Fused 1,2,4- thiadiazine derivatives, their preparation and use

Abstract

The present invention relates to 4H-thieno[3,2-e]-1,2,4-thiadiazine derivatives of the general formula: wherein X, Y, R 1 , R 2 and R 3 are defined in the description, compositions thereof and methods for preparing the compounds are described. The compounds are useful in the treatment of diseases of the central nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system.

1 . A compound of the general formula I:  
       
         
           
           
               
               
           
         
       
       wherein 
 X and Y independently are hydrogen, halogen, perhalomethyl, C 1-6 -alkyl or C 1-6 -alkoxy;  
 R 1 , R 2  and R 3  independently are C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, carboxy, C 1-6 -alkoxycarbonyl or aryl, all of which are optionally being mono- or polysubstituted with halogen, hydroxy, oxo, or aryl; or  
 R 1  is as defined above and R 2 —C—R 3  form a C 3-6 -cycloalkyl group, optionally being mono- or polysubstituted with C 1-6 -alkyl, perhalomethyl, halogen, hydroxy or aryl; or  
 —CR 1 R 2 R 3  form a 4- to 12-membered bicyclic or tricyclic carbocyclic system, optionally being mono- or polysubstituted with C 1-6 -alkyl, perhalomethyl, halogen, hydroxy or aryl; or  
 a salt thereof with a pharmaceutically acceptable acid or base including all optical isomers of compounds of formula I, some of which are optically active, and also their mixtures including racemic mixtures, or any tautomeric form thereof.  
 
     
     
         2 . A compound according to  claim 1  wherein X is halogen and Y is hydrogen.  
     
     
         3 . A compound according to  claim 2  wherein X is chloro.  
     
     
         4 . A compound according to any of the preceding claims wherein R 1 , R 2  and R 3  all are C 1-6 -alkyl.  
     
     
         5 . A compound according to any of the preceding claims wherein R 1  is C 1-6 -alkyl.  
     
     
         6 . A compound according to  claim 5  wherein R 1  is methyl.  
     
     
         7 . A compound according to any of the preceding claims wherein R 2 —C—R 3  forms a C 3-6 -cycloalkyl group.  
     
     
         8 . A compound according to any of the preceding claims wherein —CR 1 R 2 R 3  forms a tricyclic carbocyclic system.  
     
     
         9 . A compound according to any of the preceding claims wherein the C 1-6 -alkyl-group is substituted with hydroxy.  
     
     
         10 . A compound according to any of the preceding claims selected from the following: 
 3-tert-Butylamino-6-chloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;    6-Chloro-3-(1,1-dimethylpropylamino)-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;    6-Chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;    6-Chloro-3-(2-hydroxy-1,1-dimethylethylamino)-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;    6-Chloro-3-(1,1,3,3-tetramethylbutylamino)-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; or       a salt thereof with a pharmaceutically acceptable acid or base including all optical isomers of compounds of formula I, some of which are optically active, and also their mixtures including racemic mixtures, or any tautomeric form thereof.    
     
     
         11 . A compound according to any of the preceding claims  1 - 9  selected from the following: 
 3-(1-Adamantyl)amino-6-chloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;  
 1-(6-Chloro-1,4-dihydro-1,1-dioxo-thieno[3,2-e]-1λ 6 ,2,4-thiadiazin-3-ylamino)-cyclopropanecarboxylic acid ethyl ester;  
 6-Chloro-3-(1-methyl-1-phenylethyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;  
 6-Chloro-3-(1-hydroxymethylcyclopentyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;  
 1-(6-Chloro-1,4-dihydro-1,1-dioxo-thieno[3,2-e]-1λ 6 ,2,4-thiadiazin-3-ylamino)-cyclopropanecarboxylic acid;  
 6-Chloro-3-(1-methylcyclobutyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;  
 6-Chloro-3-(1-methylcyclohexyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;  
 6-Chloro-3-(1-methylcyclopentyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide;  
 6-Chloro-3-(1-ethylcyclobutyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide; or 
   
 a salt thereof with a pharmaceutically acceptable acid or base including all optical isomers of compounds of formula I, some of which are optically active, and also their mixtures including racemic mixtures, or any tautomeric form thereof.  
 
     
     
         12 . Compounds according to any one of the preceding claims which acts as openers of the K ATP -regulated potassium channels.  
     
     
         13 . A pharmaceutical composition comprising a compound according to any of the claims  1 - 12  or a or a pharmaceutical acceptable 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 form together with one or more pharmaceutically acceptable carriers or diluents.  
     
     
         14 . A pharmaceutical composition for use in the treatment of diseases of the endocrinological system such as hyperinsulinaemia and diabetes comprising a compound according to any of the claims  1 - 12  or a pharmaceutical acceptable 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 form together with one or more pharmaceutically acceptable carriers or diluents.  
     
     
         15 . A pharmaceutical composition for use in the treatment or prevention of non-insulin dependent diabetes mellitus comprising a compound according to any of the claims  1 - 12  or a pharmaceutical acceptable 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 form together with one or more pharmaceutically acceptable carriers or diluents.  
     
     
         16 . A pharmaceutical composition for use in the treatment of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) comprising a compound according to any of the claims  1 - 12  or a pharmaceutical acceptable 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 form together with one or more pharmaceutically acceptable carriers or diluents.  
     
     
         17 . The pharmaceutical composition according to  claims 13  to  16  in the form of an oral dosage unit or parenteral dosage unit.  
     
     
         18 . A pharmaceutical composition according to  claims 13  to  16  wherein said compound is administered as a dose in a range from about 0.05 to 1000, preferably from about 0.1 to 500 and especially in the range from 50 to 200 mg per day.  
     
     
         19 . A compound according to any one of the claims  1 - 12  or a pharmaceutically acceptable 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 form for therapeutical use.  
     
     
         20 . A compound according to any one of the claims  1 - 12  or a pharmaceutically acceptable 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 form for therapeutical use in the treatment or prevention of diseases of the endocrinological system, such as hyperinsulinaemia and diabetes.  
     
     
         21 . A compound according to any one of the claims  1 - 12  or a pharmaceutically acceptable 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 form for therapeutical use in the treatment or prevention non-insulin dependent diabetes mellitus.  
     
     
         22 . A compound according to any one of the claims  1 - 12  or a pharmaceutically acceptable 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 form for therapeutical use in the treatment of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT).  
     
     
         23 . The use of a compound according to any one of the claims  1 - 12  or a pharmaceutically acceptable 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 form as a medicament.  
     
     
         24 . The use of a compound according to any of the claims  1 - 12  for preparing a medicament.  
     
     
         25 . The use of a compound according to any one of the claims  1 - 12  or a pharmaceutically acceptable 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 form for the preparation of a medicament for the treatment or prevention of diseases of the endocrinological system, such as hyperinsulinaemia and diabetes.  
     
     
         26 . The use of a compound according to any one of the claims  1 - 12  or a pharmaceutically acceptable 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 form for the preparation of a medicament for the treatment or prevention of non-insulin dependent diabetes mellitus.  
     
     
         27 . The use of a compound according to any one of the claims  1 - 12  or a pharmaceutically acceptable 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 form for the preparation of a medicament for the treatment of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT).  
     
     
         28 . A method of treating or preventing diseases of the endocrinological system, such as hyperinsulinaemia and diabetes in a subject in need thereof comprising administering an effective amount of a compound according to any of the claims  1 - 12  to said subject.  
     
     
         29 . A method of treating or preventing non-insulin dependent diabetes mellitus in a subject in need thereof comprising administering an effective amount of a compound according to any of the claims  1 - 12  to said subject.  
     
     
         30 . A method of treating impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) in a subject in need thereof comprising administering an effective amount of a compound according to any of the claims  1 - 12  to said subject.  
     
     
         31 . A process for the manufacture of a medicament, particular to be used in the treatment or prevention of diseases of the endocrinological system, such as hyperinsulinaemia and diabetes which process comprising bringing a compound of formula I according to any of the claims  1 - 12  or a pharmaceutically acceptable salt thereof into a galenic dosage form.  
     
     
         32 . Methods for preparing the compounds of formula I according to  claim 1  comprising: 
 a) reacting a compound of formula II:  
                     wherein X and Y are as defined above and Z is a leaving group such as alkoxy, alkylthio, trimethylamino, methylsulfinyl, methylsulfonyl or halogen, preferentially chloro, bromo or iodo, more preferentially fluoro or chloro, with a compound of formula III:                        wherein R 1 , R 2  and R 3  are as defined above to form a compound of the general formula I, or      
 b) reacting a compound of formula IV:  
                     wherein X and Y are as defined above, with a compound of formula III                        wherein R 1 , R 2  and R 3  are as defined above, or a suitable salt thereof in the presence of P 2 O 5  and a high boiling tertiary amine or a suitable salt thereof, to form a compound of the general formula I, or      
 c) reacting a compound of formula IV:  
                     wherein X and Y are defined above, with a compound of formula III                        wherein R 1 , R 2  and R 3  are as defined above, or a suitable salt thereof in the presence of titanium tetachloride and a solvent with which it may form a complex, like e.g. tetrahydrofuran, or a mixture of toluene and anisole, to form a compound of the general formula I, or      
 d) reacting a compound of formula V  
                     wherein X and Y are as defined above, with a compound of formula VI                        wherein R 1 , R 2  and R 3  are as defined above, to form a compound of the general formula I, or      
 e) reacting a compound of the formula V  
                     wherein X and Y are as defined above, with a compound of formula VII                        wherein R 1 , R 2  and R 3  are as defined above, to form a compound of the general formula I, or      
 f) reacting in the presence of a base a compound of formula VIII  
                     
  or a suitable salt thereof, 
 wherein X and Y are as defined above and R 4  is hydrogen or R 5 OC(═O), wherein R 5  is C 1-6 -alkyl, with a compound of formula IX  
                     wherein R 1 , R 2  and R 3  are as defined above, to form an adduct which may have either of the two structures X or XI or be a mixture of the two                                                 either of which by ring-closure, e.g. by treatment with phosgene in a suitable solvent, forms a compound of the general formula I, if R 4  is hydrogen, and a compound of the general formula XII if R 4  is R 5 OC(═O), wherein R 5  is C 1-6 -alkyl;                          
 
 g) hydrolyzing and subsequently decarboxylating a compound of the general formula XII  
                     
  to form a compound of the general formula I, e.g. by heating the starting compound in aqueous base.  
 
     
     
         33 . Any novel feature or combination of features as described herein.