Antidepressant

Abstract

A PKB (Akt) activating agent comprising a compound represented by the formula (I): wherein R 1 and R 2 : H, a hydrocarbon group or a heterocyclic group or R 1 and R 2 form a ring in cooperation with the adjacent carbon atom; R 3 : H, a hydrocarbon group or a heterocyclic group; W: represents a group represented by the formulas: wherein ring A: an optionally substituted benzene ring; ring B: an optionally substituted 5- to 7-membered nitrogen-containing heterocycle; R 4 : an aliphatic hydrocarbon group substituted with an aromatic group and further optionally substituted, or an acyl group containing an aromatic group; R 5 : H, C 1-6 alkyl or acyl; R 4c : an aromatic group, an aliphatic hydrocarbon group or acyl; and X:O or S; Y:O, S or NH; and ring C: an optionally substituted benzene ring, or a salt or a prodrug thereof, and use of the activating agent in prevention or treatment of depression, anxiety, manic-depressive psychosis or PTSD are provided.

1 . A protein kinase B (PKB) activating agent, which comprises a pound represented by the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  may be the same or different, and represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R 1  and R 2  may be taken together with the adjacent carbon atom to form an optionally substituted 3- to 8-membered homocycle or heterocycle, 
 R 3  represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,  
                     
 represents a single bond or a double bond,  
 W is (i) a group represented by the formula:  
                     
 wherein the A ring represents an optionally substituted benzene ring, and the B ring represents an optionally substituted 5- to 7-membered nitrogen-containing heterocycle,  
 (ii) a group represented by the formula:  
                     
 wherein R 4  represents (1) an aliphatic hydrocarbon group substituted with an optionally substituted aromatic group and optionally further substituted, or (2) an acyl group containing an optionally substituted aromatic group, and R 5  represents a hydrogen atom, C 1-6  alkyl or an acyl group, or  
 (iii) a group represented by the formula:  
   R 4 c  —X—  (Wc)  
 wherein R 4c  represents an optionally substituted aromatic group, an optionally substituted aliphatic hydrocarbon group, or an acyl group, and X represents an oxygen atom or an optionally oxidized sulfur atom,  
 Y represents an oxygen atom, an optionally oxidized sulfur atom, or optionally substituted imino, and  
 the C ring represents a benzene ring which may be further substituted in addition to a group represented by W, or a salt thereof, or a prodrug thereof.  
 
     
     
         2 . The agent according to  claim 1 , wherein  
       
         
           
           
               
               
           
         
       
       is a single bond.  
     
     
         3 . The agent according to  claim 1 , wherein Y is an oxygen atom.  
     
     
         4 . The agent according to  claim 1 , wherein W is a group represented by the formula (Wa).  
     
     
         5 . The agent according to  claim 1 , wherein R 1  and R 2  are each a C 1-6  alkyl group, R 3  is a phenyl group optionally substituted with 1 to 3 substituents selected from C 1-6  alkyl and halogen, the C ring is a benzene ring optionally substituted with 1 to 3 substituents selected from C 1-6  alkyl and C 1-6  alkoxy,  
       
         
           
           
               
               
           
         
       
       is a single bond, Y is an oxygen atom, W is a group represented by (Wa), and a group represented by the formula (Wa) is a group represented by the formula:  
       
         
           
           
               
               
           
         
       
       wherein the A 1  ring represents a benzene ring optionally substituted with 1 to 3 substituents selected from halogen, C 1-6  alkoxy and C 1-6  alkylenedioxy.  
     
     
         6 . The agent according to  claim 1 , wherein the 5-position of the benzofuran ring is substituted with a group represented by the formula (Wa).  
     
     
         7 . The agent according to  claim 1 , which comprises [1] 2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, [2] 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, [3] 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline, [4] 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]-2H-isoindole, [5] 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole, [6] 6-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]-6H-[1,3]dioxolo[4,5-f]isoindole, [7] 6-(2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole, [8] (R)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, or [9] (R)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl] isoindoline hydrochloride.  
     
     
         8 . The agent according to  claim 1 , which comprises (R)-(+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, (R)-(+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-(1-methylethyl)phenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, (R)-(+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-bromophenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, or a salt thereof.  
     
     
         9 . The agent according to  claim 1 , which comprises (i) N-(4-fluorobenzyl)-2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine, (ii) N-benzyl-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, (iii) 3-(4-isopropylphenyl)-N-(4-methoxybenzyl)-N,2,2,4,6,7-hexamethyl-2,3-dihydro-1-benzofuran-5-amine, (iv) 3-(4-isopropylphenyl)-N-[2-(4-methoxyphenyl)ethyl]-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, (v) N-(4-fluorobenzyl)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, (vi) N-(1,3-benzodioxol-5-ylmethyl)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, (vii) N-(4-fluorobenzyl)-3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, (viii) N-(4-methoxybenzyl)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine, (ix) N-(4-fluorobenzyl)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine, (x) 3-(4-isopropylphenyl)-N-(4-methoxybenzyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine, (xi) N-(4-fluorobenzyl)-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine, (xii) N-(4-fluorobenzyl)-3-(4-fluorophenyl)-2,4,6,7-tetramethyl-1-benzofuarn-5-amine, (xiii) N-(4-fluorobenzyl)-3-(4-isopropylphenyl)-1′,4,6,7-tetramethylspiro[benzofuarn-2(3H),4′-piperidine]-5-amine or (xiv) (R)-N-(4-fluorobenzyl)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine hydrochloride.  
     
     
         10 . The agent according to  claim 1 , which comprises 3-(4-isopropylphenyl)-5-(4-methoxybenzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran, 3-(4-methylphenyl)-2,4,6,7-tetramethylbenzofuran-5-yl 4-methoxybenzoate, 3-(4-isopropylphenyl)-2,4,6,7-tetramethylbenzofuran-5-yl 4-methoxybenzoate, 3-(4-isopropylphenyl)-5-(4-methoxybenzyloxy)-2,4,6,7-tetramethylbenzofuran, 3-(4-isopropylphenyl)-5-(4-methoxybenzyloxy)-1′,4,6,7-tetramethylspiro[benzofuran-2(3H),4′-piperidine], or a salt thereof.  
     
     
         11 . The agent according to  claim 1 , which is an agent for preventing or treating depression, anxiety, manic-depressive psychosis or PTSD.  
     
     
         12 . An agent for preventing or treating Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis or Huntington's disease, which comprises a protein kinase B (PKB) activating agent.  
     
     
         13 . An agent for preventing or treating Parkinson's disease Alzheimer's disease, amyotrophic lateral sclerosis or Huntington's disease which comprises a protein kinase B (PKB) activating agent according to  claim 1 .  
     
     
         14 . An agent for preventing or treating depression, anxiety, manic-depressive psychosis or PTSD, which comprises a PKB activating agent.  
     
     
         15 . An agent for preventing or treating depression, anxiety, manic-depressive psychosis or PTSD, which comprises a nerve regeneration promoting agent and/or a stem cell and/or a neural precursor cell proliferation or differentiation promoting agent based on PKB activation.  
     
     
         16 . An agent for preventing or treating Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis or Huntington's disease, which comprises a nerve regeneration promoting agent and/or a stem cell and/or a neural precursor cell proliferation or differentiation promoting agent based on PKB activation.  
     
     
         17 . Use of a PKB activating agent for preventing or treating Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis or Huntington's disease.  
     
     
         18 . Use of a PKB activating agent for preparing a medicament for preventing or treating Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis or Huntington's disease.  
     
     
         19 . A method for preventing or treating Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis or Huntington's disease in a mammal, which comprises administering a PKB activating agent to a mammal.  
     
     
         20 . Use of a PKB activating agent for preventing or treating depression, anxiety, manic-depressive psychosis or PTSD.  
     
     
         21 . Use of the PKB activating agent according to  claim 1  for preparing a medicament for preventing or treating depression, anxiety, manic-depressive psychosis or PTSD.  
     
     
         22 . A method for preventing or treating depression, anxiety, manic-depressive psychosis or PTSD in a mammal, which comprises administering a PKB activating agent to a mammal.  
     
     
         23 . A method for preventing or treating depression, anxiety, manic-depressive psychosis or PTSD in a mammal, which comprises administering the PKB activating agent according to  claim 1  to a mammal.