Fused pyridazine derivative compounds and drugs containing these compounds as the active ingredient

Abstract

Fused pyridazine derivatives represented by formula (I) or pharmaceutically acceptable salts thereof (wherein each symbol has the meaning as defined in the specification.). Because of inhibiting poly(ADP-ribose)polymerase, the compounds represented by formula (I) are useful as preventives and/or remedies for various ischemic diseases (in brain, cord, heart, digestive tract, skeletal muscle, retina, etc.), inflammatory diseases (inflammatory bowel disease, multiple cerebrosclerosis, arthritis, etc.), neurodegenerative diseases (extrapyramidal disorder, Alzheimer's disease, muscular dystrophy, lumbar spinal canal stenosis, etc.), diabetes, shock, head trauma, renal failure, hyperalgesia, etc. Moreover, these compounds are useful as agents against retroviruses (HIV etc.), sensitizers in treating cancer and immunosuppressants.

1 . A fused pyridazine derivative compound represented by formula (I) 
       
         
           
           
               
               
           
         
         wherein R 1  is 
         (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5) halogen atom, (6) nitro, (7) NR 2 R 3 , (8) C2-8 acyl, (9) C1-8 alkoxy substituted by phenyl or (10) C2-8 acyl substituted by NR 2 R 3 ,
 R 2  and R 3  are each independently 
 
         (1) a hydrogen atom or (2) C1-8 alkyl,
 X and Y are each independently 
 
         (1) C, (2) CH or (3) N,
   is 
 
         (1) a single bond or (2) a double bond, 
       
       
         
           
           
               
               
           
         
         (1) partially or fully saturated C3-10 mono-carbocyclic aryl or (2) partially or fully saturated 3-10 membered mono-hetero aryl containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms,
 A is (1) A 1 , (2) A 2 , (3) A 3 , (4) A 4  or (5) A 5 , 
 A 1  is 
 
       
       
         
           
           
               
               
           
         
         
           A 2  is -E 1 -E 2 -E 3 -E 4    
           A 3  is 
         
       
       
         
           
           
               
               
           
         
         
           A 4  is 
         
       
       
         
           
           
               
               
           
         
         
           A 5  is 
         
       
       
         
           
           
               
               
           
         
         
           D 1  is 
         
         (1) —NR 6 C(O)—, (2) —NR 6 C(S)—, (3) —NR 6 SO 2 —, (4) —CH 2 —NR 6 —, (5) —CH 2 —O—, (6) —OC(O)—, (7) —CH 2 —NR 6 C(O)—, (8) —NR 6 C(O)NR 7 —, (9) —NR 6 C(O)O—, (10) —NR 6 C(S)NR 7 —, (11) —NR 6 — or (12) —NR 6 C(═NR 7 )—,
 R 6  and R 7  are each independently 
 
         (1) a hydrogen atom, (2) C1-8 alkyl, (3) phenyl or (4) C1-8 alkyl substituted by phenyl,
 D2 is 
 
         (1) C1-8 alkylene, (2) C2-8 alkenylene, (3) Cyc2, (4) —(C1-4 alkylene)-O—(C1-4 alkylene)-, (5) —(C1-4 alkylene)-S—(C1-4 alkylene)-, (6) —(C1-4 alkylene)-NR 8 —(C1-4 alkylene)-, (7)-(Cyc2)-(C1-8 alkylene)-, (8) —(C1-8 alkylene)-(Cyc2)- or (9) —(C1-4 alkylene)-(Cyc2)-(C1-4 alkylene)-,
 R 8  is 
 
         (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) phenyl or (5) C1-8 alkyl substituted by phenyl,
 D 3  is 
 
         (1) a hydrogen atom, (2) —NR 9 R 10 , (3) Cyc3, (4) —OR 11 , (5) COOR 12 , (6) CONR 13 R 14 , (7) cyano, (8) a halogen atom, (9) —C(═CR 15 )NR 16 R 17  or (10) —NR 18 C(═NR 19 )NR 20 R 21 ,
 R 9  and R 13  are each independently 
 
         (1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) Cyc3, (6) C1-8 alkoxy, (7) C2-8 alkenyloxy, (8) C2-8 alkynyloxy or (9) C1-8 alkyl substituted by Cyc3, C1-8 alkoxy, C1-8 alkylthio, cyano, hydroxy or 1 to 3 halogen atom(s),
 R 10  and R 14  are each independently 
 
         (1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) C1-8 alkoxycarbonyl, (6) C2-8 acyl, (7) C3-8 cycloalkyl, (8) C1-8 alkoxycarbonyl substituted by Cyc4 or 1 to 3 halogen atom(s), or (9) C1-8 alkyl substituted by C1-8 alkoxy,
 R 11  and R 12  are each independently 
 
         (1) a hydrogen atom or (2) C1-8 alkyl,
 R 15 , R 16 , R 17 , R 18 , R 19 , R 20  and R 21  are each independently 
 
         (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) phenyl or (5) C1-8 alkyl substituted by phenyl,
 R 4  is 
 
         (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5) halogen atom, (6) nitro or (7) NR 22 R 23 ,
 R 22  and R 23  are each independently 
 
         (1) a hydrogen atom or (2) C1-8 alkyl,
 E 1  is C1-4 alkylene, 
 E 2  is 
 
         (1) —C(O)NR 24 —, (2) —NR 24 C(O)—, (3) —NR 24 —, (4) —C(O)O— or (5) —S—,
 R 24  is 
 
         (1) a hydrogen atom, (2) C1-8 alkyl or (3) C1-8 alkyl substituted by phenyl,
 E 3  is 
 
         (1) a bond or (2) C1-8 alkylene,
 E 4  is 
 
         (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) Cyc5, (5) NR 25 R 26 , (6) OR 27 , (7) SR 27 , (8) COOR 27 , (9) C1-8 alkyl substituted by two of OR 25 , (10) C1-8 alkyl substituted by 1 to 3 halogen atom(s), (11) cyano or (12) C2-8 acyl,
 R 25  is 
 
         (1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) Cyc5 or (6) C1-8 alkyl substituted by Cyc5 or OR 28 ,
 R 26  is 
 
         (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) phenyl or (5) C1-8 alkyl substituted by phenyl,
 R 27  is 
 
         (1) a hydrogen atom, (2) C1-8 alkyl, (3) Cyc5 or (4) C1-8 alkyl substituted by Cyc5,
 R 28  is 
 
         (1) a hydrogen atom or (2) C1-8 alkyl,
 G 1  is C1-8 alkylene, 
 Cyc1 is 
 
         (1) partially or fully saturated C3-10 mono- or bi-carbocyclic aryl, or (2) partially or fully saturated 3-10 membered mono- or bi-hetero aryl containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms,
 G 2  is 
 
         (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxycarbonyl, (4) C2-8 acyl, (5) Cyc6, (6) C1-8 alkyl or C2-8 alkenyl substituted by 1 to 2 substituent(s) selected from Cyc6, hydroxy and C1-8 alkoxy, (7) C1-8 alkoxycarbonyl substituted by Cyc6, (8) —C(O)-Cyc6, (9) nitro, (10) NR 41 R 42 , (11) C1-8 alkoxy or (12) C1-8 alkyl substituted by NR 41 R 42 ,
 R 41  and R 42  are each dependently 
 
         (1) a hydrogen atom or (2) C1-8 alkyl,
 R 5  is 
 
         (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) hydroxy, (5) nitro, (6) NR 29 R 30 , (7) C1-8 alkyl substituted by NR 29 R 30 , (8) NHSO 2 OH, (9) amidino, (10) cyano, (11) a halogen atom, (12) Cyc8 or (13) C1-8 alkyl substituted by Cyc8,
 R 29  and R 30  are each independently 
 
         (1) a hydrogen atom or (2) C1-8 alkyl,
 Cyc2, Cyc3, Cyc4, Cyc5, Cyc6 and Cyc8 are each independently 
 
         (1) partially or fully saturated C3-10 mono- or bi-carbocyclic aryl, or (2) partially or fully saturated 3-10 membered mono- or bi-hetero aryl containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms,
 Cyc7 is 
 
         (1) partially or fully saturated C3-10 mono- or bi-carbocyclic aryl, or (2) partially or fully saturated 3-10 membered mono- or bi-hetero aryl containing 1 to 4 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms, with proviso that Cyc7 is not benzene,
 Cyc2, Cyc3, Cyc4, Cyc5, Cyc6 and Cyc8 are optionally substituted by 1 to 3 substituent(s) selected from (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C1-8 alkoxy, (4) halogen atom, (5) trihalomethyl, (6) trihalomethoxy, (7) C1-8 alkoxycarbonyl, (8) oxo, (9) C1-8 alkyl substituted by C1-8 alkoxy or phenyl, (10) hydroxy and (11) NR 29 R 30 ; 
 
         m and n are each independently 1 or 2,
 wherein 
 
         (i) when A is A 1  or A 2 , then 
       
       
         
           
           
               
               
           
         
         is not 
       
       
         
           
           
               
               
           
         
         (ii) when A is A 4  and 
       
       
         
           
           
               
               
           
         
          then
 R 5  is not hydroxy or C1-8 alkoxy, 
 
         (iii) when A is A 5 , then 
       
       
         
           
           
               
               
           
         
          is not 
       
       
         
           
           
               
               
           
         
         (iv) following compounds of (1) to (13) are excepted; 
       
       (1) 4-(3-chloro-4-methoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one, 
       (2) 4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 
       (3) 4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one, 
       (4) 4-phenyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 
       (5) 4-(4-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 
       (6) 4-(4-fluorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 
       (7) 4-(4-chlorophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 
       (8) 4-(4-bromophenyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 
       (9) 7-hydroxy-4-phenyl-6,7,8,8a-tetrahydropyrrolo[1,2-d][1,2,4]triazin-1(2H)-one, 
       (10) 4-phenyl-8,8a-dihydro[1,3]thiazolo[3,4-d][1,2,4]triazin-1(2H)-one, 
       (11) 4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 
       (12) 4-t-butoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one, 
       (13) 4-ethoxycarbonylmethyl-5,6,7,8-tetrahydrophthalazin-1(2H)-one, or
 a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The compound represented by formula (I) according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is partially or fully saturated C3-7 mono-carbocyclic aryl and A is A 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound represented by formula (I) according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is partially or fully saturated C3-7 mono-carbocyclic aryl and A is A 2 , or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The compound represented by formula (I) according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is partially or fully saturated C3-7 mono-carbocyclic aryl and A is A 3 , or a pharmaceutically acceptable salt thereof 
     
     
         5 . The compound represented by formula (I) according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is partially or fully saturated C3-7 mono-carbocyclic aryl and A is A 4  or A 5 , or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound represented by formula (I) according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is partially or fully saturated 3-7 membered mono-hetero aryl containing 1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms and A is A 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound represented by formula (I) according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is partially or fully saturated 3-7 membered mono-hetero aryl containing 1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms and A is A 2 , or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The compound represented by formula (I) according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is partially or fully saturated 3-7 membered mono-hetero aryl containing 1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms and A is A 3 , or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The compound represented by formula (I) according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
       is partially or fully saturated 3-7 membered mono-hetero aryl containing 1 to 2 hetero atom(s) selected from oxygen, nitrogen and sulfur atoms and A is A 4  or A 5 , or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The compound represented by formula (I) according to  claim 1 , wherein 
       
         
           
           
               
               
           
         
       
     
     
         11 . A poly(ADP-ribose)polymerase inhibitor comprising, as an active ingredient, the compound represented by formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A preventive and/or treatment agent for ischemic diseases, inflammatory diseases, neurodegenerative diseases, glaucoma, diabetes, diabetic complication, shock, head trauma, spinal cord injury, renal failure or hyperalgesia comprising, as an active ingredient, the compound represented by formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         13 . An antiretroviral drug comprising, as an active ingredient, the compound represented by formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         14 . A sensitizer of anticancer therapy comprising, as an active ingredient, the compound represented by formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         15 . An immunosuppressant comprising, as an active ingredient, the compound represented by formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The preventive and/or treatment agent according to  claim 12 , wherein the ischemic disease is cerebral infarction. 
     
     
         17 . The compound or the pharmaceutically acceptable salt according to  claim 1 , which is described in any one of Example 1 to 62.