Benzoxazine and benzothiazine derivatives and their use in pharmaceutical agents

Abstract

Compounds of formula (I), their tautomeric and isomeric forms and salts, as well as the process for their production and their use in pharmaceutical compositions, are described.

1 . A compound of formula I, a tautomeric or isomeric form thereof or a salt thereof:  
     
       
         
         
             
             
         
       
     
     in which 
 X is S(O) m ;  
 R 1  is —(CHR 9 ) n —NR 7 -A-NR 8 —B, —(CHR 9 ) n —NR 7 —(CH 2 ) p —CR—(CH 2 ) q —NR 8 -D, or —(CHR 9 ) n —NR 7 —B;  
 R 2  is hydrogen;  
 or  
 R 1  and R 2  together with two adjacent carbon atoms form a 5-, 6-, 7- or 8-membered ring, which is monocyclic or bicyclic, saturated or unsaturated and in which 1 or 2 CH 2  groups are optionally replaced by oxygen or carbonyl, and which is substituted with —(CHR 9 ) r —NR 7 -A-NR 8 —B, —(CHR 9 ) r —NR 7 —(CH 2 ) p —CR—(CH 2 ) q —NR 8 -D, or —(CHR 9 ) r —NR 7 —B and is optionally substituted with C 1-4 alkyl;  
 R 3  is hydrogen, halogen, NO 2 , cyano, CF 3 , —OCF 3 , —S—R 9 , —O—R 9 , C 3-7 cycloalkyl, —NR 9 —C(═NR 1 )—R 11 , —NH—CS—NR 12 R 13 , —NH—CO—NR 12 R 13 , —SO 2 NR 12 R 13 , —CO—NR 12 R 13 , —CO—R 14 , —NR 15 R 15 , C 6-10 aryl which optionally is substituted with halogen, cyano, C 1-4 alkyl, —S—R 9  or —O—R 9 ; or  
 5- or 6-membered heteroaryl with 1 to 4 oxygen, sulfur or nitrogen atoms; or  
 C 1-6 alkyl, which optionally is substituted with halogen, —OR 9 , —SR 9 , —NR 12 R 13 , ═NR 12 , ═NOC 1-6 alkyl, ═N—NH-aryl, phenyl, C 3-7 cycloalkyl or 5- or 6-membered heteroaryl; or  
 C 2-6 alkenyl, which optionally is substituted with halogen, CONH 2 , CN or phenyl; or  
 C 2-6 alkynyl, which optionally is substituted with halogen, CONH 2 , CN or phenyl;  
 R 4  is hydrogen or acyl;  
 R 5  and R 6 , independently of one another, are hydrogen, C 3-7 cycloalkyl, phenyl, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl radicals, which are optionally substituted in each case with halogen, OH, O—C 1-6 alkyl, SH, S—C 1-6 alkyl, NR 15 R 16 , 5- or 6-membered heteroaryl with 1-3 N, O or S atoms, phenyl or C 3-7 cycloalkyl;  
 R 7  is hydrogen or C 1-6 alkyl, which is optionally substituted with phenyl, COOC 1-6 alkyl or COC 1-6 alkyl;  
 R 8  is hydrogen;  
 A is straight-chain or branched C 1-6 alkylene, straight-chain or branched C 2-6 alkenylene or —(CH 2 ) p -Q-(CH 2 ) q —;  
 B is —CR—(CH 2 ) p —U, —CR—NR 15 R 16 , —SOR 12 , —SO 2 R 12 , —COO-aryl, or —COO-benzyl;  
 D is hydrogen or —(CH 2 ) p —U;  
 R is oxygen or sulfur;  
 Q is C 3-7 cycloalkylene, indanylene, 5-, 6- or 7-membered saturated heterocyclo-alkylene with 1-2 N, O or S atoms in the heterocyclo ring, C 6 -C 10  arylene, or 5- or 6-membered heteroarylene with 1-3 N, O or S atoms which is optionally annellated with benzene;  
 U is hydrogen, C 1-6 alkyl optionally substituted with halogen, C 3-7 cycloalkyl, indanyl, C 7-10 bicycloalkyl, C 6-10 aryl or 5- or 6-membered heteroaryl with 1 to 3 N, O or S atoms which is optionally annellated with benzene, whereby the aryl and heteroaryl radical are optionally substituted with halogen, C 1-4 alkyl, C 1-4 alkoxy, CF 3 , NO 2 , NH 2 , —N(C 1-4  alkyl) 2 , cyano, —CONH 2 , —O—CH 2 —O—, —O—(CH 2 ) 2 —O—, SO 2 NH 2 , OH, phenoxy or —COOC 1-4 alkyl; or  
 R 8  and B together with the nitrogen atom to which they are bonded form a 5- to 7-membered saturated heterocyclic group, which contains an oxo or thioxo group on the ring and optionally contains another oxygen, nitrogen or sulfur atom and is optionally substituted with C 1-4 alkyl or a phenyl, benzyl or benzoyl radical that is optionally substituted with halogen; or  
 R 7  and A together with the nitrogen atom to which they are bonded form a 5- to 7-membered saturated heterocyclic group, or form an unsaturated 5-membered heterocyclic group;  
 m is 0, 1 or 2;  
 n and r independently of each other are 0 to 6;  
 p and q independently of each other are 0 to 6;  
 R 9  and R 10  independently of each other are hydrogen or C 1-6 alkyl;  
 R 11  is C 1-6 alkyl, —NH 2 , —NH—CH 3 , —NH—CN, C 6-10 aryl optionally substituted with halogen, C 1-4 alkyl or CF 3 , or 5- or 6-membered heteroaryl with 1 to 4 nitrogen, sulfur or oxygen atoms that is optionally substituted with halogen, C 1-4 alkyl or CF 3 ;  
 R 12  and R 13  independently of each other are hydrogen, C 1-6 alkyl, phenyl optionally substituted with halogen or C 1-4  alkyl, benzyl optionally substituted with halogen or C 1-4 alkyl, or C 3-7 cycloalkyl;  
 R 14  is hydrogen, hydroxy, C 1-6 alkoxy, phenyl, C 1-6 alkyl (optionally substituted with CO 2 H, CO 2 C 1-6 alkyl, hydroxy, C 1-4 alkoxy, halogen, NR 15 R 15 , CONR 12 R 13 , or phenyl), or C 2-6  alkenyl (optionally substituted with phenyl, cyano, CONR 12 R 13  or CO 2 C 1-4  alkyl);  
 R 15  and R 16  independently of each other are hydrogen, C 1-6 alkyl, phenyl optionally substituted with halogen or C 1-4  alkyl, or benzyl optionally substituted with halogen or C 1-4 alkyl;  
 or  
 R 15  and R 16  together with the nitrogen atom to which they are bonded form a saturated 5-, 6-, or 7-membered ring, which optionally contains a nitrogen, oxygen or sulfur atom and is optionally substituted with C 1-4 alkyl, or a phenyl, benzyl or benzoyl radical optionally substituted with halogen.  
 
   
   
       2 . A compound of  claim 1 , in which R 6  is hydrogen.  
   
   
       3 . A compound of  claim 1 , in which R 5  is C 1-6 alkyl.  
   
   
       4 . A compound of  claim 1 , in which R 4  is hydrogen.  
   
   
       5 . A compound of  claim 1 , in which R 3  is hydrogen.  
   
   
       6 . A compound of  claim 1 , in which A is a straight-chain or branched C 1-6 alkylene.  
   
   
       7 . A compound of  claim 1 , wherein: 
 aryl is naphthyl or phenyl, each of which is optionally substituted in one to three places;    heteroaryl is imidazole, indole, isooxazole, isothiazole, furan, oxadiazole, oxazole, pyrazine, pyridazine, pyrimidine, pyridine, pyrazole, pyrrole, tetrazole, thiazole, triazole, thiophene, thiadiazole, benzimidazole, benzofuran, benzoxazole, isoquinoline, or quinoline, each of which is optionally substituted in one to three places;    saturated heterocyclic group is piperidine, pyrrolidine, morpholine, thiomorpholine, hexahydroazepine or piperazine, each of which is optionally substituted in one to three places;    when —NR 7 A-together with the nitrogen atom forms an unsaturated heterocyclic group, it is imidazole, pyrrole, pyrazole or triazole; and    acyl is the acyl residue from a straight-chain or branched aliphatic C 1-6 carboxylic acid, a benzenesulfonic acid which is optionally substituted with halogen or C 1-4 alkyl, or a C 1-4  alkanesulfonic acid.    
   
   
       8 . A compound of  claim 1 , wherein R 3 , R 4 , R 7  and R 9  are each hydrogen.  
   
   
       9 . A compound of  claim 1 , wherein R 1  is at the 6-position of the benzothiazine ring.  
   
   
       10 . A compound of  claim 1 , wherein R 8  and B together with the nitrogen atom to which they are bonded form a pyrrolidine-2-thione group.  
   
   
       11 . A compound of  claim 1 , wherein 
 R 1  is —(CHR 9 ) n —NR 7 -A-NR 8 —B or —(CHR 9 ) n —NR 7 —B; or    R 1  and R 2  together form a 5-, 6-, 7- or 8-membered ring which is substituted by —(CHR 9 ) n —NR 7 -A-NR 8 —B, or —(CHR 9 ) n —NR 7 —B; and    B is: —CR—(CH 2 ) p —U wherein —(CH 2 ) p —U is hydrogen, C 1-6 alkyl optionally substituted with halogen, or phenyl optionally substituted with halogen, C 1-4 alkyl, C 1-4 alkoxy, or CF 3 ; or 
 —CR—NR 15 R R 16 -wherein R 15  and R 16  are each hydrogen, C 1-6  alkyl or phenyl; or  
 —SO 2 R 12 , in which R 12  is C 1-6  alkyl.  
   
   
   
       12 . A compound of  claim 1 , wherein R 1  is —(CHR 9 ) r —NR 17 (CH 2 ) p —CR—(CH 2 ) q —NR 8 -D, or R 1  and R 2  together form a 5-, 6-, 7- or 8-membered ring which is substituted by —(CHR 9 ) r —NR 17 (CH 2 ) p —CR—(CH 2 ) q —NR 8 -D, and D is hydrogen or a benzyl radical that is optionally substituted with halogen, C 1-4 alkoxy, CF 3  or C 1-4 alkyl.  
   
   
       13 . A compound of  claim 1 , wherein R 1  is —(CHR 9 ) r —NR 7 —(CH 2 ) p —CR—(CH 2 ) q —NR 8 -D, or R 1  and R 2  together form a 5-, 6-, 7- or 8-membered ring which is substituted by —(CHR 9 ) r —NR 7 —(CH 2 ) p —CR—(CH 2 ) p —NR 8 -D, and at least one of (CH 2 ) p  and (CH 2 ) q  is alkylene of 1-6 carbon atoms.  
   
   
       14 . A compound of  claim 1 , wherein R 3  is —NR 9 —C(═NR 10 )—R 11 , where R 11  is thienyl.  
   
   
       15 . A pharmaceutical composition which comprises a compound according to  claim 1  and one or more pharmaceutically common vehicles or adjuvants.