throbber
(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2002/0173513 A1
`Jordan et al.
`(43) Pub. Date:
`NOV. 21, 2002
`
`US 20020173513A1
`
`(54) 5HT1A RECEPTOR SUBTYPE AGONIST
`
`(52) US. Cl. ...................................................... .. 514/253.07
`
`(76) Inventors: Shaun Jordan, GerrnantoWn, MD (US);
`Tetsuro Kikuchi, Tokushirna-shi (JP);
`Katsura Tottori, Karniita-cho (JP);
`Tsuyoshi Hirose, Tokushirna-shi (JP);
`Yasufumi Uwahodo Tokushimebshi
`(JP)
`’
`
`correspondence Address:
`Finnegan’ Henderson’ Farabow’
`Garrett & Dunner, LLP
`1300 I Street, NW.
`Washington, DC 20005-3315 (US)
`
`(21) Appl. No.:
`
`10/055,915
`
`(22) Filed:
`
`Jan. 28, 2002
`
`Related US. Application Data
`
`(57)
`
`ABSTRACT
`
`.
`.
`.
`The present invention relates to a method of treating a
`patient suffering from a disorder of the central nervous
`system associated With 5-HT1A receptor subtype, compris
`ing as an active ingredient a carbostyril derivative or a salt
`thereof represented by the formula (1):
`
`(1)
`
`C1
`
`(60) Provisional application No. 60/331,370, ?led on Jan.
`29, 2001, noW abandoned.
`
`O(CH2)4—N
`
`N
`
`Publication Classi?cation
`
`(51)
`
`Int. Cl.7 ................................................ .. A61K 31/496
`
`Wherein the carbon-carbon bond betWeen 3- and 4-positions
`in the carbostyril skeleton is a single or a double bond.
`
`
`
`Page 1 of 8
`
`OTSUKA EXHIBIT 2003
`ALKERMES v. OTSUKA
`IPR2017-00287
`
`

`

`US 2002/0173513 A1
`
`Nov. 21, 2002
`
`5HT1A RECEPTOR SUBTYPE AGONIST
`
`BACKGROUND OF THE INVENTION
`
`[0001] 1. Field of the Invention
`
`[0002] The present invention relates to a method of treat
`ing 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.
`
`[0003] 2. Related Art
`[0004] US. 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 bene?cial drug treatments
`for schiZophrenia.
`[0005] Carbostyril compounds, as Well as those disclosed
`in Japanese Patent Kokai (Laid-open)9-301,867 (1997) are
`useful for the treatment of anxiety.
`[0006] The carbostyril derivatives disclosed in European
`Patent No. 226,441 have the genus of the carbostyril deriva
`tives in the present invention, and they are useful for the
`treatment of hypoxia.
`
`[0007] In addition to the above, the carbostyril derivatives
`disclosed in US. Pat. No. 4,734,416; Canadian Patent No.
`1,117,110; British Patent No. 2,017,701; German Patent
`Nos. 2,911,108, 1,912,105 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 car
`bostyril derivatives in the present invention, and they have
`antihistaminic activities and central nervous controlling
`activities.
`
`[0008] It is reported that aripipraZole (7-{4-[4-(2,3-dichlo
`rophenyl)-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).
`[0009] Further, it is reported that aripipraZole possesses
`presynaptic dopaminergic autoreceptor agonistic activity,
`postsynaptic D2 receptor antagonistic activity, and D2 recep
`tor 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)).
`[0010] HoWever, it has not been reported that compounds
`in the present invention have agonistic activity at 5-HT1A
`receptor subtype.
`[0011] It has been reported that therapeutic interventions
`using 5-HT1A receptor ligands may be useful drug treat
`ments for alcohol abuse (Mark Kleven et al., European
`Journal of Pharmacology, Vol. 281, (1995) pp. 219-228).
`[0012] 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 (US. Pat. No. 5,162,375).
`
`[0013] It is also reported that 5-HT1A receptor hypersen
`sitivity could be the biological basis for the increased
`frequency of migraine attack in stressful and anxious con
`ditions (Massimo Leone et al., Neuro Report, Vol. 9, pp.
`2605-2608(1998)).
`[0014] 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 neuroprotec
`tive, anxiolytic- and antidepressant-like effects in animal
`models (Jean De Vry et al., European Journal of Pharma
`cology, Vol. 357, (1998), pp. 1-8).
`[0015] 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; AB Al?eri 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).
`[0016] 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 dis
`closes 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 Parkin
`son’s disease.
`
`[0017] 5HT1A agonists are effective in the treatment of
`cognitive impairment in AlZheimer’s disease, Parkinson’s
`disease or senile dementia. US. Pat. No. 5,824,680 discloses
`that a 5-HT1A agonist, ipsapirone, is effective in treating
`AlZheimer’s disease by improving memory. US. Pat. No.
`4,687,772 describes that a 5 -HT1Apartial 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 AlZhe
`imer’s disease, Parkinson’s disease or senile dementia.
`
`[0018] 5HT1A agonists are also effective in the treatment
`of depression. US. Pat. No. 4,771,053 describes that a
`5-HT1A receptor partial agonist, gepirone, is useful in alle
`viation 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 effec
`tively treat depression.
`[0019] The 5 -HT1A receptor partial agonist buspirone alle
`viates motor disorders such as neuroleptic induced parkin
`sonism and extrapyramidal symptoms. These observations
`are disclosed in US. 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 Pharmacol
`ogy and Experimental Therapeutics, 2000, Vol. 295, p853
`861). Thus, aripipraZole can be used to manage psychosis in
`
`
`
`Page 2 of 8
`
`

`

`US 2002/0173513 A1
`
`Nov. 21, 2002
`
`geriatric patients, AlZheimer’s disease, Parkinson’s disease
`or senile dementia, since it possesses potent, partial agonis
`tic activities at D2 and 5-HT1A receptors. In addition, these
`patients might not experience extrapyramidal symptoms due
`to this property of aripipraZole.
`[0020] 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 halluci
`nations, delusions and the like. During the last decade, a
`variety of atypical antipsychotic drugs have been developed,
`Which include cloZapine, risperidone, olanZapine, quetiap
`ine. These drugs have less extrapyramidal side effects, and
`have other activities in addition to their DA-receptor block
`ing activities. In contrast to typical antipsychotic 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 pharmaco
`therapy 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.
`[0021] At present, a number of treatment-resistant and
`treatment-refractory schiZophrenic patients display symp
`toms that do not respond adequately to a variety of knoWn
`effective classes and doses of typical or atypical antipsy
`chotic drugs. Furthermore, these patients may also be invet
`erate 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)).
`[0022] 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 distur
`bances)
`Akiyama and S. Watanabe: Jpn. J. Clin. Psy
`chopharmacol., Vol. 3, pp. 423, (2000)).
`[0023] 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. Psychopharmacol., Vol. 18, (Suppl. 1), pp.
`128, (1998)).
`[0024] At present, cloZapine is an antipsychotic drug that
`is effective against treatment-resistant schiZophrenia. CloZa
`pine (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: Pharmaco
`therapy, 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, ?uent-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)).
`[0025] The 5-HT1A receptor has been demonstrated to
`play a role in the therapeutic efficacy of cloZapine against
`treatment-resistant schiZophrenia and cognitive impair
`ments. This relation ship Was revealed by a binding experi
`ment 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 pharma
`cology, it is clearly understood that 5-HT1A receptor ago
`nistic 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 classi?ed treat
`ment-resistant. This observation Was explained by a com
`pensatory 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)). There
`fore, a loWering in neuronal transmission mediated through
`5-HT1A receptors is expected in treatment-resistant schiZo
`phrenics. Thus the clinical efficacy of cloZapine may be
`related to its partial agonist ef?cacy 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
`H. Chou, C. Halldin
`and L. Farde: Int. J. Neuropsychopharmacol., Vol. 4 (Suppl.
`3), pp. S130, (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
`
`
`
`Page 3 of 8
`
`

`

`US 2002/0173513 A1
`
`Nov. 21, 2002
`
`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 improve
`ments 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)).
`[0026] Atypical antipsychotic drugs, such as risperidone
`and olanZapine, Were marketed after cloZapine, and it is
`reported that these drugs improve treatment-resistant schiZo
`phrenia 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. Bondoli?, 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)).
`[0027] In contrast to reports that cloZapine Was moderately
`effective against treatment-resistant schiZophrenia, risperi
`done and olanZapine Were not consistently superior to typi
`cal antipsychotic drugs in their effectiveness against treat
`ment-resistant schiZophrenia. Thus, risperidone and
`olanZapine bind With lower affinity to human 5-HT1A recep
`tors (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 recep
`tors at clinical effective doses.
`
`[0028] Therefore, at present, it is understood that cloZap
`ine is effective against treatment-resistant schiZophrenia (D.
`W. Bradford, M. H. Chakos, B. B. Sheitman, J. A. Lieber
`man: Psychiatry Annals, Vol. 28, pp. 618, (1998); A. Ina
`gaki: Jpn. J. Clin. Psychopharmacol., Vol. 3, pp. 787,
`(2000)).
`[0029] 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 treat
`ment-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-psy
`chotic drug With potent, full or partial agonist activity at
`5-HT1A receptors is earnestly desired.
`[0030] 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 car
`bostyril compound may represent a more potent and highly
`safe drug for curing treatment-resistant schiZophrenia, cog
`nitive impairments caused by treatment-resistant schiZo
`phrenia, 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 phar
`macotherapeutic 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 cogni
`tive impairments caused by chronic schiZophrenia, etc.,
`Which fail to respond adequately to currently available
`antipsychotic drugs such as chlorpromaZine, haloperidol,
`sulpiride,
`?uphenaZine,
`perphenaZine,
`thioridaZine,
`pimoZide, Zotepine, risperidone, olanZapine, quetiapine,
`amisulpride, etc.
`
`[0031] 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 antipsy
`chotic drugs selected from the group consisting of chlorpro
`maZine, haloperidol and perphenaZine, and one atypical
`antipsychotic drug selected from the group consisting of
`risperidone, olanZapine, quetiapine and amisulpride.
`
`[0032] 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 impair
`ment caused by chronic schiZophrenia, etc. Which fail to
`respond adequately to both of 2 typical antipsychotic drugs
`selected from the group consisting of chlorpromaZine, halo
`peridol and perphenaZine, and one atypical antipsychotic
`drug selected from the group consisting of risperidone,
`olanZapine, quetiapine and amisulpride.
`
`[0033] 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, cognitive impair
`ments 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, olanZap
`ine, quetiapine and amisulpride.
`
`[0034] 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 impair
`ment 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, que
`tiapine and amisulpride.
`
`
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`US 2002/0173513 A1
`
`Nov. 21, 2002
`
`SUMMARY OF THE INVENTION
`
`[0035] It is an object of the present invention to provide a
`method of treating a patient suffering from a disorder of the
`central nervous system associated With the 5-HT1A receptor
`subtype.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0036] As the 5 -HT1A receptor subtype agonist compound
`for use in accordance With the present invention, carbostyril
`derivatives represented by the following formula (1) are
`used:
`
`(1)
`
`Cl
`
`[0037] Wherein the carbon-carbon bond betWeen 3- and
`4-positions in the carbostyril skeleton is a single or a double
`bond.
`[0038] The compounds of the forgoing general formula (1)
`are knoWn compounds, Which are disclosed in publication
`such as US. Pat. No. 5,006,528 or Which can be readily
`prepared by the processes described in the above publica
`tion.
`[0039] The carbostyril derivative represented by the for
`mula (1) in the present invention can easily be converted into
`its acid-addition salt by reacting it With a pharmaceutically
`acceptable acid. Examples of such acid include inorganic
`acids, such as hydrochloric acid, sulfuric acid, phosphoric
`acid, hydrobromic acid and the like; organic acids, such as
`oxalic acid, maleic acid, fumaric acid, malic acid, tartaric
`acid, citric acid, benZoic acid and the like.
`
`[0040] The solvent of solvates is a solvent conventionally
`used in recrystalliZation. Examples of solvates include hemi
`hydrates, hydrates, and alcoholates, such as ethanolates,
`methanolates, isopropanolates and the like.
`[0041] The desired compounds, prepared by the reactions
`mentioned above, can easily be isolated and puri?ed by
`usual separation procedures such as solvent extraction, dilu
`tion, recrystalliZation, column chromatography, preparative
`thin layer chromatography and the like.
`[0042] The potent, partial 5-HT1A receptor agonist in the
`present invention is useful for various disorders of the
`central nervous system associated With the 5-HT1A receptor
`subtype that induces bipolar disorders, such as bipolar I
`disorder With most recent hypomanic, manic, mixed,
`depressed or unspeci?ed episode; bipolar II disorder With
`recurrent major depressive episodes With hypomanic epi
`sodes, and cyclothymic disorder; depression, such as endog
`enous depression, major depression, melancholia, and treat
`ment-resistant depression; panic disorder; obsessive
`
`compulsive disorder (OCD); sleep disorders; sexual dys
`function; alcohol abuse and drug addiction; cognitive
`impairment; neurodegenerative diseases, such as AlZhe
`imer’s disease, Parkinson’s disease and the like, cognitive
`impairments caused by neurodegenerative diseases such as
`AlZheimer’s disease, Parkinson’s disease and related disor
`ders; emesis; motion sickness; obesity; migraine; autism;
`DoWn’s syndrome; attention-de?cit hyper-activity disorder
`(ADHD); treatment-resistant, inveterate or chronic schiZo
`phrenia, (Which fail to respond adequately to currently
`available antipsychotic drugs); cognitive impairments
`caused by treatment-resistant schiZophrenia, inveterate
`schiZophrenia or chronic schiZophrenia and the like.
`
`[0043] Compounds of the present invention may be suit
`ably prepared into pharmaceutically acceptable formulations
`(see US. Pat. No. 5,006,528, European Patent No. 367,141
`and Japanese Kokai (Laid-open) 7-304,740 (1995), and
`Japanese Patent Application No. 2000-194976 incorporated
`by reference herein).
`[0044] The dosage of these pharmaceutical preparations of
`the invention may be selected appropriately depending on
`the method of administration, the patient’s age, sex and
`other factors, severity of the disease and other factors.
`Generally, hoWever, the daily dose of the active ingredient
`compound is preferably Within the range of about 0.0001 to
`about 50 mg per kilogram of body Weight. It is desirable that
`the active ingredient compound be contained in each unit
`dosage form in an amount of about 0.001 to about 1,000 mg,
`particularly 0.01 to 100 mg, more particularly 0.1 to 50 mg,
`yet more particularly 1 mg to 20 mg.
`[0045] Pharmacological Tests
`[0046] 1. Materials and Methods
`[0047] 1.1 Test Compound
`[0048] 7-{4-[4-(2,3-Dichlorophenyl)-1-piperaZinyl]-bu
`toxy}-3,4-dihydrocarbostyril (aripipraZole) Was used as test
`compound.
`[0049] 1.2 Reference Compounds
`[0050] Serotonin (5-HT) and WAY-100635 (N-[2-[4-(2
`methoxyphenyl)-1-piperaZinyl]ethyl]-N-(2-pyridimyl)-cy
`clohexanecarboxamide, a 5-HT1A receptor antagonist,
`manufactured by RBI (Natick, Mass.) Were used as refer
`ence compounds.
`
`[0051] 1.3 Vehicle
`[0052] Dimethyl sulfoxide (DMSO) manufactured by
`Sigma Chemical Co. (St. Louis, Mo.) Was used as vehicle.
`[0053] 1.4 Preparation of Test and Reference Compounds
`
`[0054] Test compound Was dissolved in 100% dimethyl
`sulfoxide (DMSO) to yield 100 pM stock solutions (?nal
`concentration of DMSO in all tubes containing test com
`pound Was 1%, v/v). All other reference compounds Were
`prepared by the same method using double-distilled Water
`rather than DMSO.
`
`[0055] 1.5 Experimental Procedure for the [3SS]GTPYS
`Binding Assay
`[0056] Test and reference compounds Were studied in
`triplicate at 10 different concentrations (0.01, 0.1, 1, 5, 10,
`50, 100, 1000, 10000 and 50000 nM) for their effects upon
`
`
`
`Page 5 of 8
`
`

`

`US 2002/0173513 A1
`
`Nov. 21, 2002
`
`basal [35S] GTP S binding to h5-HT1A CHO cell mem
`branes. Reactions Were performed in 5 ml glass test tubes
`containing 8 pl of test/reference drug mixed With 792 pl of
`buffer (25 mM Tris HCl, 50 mM NaCl, 5 mM MgCl2, 0.1
`mM EGTA, pH=7.4) containing GDP (1 pM), [3SS]GTPYS
`(0.1 nM) and hS-HT1A CHO cell membranes (10 pg protein/
`reaction; NEN Life Science Products, Boston, Mass.; cata
`log #CRM035, lot #501-60024, GenBank # X13556). Reac
`tions proceeded for 60 min at room temperature and Were
`terminated by rapid ?ltration through Whatman GF/B ?lter
`paper, using a Brandel harvester and 4x3 ml ice-cold buffer
`Washes. S radioactivity bound to the ?lter paper Was mea
`sured using liquid scintillation counting (1272 Clinigamma,
`LKB/Wallach).
`[0057] 1.6 Experimental Procedure to Determine the
`Binding Af?nity of Test compound (aripipraZole) at the
`h5 -HT1A Receptor
`
`[0058] Test compound Was studied in triplicate at 10
`different concentrations (0.01, 0.1, 1, 10, 50, 100, 500, 1000,
`5000 and 10000 nM) to determine its displacement of
`[3H]8-OH-DPAT (1 nM; NEN Life Sciences; catalog #NET
`929, lot #3406035, Speci?c Activity =124.9 Ci/mmol) bind
`ing to h5-HT1A receptors in CHO cell membranes (15-20 pg
`protein; NEN Life Science Products, catalog #CRM035, lot
`#501-60024). Membranes (396 pl) Were incubated in 5 ml
`glass tubes containing [3H]8-OH-DPAT (396 pl), test com
`pound or vehicle (8 pl) and buffer A (50 mM Tris.HCl, 10
`mM MgSO41 0.5 mM EDTA, 0.1% (W/v) ascorbic acid, pH
`=7.4). All assays proceeded for 60 min at room temperature
`and Were terminated by rapid ?ltration through Whatman
`GF/B ?lter paper (presoaked in buffer B; 50 mM Tris.HCl,
`pH=7.4), using a Brandel harvester and 4x1 ml ice-cold
`Washes With buffer B. Non-speci?c binding Was determined
`in the presence of 10 pM (+)8-OH-DPAT. 1.7 Parameters
`Determined Serotonin (5-HT) is a full 5-HT1A receptor
`agonist Which stimulates increases in basal [3SS]GTPYS
`binding to h5-HT1A receptors in recombinant CHO cell
`membranes. Test compound Was studied at 10 concentra
`tions to determine their effects upon basal [3SS]GTPYS
`binding relative to that produced by 10 pM 5-HT. The
`relative potency (ECSO, 95% con?dence interval) and intrin
`sic agonist activity (% of ErnaX for 10 pM 5-HT) Was
`calculated for each compound by computeriZed non-linear
`regression analysis of complete concentration-effect data.
`The binding affinity of test compound at the h5-HT1A
`receptor Was determined by its ability to prevent [3H]8-OH
`DPAT binding to CH0 cell membranes that express this
`receptor. Non-linear regression analysis of the competition
`binding data Was used to calculate an inhibition constant
`(ICSO, 95% con?dence interval), Which is the concentration
`of test compound that occupies half of the h5-HT1A sites
`speci?cally bound by [3H]8-OH-DPAT. The af?nity of
`h5-HT1A receptors for test compound (Ki, 95% con?dence
`interval) Was calculated by the equation, Ki=(IC5O)/(1+(
`[[3H]8-OH-DPAT]/Kd), Where the Kd for [3H]8-OH-DPAT
`at h5-HT1A=0.69 nM (NEN Life Sciences). All estimates of
`drug binding affinity, potency and intrinsic ef?cacy at the
`h5-HT1A receptor Were calculated using GraphPad Prism
`version 3.00 for WindoWs (GraphPad SoftWare, San Diego,
`Calif.).
`
`[0059] 2. Results
`
`[0060] Test compound and 5-HT produced concentration
`dependent increases above basal [3SS]GTPYS binding. 1%
`DMSO tested alone had no effect upon basal or drug
`induced [3SS]GTPYS binding.
`[0061] Test compound (EC5O=2.12 nM), 5-HT (EC5O=
`3.67 nM), potently stimulated basal [3SS]GTPYS binding.
`Potency and intrinsic agonist ef?cacy estimates Were derived
`by non-linear regression analysis With correlation coef?
`cients (r2)>0.98 in each case (Table 1). Test compound
`exerted partial agonist ef?cacies in the 65-70% range. WAY
`100635 produced no signi?cant change (unpaired Student’s
`t-test) in basal [3SS]GTPYS 5 binding at all concentrations
`tested (Table 1). WAY-100635 did, hoWever, completely
`inhibit the effects of 5-HT and test compound upon [35S]
`GTPYS binding to h5-HT1A receptors in CHO cell mem
`branes (Table 2). Tables 1 and 2 are shoWn beloW.
`[0062] Test compound demonstrated high affinity binding
`to h5-HT1A receptors in CHO cell membranes (IC504.03
`nM, 95% con?dence interval=2.67 to 6.08 nM; Ki=1.65 nM,
`95% con?dence interval=1.09 to 2.48
`
`TABLE 1
`
`Potency (ECSU) and Intrinsic Agonist E?icacy
`(Em) of Test compound and Reference Drugs in a
`h5-HT1a 35S GTP S CHO-cell Membrane Binding Assay.
`
`Drug
`
`Test
`Compound
`5-HT
`
`ECSU, nM
`(95% Con?dence
`Interval)
`
`2.12
`(0.87 to 5.16)
`3.67
`(1.56 to 8.63)
`
`Emax
`(% 1 SEM)
`
`Goodness of Fit
`(r2)
`
`68.13 1 3.16
`
`0.986
`
`98.35 1 4.47
`
`0.986
`
`WAY-100635
`
`—
`
`—
`
`—
`
`[0063]
`
`TABLE 2
`
`Inhibitory Potency (ICSU) of WAY-100635 versus
`1 pM Concentration of 5-HT and Test compound
`in a h5-HT1 [35S]GTP S CHO-cell Membrane Binding Assay.
`
`Drug Combination
`
`5-HT + WAY-100635
`
`Test compound +
`WAY-100635
`
`WAY- 1 000635 Inhibition
`Potency, IC50,nM
`(95% Con?dence
`Interval)
`
`Goodness of
`Fit
`(r2)
`
`217.1
`(127.4 to 369.7)
`392.2
`(224.1 to 686.2)
`
`0.988
`
`0.989
`
`What is claimed is:
`1. A method of treating a patient suffering from a disorder
`of the central nervous system associated With 5-HT1A recep
`tor subtype, Which comprises administering to said patient a
`therapeutically effective amount of a carbostyril compound
`of formula (1), pharmaceutically accept

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