Methods of Making and Using Therapeutically Active Thiophenepyrimidinone Compounds

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 method of preparing a compound corresponding to formula (I) 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  and R 2  represent the same or different alkyl, or one is 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 optionally contains up to two heteroatoms in addition to the nitrogen atom where R 1  is attached, the number of N atoms being 0-2 and the number of O or S atoms each being 0-1, 
 wherein said ring is optionally substituted with up to three 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; 
 R 3  and R 4  form together with their binding sites a cyclic 5-, 6-, 7- or 8-membered hydrocarbon ring system, which is saturated or contains one or more double bonds between the carbon atoms, and 
 wherein said ring is optionally substituted with up to three 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; 
 
     or a physiologically acceptable salt thereof; 
     said method comprising:
 a) oxidizing a compound of formula 2 
 
     
       
         
         
             
             
         
       
       
         or a ring-substituted or ring-modified analogue thereof to give an oxo-substituted compound of formula 3 or an analogue thereof, 
       
     
     
       
         
         
             
             
         
       
       b) optionally further subjecting the oxo-substituted compound obtained in a) to a Vilsmeier reaction to give a carbonylsubstituted compound of formula 4 or an analogue thereof, 
     
     
       
         
         
             
             
         
       
       c) optionally replacing the chlorosubstituent in the carbonylsubstituted compound obtained in b) by an alkylthio or an arylthio group by subjecting to an appropriate thiol in the presence of a base to give an arylthio- or alkylthiosubstituted compound of formula 5 or an analogue thereof, 
     
     
       
         
         
             
             
         
       
       d) the arylthio- or alkylthiosubstituted compound obtained in c) is optionally further
 i) reduced to a compound of formula 6, 
 
     
     
       
         
         
             
             
         
       
       
         ii) reacted with NH2OH to give a compound of formula 7, 
       
     
     
       
         
         
             
             
         
       
     
     Or
 e) the compound obtained in b) is optionally further
 i) reduced so as to replace the carbonyl group with hydroxyalkyl, or 
 ii) subjected to an appropriate thiol in the presence of a base and acetone, so as to replace the chloro substituent by a thiol group and to replace the carbonyl group with an oxosubstituted alkenyl. 
 
 
     or
 f) optionally subjecting the compound obtained in a) to DMF acetal so as to introduce a dimethylaminomethylene substituent in the ring next to the oxo substituent. 
 
   
   
       2 . A method according to  claim 1 , wherein the oxidation in step a) is effected by subjecting the compound to PCC and celite. 
   
   
       3 . A method according to  claim 1 , wherein in b) the Vilsmeier reaction is effected by POCl 3 -DMF. 
   
   
       4 . A method of treating or inhibiting a steroid hormone dependent disease or disorder, said method comprising administering to a patient in need thereof an effective amount of a compound corresponding to formula (I) 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  and R 2  represent the same or different alkyl, or one is alkyl and the other is H; 
 R 3  and R 4  form together with their binding sites a cyclic 5-, 6-, 7- or 8-membered hydrocarbon ring system, which is saturated or contains one or more double bonds between the carbon atoms, and 
 wherein said ring is optionally substituted with up to three 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; 
 
     or a physiologically acceptable salt thereof. 
   
   
       5 . A method according to  claim 4 , wherein said steroid hormone dependent disease or disorder is a steroid hormone dependent disease or disorder requiring the inhibition of a 17β-hydroxysteroid dehydrogenase enzyme. 
   
   
       6 . A method according to  claim 5 , wherein said steroid hormone dependent disease or disorder is a steroid hormone dependent disease or disorder requiring the inhibition of the 17β-hydroxysteroid dehydrogenase type 1, 17β-hydroxysteroid dehydrogenase type 2 or 17β-hydroxysteroid dehydrogenase type 3 enzyme. 
   
   
       7 . A method according to  claim 4 , wherein said compound corresponds 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; 
 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. 
 
   
   
       8 . A method according to  claim 1 , wherein the steroid hormone dependent disease or disorder is selected from the group consisting of breast cancer, prostate carcinoma, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyperplasia, endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia, prostadynia, benign prostatic hyperplasia, prostatitis, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, polycystic ovarian syndrome, urinary dysfunction, osteoporosis, multiple sclerosis, rheumatoid arthritis, Alzheimer's disease, colon cancer, tissue wounds, skin wrinkles and cataracts.