1.  Field of the Invention
The present invention relates to a method of treating a patient suffering from a-disorder of the central nervous system associated with the 5-HT1A receptor subtype.  The active ingredient comprise a carbostyril derivative or a salt thereof. 
2.  Related Art
U.S. Pat.  No.  5,006,528; European Patent No.  367,141 and Japanese Patent Kokai (Laid-open) 7-304,740 (1995) contain the same chemical structural formula as the carbostyril derivatives in the present invention, and their pharmacological properties are beneficial drug treatments for schizophrenia. 
Carbostyril compounds, as well as those disclosed in Japanese Patent Kokai (Laid-open) 9-301,867 (1997) are useful for the treatment of anxiety. 
The carbostyril derivatives disclosed in European Patent No.  226,441 have the genus of the carbostyril derivatives in the present invention, and they are useful for the treatment of hypoxia. 
In addition to the above, the carbostyril derivatives disclosed in U.S. Pat.  No.  4,734,416; Canadian Patent No.  1,117,110; British Patent No.  2,017,701; German Patent Nos.  2,912,105 and 2,953,723; Japanese Patent Kokai (Laid-open) Nos.  54-130,587 (1979), 55-127,371 (1980) and 62-149,664 (1987) have the genus of the carbostyril derivatives in the present invention, and they have antihistaminic activities and central nervous controlling activities. 
It is reported that aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril, also known as, OPC-14597, BMS-337,039 and OPS-31) binds with high affinity to dopamine D2 receptors and with moderate affinity to dopamine D3 and 5-HT7 receptors (Masashi Sasa et al.,  CNS Drug Reviews, Vol.  3, No.  1, pp.  24-33). 
Further, it is reported that aripiprazole possesses presynaptic dopaminergic autoreceptor agonistic activity, postsynaptic D2 receptor antagonistic activity, and D2 receptor partial agonistic activity (T. Kikuchi, K. Tottori, Y. Uwahodo, T. Hirose, T. Miwa, Y. Oshiro and S. Morita: J. Pharmacol.  Exp.  Ther.,  Vol.  274, pp.  329, (1995); T. Inoue, M. Domae, K. Yamada and T. Furukawa: J. Pharmacol.  Exp.  Ther.,  Vol.  277, pp.  137, (1996)). 
However, it has not been reported that compounds in the present invention have agonistic activity at 5-HT1A receptor subtype. 
It has been reported that therapeutic interventions using 5-HT1A receptor ligands may be useful drug treatments for alcohol abuse (Mark Kleven et al.,  European Journal of Pharmacology, Vol.  281, (1995) pp.  219-228). 
It is also reported that 5-HT1A agonist drugs may be useful for the treatment and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischemic events in mammals (U.S. Pat.  No.  5,162,375). 
It is also reported that 5-HT1A receptor hypersensitivity could be the biological basis for the increased frequency of migraine attack in stressful and anxious conditions (Massimo Leone et al.,  Neuro Report, Vol.  9, pp.  2605-2608 (1998)). 
It has recently been reported that (−)-(R)-2-[4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]-butyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide monohydrochrolide (BAY-3702), a 5-HT1A receptor agonist, has neuroprotective, anxiolytic- and antidepressant-like effects in animal models (Jean De Vry et al.,  European Journal of Pharmacology, Vol.  357, (1998), pp.  1-8). 
It is also reported that 5-HT1A receptor agonists appear to be broad spectrum antiemetic agents (Mary C. Wolff et al.,  European Journal of Pharmacology, Vol.  340, (1997), pp.  217-220; A B Alfieri et al.,  British Journal of Cancer, (1995), Vol.  72, pp.  1013-1015; Mary C. Wolff et al.,  Pharmacology Biochemistry and Behavior, 1995, Vol.  52, No.  3, pp.  571-575; James B. Lucot, European Journal of Pharmacology, 1997, Vol.  253, pp.  53-60). 
Serotonin plays a role in several neurological and psychiatric disorders, including Alzheimer's disease, depression, nausea and vomiting, eating disorders, and migraine. ( See Rasmussen et al., “ Chapter 1.  Recent Progress in Serotonin 5HT1A Receptor Modulators”, in Annual Reports in Medicinal Chemistry, Vol.  30, Section I, pp.  1-9, 1995, Academic Press, Inc.).  WO 00/16777 discloses that a 5HT1A receptor agonist, buspirone is efficacious in treating a variety of symptoms associated with ADHD, and that combined use of a D2 receptor agonist and 5-HT1A agonist provides effective treatments for ADHD and Parkinson's disease. 
5HT1A agonists are effective in the treatment of cognitive impairment in Alzheimer's disease, Parkinson's disease or senile dementia.  U.S. Pat.  No.  5,824,680 discloses that a 5-HT1A agonist, ipsapirone, is effective in treating Alzheimer's disease by improving memory.  U.S. Pat.  No.  4,687,772 describes that a 5-HT1A partial agonist, buspirone, is useful for improving short term memory in patients in need of treatment.  WO 93/04681 discloses that use of 5-HT1A partial agonists have been used for the treatment or prevention of cognitive disorders associated with Alzheimer's disease, Parkinson's disease or senile dementia. 
5HT1A agonists are also effective in the treatment of depression.  U.S. Pat.  No.  4,771,053 describes that a 5-HT1A receptor partial agonist, gepirone, is useful in alleviation of certain primary depressive disorders, such as severe depression, endogenous depression, major depression with melancholia, and atypical depression.  WO 01/52855 discloses that the combined use of the 5-HT1A receptor partial agonist gepirone with an antidepressant can effectively treat depression. 
The 5-HT1A receptor partial agonist buspirone alleviates motor disorders such as neuroleptic induced parkinsonism and extrapyramidal symptoms.  These observations are disclosed in U.S. Pat.  No.  4,438,119.  Furthermore 5-HT1A agonists reverse neuroleptic-induced catalepsy in rodents, which mimic movement impairments observed in Parkinson's disease (Mark J. Millan, Journal of Pharmacology and Experimental Therapeutics, 2000, Vol.  295, p 853-861).  Thus, aripiprazole can be used to manage psychosis in geriatric patients, Alzheimer's disease, Parkinson's disease or senile dementia, since it possesses potent, partial agonistic activities at D2 and 5-HT1A receptors.  In addition, these patients might not experience extrapyramidal symptoms due to this property of aripiprazole. 
Heretofore, schizophrenia is understood to be caused by hyperactivity in the brain dopaminergic system.  For this reason, some drugs were developed with strong dopaminergic receptor blocking activity.  These typical antipsychotic drugs are effective in the treatments for the positive symptoms of schizophrenia, which include hallucinations, delusions and the like.  During the last decade, a variety of atypical anti-psychotic drugs have been developed, which include clozapine, risperidone, olanzapine, quetiapine.  These drugs have less extrapyramidal side effects, and have other activities in addition to their DA-receptor blocking activities.  In contrast to typical anti-psychotic drugs, such as chlorpromazine, haloperidol, etc.,  it is reported that atypical antipsychotic drugs are more effective against the negative symptoms and cognitive impairments associated with schizophrenia than typical antipsychotic drugs, and atypical antipsychotic drugs also have less extrapyramidal side effects (S. Miyamoto, G. E. Duncan, R. B. Mailman and J. A. Lieberman: Current Opinion in CPNS Investigational Drugs, Vol.  2, pp.  25, (2000)).  However, even though atypical antipsychotic drugs provide a suitable pharmacotherapy for schizophrenia, certain patients are resistant to the antipsychotic therapies of these drugs.  These patients may either not respond or may become refractory (i.e. may feel more anxious, depressed or cognitive dysfunction) in response to antipsychotic therapy.  These treatment-resistant patients pose a problem for how a physician may provide an appropriate therapy. 
At present, a number of treatment-resistant and treatment-refractory schizophrenic patients display symptoms that do not respond adequately to a variety of known effective classes and doses of typical or atypical antipsychotic drugs.  Furthermore, these patients may also be inveterate schizophrenia or chronic schizophrenics who are often repeatedly admitted to and discharged from hospitals (R. R. Conely and R. W. Buchanan: Schizophr.  Bull.,  Vol.  23, pp.  663, (1997)). 
Symptoms of patients corresponding to treatment-resistant and treatment-refractory schizophrenics involve not only the positive symptoms, but also the negative symptoms and emotional disorders, as well as cognitive impairments (i.e., cognitive dysfunction or cognitive disturbances) (K. Akiyama and S. Watanabe: Jpn.  J. Clin.  Psychopharmacol.,  Vol.  3, pp.  423, (2000)). 
Cognitive impairment exists separately from the psychic symptoms in a schizophrenic individual.  Thus, medical treatment is therefore quite important, because the cognitive impairment may disturb the socially adaptable behavior of these individuals (C. Hagger, P. Buckley, J. T. Kenny, L. Friedman, D. Ubogy and H. Y. Meltzer: Biol.  Psychiatry, Vol.  34, pp.  702, (1993); T. Sharma and D. Mockler: J. Clin.  Psycho-pharmacol.,  Vol.  18, (Supp).  1), pp.  128, (1998)). 
At present, clozapine is an antipsychotic drug that is effective against treatment-resistant schizophrenia.  Clozapine (marketed under the name of Clozaril) was approved in 1990 by FDA for the treatment and management of severely ill schizophrenics who failed to respond adequately to standard antipsychotic therapy (M. W. Jann: Pharmacotherapy, Vol.  11, pp.  179, (1991)).  Clozapine has been reported to be effective against cognitive impairments in treatment-resistant schizophrenics (C. Hagger, P. Buckley, J. T. Kenny, L. Friedman, D. Ubogy and H. Y. Meltzer: Biol.  Psychiatry, Vol.  34, pp.  702, (1993); M. A. Lee, P. A. Thompson and H. Y. Meltzer: J. Clin.  Psychiatry, Vol.  55 (Suppl.  B), pp.  82, (1994); D. E. M. Fujii, I. Ahmed, M. Jokumsen and J. M. Compton: J. Neuropsychiatry Clin.  Neurosci.,  Vol.  9, pp.  240, (1997)).  For example, it is reported that clozapine improves cognitive impairments in attention, response time, fluent-speech, etc.  in treatment-resistant schizophrenics (M. A. Lee, P. A. Thompson and H. Y. Meltzer: J. Clin.  Psychiatry, Vol.  55 (Suppl.  B), pp.  82, (1994)).  It has been also reported that clozapine provides effective improvements in cognitive impairments in an objective evaluation scale of the Wechsler Adult Intelligence Scale-Revised Full Scale (D. E. M. Fujii, I. Ahmed, M. Jokumsen and J. M. Compton: J. Neuropsychiatry Clin.  Neurosci.,  Vol.  9, pp.  240, (1997)). 
The 5-HT1A receptor has been demonstrated to play a role in the therapeutic efficacy of clozapine against treatment-resistant schizophrenia and cognitive impairments.  This relation ship was revealed by a binding experiment using human the 5-HT1A receptors (S. L. Mason and G. P. Reynolds: Eur.  J. Pharmacol.,  Vol.  221, pp.  397, (1992)).  Further, in accordance with progress in molecular pharmacology, it is clearly understood that 5-HT1A receptor agonistic activity or 5-HT1A receptor partial agonistic activity plays an important role in treatment-resistant schizophrenia and cognitive impairments (A. Newman-Tancredi, C. Chaput, L. Verriele and M. J. Millan: Neuropharmacology, Vol.  35, pp.  119, (1996)).  Additionally, it was reported that the number of 5-HT1A receptor is increased in the prefrontal cortex of chronic schizophrenics who were classified treatment-resistant.  This observation was explained by a compensatory process where by the manifestation of severe symptoms of chronic schizophrenia are a result of impaired neuronal function mediated by hypofunctional 5-HT1A receptors (T. Hashimoto, N. Kitamura, Y. Kajimoto, Y. Shirai, O, Shirakawa, T. Mita, N. Nishino and C. Tanaka: Psycho-pharmacology, Vol.  112, pp.  S35, (1993)).  Therefore, a lowering in neuronal transmission mediated through 5-HT1A receptors is expected in treatment-resistant schizophrenics.  Thus the clinical efficacy of clozapine may be related to its partial agonist efficacy at the 5-HT1A receptors (A. Newman-Tancredi, C. Chaput, L. Verriele and M. J. Millan: Neuropharmacology, Vol.  35, pp.  119, (1996)).  5-HT1A receptor agonistic activity may be related to the clinical effects of clozapine, and this hypothesis is supported by a positron emission tomography study in primates which showed that clozapine interacts with brain 5-HT1A receptors at a therapeutically effective dose (Y. H. Chou, C. Halldin and L. Farde: Int.  J. Neuropsycho-pharmacol.,  Vol.  4 (Suppl.  3), pp.  5130, (2000)).  Furthermore tandospirone, which is known as a selective 5-HT1A receptor agonist, improved cognitive impairments in chronic schizophrenic patients (T. Sumiyoshi, M. Matsui, I. Yamashita, S, Nohara, T. Uehara, M. Kurachi and H. Y. Meltzer: J. Clin.  Pharmacol.,  Vol.  20, pp.  386, (2000)).  While, in animal tests, all reports do not always suggest that 5-HT1A receptor agonist activity may be related to cognitive impairment, however, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), which is known as a selective 5-HT1A receptor agonist, improves learning and memory impairments induced by scopolamine known as a muscarinic receptor antagonist, suggesting a relationship between 5-HT1A receptor agonistic activity and improvements in cognitive impairments (M. Carli, P. Bonalumi, R. Samanin: Eur.  J. Neurosci.,  Vol.  10, pp.  221, (1998); A. Meneses and E. Hong: Neurobiol.  Learn.  Mem.,  Vol.  71, pp.  207, (1999)). 
Atypical antipsychotic drugs, such as risperidone and olanzapine, were marketed after clozapine, and it is reported that these drugs improve treatment-resistant schizophrenia or cognitive impairments in treatment-resistant schizophrenics (M. F. Green, B. D. Marshall, Jr., W. C. Wirshing, D. Ames, S. R. Marder, S. McGurck, R. S. Kern and J. Mintz: Am.  J. Psychiatry, Vol.  154, pp.  799, (1997); G. Bondolifi, H. Dufour, M. Patris, J. P. May, U. Billeter, C. B. Eap.  and P. Baumann, on behalf of the risperidone Study Group: Am.  J. Psychiatry, Vol.  155, pp.  499, (1998); A. Breier, S. H. Hamilton: Biol.  Psychiatry, Vol.  45, pp.  403, (1999)). 
In contrast to reports that clozapine was moderately effective against treatment-resistant schizophrenia, risperidone and olanzapine were not consistently superior to typical antipsychotic drugs in their effectiveness against treatment-resistant schizophrenia.  Thus, risperidone and olanzapine bind with lower affinity to human 5-HT1A receptors (S. Miyamoto, G. E. Duncan, R. B. Mailman and J. A. Lieberman: Current Opinion in CPNS Investigational Drugs, Vol.  2, pp.  25, (2000)), and as such these drugs can not clearly perform activities through human 5-HT1A receptors at clinical effective doses. 
Therefore, at present, it is understood that clozapine is effective against treatment-resistant schizophrenia (D. W. Bradford, M. H. Chakos, B. B. Sheitman, J. A. Lieberman: Psychiatry Annals, Vol.  28, pp.  618, (1998); A. Inagaki: Jpn.  J. Clin.  Psychopharmacol.,  Vol.  3, pp.  787, (2000)). 
As explained above, 5-HT1A receptor agonistic activity is important for improving treatment-resistant schizophrenia or cognitive impairment caused by treatment-resistant schizophrenia.  Clozapine is effective against treatment-resistant schizophrenia, however, its use is limited due to its severe side-effect of producing agranulocytosis which requires patients to undergo periodical blood tests.  Under these circumstances, the development of a safe anti-psychotic drug with potent, full or partial agonist activity at 5-HT1A receptors is earnestly desired. 
The carbostyril compound in the present invention binds with high affinity, and displays a potent, partial agonist activity at the 5-HT1A receptors and it has higher intrinsic activity (about 68%) as compared with that of clozapine.  Therefore, the compound in the present invention has a 5-HT1A receptor agonistic activity that is more potent than the agonistic activity of clozapine.  Thus, the present carbostyril compound may represent a more potent and highly safe drug for curing treatment-resistant schizophrenia, cognitive impairments caused by treatment-resistant schizophrenia, inveterate schizophrenia, cognitive impairments caused by inveterate schizophrenia, chronic schizophrenia, cognitive impairments caused by chronic schizophrenia and the like, as compared with other currently available pharmacotherapeutic treatments.  That is, the compound in the present invention may prove to be a potent and safer drug therapy for treatment-resistant schizophrenia, cognitive impairments caused by treatment-resistant schizophrenia, inveterate schizophrenia, cognitive impairments caused by inveterate schizophrenia, chronic schizophrenia, or cognitive impairments caused by chronic schizophrenia, etc.,  which fail to respond adequately to currently available antipsychotic drugs such as chlorpromazine, haloperidol, sulpiride, fluphenazine, perphenazine, thioridazine, pimozide, zotepine, risperidone, olanzapine, quetiapine, amisulpride, etc. 
In particular, the carbostyril compound in the present invention may be a potent and highly safe drug therapy against treatment-resistant schizophrenia, cognitive impairments caused by treatment-resistant schizophrenia, inveterate schizophrenia, cognitive impairments caused by inveterate schizophrenia, chronic schizophrenia or cognitive impairments caused by chronic schizophrenia, etc.  which fail to respond adequately to both of 1 to 3 typical antipsychotic drugs selected from the group consisting of chlorpromazine, haloperidol and perphenazine, and one atypical antipsychotic drug selected from the group consisting of risperidone, olanzapine, quetiapine and amisulpride. 
Moreover, the compound in the present invention may be a potent and highly safe drug therapy against treatment-resistant schizophrenia, cognitive impairments caused by treatment-resistant schizophrenia, inveterate schizophrenia, cognitive impairment caused by inveterate schizophrenia, chronic schizophrenia or cognitive impairment caused by chronic schizophrenia, etc.  which fail to respond adequately to both of 2 typical antipsychotic drugs selected from the group consisting of chlorpromazine, haloperidol and perphenazine, and one atypical antipsychotic drug selected from the group consisting of risperidone, olanzapine, quetiapine and amisulpride. 
Moreover, the compound in the present invention may be a potent and highly safe drug therapy against treatment-resistant schizophrenia, cognitive impairments caused by treatment-resistant schizophrenia, inveterate schizophrenia, cognitive impairments caused by inveterate schizophrenia, chronic schizophrenia, or cognitive impairment caused by chronic schizophrenia, etc.  which fail to respond adequately to both of 1 to 2 typical antipsychotic drugs selected from the group consisting of chlorpromazine and haloperidol, and one atypical antipsychotic drug selected from the group consisting of risperidone, olanzapine, quetiapine and amisulpride. 
Moreover, the compound in the present invention may be a potent and highly safe drug therapy against treatment-resistant schizophrenia, cognitive impairments caused by treatment-resistant schizophrenia, inveterate schizophrenia, cognitive impairment caused by inveterate schizophrenia, chronic schizophrenia or cognitive impairment caused by chronic schizophrenia, etc.  which fail to respond adequately to both of 2 typical antipsychotic drugs selected from the group consisting of chlorpromazine and haloperidol, and one atypical antipsychotic drug selected from the group consisting of risperidone, olanzapine, quetiapine and amisulpride.