16 . A process according to  claim 12 , wherein the cross coupling catalyst is a palladium compound.  
     
     
         17 . A compound selected from: 
 sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1,5-dimethylpyrazol-3-yl)carbapen-2-em-3-carboxylate,    sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1-phenylpyrazol-3-yl)carbapen-2-em-3-carboxylate,    sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1-methylpyrazol-3-yl)carbapen-2-em-3-carboxylate,    sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(5-methyl-1-phenethylpyrazol-3-yl)carbapen-2-em-3-carboxylate,    sodium (5R,6S)-6-[(R)-1-hydroxyethyl)]-2-[1-(2-phenethyl)pyrazol-3-yl]carbapen-2-em-3-carboxylate,    sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[4,5,6,7-tetrahydropyridino-(1,2-b)-pyrazol-2-yl]carbapen-2-em-3-carboxylate,    sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(5-methyl-1-phenylpyrazol-3-yl)carbapen-2-em-3-carboxylate,    sodium (5R,6S)-2-[5,6-dihydro-4H-pyrrolo(1,2-b)-pyrazol-2-yl]-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,    sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1,5-diethylpyrazol-3-yl)carbapen-2-em-3-carboxylate,    sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1-ethyl-5-methylpyrazol-3-yl)carbapen-2-em-3-carboxylate,    sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[1-(2-hydroxyethyl)-5-methylpyrazol-3-yl]carbapen-2-em-3-carboxylate,    sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[1-(2-methoxyethyl)-5-methylpyrazol-3-yl]carbapen-2-em-3-carboxylate,    sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(5-benzyl-1-methylpyrazol-3-yl)carbapen-2-em-3-carboxylate,    sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-{5-methyl-1-[2-(1-methyl-tetrazol-5-ylthio)ethyl]pyrazol-3-yl}carbapen-2-em-3-carboxylate,    sodium (5R,6S)-2-[1-(2-acetamidoethyl)-5-methylpyrazol-3-yl]-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,    sodium (5R,6S)-2-[1-(2-methylthioethyl)-5-methylpyrazol-3-yl]-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,    sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1-methyl-5-ethylpyrazol-3-yl)carbapen-2-em-3-carboxylate,    t-butyloxycarbonyloxymethyl (5R,6S)-2-(1,5-dimethylpyrazol-3-yl)-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,    cyclohexyloxycarbonyloxymethyl (5R,6S)-2-(1,5-dimethylpyrazol-3-yl)-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,    cyclohexyloxycarbonyloxymethyl (5R,6S)-2-(1-ethyl-5-methylpyrazol-3-yl)-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,    sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[5-methyl-1-(2-methylsulphonylethyl)pyrazol-3-yl]carbapen-2-em-3-carboxylate,    sodium (5R,6S)-2-[1-[2-(N,N-dimethylaminocarbonyloxy)ethyl]-5-methylpyrazol-3-yl]-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,    2-ethoxycarbonyl-E-but-2-enyl (5R,6S)-2-(1-ethyl-5-methyl-1,2-pyrazol-5-yl)-6-[1-hydroxyethyl]carbapen-2-em-3-carboxylate,    1-methylcyclohexyloxycarbonyloxymethyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1-ethyl-5-methyl-pyrazol-3-yl)carbapen-2-em-3-carboxylate,    2-methoxyprop-2-ylcarbonyloxymethyl (5R,6S)-2-(1-ethyl-5-methylpyrazol-3-yl)-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate.    isobutyryloxymethyl (5R,6S)-2-[1-ethyl-5-methylpyrazol-3-yl]-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,    (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl (5R,6S)-2-[1-ethyl-5-methylpyrazol-3-yl ]-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate, and    benzoyloxymethyl (5R,6S)-2-[1-ethyl-5-methylpyrazol-3-yl]-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate.    
     
     
         18 . A pharmaceutical composition comprising a compound according to formula (Ia) as defined in  claim 2 , or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, and a pharmaceutically acceptable carrier.  
     
     
         19 . A compound according to formula (Ia) as defined in  claim 2 , or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for use as a therapeutic substance.  
     
     
         20 . A method of treating bacterial infections in humans and animals which method comprises administering a therapeutically effective amount of an antibiotic compound of the present invention of the formula (Ia) as defined in  claim 2 , or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.