Enzyme inhibitors

Abstract

A compound of formula (I) wherein R 1 is a C 1-6 straight or branched chain alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-6 cycloalkyl group or a C 3-6 cycloalkylC 1-6 alkyl group, each optionally substituted by one to three groups independently selected from: —CN; —NO 2 ; a group —COR 2 wherein R 2 is hydrogen, C 1-6 alkyl, —OR 3 wherein R 3 is hydrogen or C 1-6 alkyl or NR 4 R 5 wherein R 4 and R 5 are independently selected from hydrogen or C 1-6 alkyl; a group —S(O) m R 6 wherein m is 0, 1 or 2, R 6 is hydrogen, C 1-6 alkyl, hydroxy or NR 7 R 8 wherein R 7 and R 8 are independently hydrogen or C 1-6 alkyl; a group PO(OR 9 ) 2 wherein R 9 is hydrogen or C 1-6 alkyl; a group NR 10 R 11 wherein R 10 and R 11 are independently selected from hydrogen, C 1-6 alkyl, —COR 12 wherein R 12 is hydrogen or C 1-6 alkyl, or —S(O) m′ R 13 wherein m′ is 0, 1 or 2 and R 13 is hydrogen or C 1-6 alkyl; halo; or a group —OR 14 wherein R 14 is hydrogen, C 1-6 alkyl optionally substituted by one to three halo atoms, C 6-10 aryl or —COR 15 wherein R 15 is hydrogen or C 1-6 alkyl; p is 2 or 3, q is 1 or 2 and n is 0 or 1 and all salts, esters, amides and physiologically acceptable prodrugs thereof; pharmaceutical uses and formulations therefor; and processes for their preparation are disclosed.

1. A compound of formula (I) 
                 
 
       wherein R 1  methyl, or fluoromethyl  or a salt, ester, amide or physiologically acceptable prodrug thereof  of said compound. 
     
     
       2. A compound of formula (I) according to  claim 1  wherein the compound is selected from acid; and 
       2-amino-6-(1-imino-2-fluoroethylamino)-4,4-dioxo-4-thiahexanoic acid  
       or a salt, ester, amide or physiologically acceptable prodrug thereof. 
     
     
       3. 2-amino-6-(1-iminoethylamino)-4,4-thiahexanoic acid. 
     
     
       4. (R)-2-amino-6-(1-iminoethylamino)-4,4-dioxo-4-thiahexanoic acid. 
     
     
       5. A method for the treatment of a condition where there is an advantage in inhibiting NO production from arginine by the action of NO synthase, said method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of  claim 1 . 
     
     
       6. A method according to claim  4   5  wherein the condition is a shock state resulting from overproduction of NO by iNOS. 
     
     
       7. A pharmaceutical formulation comprising a compound of  claim 1 , together with one or more pharmaceutically acceptable carriers therefor and optionally one or more other therapeutic ingredients. 
     
     
       8. A process of the preparation of a compound of  claim 1  which comprises:
 (a) oxidizing a compound of the formula (II): 
                 
 
 wherein R 1  is as defined in  claim 1  methyl, or  
 (b) the deprotection of a compound of formula (V) 
                 
 
 wherein R 1  ,  is as defined above  methyl, Q is hydrogen or a carboxyl protecting group and Q′ is a protecting group, and optionally followed by  conversion into another compound of formula (I) a salt, ester, amide or physiologically acceptable prodrug.  
 
     
     
       9. An intermediate of formula (VI) 
                 
 excluding compounds β-(β- aminoethylsulphonyl )- N - toluene - p - sulphonyl - L - alanine and β -(β- aminoethylsulphonyl )- N - toluene - p - sulphonyl - L - alanine methyl ester hydrochloride,  or a protected derivative thereof, wherein Q and Q′ are as defined in  claim 8 .