Pharmaceutical use of fused 1,2,4-triazoles

Abstract

Methods of using fused 1,2,4-triazoles for modulating the activity of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) are described. The present compounds are modulators and more specifically inhibitors of the activity of 11βHSD1 and may be useful in the treatment, prevention and/or prophylaxis of a range of medical disorders where a decreased intracellular concentration of active glucocorticoid is desirable, including type 2 diabetes and metabolic syndrome.

1 . A method of treating type 2 diabetes in a human comprising administering to a human a fused 1,2,4-triazole of general formula (I), or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms: 
     
       
         
         
             
             
         
       
       wherein 
       R 1  is C 5 -C 10 cycloalkyl, C 5 -C 10 hetcycloalkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl, wherein the cycloalkyl, hetcycloalkyl, aryl, hetaryl and arylalkyl groups independently are optionally substituted with one or more of R 7 ; 
       R 2  and R 3  independently are hydrogen, C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl, hetarylC 1 -C 6 -alkyl, aryloxy, hetaryloxy, arylC 1 -C 6 alkyloxy or hetarylC 1 -C 6 alkyloxy wherein the alkyl, aryl, hetaryl, arylalkyl and hetarylalkyl groups independently are optionally substituted with one or more of R 8 ; or 
       R 2  and R 3  together with the carbon atom to which they are attached, are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl, hetarylC 1 -C 6 alkyl, hydroxy, oxo, C 1 -C 6 alkyloxy, aryloxy, arylC 1 -C 6 alkyloxy or hetarylC 1 -C 6 alkyloxy; 
       R 4  and R 5  independently are hydrogen, halo, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyloxy, aryl, hetaryl, aryloxyC 1 -C 6 alkyl, aryloxyaryl, hetaryloxyaryl, aryloxyhetaryl, hetaryloxyhetaryl or arylC 1 -C 6 alkyloxyC 1 -C 6 alkyl wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 9 ; or 
       R 4  and R 5  together with the carbon atoms to which they are attached, are forming a saturated or partially saturated ring system containing from 5 to 8 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C 1 -C 6 alkyl, aryl, arylC 1 -C 6 alkyl, NR 10 R 11 , halo, trihalomethyl, trihalomethoxy, hydroxy, oxo, C 1 -C 6 alkyloxy, arylC 1 -C 6 alkyloxy, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, arylcarbonyl, arylC 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarboxy, arylcarboxy or arylC 1 -C 6 alkylcarboxy; or 
       R 4  and either R 2  or R 3  together are forming a saturated or partially saturated bridge containing from 1 to 4 carbon atoms, the bridge can optionally be substituted with at least one of C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl; 
       R 6  is hydrogen, C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl; or 
       R 6  and either R 4  or R 5  together with the carbon atoms to which they are attached, are forming a saturated, partially saturated or aromatic ring system containing from 5 to 8 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C 1 -C 6 alkyl, aryl, arylC 1 -C 6 alkyl, NR 10 R 11 , halo, trihalomethyl, trihalomethoxy, hydroxy, oxo, C 1 -C 6 alkyloxy, arylC 1 -C 6 alkyloxy, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, arylcarbonyl, arylC 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarboxy, arylcarboxy or arylC 1 -C 6 alkylcarboxy; 
       R 7  and R 8  independently are hydrogen, halo, hydroxy, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, trihalomethyl, trihalomethoxy, aryloxy, hetaryloxy, arylC 1 -C 6 alkyloxy, hetarylC 1 -C 6 alkyloxy, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, aryloxyC 1 -C 6 alkyl, arylC 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC 1 -C 6 alkylcarbonyl, hetarylC 1 -C 6 alkylcarbonyl, C 1 -C 6 alkyl-carboxy, arylcarboxy, hetarylcarboxy, arylC 1 -C 6 alkylcarboxy or hetarylC 1 -C 6 alkylcarboxy; 
       R 9  is hydrogen, halo, hydroxy, cyano, C 1 -C 6 alkyl, methylendioxo, trihalomethyl, trihalomethoxy, aryl, arylC 1 -C 6 alkyl, aryloxy, NR 10 R 11  or aryloxyC 1 -C 6 alkyl, wherein the aryl group is optionally substituted with one or more of R 12 ; 
       R 10  and R 11  independently are hydrogen, C 1 -C 6 alkyl, aryl or arylC 1 -C 6 alkyl wherein the alkyl and aryl groups independently are optionally substituted with one or more of R 13 ; or 
       R 10  and R 11  together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one of C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl, hydroxy, oxo, C 1 -C 6 alkyloxy, arylC 1 -C 6 alkyloxy, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, arylcarbonyl, arylC 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarboxy, arylcarboxy or arylC 1 -C 6 alkyl-carboxy; 
       R 12  is oxo or halo; 
       R 13  is halo, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, NR 14 R 15 , methylendioxo, trihalomethyl, or trihalomethoxy; 
       R 14  and R 15  independently are hydrogen, C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 -alkyl; 
       A is a single, double, triple or aromatic bond; 
       X is a chemical bond, (CR 16 R 17 ) n  or NR 10 , wherein R 16  and R 17  independently are hydrogen, oxo or C 1 -C 6 alkyl, or 
       X, together with either R 2  or R 3 , is a double bond; 
       Y is CR 18  or nitrogen, wherein R 18  is hydrogen, C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl; or 
       R 18  and either R 2  or R 3  together are forming a saturated or partially saturated cyclic ring system containing from 1 to 4 carbon atoms, the ring system can optionally be substituted with at least one of C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl; or 
       R 18  with either R 2  or R 3  and either R 4  or R 5  together are forming a saturated or partially saturated cyclic ring system having one common carbon atom containing from 8 to 12 carbon atoms, the ring system can optionally be substituted with at least one of C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl; and 
       n is 0, 1 or 2. 
     
   
   
       2 . The method according to  claim 1 , wherein R 1  is C 5 -C 10 cycloalkyl, C 5 -C 10 hetcycloalkyl, aryl, hetaryl, or arylC 1 -C 6 alkyl, wherein the cycloalkyl, hetcycloalkyl, aryl, hetaryl and arylalkyl groups independently are optionally substituted with one or more of R 7 . 
   
   
       3 . The method according to  claim 1 , wherein R 1  is C 5 -C 10 hetcycloalkyl or aryl, wherein the cycloalkyl, hetcycloalkyl and aryl groups independently are optionally substituted with one or more of R 7 . 
   
   
       4 . The method according to  claim 1 , wherein in R 2  and R 3  independently are hydrogen or C 1 -C 6 alkyl. 
   
   
       5 . The method according to  claim 1 , wherein R 2  and R 3  together with the carbon atom to which they are attached, are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl, hetarylC 1 -C 6 alkyl, hydroxy, oxo, C 1 -C 6 alkyloxy, aryloxy, arylC 1 -C 6 alkyloxy or hetarylC 1 -C 6 alkyloxy. 
   
   
       6 . The method according to  claim 1 , wherein in R 4  and R 5  independently are hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, or aryloxyC 1 -C 6 alkyl, wherein the alkyl and aryl groups independently are optionally substituted with one or more of R 9 . 
   
   
       7 . The method according to  claim 1 , wherein R 4  and R 5  together with the carbon atoms to which they are attached, are forming a saturated or partially saturated ring system containing from 5 to 8 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of C 1 -C 6 alkyl. 
   
   
       8 . The method according to  claim 1  wherein R 4  and either R 2  or R 3  together are forming a saturated or partially saturated bridge containing from 1 to 4 carbon atoms, the bridge can optionally be substituted with at least one of C 1 -C 6 alkyl or arylC 1 -C 6 alkyl. 
   
   
       9 . The method according to  claim 1 , wherein R 6  is hydrogen or C 1 -C 6 alkyl. 
   
   
       10 . The method according to  claim 1 , wherein R 6  and either R 4  or R 5  together with the carbon atoms to which they are attached, are forming a saturated, partially saturated or aromatic ring system containing from 5 to 8 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen or sulphur, the ring system optionally being substituted with at least one of C 1 -C 6 alkyl, halo, trihalomethyl, C 1 -C 6 alkyloxy or arylC 1 -C 6 alkyloxy. 
   
   
       11 . The method according to  claim 1 , wherein in R 7  and R 8  independently are hydrogen, halo, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, trihalomethyl, trihalomethoxy, aryloxy, hetaryloxy, arylC 1 -C 6 alkyloxy, hetarylC 1 -C 6 alkyloxy, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, aryloxyC 1 -C 6 alkyl or arylC 1 -C 6 alkyloxyC 1 -C 6 alkyl. 
   
   
       12 . The method according to  claim 1 , wherein R 9  is hydrogen. 
   
   
       13 . The method according to  claim 1 , wherein A is a double or aromatic bond; X is (CR 16 R 17 ) n , wherein R 16  and R 17  independently are hydrogen or C 1 -C 6 alkyl and n is 1;
 Y is CR 18  wherein R 18  is hydrogen, C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl;   R 6  and either R 4  or R 5  together with the carbon atoms to which they are attached, are forming an aromatic ring system containing 6 carbon atoms, the ring system optionally being substituted with at least one of C 1 -C 6 alkyl, aryl, arylC 1 -C 6 alkyl, NR 10 R 11 , halo, trihalomethyl, trihalomethoxy, hydroxy, oxo, C 1 -C 6 alkyloxy, arylC 1 -C 6 alkyloxy, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, arylcarbonyl, arylC 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarboxy, arylcarboxy or arylC 1 -C 6 alkylcarboxy.   
   
   
       14 . The method according to  claim 1 , wherein said fused 1,2,4-triazole of general formula (I) is selected from the group consisting of:
 3-(2-Bromo-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine;   3-Phenyl-[1,2,4]triazolo[3,4-a]isoquinoline;   (2-Methoxy-benzyl)-(3-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-amine;   3-(2-Fluoro-phenyl)-5-(4-methoxy-phenoxy)-[1,2,4]triazolo[4,3-c]quinazoline;   3-Phenyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine;   3-(4-Chloro-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine;   3-(3-Chloro-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine;   3-(3,4-Dichloro-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine;   5,5-Dimethyl-3-thiophen-2-yl-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinoline;   3-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine;   5,5-Dimethyl-3-(3,4,5-trimethoxy-phenyl)-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinoline;   3-Furan-2-yl-5,5-dimethyl-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinoline;   3-(3-Bromo-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine;   3-(4-Bromo-phenyl)-5,5-dimethyl-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinoline;   4-(5,5-Dimethyl-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-phenol;   3-(4-Methoxy-phenyl)-5,5,8,9-tetramethyl-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinoline;   5,5-Dimethyl-3-phenyl-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinoline;   3-(5,5-Dimethyl-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-phenol;   5,5-Dimethyl-3-p-tolyl-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinoline;   5,5-Dimethyl-3-thiophen-2-yl-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinoline;   7,10-Dimethoxy-5,5-dimethyl-3-phenyl-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinoline;   3-(2,4-Dichloro-phenyl)-6,6-dimethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine;   2-(6,6-Dimethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-3-yl)-phenol;   3-(2-Chloro-phenyl)-6,6-dimethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine;   4-Benzyl-3,5-di-p-tolyl-4H-[1,2,4]triazole;   3-p-Tolyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine;   3-(4-Methoxy-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine;   3-Pyridin-4-yl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine;   3-(4-Bromo-phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine;   3-Furan-2-yl-5,5,8,9-tetramethyl-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinoline;   6,6-Dimethyl-3-(2-nitro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine; and   3-(2,4-Dichloro-phenyl)-5,5-dimethyl-5,6-dihydro-[1,2,4]triazolo[3,4-a]isoquinoline.   
   
   
       15 . A method of treating metabolic syndrome in a human comprising administering to a human a fused 1,2,4-triazole of general formula (I), or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms: 
     
       
         
         
             
             
         
       
       wherein 
       R 1  is C 5 -C 10 cycloalkyl, C 5 -C 10 hetcycloalkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl, wherein the cycloalkyl, hetcycloalkyl, aryl, hetaryl and arylalkyl groups independently are optionally substituted with one or more of R 7 ; 
       R 2  and R 3  independently are hydrogen, C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl, hetarylC 1 -C 6 -alkyl, aryloxy, hetaryloxy, arylC 1 -C 6 alkyloxy or hetarylC 1 -C 6 alkyloxy wherein the alkyl, aryl, hetaryl, arylalkyl and hetarylalkyl groups independently are optionally substituted with one or more of R 8 ; or 
       R 2  and R 3  together with the carbon atom to which they are attached, are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl, hetarylC 1 -C 6 alkyl, hydroxy, oxo, C 1 -C 6 alkyloxy, aryloxy, arylC 1 -C 6 alkyloxy or hetarylC 1 -C 6 alkyloxy; 
       R 4  and R 5  independently are hydrogen, halo, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyloxy, aryl, hetaryl, aryloxyC 1 -C 6 alkyl, aryloxyaryl, hetaryloxyaryl, aryloxyhetaryl, hetaryloxyhetaryl or arylC 1 -C 6 alkyloxyC 1 -C 6 alkyl wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 9 ; or 
       R 4  and R 5  together with the carbon atoms to which they are attached, are forming a saturated or partially saturated ring system containing from 5 to 8 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C 1 -C 6 alkyl, aryl, arylC 1 -C 6 alkyl, NR 10 R 11 , halo, trihalomethyl, trihalomethoxy, hydroxy, oxo, C 1 -C 6 alkyloxy, arylC 1 -C 6 alkyloxy, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, arylcarbonyl, arylC 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarboxy, arylcarboxy or arylC 1 -C 6 alkylcarboxy; or 
       R 4  and either R 2  or R 3  together are forming a saturated or partially saturated bridge containing from 1 to 4 carbon atoms, the bridge can optionally be substituted with at least one of C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl; 
       R 6  is hydrogen, C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl; or 
       R 6  and either R 4  or R 5  together with the carbon atoms to which they are attached, are forming a saturated, partially saturated or aromatic ring system containing from 5 to 8 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C 1 -C 6 alkyl, aryl, arylC 1 -C 6 alkyl, NR 10 R 11 , halo, trihalomethyl, trihalomethoxy, hydroxy, oxo, C 1 -C 6 alkyloxy, arylC 1 -C 6 alkyloxy, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, arylcarbonyl, arylC 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarboxy, arylcarboxy or arylC 1 -C 6 alkylcarboxy; 
       R 7  and R 8  independently are hydrogen, halo, hydroxy, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, trihalomethyl, trihalomethoxy, aryloxy, hetaryloxy, arylC 1 -C 6 alkyloxy, hetarylC 1 -C 6 alkyloxy, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, aryloxyC 1 -C 6 alkyl, arylC 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC 1 -C 6 alkylcarbonyl, hetarylC 1 -C 6 alkylcarbonyl, C 1 -C 6 alkyl-carboxy, arylcarboxy, hetarylcarboxy, arylC 1 -C 6 alkylcarboxy or hetarylC 1 -C 6 alkylcarboxy; 
       R 9  is hydrogen, halo, hydroxy, cyano, C 1 -C 6 alkyl, methylendioxo, trihalomethyl, trihalomethoxy, aryl, arylC 1 -C 6 alkyl, aryloxy, NR 10 R 11  or aryloxyC 1 -C 6 alkyl, wherein the aryl group is optionally substituted with one or more of R 12 ; 
       R 10  and R 11  independently are hydrogen, C 1 -C 6 alkyl, aryl or arylC 1 -C 6 alkyl wherein the alkyl and aryl groups independently are optionally substituted with one or more of R 13 ; or 
       R 10  and R 11  together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one of C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl, hydroxy, oxo, C 1 -C 6 alkyloxy, arylC 1 -C 6 alkyloxy, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, arylcarbonyl, arylC 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarboxy, arylcarboxy or arylC 1 -C 6 alkyl-carboxy; 
       R 12  is oxo or halo; 
       R 13  is halo, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, NR 14 R 15 , methylendioxo, trihalomethyl, or trihalomethoxy; 
       R 14  and R 15  independently are hydrogen, C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 -alkyl; 
       A is a single, double, triple or aromatic bond; 
       X is a chemical bond, (CR 16 R 17 ) n  or NR 10 , wherein R 16  and R 17  independently are hydrogen, oxo or C 1 -C 6 alkyl, or 
       X, together with either R 2  or R 3 , is a double bond; 
       Y is CR 18  or nitrogen, wherein R 18  is hydrogen, C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl; or 
       R 18  and either R 2  or R 3  together are forming a saturated or partially saturated cyclic ring system containing from 1 to 4 carbon atoms, the ring system can optionally be substituted with at least one of C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl; or 
       R 18  with either R 2  or R 3  and either R 4  or R 5  together are forming a saturated or partially saturated cyclic ring system having one common carbon atom containing from 8 to 12 carbon atoms, the ring system can optionally be substituted with at least one of C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl; and 
       n is 0, 1 or 2. 
     
   
   
       16 . A method of modulating intracellular levels of glucocorticoid in a human comprising administering to a human a fused 1,2,4-triazole of general formula (I), or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms: 
     
       
         
         
             
             
         
       
       wherein 
       R 1  is C 5 -C 10 cycloalkyl, C 5 -C 10 hetcycloalkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl, wherein the cycloalkyl, hetcycloalkyl, aryl, hetaryl and arylalkyl groups independently are optionally substituted with one or more of R 7 ; 
       R 2  and R 3  independently are hydrogen, C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl, hetarylC 1 -C 6 -alkyl, aryloxy, hetaryloxy, arylC 1 -C 6 alkyloxy or hetarylC 1 -C 6 alkyloxy wherein the alkyl, aryl, hetaryl, arylalkyl and hetarylalkyl groups independently are optionally substituted with one or more of R 8 ; or 
       R 2  and R 3  together with the carbon atom to which they are attached, are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl, hetarylC 1 -C 6 alkyl, hydroxy, oxo, C 1 -C 6 alkyloxy, aryloxy, arylC 1 -C 6 alkyloxy or hetarylC 1 -C 6 alkyloxy; 
       R 4  and R 5  independently are hydrogen, halo, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyloxy, aryl, hetaryl, aryloxyC 1 -C 6 alkyl, aryloxyaryl, hetaryloxyaryl, aryloxyhetaryl, hetaryloxyhetaryl or arylC 1 -C 6 alkyloxyC 1 -C 6 alkyl wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 9 ; or 
       R 4  and R 5  together with the carbon atoms to which they are attached, are forming a saturated or partially saturated ring system containing from 5 to 8 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C 1 -C 6 alkyl, aryl, arylC 1 -C 6 alkyl, NR 10 R 11 , halo, trihalomethyl, trihalomethoxy, hydroxy, oxo, C 1 -C 6 alkyloxy, arylC 1 -C 6 alkyloxy, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, arylcarbonyl, arylC 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarboxy, arylcarboxy or arylC 1 -C 6 alkylcarboxy; or 
       R 4  and either R 2  or R 3  together are forming a saturated or partially saturated bridge containing from 1 to 4 carbon atoms, the bridge can optionally be substituted with at least one of C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl; 
       R 6  is hydrogen, C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl; or 
       R 6  and either R 4  or R 5  together with the carbon atoms to which they are attached, are forming a saturated, partially saturated or aromatic ring system containing from 5 to 8 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C 1 -C 6 alkyl, aryl, arylC 1 -C 6 alkyl, NR 10 R 11 , halo, trihalomethyl, trihalomethoxy, hydroxy, oxo, C 1 -C 6 alkyloxy, arylC 1 -C 6 alkyloxy, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, arylcarbonyl, arylC 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarboxy, arylcarboxy or arylC 1 -C 6 alkylcarboxy; 
       R 7  and R 8  independently are hydrogen, halo, hydroxy, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, trihalomethyl, trihalomethoxy, aryloxy, hetaryloxy, arylC 1 -C 6 alkyloxy, hetarylC 1 -C 6 alkyloxy, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, aryloxyC 1 -C 6 alkyl, arylC 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC 1 -C 6 alkylcarbonyl, hetarylC 1 -C 6 alkylcarbonyl, C 1 -C 6 alkyl-carboxy, arylcarboxy, hetarylcarboxy, arylC 1 -C 6 alkylcarboxy or hetarylC 1 -C 6 alkylcarboxy; 
       R 9  is hydrogen, halo, hydroxy, cyano, C 1 -C 6 alkyl, methylendioxo, trihalomethyl, trihalomethoxy, aryl, arylC 1 -C 6 alkyl, aryloxy, NR 10 R 11  or aryloxyC 1 -C 6 alkyl, wherein the aryl group is optionally substituted with one or more of R 12 ; 
       R 10  and R 11  independently are hydrogen, C 1 -C 6 alkyl, aryl or arylC 1 -C 6 alkyl wherein the alkyl and aryl groups independently are optionally substituted with one or more of R 13 ; or 
       R 10  and R 11  together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one of C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl, hydroxy, oxo, C 1 -C 6 alkyloxy, arylC 1 -C 6 alkyloxy, C 1 -C 6 alkyloxyC 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, arylcarbonyl, arylC 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarboxy, arylcarboxy or arylC 1 -C 6 alkyl-carboxy; 
       R 12  is oxo or halo; 
       R 13  is halo, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, NR 14 R 15 , methylendioxo, trihalomethyl, or trihalomethoxy; 
       R 14  and R 15  independently are hydrogen, C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 -alkyl; 
       A is a single, double, triple or aromatic bond; 
       X is a chemical bond, (CR 16 R 17 ) n  or NR 10 , wherein R 16  and R 17  independently are hydrogen, oxo or C 1 -C 6 alkyl, or 
       X, together with either R 2  or R 3 , is a double bond; 
       Y is CR 18  or nitrogen, wherein R 18  is hydrogen, C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl; or 
       R 18  and either R 2  or R 3  together are forming a saturated or partially saturated cyclic ring system containing from 1 to 4 carbon atoms, the ring system can optionally be substituted with at least one of C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl; or 
       R 18  with either R 2  or R 3  and either R 4  or R 5  together are forming a saturated or partially saturated cyclic ring system having one common carbon atom containing from 8 to 12 carbon atoms, the ring system can optionally be substituted with at least one of C 1 -C 6 alkyl, aryl, hetaryl, arylC 1 -C 6 alkyl or hetarylC 1 -C 6 alkyl; and n is 0, 1 or 2.