Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1

Abstract

The present invention relates to compounds with the formula (I) and also to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human 11-β-hydroxysteroid dehydrogenase type 1 enzyme.

1 - 12 . (canceled)  
   
   
       13 . A compound of the formula (I)  
     
       
         
         
             
             
         
       
     
     wherein 
 T is a monocyclic heteroaryl ring, optionally independently substituted by [R] n , wherein n is an integer 0-5, and R is hydrogen, C 1-6 -alkyl, halogen, aryl or aryloxy, wherein the aryloxy residue can further be optionally substituted in one or more positions independently of each other by cyano and halogen;  
 A is C 1-6 -alkyl, vinyl or 3-(ethyl 3-methylbutanoate);  
 B is hydrogen, methyl, ethyl, n-propyl, n-butyl, halogenated C 1-6 -alkyl, C 1-6 -acyl or C 1-6 -alkoxycarbonyl;  
 as well as pharmaceutically acceptable salts, hydrates and solvates thereof.  
 
   
   
       14 . A compound according to  claim 13 , wherein 
 T is 4-bromo-5-chloro-2-thienyl    A is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, vinyl or 3-(ethyl 3-methylbutanoate);    B is selected from hydrogen, methyl, ethyl, n-propyl, n-butyl, 2,2,2-trichloroethyl, acetyl and carbethoxy.    
   
   
       15 . A compound of  claim 13  that is 
 N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-bromo-5-chloro-2-thienylsulfonamide,    
   
   
       16 . A process for the preparation of a compound according to  claim 13  comprising at least one of the following steps: 
 a) sulfonamide coupling by reacting a 2-aminothiazole with a sulfonylchloride in the presence of a base,    b) sulfonamide coupling by reacting a 2-aminothiazole derivative with a sulfonylchloride in the presence of a base,    c) saponification by treatment of a carboxylic acid ester with aqueous hydroxide,    d) amide coupling by reacting a carboxylic acid with an amine in the presence of EDCI,    e) formation of a thiazole ring by reacting an optionally substituted thiourea with an α-haloketone,    f) formation of a thiazole ring by reacting a thiourea with a ketone,    g) reduction of an ester with lithium aluminium hydride,    h) conversion of an alcohol to a bromide with triphenylphosphine and carbon tetrabromide,    i) elimination of a bromide with a base to an alkene.    
   
   
       17 . A method for the treatment or prevention of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, cognitive impairment, depression, virus diseases and inflammatory disorders and to achieve immuno-modulation, said method comprising administering to a mammal, including man, in need of such treatment an effective amount of a compound of the formula (I)  
     
       
         
         
             
             
         
       
     
     wherein 
 T is an aryl ring or heteroaryl ring, optionally independently substituted by [R] n , wherein n is an integer 0-5, and R is hydrogen, C 1-6 -alkyl, halogen, aryl or aryloxy, wherein the aryloxy residue can further be optionally substituted in one or more positions independently of each other by cyano and halogen;  
 A is C 1-6 -alkyl, vinyl or 3-(ethyl 3-methylbutanoate);  
 B is hydrogen, halogen, C 1-6 -alkyl, halogenated C 1-6 -alkyl, C 1-6 -acyl or C 1-6 -alkoxycarbonyl;  
 as well as pharmaceutically acceptable salts, hydrates and solvates thereof.  
 
   
   
       18 . A method according to  claim 17 , wherein the immuno-modulation is achieved by the treatment or prevention of tuberculosis, lepra and psoriasis.  
   
   
       19 . A method according to  claim 17 , wherein 
 T is selected from 4-bromo-5-chloro-2-thienyl and phenyl substituted with one or more of bromo, chloro, 3-chloro-2-cyanophenoxy, fluoro, methyl, phenyl, n-propyl;    A is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, vinyl or 3-(ethyl 3-methylbutanoate);    B is selected from hydrogen, bromo, methyl, ethyl, n-propyl, n-butyl, 2,2,2-trichloroethyl, acetyl and carbethoxy.    
   
   
       20 . A method according to  claim 17 , wherein the compound is selected from: 
 4-chloro-N-(4-methyl-1,3-thiazol-2-yl)benzenesulfonamide,    N-(4-methyl-1,3-thiazol-2-yl)benzenesulfonamide,    3-chloro-2-methyl-N-(4-methyl-1,3-thiazol-2-yl)benzenesulfonamide,    4-chloro-N-[4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-yl]benzenesulfonamide,    3-chloro-2-methyl-N-[4-methyl-5-(2,2,2-trichloroethyl)-1,3-thiazol-2-yl]benzenesulfonamide,    N-[4-methyl-5-(2,2,2-trichloroethyl )-1,3-thiazol-2-yl]-2,4,6-trichlorobenzene sulfonamide,    3-chloro-N-(5-ethyl-4-methyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide,    3-chloro-2-methyl-N-(4-methyl-5-propyl-1,3-thiazol-2-yl)benzenesulfonamide,    3-chloro-N-(4-ethyl-1,3-thiazol-2-yl )-2-methylbenzenesulfonamide,    3-chloro-N-(4-ethyl-5-methyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide,    3-chloro-2-methyl-N-(4-propyl-1,3-thiazol-2-yl)benzenesulfonamide,    3-chloro-N-(4-isopropyl-1,3-thiazol-2-yl)-2-methylbenzenesulfonamide,    N-(4-butyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide,    N-(5-butyl-4-methyl-1,3-thiazol-2-yl)-2,4-dichloro-6-methylbenzenesulfonamide,    N-(4-tert-butyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide,    ethyl 3-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl )-3-methylbutanoate,    2,4-dichloro-6-methyl-N-(4-pentyl-1,3-thiazol-2-yl)benzenesulfonamide,    3-chloro-2-methyl-N-(4-vinyl-1,3-thiazol-2-yl)benzenesulfonamide,    N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-chlorobenzenesulfonamide,    N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzenesulfonamide,    N-(5-acetyl-4-methyl-1,3-thiazol-2-yl) [1,1′-biphenyl]-4-sulfonamide,    N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-(3-chloro-2-cyanophenoxy)benzene sulfonamide,    N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-2,4,5-trichlorobenzenesulfonamide,    N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-bromo-5-chloro-2-thienylsulfonamide,    N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-4-bromo-2,5-difluoro-2-benzenesulfonamide,    N-(5-acetyl-4-methyl-1,3 -thiazol-2-yl)-2,6-dichlorobenzenesulfonamide,    N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)-3-chloro-2-methylbenzene sulfonamide,    N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)[1,1′-biphenyl]-4-sulfonamide,    N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl )-4-propylbenzenesulfonamide,    N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)-2,4-dichloro-6-methylbenzene sulfonamide,    N-(5-carbethoxy-4-methyl-1,3-thiazol-2-yl)-2,4,6-trichlorobenzenesulfonamide,    N-[5-bromo-4-(tert-butyl )-1,3-thiazol-2-yl]-4-chlorobenzenesulfonamide.    
   
   
       21 . A pharmaceutical composition comprising at least one compound of the formula (I) as defined in  claim 13 , and a pharmaceutically acceptable carrier.