Piperazine-Substituted Benzothiophenes For Treatment of Mental Disorders

Abstract

The present invention provides a heterocyclic compound represented by the general formula (1): The compound of the present invention has a wide treatment spectrum for mental disorders including central nervous system disorders, no side effects and high safety.

1 . A heterocyclic compound represented by the formula (1): 
       
         
           
           
               
               
           
         
         [wherein ring Q represented by 
       
       
         
           
           
               
               
           
         
         represents 
       
       
         
           
           
               
               
           
         
         (wherein 
       
       
         
           
           
               
               
           
         
         represents —NH—CH 2 —, —N═CH—, —CH 2 —NH— or —CH═N—; and the carbon-carbon bond
     
 
         between the 3-position and 4-position of the heterocyclic skeleton containing Z and Y represents a single bond or a double bond);
 the ring Q may have at least one substituent selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, an aryl group, an aryl lower alkyl group, an aryl lower alkoxy group, an arylcarbonyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cycloalkyl group, a cycloalkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group which may have a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a thienyl group, a saturated 3- to 8-membered heteromonocyclic group containing 1 to 2 nitrogen atoms-substituted lower alkyl group and an oxo group; 
 R 2  represents a hydrogen atom or a lower alkyl group; and 
 A represents —O-A 1 - (wherein A 1  represents an alkylene group which may be substituted with a hydroxy group (wherein the alkylene group may contain one oxygen atom) or a lower alkenylene group) or a lower alkylene group; 
 provided that when A represents a lower alkylene group, the ring Q represents a bicyclic group selected from the group consisting of: 
 
       
       
         
           
           
               
               
           
         
         (wherein the carbon-carbon bond
     
 
         represents a single bond or a double bond)] or a salt thereof. 
       
     
     
         2 . The heterocyclic compound of the formula (1) according to  claim 1 , wherein the ring Q represents a bicyclic group selected from the group consisting of: 
       
         
           
           
               
               
           
         
         (wherein the carbon-carbon bond
     
 
         between the 3-position and 4-position of the bicyclic heterocyclic skeleton represents a single bond or a double bond);
 the ring Q may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, a phenyl group, a phenyl lower alkyl group, a naphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyl lower alkoxy group, a benzoyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, a cyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group which may have a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a thienyl group and a saturated 5- to 6-membered heteromonocyclic group containing 1 to 2 nitrogen atoms-substituted lower alkyl group; and 
 A represents —O-A 1 - (wherein A 1  represents a C1-C6 alkylene group which may be substituted with a hydroxy group (wherein the alkylene group may contain one oxygen atom)), or a salt thereof. 
 
       
     
     
         3 . The heterocyclic compound of the formula (1) according to  claim 2 , wherein the ring Q represents a bicyclic group selected from the group consisting of: 
       
         
           
           
               
               
           
         
         the ring Q may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, a phenyl group, a phenyl lower alkyl group, a naphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyl lower alkoxy group, a benzoyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, a cyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group which may have a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a phenyl group, a thienyl group and a pyrrolidinyl lower alkyl group; and 
         A represents —O-A 1 - (wherein A 1  represents a C1-C6 alkylene group which may be substituted with a hydroxy group (wherein the alkylene group may contain one oxygen atom)), or a salt thereof. 
       
     
     
         4 . The heterocyclic compound of the formula (1) according to  claim 2 , wherein the ring Q represents a bicyclic group selected from the group consisting of: 
       
         
           
           
               
               
           
         
         (the ring Q may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, a phenyl group, a phenyl lower alkyl group, a naphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyl lower alkoxy group, a benzoyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, a cyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group which may have a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a thienyl group and a pyrrolidinyl lower alkyl group) or a salt thereof. 
       
     
     
         5 . The heterocyclic compound of the formula (1) according to  claim 1 , wherein the ring Q represents a bicyclic group selected from the group consisting of: 
       
         
           
           
               
               
           
         
         (wherein the carbon-carbon bond
     
 
         between the 3-position and 4-position of the bicyclic heterocyclic skeleton represents a single bond or a double bond);
 the ring Q may have 1 to 3 substituents thereon selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, a phenyl group, a phenyl lower alkyl group, a naphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyl lower alkoxy group, a benzoyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, a cyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group which may have a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a thienyl group, a pyrrolidinyl lower alkyl group and an oxo group; and 
 A represents a lower alkylene group, or a salt thereof. 
 
       
     
     
         6 . The heterocyclic compound of the formula (1) according to  claim 5 , wherein the ring Q represents a bicyclic group selected from the group consisting of: 
       
         
           
           
               
               
           
         
         (wherein the carbon-carbon bond
     
 
         between the 3-position and 4-position of the bicyclic heterocyclic skeleton represents a single bond or a double bond);
 the ring Q may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, a phenyl group, a phenyl lower alkyl group, a naphthyl lower alkyl group, a phenyl lower alkoxy group, a naphthyl lower alkoxy group, a benzoyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cyclo C3-C8 alkyl group, a cyclo C3-C8 alkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group which may have a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a thienyl group and a pyrrolidinyl lower alkyl group, or a salt thereof. 
 
       
     
     
         7 . The heterocyclic compound of the formula (1) according to  claim 3  selected from the group consisting of:
 (1) 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one, 
 (2) 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl) propoxy]-1H-quinolin-2-one, 
 (3) 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-1H-quinolin-2-one, 
 (4) 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-1H-quinolin-2-one, 
 (5) 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1-methyl-3,4-dihydro-1H-quinolin-2-one and 
 (6) 6-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-1H-quinolin-2-one; 
 or a salt thereof. 
 
     
     
         8 . The heterocyclic compound of the formula (1) according to  claim 4  selected from the group consisting of:
 (1) 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3,4-dihydro-2H-isoquinolin-1-one 
 (2) 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-one, 
 (3) 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl) butoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-one, 
 (4) 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-3,4-dihydro-2H-isoquinoline-1-one, 
 (5) 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-2H-isoquinolin-1-one and 
 (6) 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl) propoxy]-2-methyl-2H-isoquinolin-1-one; 
 or a salt thereof. 
 
     
     
         9 . A pharmaceutical composition comprising a heterocyclic compound of the formula (1) or a salt thereof according to any one of  claims 1  to  8 , as an active ingredient and a pharmaceutically acceptable carrier. 
     
     
         10 . The pharmaceutical composition according to  claim 9  for treating or preventing central nervous system disorders. 
     
     
         11 . The pharmaceutical composition according to  claim 10  for treating or preventing central nervous system disorders selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; emotional disturbance; psychotic disorder; mood disorder; bipolar I type disorder; bipolar II type disorder; depression; endogenous depression; major depression; melancholy and refractory depression; dysthymic disorder; cyclothymic disorder; panic attack; panic disorder; agoraphobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; generalized anxiety disorder; acute stress disorder; hysteria; somatization disorder; conversion disorder; pain disorder; hypochondriasis; factitious disorder; dissociative disorder; sexual dysfunction; sexual desire disorder; sexual arousal disorder; erectile dysfunction; anorexia nervosa; bulimia nervosa; sleep disorder; adjustment disorder; alcohol abuse; alcohol intoxication; drug addiction; stimulant intoxication; narcotism; anhedonia; iatrogenic anhedonia; anhedonia of a psychic or mental cause; anhedonia associated with depression; anhedonia associated with schizophrenia; delirium; cognitive impairment; cognitive impairment associated with Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases; cognitive impairment caused by Alzheimer's disease; Parkinson's disease and associated neurodegenerative diseases; cognitive impairment of schizophrenia; cognitive impairment caused by refractory, intractable or chronic schizophrenia; vomiting; motion sickness; obesity; migraine; pain (ache); mental retardation; autism disorder (autism); Tourette's disorder; tic disorder; attention-deficit/hyperactivity disorder; conduct disorder; and Down's syndrome. 
     
     
         12 . A process for producing a pharmaceutical composition comprising mixing a heterocyclic compound of the formula (1) or a salt thereof according to any one of  claims 1  to  8  with a pharmaceutically acceptable carrier. 
     
     
         13 . Use of a heterocyclic compound of the formula (1) or a salt thereof according to any one of  claims 1  to  8  as a drug. 
     
     
         14 . Use of a heterocyclic compound of the formula (1) or a salt thereof according to any one of  claims 1  to  8  as a dopamine D 2  receptor partial agonist and/or a serotonin 5-HT 2A  receptor antagonist and/or an adrenaline α 1  receptor antagonist and/or a serotonin uptake inhibitor and/or a serotonin reuptake inhibitor. 
     
     
         15 . A method for treating or preventing a central nervous system disorder comprising administering a heterocyclic compound of the formula (1) or a salt thereof according to any one of  claims 1  to  8  to human or animal. 
     
     
         16 . A process for producing a heterocyclic compound represented by the formula (1): 
       
         
           
           
               
               
           
         
         [wherein ring Q represented by 
       
       
         
           
           
               
               
           
         
         represents 
       
       
         
           
           
               
               
           
         
         (wherein 
       
       
         
           
           
               
               
           
         
         represents —NH—CH 2 —, —N═CH—, —CH 2 —NH— or —CH═N—; and the carbon-carbon bond
     
 
         between the 3-position and 4-position of the heterocyclic skeleton containing Z and Y represents a single bond or a double bond);
 the ring Q may have at least one substituent selected from the group consisting of a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a hydroxy group, a lower alkoxy group, a halogenated lower alkyl group, an aryl group, an aryl lower alkyl group, an aryl lower alkoxy group, an arylcarbonyl group, a lower alkenyloxy group, a lower alkanoyl group, a lower alkanoyloxy group, a cycloalkyl group, a cycloalkyl lower alkyl group, a halogen atom, a carbamoyl group which may have a lower alkyl group, a carboxy group, a lower alkoxycarbonyl group, an amino group which may have a lower alkanoyl group, a nitro group, a hydroxy lower alkyl group, an amino lower alkyl group which may have a lower alkyl group, a thienyl group, a saturated 3- to 8-membered heteromonocyclic group containing 1 to 2 nitrogen atoms-substituted lower alkyl group and an oxo group; 
 R 2  represents a hydrogen atom or a lower alkyl group; and 
 A represents —O-A 1 - (wherein A 1  represents an alkylene group which may be substituted with a hydroxy group (wherein the alkylene group may contain one oxygen atom) or a lower alkenylene group) or a lower alkylene group; 
 provided that when A represents a lower alkylene group, the ring Q represents a bicyclic group selected from the group consisting of: 
 
       
       
         
           
           
               
               
           
         
         (wherein the carbon-carbon bond
     
 
         represents a single bond or a double bond)] or a salt thereof,
 characterized by comprising a reaction of a compound represented by the formula: 
 
       
       
         
           
           
               
               
           
         
         (wherein the ring Q and A are the same as defined above, and X 1  represents a halogen atom or a group which causes a substitution reaction the same as in a halogen atom) or a salt thereof with a compound represented by the formula: 
       
       
         
           
           
               
               
           
         
         (wherein R 2  is the same as defined above) or a salt thereof.