Novel substituted 2,3-benzodiazepine derivatives

Abstract

The invention relates to new 2,3-benzodiazepine derivatives of formula (I), isomers and acid addition salts thereof and to pharmaceutical compositions containing the same, as well as to pharmaceutical compositions and methods of using the same suitable for treating conditions associated with muscle spasms, epilepsy, acute and chronic forms of neurodegenerative diseases as well as preventing, treating or alleviating the symptoms of acute and chronic inflammatory disorders.

1 . A compound of formula (I), wherein  
     
       
         
         
             
             
         
       
       R 3  represents a substituted or unsubstituted 5- or 6-membered, aromatic, saturated or partially saturated heterocyclic ring containing at least 2 hetero atoms, in which the hetero atom can be oxygen-, sulfur- or nitrogen atom and in the case when the heterocyclic ring contains 2 heteroatoms one of them is different from nitrogen;  
       R 4 , R 5 , R 6 , and R 7  independently from each other represent hydrogen atom, halogen atom, C 1 -C 3  alkyl group, nitro group, amino group, wherein the amino group can be substituted independently from each other with one or two C 1 -C 3  alkyl group, C 2 -C 5  acyl group, or C 2 -C 5  alkoxycarbonyl group, or aminocarbonyl group, or C 2 -C 5 alkylaminocarbonyl group,  
       R 9  represents C 1 -C 3  alkoxy group or halogen atom,  
       R 10  represents hydrogen or halogen atom or  
       R 9  and R 10  together can be C 1 -C 3  alkylendioxy group; and  
       stereoisomers and acid-addition salts of said compound.  
     
   
   
       2 . The compound according to  claim 1 , wherein the heterocyclic ring of R 3  can be further substituted with one or more C 1 -C 5  alkyl group, a C 2 -C 3  alkenyl, a C 3 -C 7  cycloalkyl, a trifluoromethyl, a C 1 -C 3  alkoxy or a phenyl group, an oxo, a formyl, a carboxyl or a C 2 -C 4  alkoxycarbonyl group, a C 1 -C 3  alkoxymethyl group, a halogen atom a hydroxymethyl group, wherein the hydroxyl group can be alkylated or acylated, a C 1 -C 3  alkylthiomethyl group, a cyanomethyl group or an aminomethyl group, wherein the amino group can be alkylated or acylated.  
   
   
       3 . The compound according to  claim 1 , wherein R 3  is selected from the group of substituted and unsubstituted isoxazole, isothiazole, thiazole, thiazoline, 4-thiazolinone, oxazole, oxazoline, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,3,4-thiadiazolin-2-one, 1,2,4-thiadiazolin-3-one, 1,4,2-oxathiazoline, 1,3,4-oxadiazole, 1,2,3-triazole, 1,3,4-triazole, 1,2,3,4-thiatriazole, tetrazole, 1,3-thiazin-4-one and 1,3,4-thiadiazin-4-one ring.  
   
   
       4 . The compound according to  claim 1 , wherein R 3  is a substituted or unsubstituted 1,3,4-thiadiazol-2-yl, 4,5-dihydro-thiazol-2-yl, 2-thiazolyl or 1,3,4-oxadiazolyl group, R 5  is a hydrogen atom or methyl group, R 6  substituent is an amino group, and R 9  and R 10  represent together a methylenedioxy group, or R 9  is a chlorine atom or methoxy group and R 10  is a hydrogen or chlorine atom.  
   
   
       5 . The compound according to  claim 1  selected from the group consisting of (R)-5-(4-aminophenyl)-8-methyl-7-(5-methyl-1,3,4-thiadiazol-2-yl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine; (R)-5-(4-aminophenyl)-8-methyl-7-(1,3,4-thiadiazol-2-yl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine; (R)-5-(4-aminophenyl)-8-methyl-7-(2-thiazolyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine; (R)-5-(4-aminophenyl)-7-(4,5-dihydro-thiazol-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine; (R)-5-(4-aminophenyl)-7-(5-ethyl-1,3,4-thiadiazol-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine; (R)-5-(4-aminophenyl)-8-methyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine; (R)-5-(4-amino-3-methylphenyl)-8-methyl-7-(5-methyl-1,3,4-thiadiazol-2-yl)-8,9-dihydro-7H-1,3-dioxolo-[4,5-h][2,3]benzo-diazepine; (R)-5-(4-Amino-3-methylphenyl)-7-(5-ethyl-1,3,4-thiadiazol-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxolo-[4,5-h][2,3]benzodiazepine; (R)-5-(4-amino-3-methylphenyl)-8-methyl-7-(5-propyl-1,3,4-thiadiazol-2-yl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzo-diazepine; (R)-5-(4-amino-3-methylphenyl)-8-methyl-7-(1,3,4-thiadiazol-2-yl)-8,9-dihydro-7H-1,3-dioxolo-[4,5-h][2,3]benzodiazepine; (R)-5-(4-amino-3-methylphenyl-8-methyl-7-(5-methoxymethyl-1,3,4-thiadiazol-2-yl)-8,9-dihydro-7H-1,3-dioxolo-[4,5-h][2,3]benzo-diazepine; (R)-5-(4-amino-3-methylphenyl)-8-methyl-7-{5-[1-(1E)-propen-1-yl]-1,3,4-thiadiazol-2-yl}-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine; (R)-5-(4-amino-3-chlorophenyl)-8-methyl-7-(5-methyl-1,3,4-thiadiazol-2-yl)-8,9-dihydro-7H-1,3-dioxolo-[4,5-h][2,3]benzodiazepine; and (R)-5-(4-amino-3-chlorophenyl)-8-methyl-7-(5-methoxy-methyl-1,3,4-thiadiazol-2-yl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine and the acid addition salts thereof.  
   
   
       6 . The compound according to  claim 1 , wherein the compound is (R)-5-(4-amino-3-methylphenyl)-8-methyl-7-(5-methyl-1,3,4-thiadiazol-2-yl)-8,9-dihydro-7H-1,3-dioxolo-[4,5-h][2,3]benzodiazepine or the addition salt thereof.  
   
   
       7 . The compound according to  claim 1 , wherein the compound is (R)-5-(4-amino-3-methylphenyl)-7-(5-ethyl-1,3,4-thiadiazol-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxolo-[4,5-h][2,3]benzodiazepine or the acid addition salt thereof.  
   
   
       8 . The compound according to  claim 1 , wherein the compound is (R)-5-(4-amino-3-methylphenyl)-8-methyl-7-(5-propyl-1,3,4-thiadiazol-2-yl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine or the acid addition salt thereof.  
   
   
       9 . The compound according to  claim 1 , wherein the compound is (R)-5-(4-amino-3-methylphenyl)-8-methyl-7-(1,3,4-thiadiazol-2-yl)-8,9-dihydro-7H-1,3-dioxolo-[4,5-h][2,3]benzodiazepine or the acid addition salt thereof.  
   
   
       10 . The compound according to  claim 1 , wherein the compound is (R)-5-(4-amino-3-methylphenyl)-8-methyl-7-(5-methoxymethyl-1,3,4-thiadiazol-2-yl)-8,9-dihydro-7H-1,3-dioxolo-[4,5-h][2,3]benzodiazepine or the acid addition salt thereof.  
   
   
       11 . The compound according to  claim 1 , wherein the compound is (R)-5-(4-amino-3-methylphenyl)-8-methyl-7-{5-[1-(1E)-propen-1-yl]-1,3,4-thiadiazol-2-yl}-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine or the acid addition salt thereof.  
   
   
       12 . The compound according to  claim 1 , wherein the compound is (R)-5-(4-amino-3-chlorophenyl)-8-methyl-7-(5-methyl-1,3,4-thiadiazol-2-yl)-8,9-dihydro-7H-1,3-dioxolo-[4,5-h][2,3]benzodiazepine or the acid addition salt thereof.  
   
   
       13 . The compound according to  claim 1 , wherein the compound is (R)-5-(4-amino-3-chlorophenyl)-8-methyl-7-(5-methoxymethyl-1,3,4-thiadiazol-2-yl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine or the acid addition salts thereof.  
   
   
       14 . A pharmaceutical composition, comprising a compound of formula (I) according to any one of  claims 1  to  14 , or a stereoisomer or a pharmaceutically acceptable salt thereof.  
   
   
       15 . A method for treating glutamate dysfunction associated with an acute or chronic neurodegenerative disease, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of  claim 1 .  
   
   
       16 . The method of  claim 8 , wherein the neurodegenerative disease is selected from the group consisting of cerebral ischemia (stroke), brain and spinal cord trauma, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, AIDS-induced dementia, essential tremor, Parkinson's disease, multiple sclerosis and urinary incontinence.  
   
   
       17 . A method for treating epilepsy comprising administering to a subject in need of such treatment a therapeutically effective antiepileptic amount of a compound of  claim 1 .  
   
   
       18 . A method for reducing muscle spasms comprising administering to a subject in need of such treatment a therapeutically effective muscle relaxing amount of a compound of  claim 1 .  
   
   
       19 . A method for treating acute and chronic inflammatory disorders, comprising administering to a mammal in need of such treatment a therapeutically effective anti-inflammatory amount of a compound of  claim 1 .  
   
   
       20 . The method of  claim 19  wherein the inflammatory disorder treated is an allergic inflammatory disorder of the airways.  
   
   
       21 . The method of  claim 20  wherein the allergic inflammatory disorders of the airways is selected from the group consisting of allergic rhinitis, intrinsic or extrinsic asthma bronchiale, acute or chronic bronchitis, chronic obstructive pulmonary disease and pulmonary fibrosis.  
   
   
       22 . A method for relief of pathological pain comprising administering to a subject in need of such treatment a pain reducing therapeutically effective amount of a compound of  claim 1 .  
   
   
       23 . A method for treating glutamate dysfunction in acute or chronic disease of the eyes associated with glutamate dysfunction, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of  claim 1 .  
   
   
       24 . The method of  claim 23 , wherein the disease treated is selected from glaucoma or diabetic retinopathy.