Therapeutically Active Thiophenepyrimidinone Compounds and Their Use

Abstract

Thiopheneprymidinone compounds useful in therapy, especially for use in the treatment and/or prevention of a steroid hormone dependent disorder, preferably a steroid hormone dependent disease or disorder requiring the inhibition of a 17β-hydroxysteroid dehydrogenase (17β-HSD) such as 17β-HSD type 1, type 2 or type 3 enzyme.

1 . A compound corresponding to formula (II)  
       
         
           
           
               
               
           
         
         wherein  
         R 1  and R 2  represent the same or different C 1 -C 8 -alkyl, or one is C 1 -C 8 -alkyl and the other is H, or  
         R 1  and R 2  form together with their binding sites a cyclic 5-, 6-, 7- or 8-membered ring system, which is saturated or contains one or more double bonds between the ring atoms, and which ring contains zero, one or two N-atoms in addition to the nitrogen atom where R 1  is attached,  
         wherein said ring is optionally substituted with up to two substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl, or arylalkyl, wherein the aryl group is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxime, acyl, carboxyl, thiocarboxyl, and amido;  
         the hydrocarbon chain —C(R5)-C(R6)-(CH) n — of the ring-system adjacent the thiophene-ring is saturated or contains one or more double bonds between the carbon atoms;  
         n is an integer from 1 to 4, and  
         R5 and R6 are individually selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl or arylalkyl, wherein the aryl group is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxime, acyl, carboxyl, thiocarboxyl, and amido;  
         or a physiologically acceptable salt thereof;  
         wherein  
         if n represents 1, 2 or 3, and R1 and R2 independently are selected from hydrogen or C 1 -C 4  alkyl or together form an unsubstituted alkylene group of 3-5 methylene groups or a iminoalkylene group of 2-4 methylene groups in the alkylene group, optionally substituted at the N-atom, then at least 
 (i) one of R5 or R6 is different from hydrogen, C 1 -C 4  alkyl or alkylcarboxyl, or  
 (ii) the hydrocarbon chain —C(R5)-C(R6)-(CH) n — of the ring-system adjacent the thiophene-ring is unsaturated or aromatic;  
 
         if n represents 2, and R1—R2 form an unsubstituted alkylene group of 3-5 methylene groups, and R5 represents a hydroxyl or oxo group, then R6 is different from bromo, di-bromo or phenylthio; and  
         if n represents 2, R1—R2 form an unsubstituted pentamethylene group and R6 represents carbonyl, then R5 is different from phenylthio.  
       
     
     
         2 . A compound corresponding to formula (II)  
       
         
           
           
               
               
           
         
         wherein  
         R 1  and R 2  represent the same or different C 1 -C 8 -alkyl, or one is C 1 -C 8 -alkyl and the other is H, or  
         R 1  and R 2  together with their binding sites form a cyclic 5-, 6-, 7- or 8-membered ring system, which is saturated or contains one or more double bonds between the ring atoms, and which ring contains zero, one or two N-atoms in addition to the nitrogen atom where R 1  is attached,  
         wherein said ring is optionally substituted with up to two substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl, or arylalkyl, wherein the aryl group is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxime, acyl, carboxyl, thiocarboxyl, and amido;  
         the hydrocarbon chain —C(R5)-C(R6)-(CH) n — of the ring-system adjacent the thiophene-ring is saturated or contains one or more double bonds between the carbon atoms;  
         n is an integer from 1 to 4, and  
         R5 and R6 are individually selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl or arylalkyl, wherein the aryl group is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxime, acyl, carboxyl, thiocarboxyl, and amido;  
         wherein  
         if n represents 1, 2 or 3, and R1 and R2 are independently selected from hydrogen or C 1 -C 4  alkyl or together form an unsubstituted alkylene group of 3-5 methylene groups or a iminoalkylene group with 2-4 methylene groups in the alkylene group, optionally substituted at the N-atom, then at least 
 (i) one of R5 and or R6 is different from hydrogen, C 1 -C 4  alkyl, alkylcarboxyl, and ═N—OH, or  
 (ii) the hydrocarbon chain —C(R5)-C(R6)-(CH) n — of the ring-system adjacent the thio-phene-ring is unsaturated or aromatic;  
 
         if n represents 2, R1—R2 form an unsubstituted alkylene group of 3 or 5 methylene groups and R5 represents a hydroxyl or oxo group, then R6 is different from hydrogen, bromo, dibromo or phenylthio;  
         if n represents 2, R1—R2 form an unsubstituted pentamethylene group and R6 represents carbonyl, then R5 is different from phenylthio or chloro;  
         if n represents 2, the hydrocarbon chain —C(R5)-C(R6)-(CH) n — of the ring-system adjacent the thiophene-ring is saturated and R1—R2 together with their binding sites form an un-substituted pyridine-ring, then at least one of R5 or R6 is different from hydrogen; and  
         if —C(R5)-C(R6)-(CH) n — represents an unsubstituted tetramethylene group, then R1—R2 is different from a tetramethylene group substituted with a carboxylethylester group.  
       
     
     
         3 . A compound according to  claim 2 , wherein R 1  and R 2  together form a cyclic 5-, 6-, 7- or 8-membered ring system substituted with zero, one or two substituents independently selected from the group consisting of oxo, —CO—R, —CO—O—R, —O—R, and —C 1 -C 4 -alkyl, optionally substituted with —O—R, —S—R or —N(R) 2 , wherein R represents hydrogen or C 1 -C 4 -alkyl.  
     
     
         4 . A compound according to  claim 2 , wherein R 1  and R 2  together with their binding sites form an optionally substituted cyclic 5-, 6-, 7- or 8-membered ring system, which is saturated or contains one or more double bonds between the ring atoms, and which ring contains zero, one or two N-atoms in addition to the nitrogen atom where R 1  is attached.  
     
     
         5 . A compound according to  claim 2 , wherein R 5  and R 6  are individually selected from the group consisting of hydrogen, oxo, halogen, —O—R′, —S—R′, —SO—R′, —CO—R, —CO—O—R, —C 1 -C 4 -alkyl, —C 1 -C 4 -alkenyl or ═C 1 -C 4 -alkylene, optionally substituted in the alkyl chain with —O—R, —S—R, —N(R) 2 , —CO—R, or ═N—O—R, wherein 
 R represents hydrogen or C 1 -C 4 -alkyl; and    R′ represents hydrogen, C 1 -C 8 -alkyl, which can be linear, cyclic or branched; aryl-C 1 -C 4 -alkyl, or aryl.    
     
     
         6 . A compound according to  claim 5 , wherein R′ represents benzyl or phenyl.  
     
     
         7 . A compound according to  claim 5 , wherein R5 is selected from the group consisting of hydrogen, oxo, halogen, —OH, —O—C 1 -C 4 -alkyl; —S—C 1 -C 4 -alkyl, —S—C 3 -C 8 -cycloalkyl, —S-phenyl, —SO-phenyl.  
     
     
         8 . A compound according to  claim 7 , wherein R6 is selected from the group consisting of hydrogen, carbonyl, alkylcarboxyl, —C 1 -C 4 -alkyl, —C 1 -C 4 -alkenyl or ═C 1 -C 4 -alkylene, option-ally substituted in the alkyl chain with —O—R, —N(R) 2 , —CO—R, or ═N—O—R, wherein R represents hydrogen or C 1 -C 4 -alkyl.  
     
     
         9 . A compound according to  claim 8 , wherein R6 is —CHO.  
     
     
         10 . A compound according to  claim 2 , selected from the group consisting of: 
 2,3,8,9,10,11-hexahydro[1]Benzothieno[2′,3′:4,5]pyrimido[1,2-a]azepine-4, 13(1H,7H)-dione;    1,2,6,7,8,9,10-heptahydrocyclopenta[4′,5′]thieno[2′,3′:4,5]pyrimido[1,2-a]-azepin-3,12-dione;    1,2,3,4,8,9,10,11,12-nonahydrocyclohepta[4′,5′]thieno[2′,3′:4,5]pyrimido-[1,2-a]azepine-5(5aH), 14-dione;    1,2,7,8,9,10,11,12-octahydro[1]benzothieno[2′,3′:4,5]pyrimido-[1,2-a]azocin-4, 14(3H)-dione;    1,2,3,4,7,8,9,10-octahydro-12H-[1]benzothieno[2,3-d]pyrido[1,2-a]pyrimidin-12-one;    5,6-dihydro-2,3-dimethyl[1]benzothieno[2,3-d]pyrimidin-4,8(3H,7H)-dione;    5,6-dihydro-3-methyl[1]benzothieno[2,3-d]pyrimidin-4,8(3H,7H)-dione;    5,6-dihydro-3-ethyl-2-methyl[1]benzothieno[2,3-d]pyrimidin-4,8(3H,7H)-dione;    4-chloro-1,2,3,7,8,9,10,11,12-octahydro[1]benzothieno[2′,3′:4,5]pyrimido-[1,2-a]-azocin-14-one-4-carboxyaldehyde;    1,2,3,4,5,8,9,10,11,12-decahydro-14H-cyclohepta[4′,5′]thieno[2′,3′:4,5]-pyrimido[1,2-a]azepin-14-one;    8-chloro-5,6-dihydro-3-methyl[1]benzothieno[2,3-d]pyrimidin-4(3H)-one-7-carboxyaldehyde;    1,2,7,8,9,10,11,13-octahydro-13-oxo-4-(ethylthio)[1]benzothieno[2′,3′:4,5]-pyrimido-[1,2-a]azepine-3-carboxaldehyde;    1,2,7,8,9,10,11,13-octahydro-13-oxo-4-(propylthio)[1]benzothieno[2′,3′:4,5]-pyrimido-[1,2-a]azepine-3-carboxaldehyde;    1,2,7,8,9,10,11,13-octahydro-13-oxo-4-(butylthio)[1]benzothieno[2′,3′:4,5]-pyrimido-[1,2-a]azepine-3-carboxaldehyde;    1,2,7,8,9,10,11,13-octahydro-13-oxo-4-(isopropylthio)[1]benzothieno[2′,3′:4,5]-pyrimido-[1,2-a]azepine-3-carboxaldehyde;    1,2,7,8,9,10,11,13-octahydro-13-oxo-4-(t-butylthio)[1]benzothieno[2′,3′:4,5]-pyrimido-[1,2-a]azepine-3-carboxaldehyde;    1,2,7,8,9,10,11,13-octahydro-13-oxo-4-(cyclopentylthio)[1]benzothieno[2′,3′:4,5]-pyrimido-[(1,2-a]azepine-3-carboxaldehyde;    1,2,7,8,9,10,11,13-octahydro-13-oxo-4-(cyclohexylthio)[1]benzothieno[2′,3′:4,5]-pyrimido-[1,2-a]azepine-3-carboxaldehyde;    1,2,7,8,9,10,11,13-octahydro-13-oxo-4-(phenylthio)[1]benzothieno[2′,3′:4,5]-pyrimido-[1,2-a]azepine-3-hydroxymethyl;    1,2,7,8,9,10,11,13-octahydro-13-oxo-4-(cyclohexylthio)[1]benzothieno-[2′,3′:4,5]pyrimido[1,2-a]azepine-3-hydroxymethyl;    octahydro-13-oxo-4-(phenylthio)[1]benzothieno[2′,3′:4,5]-pyrimido-[1,2-a]azepine-3-oxime-methyl;    4-chloro-1,2,7,8,9,10,11,13-octahydro-13-oxo[1]benzothieno[2′,3′:4,5]-pyrimido[1,2-a]azepine-3-hydroxymethyl;    3-N,N-dimethylamino-methylen-2,3,8,9,10,11-hexahydro[1]benzothieno[2′,3′:4,5]-pyrimido[1,2-a]azepine-4,13(1H,7H)-dione;    1,2,7,8,9,10,11,13-octahydro-13-oxo-4-(propylthio)[1]benzothieno[2′,3′:4,5]-pyrimido-[1,2-a]azepine-3-(3-oxo)but-1-ene;    1,2,7,8,9,10,11,13-octahydro-13-oxo-4-(butylthio)[1]benzothieno[2′,3′:4,5]-pyrimido-[1,2-a]azepine-3-(3-oxo)but-1-ene, and physiologically acceptable salts thereof.    
     
     
         11 . A pharmaceutical composition comprising at least one compound corresponding to formula (II) as defined in  claim 1 , and a pharmaceutically acceptable carrier or adjuvant.  
     
     
         12 . A pharmaceutical composition comprising at least one compound corresponding to formula (II) as defined in  claim 2 , and a pharmaceutically acceptable carrier or adjuvant.