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WO2005051399A1 - Derives de 7-phenylsulfonyl-tetrahydro-3-benzazepine utilises en tant qu'agents antipsychotiques - Google Patents

Derives de 7-phenylsulfonyl-tetrahydro-3-benzazepine utilises en tant qu'agents antipsychotiques Download PDF

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Publication number
WO2005051399A1
WO2005051399A1 PCT/EP2004/013551 EP2004013551W WO2005051399A1 WO 2005051399 A1 WO2005051399 A1 WO 2005051399A1 EP 2004013551 W EP2004013551 W EP 2004013551W WO 2005051399 A1 WO2005051399 A1 WO 2005051399A1
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methyl
disorder
tetrahydro
compound
pharmaceutically acceptable
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Carlo Castagnoli
Gabriella Gentile
Andrew H. Payne
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Glaxo Group Ltd
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Glaxo Group Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • This invention relates to the novel compound 7-[4-(3-fluoro-4-methyl-benzyl)- benzenesuIfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and pharmaceutically acceptable salts and solvates thereof, pharmaceutical compositions containing the compound and salts and solvates thereof and their use in therapy, in particular as antipsychotic agents.
  • novel compound of formula (I) and its pharmaceutically acceptable salts and solvates thereof have high affinities at desired receptors, exhibits good in vivo profiles and have good Drug Metabolism and Pharmacokinetics (DMPK) properties.
  • one or more chemical entities selected from 7-[4-(3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyI-2,3,4,5- tetrahydro-1H-3-benzazepine and a pharmaceutically acceptable salt and solvate thereof.
  • the terms “compound”, “compound of formula (I)” or “compound of the present invention” refer to the compound 7-[4-(3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8- methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (free base) and pharmaceutically acceptable salts and solvates thereof.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include water, methanol, ethanol and acetic acid.
  • the solvent used is water and the resulting solvate may also be referred to as a hydrate.
  • salts of formula (I) should be pharmaceutically acceptable.
  • suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include for example acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, malic, mandelic, acetic, fumaric, glutamic, lactic, citric, tartaric, benzoic, benzenesulfonic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
  • inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid
  • organic acids e.g. succinic, maleic, malic, mandelic, acetic, fumaric, glutamic, lactic, citric, tartaric, benzoic, benzenesulfonic, p-
  • salts of compounds of formula (I) include the hydrochloride, maleate, tosylate or mesylate salts or pharmaceutically acceptable solvates thereof.
  • Other non-physiologically acceptable salts e.g. oxalates, may be used, for example in the isolation of a compound of formula (I) and are included within the scope of this invention.
  • the scope of the invention includes salts, solvates and hydrates of the compound of formula (I).
  • the compound of formula (I) may form acid addition salts with one or more equivalents of the acid.
  • the present invention includes within its scope all possible stoichiometric and non- stoichiometric forms thereof.
  • one or more chemical entities selected from a salt of 7-[4-(3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine and solvates thereof.
  • one or more chemical entities selected from the tosylate salt of 7-[4-(3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8- methoxy-3-methyl-2,3,4,5-tetrahydro-1f -3-benzazepine and solvates thereof.
  • the tosylate may be obtained as a solvate and such a solvate also forms one aspect of the present invention.
  • the solvate may be a pharmaceutically acceptable solvate.
  • Suitable solvates include hydrates, such as monohydrate and trihydrate solvates.
  • tosylate is obtained as an anhydrate.
  • the anhydrate may contain less than 2% water, for example less than 1 % water.
  • one or more chemical entities selected from the tosylate and a pharmaceutically acceptable solvate thereof in isolated form In another aspect there is provided one or more chemical entities selected from the tosylate and a pharmaceutically acceptable solvate thereof which is substantially free of alternative salts, alternative solvates or free base of a compound of formula (I) or other impurity.
  • alternative solvates or free base of 7-[4-(3-fluoro-4- methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1/-/-3-benzazepine or other impurity is meant containing less than 10%, for example less than 5%, such as less than 2%, of alternative salts, alternative solvates or free base of 7-[4-(3-fluoro-4-methyl- benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine or other impurity.
  • other impurity includes any compound other than the 7-[4-(3-fluoro-4- methyl-benzyl)-benzenesulfonyI]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
  • the tosylate and a pharmaceutically acceptable solvate thereof may each be obtained in a non-crystalline or crystalline or alternative polymorphic form.
  • a tosylate hydrate of a compound of formula (I) for example, tosylate monohydrate or tosylate trihydrate.
  • precursors to the compound of formula (I) may possess a suitable protecting group R on the nitrogen atom of the benzazepine ring, (for example a t-butyloxycarbonyl group [BOC]), instead of the methyl group.
  • a suitable protecting group R on the nitrogen atom of the benzazepine ring for example a t-butyloxycarbonyl group [BOC]
  • Such protecting groups are used for example when it is easier to introduce the methyl substituent at the end of a synthetic route.
  • a suitable solvent such as tetrahydrofuran (THF)
  • Y zinc halide such as zinc chloride (ZnCI) or zinc bromide (ZnBr)
  • R is methyl or a suitable protecting group as described hereinbefore
  • W is a leaving group, such as chloro, bromo, iodo, or trifluoromethanesulfonate
  • a palladium catalyst for example palladium tetrakis(triphenylphosphine) [(Pd(Ph 3 ) 4 ] optionally at elevated temperature e.g. 60°C; and thereafter optionally for process (A): • removing any protecting groups;
  • W is Br and Y is ZnCI which can be conveniently carried out in an inert solvent e.g. tetrahydrofuran in the presence of palladium tetrakis(triphenylphosphine) at elevated temperature e.g. 60°C.
  • an inert solvent e.g. tetrahydrofuran in the presence of palladium tetrakis(triphenylphosphine) at elevated temperature e.g. 60°C.
  • the present invention also provides a general process (B) for preparing the compound of formula (I) which process comprises:
  • L is a leaving group, such as fluoro, chloro, C 1-6 alkoxy or aryloxy, R is methyl or a suitable protecting group as described hereinbefore and M is a metal, such as lithium or magnesium; and thereafter optionally for process (B):
  • This general method (B) can be conveniently performed by mixing the two components at preferably -78°C to room temperature in a suitable solvent such as tetrahydrofuran or ether for 10 minutes to 18 hours. Removal of certain R protecting groups e.g. trifluoroacetyl, can also take place simultaneously during this process.
  • a Lewis acid for example, indium(lll) trifluromethanesulfonate, tin(ll) trifluromethanesulfonate, bismuth(lll) chloride, or indium(lll) chloride, or mixtures thereof, and trifluoromethanesulfonic acid in a suitable solvent, for example, trifluoroacetic acid and, optionally, a co-solvent, for example dichloromethane.
  • Compounds of formula (IV) may be prepared by known processes, for example, chlorosulfonation of the aromatic ring of the benzazepine using chlorosulfonic acid. Conversion to the sulfonyl fluoride can be achieved, if required, by reaction with potassium fluoride in acetonitrile at room temperature. Suitable examples of an R group are methyl or protecting groups such as a trifluoroacetyl group.
  • L is bromo, for example by treatment with n-butyllithium at -78°C in a suitable solvent such as tetrahydrofuran.
  • a compound of formula (VI) may be prepared using methods as described in the literature, for example using the route as described in European Patent EP285287.
  • Compounds of formula (VII) may be prepared from 2-fluoro-4-bromotoluene, which is commercially available. Metallation by treatment with n-butyllithium in a suitable inert solvent such as tetrahydrofuran at -78°C or by formation of the corresponding Grignard reagent with magnesium turnings, followed by addition into 4-bromobenzaldehyde gives the corresponding benzhydrol. This in turn may be converted to the compound of formula (VII) wherein L is Br by treatment with triethylsilane and trifluoromethanesulfonic acid in an inert solvent such as chloroform, at 0°C to ambient temperature.
  • an inert solvent such as chloroform
  • R is other than a methyl group
  • R is used as a precursor to the compound of formula (I), or when it is easier to introduce the methyl substituent at the end of a synthetic sequence.
  • conversion of R from a t-butoxycarbonyl (BOC) group to hydrogen is conducted by the treatment of the N-BOC protected compound with hydrogen chloride in ethanol or dioxan at room temperature.
  • Conversion of R from hydrogen to methyl is conducted by the treatment of the NH compound with formaldehyde in dichloroethane in the presence of a reducing agent, such as sodium triacetoxyborohydride, or by the treatment of the NH compound with the appropriate methyl halide, such as iodomethane, under standard alkylation conditions [potassium carbonate in dimethylformamide (DMF) at 40°C].
  • a reducing agent such as sodium triacetoxyborohydride
  • a process for the preparation of the tosylate salt of 7-[4-(3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5- tetrahydro-1W-3-benzazepine comprising reacting 7-[4-(3-fluoro-4-methyl-benzyl)-benzene- sulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine with anhydrous p- toluenesulfonic acid in a suitable solvent, for example, ethyl acetate, tetrahydrofuran or acetic acid, at optionally elevated temperature, e.g. 60°C.
  • a suitable solvent for example, ethyl acetate, tetrahydrofuran or acetic acid
  • Solvates of a salt of 7-[4-(3-fluoro-4-methyl-benzyl)-benzenesulfonyI]-8-methoxy-3-methyl- 2,3,4,5-tetrahydro-1H-3-benzazepine may be prepared by conventional means from a solution of the salt of 7-[4-(3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyl- 2,3,4,5-tetrahydro-1H-3-benzazepine.
  • the monohydrate solvate of the tosylate salt may be prepared by reaction of 7-[4-(3-fluoro-4-methyl-benzyl)-benzene-sulfonyl]-8- methoxy-3-methyl-2,3,4,5-tetrahydro-1W-3-benzazepine with p-toluenesulfonic acid monohydrate in a suitable solvent, for example ethyl acetate, methanol, tetrahydrofuran or water, either at room temperature or elevated temperatures (for example up to the boiling point of the solvent used).
  • a suitable solvent for example ethyl acetate, methanol, tetrahydrofuran or water
  • Anhydrous p-toluenesulfonic acid in acetic acid and p-toluenesulfonic acid monohydrate are commercially available.
  • the phrase "7-[4-(3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3- methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and a pharmaceutically acceptable salt and solvate thereof is intended to mean 7-[4-(3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8- methoxy-3-methyl-2,3,4,5-tetrahydro-1 /-3-benzazepine or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate independently or mixtures of 7-[4-(3-fIuoro-4- methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, one or more pharmaceutically acceptable salts and one or more pharmaceutically acceptable solvates.
  • Figure I shows X-Ray powder diffraction (XPRD) data obtained for 7-[4-(3-fluoro-4-methyI- benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinium tosylate prepared as described in Example 3.
  • XPRD X-Ray powder diffraction
  • Example 3 The 7-[4-(3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro- 1H-3-benzazepinium tosylate as described in Example 3 is characterised by having an XRPD pattern with signals substantially as listed in Table 1.
  • Figure 2 shows the Raman spectrum of 7-[4-(3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8- methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinium tosylate prepared as described in Example 3.
  • Figure 3 shows a DSC thermogram of 7-[4-(3-fIuoro-4-methyl-benzyl)-benzenesulfonyl]-8- methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinium tosylate prepared as described in Example 3.
  • Figure 4 shows X-Ray powder diffraction (XPRD) data obtained for 7-[4-(3-fluoro-4-methyl- benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinium tosylate, monohydrate prepared as described in Example 4.
  • XPRD X-Ray powder diffraction
  • Figure 5 shows the Raman spectrum of 7-[4-(3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8- methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinium tosylate, monohydrate prepared as described in Example 4.
  • Figure 6 shows a DSC thermogram of 7-[4-(3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8- methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinium tosylate, monohydrate prepared as described in Example 4.
  • anhydrous tosylate salt of 7- [4-(4-chlorobenzyloxy)benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine characterised in that it provides an XRPD spectrum with signals substantially as listed in Table 1.
  • the monohydrate, tosylate salt of 7_[4-(4-chlorobenzyloxy)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine characterised in that it provides an XRPD spectrum substantially as illustrated in Figure 4.
  • the monohydrate, tosylate salt of 7-[4-(4-chlorobenzyloxy)benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine characterised in that it provides an XRPD spectrum with signals substantially as listed in Table 2.
  • the compound of formula (I) and its pharmaceutically acceptable salts and solvates thereof have also been found to exhibit affinity for the serotonin 5-HT2C. 5_ HT2A and 5-HTg receptors. These properties may give rise to anti-psychotic activity (e.g. improved effects on cognitive dysfunction) activity with reduced eps, and/or anxiolytic/antidepressant activity. These could include, but are not limited to, attenuation of cognitive symptoms via 5-HT 6 receptor blockade (see Reavill, C.
  • the invention provides one or more chemical entities selected from 7-[4-(3-fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5- tetrahydro-1AV-3-benzazepine and a pharmaceutically acceptable salt and solvate thereof for use in therapy.
  • the invention provides one or more chemical entities selected from 7-[4-(3- fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine and a pharmaceutically acceptable salt and solvate thereof for use in the treatment of a condition which requires modulation of a dopamine D3 receptor.
  • the invention provides one or more chemical entities selected from 7-[4-(3- fluoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine and a pharmaceutically acceptable salt and solvate thereof for use in the treatment of psychotic disorders.
  • the invention provides the use of one or more chemical entities selected from 7-[4-(3-fIuoro-4-methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine and a pharmaceutically acceptable salt and solvate thereof in the manufacture of a medicament for the treatment of a condition which requires modulation of a dopamine D3 receptor.
  • the invention provides the use of one or more chemical entities selected from 7-[4-(3-fluoro-4-methyl-benzyi)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine and a pharmaceutically acceptable salt and solvate thereof in the manufacture of a medicament for the treatment of psychotic disorders.
  • the invention provides a method of treating a condition which requires modulation of a dopamine D3 receptor, which comprises administering to a mammal in need thereof an effective amount of one or more chemical entities selected from 7-[4-(3-fluoro-4- methyl-benzyl)-benzenesulfonyI]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1 -3-benzazepine and a pharmaceutically acceptable salt and solvate thereof.
  • the invention provides a method of treating psychotic disorders which comprises administering to a mammal in need thereof an effective amount of one or more chemical entities selected from 7-[4-(3-fluoro-4-methyl-benzyl)-ben ⁇ enesulfonyl]-8-methoxy- 3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and a pharmaceutically acceptable salt and solvate thereof.
  • the term "psychotic disorder” includes Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).
  • Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311); Bipolar Disorders including Bipolar I Disorder, Bipolar II Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90): Anxiety disorders including Social Anxiety Disorder, Panic Attack, Agoraphobia, Panic Disorder, Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29) including the subtype
  • Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance- Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance- Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced sexual Dysfunction, Substance-Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol
  • Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type:
  • Eating disorders such as Anorexia Nervosa (307.1) including the subtypes Restricting Type and Binge-Eating/Purging Type; Bulimia Nervosa (307.51) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50): Autistic Disorder (299.00); Attention-Deficit /Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01) and Attention-Deficit /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81), Adolescent-Onset Type (312.82) and Unspecified On
  • Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301,81), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9):
  • Enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease: and
  • Sexual dysfunctions including sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71), and sexual Aversion Disorder (302.79); sexual arousal disorders such as Female sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51); sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81), Frotteurism (302.89), Pedophilia (302.2), sexual Masochism (302.83), sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and Sexual Disorder Not
  • Treatment includes prophylaxis, where this is appropriate for the relevant condition(s).
  • 7-[4-(3-fluoro-4-methyl-benzyl)- benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1W-3-benzazepine or a salt or solvate thereof according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, 5HT 3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), non-selective reuptake inhibitors of one or more of serotonin, noradrenaline and norepinephrine, CRF-1 antagonists, tricyclic antidepressants, dopaminergic antidepressants, H 3 antagonists, 5HT 1A antagonists, 5HT 1B antagonists, 5HT 1D antagonists, 5HT partial agonists, D1 agonists, M1 agonists,
  • 5HT 3 antagonists seroton
  • the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.
  • Suitable 5HT 3 antagonists which may be used in combination with the compound of the invention for example one or more chemical entities selected from ondansetron, granisetron and metoclopramide.
  • Suitable serotonin agonists which may be used in combination with the compound of the invention include for example one or more chemical entities selected from sumatriptan, rauwolscine, yohimbine and metoclopramide.
  • Suitable SSRIs which may be used in combination with the compound of the invention include for example one or more chemical entities selected from fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline and zimeldine.
  • Suitable SNRIs which may be used in combination with the compound of the invention include for example one or more chemical entities selected from venlafaxine and reboxetine.
  • Suitable tricyclic antidepressants which may be used in combination with the compound of the invention include for example one or more chemical entities selected from imipramine, amitriptiline, chlomipramine and nortriptiline.
  • Suitable dopaminergic antidepressants which may be used in combination with the compound of the invention include for example one or more chemical entities selected from bupropion and amineptine.
  • Suitable anticonvulsant agents which may be used in combination of the compound of the invention include for example one or more chemical entities selected from divalproex, carbamazepine and diazepam.
  • Suitable NSAID agents which may be used in combination with the compound of the invention include for example one or more chemical entities selected from ibuprofen, aspirin and its active metabolite salicylate.
  • Suitable COX-2 inhibitors include rofecoxib (available under the tradename VIOXX®, from Merck, US patent number 5,474,995); celecoxib (available under the tradename CELEBREX®, from Pfizer, US patent number 5,466,823); valdecoxib (available under the tradename BEXTRA®, from Pfizer, US patent number 6,633,272); etoricoxib (available under
  • the compound of formula (I) and its pharmaceutically acceptable salts and solvates thereof are also suitable for combination with other typical and atypical antipsychotics to provide improved treatment of psychotic disorders. Particular advantages associated with the
  • uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately or who are resistant to treatment with certain antipsychotic agents (also known as neuroleptic agents).
  • certain antipsychotic agents also known as neuroleptic agents.
  • the combination therapies of the invention may be administered adjunctively.
  • adjunctive therapy may be administered adjunctively.
  • !5 administration is meant the coterminous or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices.
  • This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as addon therapeutic administration. Any and all treatment regimes in which a patient receives
  • adjunctive therapeutic administration of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one antipsychotic agent are within the scope of the current invention.
  • a patient is typically stabilised on a therapeutic administration of one or more of the components for a period of time and then
  • the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof may be administered as adjunctive therapeutic treatment to patients who are receiving administration of at least one antipsychotic agent, but the scope of the invention " also includes the adjunctive therapeutic administration of at least one antipsychotic agent to patients who are receiving administration
  • the combination therapies of the invention may also be administered simultaneously.
  • simultaneous administration is meant a treatment regime wherein the individual components are administered together, either in the form of a single pharmaceutical composition or device comprising or containing both components, or as separate compositions or devices, each comprising one of the components, administered simultaneously.
  • Such combinations of the separate individual components for simultaneous combination may be provided in the -form of a kit-of-parts.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to a patient receiving therapeutic administration of at least one antipsychotic agent.
  • the invention provides the use of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent.
  • the invention further provides the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of at least one antipsychotic agent to a patient receiving therapeutic administration of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides the use of at least one antipsychotic agent in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the invention further provides at least one antipsychotic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in combination with at least one antipsychotic agent.
  • the invention further provides the use of a combination of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder.
  • the invention further provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder.
  • the invention further provides the compound of formula (I) or a pharmaceutically acceptable salt thereof for use for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder.
  • the invention further provides the use of at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration with the compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder.
  • the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent, a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent, the use of a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent in the manufacture of a medicament for the treatment of a psychotic disorder, and a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one mood stabilising or antimanic agent for use in the treatment of a psychotic disorder.
  • the invention provides a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and one or more further dosage forms each comprising a antipsychotic agent for simultaneous therapeutic administration.
  • antipsychotic drugs examples include, but are not limited to: butyrophenones, such as haloperidol, pimozide, and droperidol; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes, such as thiothixene and chlorprothixene; thienobenzodiazepines; dibenzodiazepines; benzisoxazoles; dibenzothiazepines; imidazolidinones ; benzisothiazolyl-piperazines; triazine such as lamotrigine; dibenzoxazepines, such as loxapine; dihydroindolones, such as molindone; aripiprazole;
  • tradenames and suppliers of selected antipsychotic drugs that are suitable for use in the present invention are as follows : clozapine (available under the tradename CLOZARIL®, from Mylan, Zenith Goldline, UDL, Novartis); olanzapine (available under the tradename ZYPREXA®, from Lilly ; ziprasidone (available under the tradename GEODON®, from Pfizer); risperidone (available under the tradename RISPERDAL®, from Janssen); quetiapine fumarate (available under the tradename SEROQUEL®, from AstraZeneca); sertindole (available under the tradename SERLECT®); amisulpride (available under the tradename SOLION®, from Sanofi-Synthelabo); haloperidol (available under the tradename HALDOL®, from Ortho-McNeil); haloperidol decanoate (available under the tradename HALDOL decanoate®
  • antipsychotic drugs include promazine (available under the tradename SPARINE®), triflurpromazine (available under the tradename VESPRIN®), chlorprothixene (available under the tradename TARACTAN®), droperidol (available under the tradename INAPSINE®), acetophenazine (available under the tradename TINDAL®;), prochlorperazine (available under the tradename COMPAZINE®), methotrimeprazine (available under the tradename NOZINAN®), pipotiazine (available under the tradename PIPOTRIL®), iloperidone, pimozide and flupenthixol.
  • promazine available under the tradename SPARINE®
  • triflurpromazine available under the tradename VESPRIN®
  • chlorprothixene available under the tradename TARACTAN®
  • droperidol available under the tradename INAPSINE®
  • acetophenazine available under the tradename TINDAL®
  • suitable antipsychotic agents include olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.
  • the compound of the present invention is usually administered as a standard pharmaceutical composition. Therefore in a further aspect of the present invention there is provided a pharmaceutical composition comprising one or more chemical entities selected from 7-[4-(3-fluoro-4-methyl-benzyl)-benzenesulfonyI]-8-methoxy-3-methyl-2,3,4,5- tetrahydro-1 H-3-benzazepine and a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be for use in the treatment of any of the conditions described herein.
  • the compound of the invention may be administered by any convenient method, for example by oral, parenteral (e.g. intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
  • the compound of the invention as hereinbefore described and its pharmaceutically acceptable salts which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a * capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
  • the dosage form comprises an aerosol dispenser
  • a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomiser.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • compositions suitable for transdermal administration include ointments, gels and patches.
  • the composition is suitably in unit dose form such as a tablet, capsule or ampoule.
  • the pharmaceutically acceptable compound of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 250 mg, for example between 1 mg and 150 mg, such as between 2 mg and 100 mg, e.g. between 2 and 50 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, such as between 0.1 mg and 50 mg, e.g.
  • the compound being administered 1 to 4 times per day.
  • the compound will be administered for a period of continuous therapy, for example for a week or more.
  • Cultures were grown as monolayers or in suspension in standard cell culture media. Cells were recovered by scraping (from monolayers) or by centrifugation (from suspension cultures), and were washed two or three times by suspension in phosphate buffered saline followed by collection by centrifugation. Cell pellets were stored frozen at -80°C. Crude cell membranes were prepared by homogenisation followed by high-speed centrifugation, and characterisation of cloned receptors achieved by radioligand binding.
  • CHO cell membranes Preparation of CHO cell membranes: Cell pellets were gently thawed at room temperature, and resuspended in about 20 volumes of ice-cold Extraction buffer; 5mM EDTA, 50mM Trizma pre-set crystals (pH7.4@37°C), 1mM MgCl2, 5mM KCI and 120mM NaCI. The suspension was homogenised using an Ultra-Turrax at full speed for 15 seconds. The homogenate was centrifuged at 18,000 r.p.m for 15 min at 4°C in a Sorvall RC5C centrifuge. Supernatant was discarded, and homogenate re-suspended in extraction buffer then centrifugation was repeated.
  • the protein content was determined using a BCA protocol and bovine serum albumin as a standard (Smith, P. K., et al., Measurement of protein using bicinchoninic acid. Anal. Biochem. 150, 76-85 (1985)).
  • Binding experiments Crude D2/D3 cell membranes were incubated with 0.03nM [ 125 lj- lodosulpride ( ⁇ 2000 Ci/mmol; Amersham, U. K., and the test compound in a buffer containing 50mM Trizma pre-set crystals (pH 7.4 @ 37°C), 120mM NaCI, 5mM KCI, 2mM CaCl2, 1mM MgCl2, 0.3% (w/v) bovine serum albumin. The total volume is 0.2ml and incubated in a water bath at 37°C for 40 minutes.
  • the exemplified compound has a pKj value of > 8.0 at the dopamine D 3 receptor.
  • the exemplified compound has a pKj value of >7.0 at the dopamine D 2 receptor.
  • the exemplified compound has a pKj value of >8.0 at the serotonin 5-HT 6 receptor.
  • Compounds can be tested following the procedures outlined in WO 94/04533.
  • the exemplified compound has a pKj value of >8.0 at the serotonin 5-HT 2C receptor and >8.0 at the serotonin 5-HTaa, receptor.
  • Trifluoromethanesulfonic acid (7 ml, 0.78 mole) was added over 30 minutes. The solution was stirred for 1 hour then washed with saturated sodium bicarbonate solution and brine.
  • Trifluoromethanesulfonic acid (8.8 mL) was added to a mixture of 7-methoxy-3-methyl- 2,3,4,5-tetrahydro-1H-3-benzazepinium trifluoroacetate (20 g, 65.5 mmol), 4-bromobenzene- sulfonyl chloride chloride (25 g, 97.8 mmol), and indium(lll) chloride (1.44 g, 6.5 mmol) in trifluoroacetic acid (60 mL), under a nitrogen atmosphere. The resulting mixture was heated under reflux for 24 hours then cooled, diluted with dichloromethane (200 mL), and methanol
  • Table 1 X-Ray powder diffraction (XRPD) angles and d spacings for 7-[4-(3-Fluoro-4- methyl-benzyl)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepinium p-toluenesulfonate
  • Tetrakis(triphenylphosphine)palladium(0) (5.8 mg, 0.005 mmol) was added followed by a solution of 7-(4-Bromobenzenesulfonyl)-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine (D4) (2.05 g, 5mmol) in tetrahydrofuran (20.5 mL) and the resulting mixture heated under reflux for 4 hours. The reaction was cooled to ambient temperature and 5% w/w aqueous sodium bicarbonate (20.5 mL) added. The resulting mixture was stirred for 15 minutes, filtered through celite and the phases of the filtrate separated.
  • the organic phase was washed with 10% w/w aqueous sodium chloride (3 x 20.5 mL) and the resulting aqueous phases combined and extracted with ethyl acetate (20.5 mL).
  • the two organic phases obtained were combined and treated with trithiocyanuric acid (4.43 mg, 0.025 mmol) for 1 hour at 18 - 25°C.
  • the suspension was filtered through celite and the filtrate extracted with water (2 x 20.5 mL).
  • the aqueous phases were combined and treated with p-toluenesulfonic acid monohydrate (952 mg, 5 mmol).
  • the solution was concentrated under vacuum, the resulting slurry cooled to ambient temperature and stirred for 2 hours.
  • X-Ray Powder Diffraction X-Ray Powder Diffraction (XRPD) analysis was performed on a Phillips X'pert Pro powder diffractometer, using an X'Celerator detector.
  • the acquisition conditions were; radiation: Cu K ⁇ , generator tension: 40 kV, generator current: 45mA, start angle: 2.0 °2 ⁇ , end angle: 40.0 °2 ⁇ , step size: 0.0167 °2 ⁇ , time per step: 31.75 seconds.
  • the sample was prepared using silicon wafer technique.
  • Raman Spectroscopy Raman spectra were recorded in an NMR tube using a Nicolet 960 E.S.P. FT-Raman spectrometer, at 4 cm ⁇ 1 resolution with excitation from a Nd:VO 4 laser (1064 nm) with a power output of 400mW. An absolute threshold of 0.5 and sensitivity of 65% were applied for the purpose of peak selection.
  • DSC Differential Scanning Calorimetry

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Abstract

L'invention concerne une ou plusieurs entités chimiques sélectionnées entre un composé de formule (I) et un sel pharmaceutiquement acceptable ou un solvate dudit composé. Les composés de formule (I) ainsi que les sels pharmaceutiquement acceptables ou les solvates de ces composés peuvent être utilisés à des fins de traitement, en particulier en tant qu'agents antipsychotiques.
PCT/EP2004/013551 2003-11-28 2004-11-25 Derives de 7-phenylsulfonyl-tetrahydro-3-benzazepine utilises en tant qu'agents antipsychotiques Ceased WO2005051399A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7897595B2 (en) 2006-05-26 2011-03-01 Forest Laboratories Holdings Limited Pyridoazepine derivatives

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003062205A1 (fr) * 2001-12-21 2003-07-31 Smithkline Beecham P.L.C. Derives de 7-sulfonyl-3-benzazepine utilises comme modulateurs du recepteur a la dopamine et utilisation de ces derniers dans le traitement des troubles du systeme nerveux central
WO2003068752A1 (fr) * 2002-02-13 2003-08-21 Glaxo Group Limited Derives benzenesulfonamide utilises comme antipsychotiques
WO2003099786A2 (fr) * 2002-05-29 2003-12-04 Glaxo Group Limited Composes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003062205A1 (fr) * 2001-12-21 2003-07-31 Smithkline Beecham P.L.C. Derives de 7-sulfonyl-3-benzazepine utilises comme modulateurs du recepteur a la dopamine et utilisation de ces derniers dans le traitement des troubles du systeme nerveux central
WO2003068752A1 (fr) * 2002-02-13 2003-08-21 Glaxo Group Limited Derives benzenesulfonamide utilises comme antipsychotiques
WO2003099786A2 (fr) * 2002-05-29 2003-12-04 Glaxo Group Limited Composes

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7897595B2 (en) 2006-05-26 2011-03-01 Forest Laboratories Holdings Limited Pyridoazepine derivatives

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