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WO2010142652A1 - Composés imidazobenzazépine pour le traitement des maladies du système nerveux central (snc) - Google Patents

Composés imidazobenzazépine pour le traitement des maladies du système nerveux central (snc) Download PDF

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Publication number
WO2010142652A1
WO2010142652A1 PCT/EP2010/057948 EP2010057948W WO2010142652A1 WO 2010142652 A1 WO2010142652 A1 WO 2010142652A1 EP 2010057948 W EP2010057948 W EP 2010057948W WO 2010142652 A1 WO2010142652 A1 WO 2010142652A1
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Prior art keywords
piperazinyl
benzazepin
mmol
imidazo
pharmaceutically acceptable
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English (en)
Inventor
Romano Di Fabio
Massimo Gianotti
Colin Philip Leslie
Luigi Piero Stasi
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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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Definitions

  • This invention relates to novel imidazobenzazepine derivatives.
  • the invention also relates to the use of the derivatives in treating diseases and conditions of the central nervous system (CNS), in particular sleep disorders.
  • the invention relates to compositions containing the derivatives and processes for their preparation.
  • Common symptoms of those suffering with a sleep disorder include abnormal sleep behaviour and difficulties in one or more of, falling asleep, remaining asleep, sleeping for adequate lengths of time and achievement of restorative sleep.
  • over-the-counter antihistamines e.g. diphenhydramine and dimenhydrinate.
  • diphenhydramine and dimenhydrinate are not designed to be strictly sedative in their activity and as such, this method of treatment has been associated with a number of adverse side effects, e.g. persistence of the sedating medication after the prescribed time of treatment, or the so-called "hangover effect". Many of these side effects result from non-specific activity in both the periphery as well as the CNS during this period of extended medication.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof
  • R1 is carboxyC3_gcycloalkyl, carboxyC3_gcycloalkylmethyl, carboxymethylC3_gcycloalkyl, -(CR 1 aR 1 b)2_ 6 CO 2 H or -(CR 1 aR 1 b) ⁇ (CR 1 C Rid)(CRiaRi b )yC o 2 H;
  • R1 a and R-" 3 which may be the same or different are H or C-
  • _4alkyl or R ⁇ a and R-" 3 can together form methylene ( CH2);
  • R2 and R ⁇ are each independently selected from H, C-
  • each R ⁇ is independently selected from halo, C-
  • R5 and R ⁇ are each independently selected from H, F, Cl, C-
  • x is 0-6;
  • y is 0-6 provided that x+y is 1-6;
  • halogen and its abbreviation “halo” refer to fluorine, chlorine, bromine or iodine. In an embodiment unless otherwise indicated such a halo substituent is fluoro or chloro.
  • _4alkyl substituent is a univalent radical derived by removal of a hydrogen atom from an acyclic C-
  • _4alkyl substituents include methyl and ethyl, and may be straight chain (i.e. n-propyl, n-butyl) or branched chain (for example, isopropyl, isobutyl).
  • _3alkoxy substituent is group of formula "R-O-" where R is C-
  • alkoxy substituents include methoxy and ethoxy and may be straight chain (i.e. n-propoxy) or branched chain (for example, isopropoxy).
  • _3haloalkyl substituent is an C-
  • . 3haloalkyl substituents include monofluoromethyl, difluoromethyl, trifluoromethyl and 1- chloro-2-fluoroethyl.
  • _3haloalkoxy substituent is of formula "R x -O-" where R x is C-
  • _3haloalkoxy substituents include monofluoromethoxy, difluoromethoxy, trifluoromethoxy and 1-chloro-2-fluoroethoxy and may be straight chain or branched chain.
  • a carboxy substituent is -C(O)-OH.
  • a carboxyC3_gcycloalkyl substituent is for example, HO-C(O)-CgHg-.
  • R ⁇ is carboxyC3_gcycloalkyl or -(CR-' a R ' " :) )2_g-C ⁇ 2H.
  • R ⁇ is carboxycyclohexyl, carboxycyclobutyl-CO2H or -(CR ' ' a R ' " :) )2-C ⁇ 2H.
  • R 1 is -(CR 1 a R 1 b )2-CO2H.
  • R 1 is -CH 2 (CR 1 a R 1 b )-CO 2 H.
  • R 1 a and R 1 b which may be the same or different are H or methyl.
  • R 1 a and R-" 3 are both methyl.
  • R ⁇ and R ⁇ are each independently selected from H and C-
  • R2 and R ⁇ are each H.
  • R ⁇ and R ⁇ are each independently selected from H, Cl, F and methyl. In a further embodiment R ⁇ and R ⁇ are each independently selected from H, Cl, F and methyl provided that at least one of R ⁇ and R ⁇ is H. In another embodiment R ⁇ and R ⁇ are each independently selected from H, Cl and F. In a further embodiment R ⁇ and R ⁇ are each independently selected from H, Cl and F provided that at least one of R ⁇ and R ⁇ is H. In a further embodiment R ⁇ and R ⁇ are each H. In a yet further embodiment R ⁇ and R6 are each independently selected from H, Cl and F provided that at least one of R ⁇ and R6 is Cl or F. In a yet further embodiment one of R ⁇ and R ⁇ is selected from Cl and F and the other of R 5 and R 6 is H.
  • x is 1 and y is 0. In an embodiment x is 0 and y is 1.
  • n is 0 or 1. In a further embodiment m is 0.
  • the compound is 3-[4-(5H-lmidazo[1 ,2-b][2]benzazepin-11-yl)-1- piperazinyl]-2,2-dimethylpropanoic acid or a pharmaceutically acceptable salt thereof.
  • the compound is selected from 3-[4-(3-Chloro-5H-imidazo[1 ,2- b][2]benzazepin-11-yl)-1-piperazinyl]-2,2-dimethylpropanoic acid; 3-[4-(2-Chloro-5H- imidazo[1 ,2-b][2]benzazepin-11-yl)-1-piperazinyl]-2,2-dimethylpropanoic acid; and 3-[4-(2-Fluoro-5H-imidazo[1 ,2-b][2]benzazepin-1 1-yl)-1-piperazinyl]-2,2-dimethylpropanoic acid, or a pharmaceutically acceptable salt thereof.
  • substituted means substituted by one or more defined groups.
  • groups may be selected from a number of alternative groups, the selected groups may be the same or different.
  • the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • the compounds of formula (I) may form pharmaceutically acceptable salts, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids.
  • inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid
  • carboxylic acids or with organo-sulfonic acids.
  • Examples include the HCI, HBr, HI, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts.
  • pharmaceutically acceptable base addition salts can be formed with a suitable inorganic or organic base such as triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine, optionally in a suitable solvent such as an organic solvent, to give the base addition salt which is usually isolated for example by crystallisation and filtration.
  • suitable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of one or more carboxylic acid moieties that may be present in the compound of formula (I).
  • suitable pharmaceutical salts see Berge et al, J.
  • the compounds of the invention may exist in solvated or hydrated form.
  • the compounds of the invention or solvates/hyd rates of the compounds or salts may exist in one or more polymorphic forms. Therefore, according to a further aspect, the invention includes a solvate, hydrate or prodrug of the compounds of the invention.
  • the compounds of the invention may exist in zwitterionic form.
  • Certain compounds of the invention may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included in the scope of the present invention.
  • Certain compounds of the invention possess one or more chiral centres and so exist in a number of stereoisomeric forms.
  • Compounds having one chiral centre may exist as enantiomers or a racemic mixture containing enantiomers.
  • Compounds having two or more chiral centres may exist as diastereoismomers or enantiomers. All stereoisomers (for example enantiomers and diastereoisomers) and mixtures thereof are included in the scope of the present invention.
  • Racemic mixtures may be separated to give their individual enantiomers using preparative HPLC using a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to those skilled in the art.
  • chiral intermediate compounds may be resolved and used to prepare individual enantiomers.
  • the invention also includes all suitable isotopic variations of the compounds of the invention.
  • An isotopic variation of the compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 35 S, 18 F and 36 CI respectively.
  • Certain isotopic variations of the invention for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, are useful in drug and/or substrate tissue distribution studies.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples and Preparations hereafter using appropriate isotopic variations of suitable reagents. Compounds of the invention may be prepared in a variety of ways. In the following reaction schemes and hereinafter, unless otherwise stated R 1 to R ⁇ , x, y and m are as defined in the first aspect. These processes form further aspects of the invention.
  • R-I is -(CR 1 a R 1 b ) ⁇ (CR 1 C R 1 d )(CR 1 a R 1 b ) y CO 2 H
  • R-I is -(CR 1 a R 1 b ) ⁇ (CR 1 C R 1 d )(CR 1 a R 1 b ) y CO 2 H may be prepared following similar procedures as those prepared from compounds of formula (Na).
  • Compounds of formula (Na) may be prepared from compounds of formula (III) according to reaction scheme 2 by reaction with aldehydes of formula (IV) in the presence of a reducing agent such as NaBH(OAc)3 in an organic solvent, such as DCE, at room temperature.
  • a reducing agent such as NaBH(OAc)3 in an organic solvent, such as DCE
  • Aldehydes of formula (IV) are either commercially available or may be prepared by procedures known to the skilled person.
  • compounds of formula (Na') which respresent a subset of compounds of formula (Na) may be prepared from compounds of formula (III) according to reaction scheme 3 by reaction with ⁇ , ⁇ -unsaturated esters of formula (V) in the presence of a base, such as DBU, in an organic solvent such as DMF.
  • a base such as DBU
  • Compounds of formula (lib) may be prepared from compounds of formula (III) according to reaction scheme 4 by reaction with aldehydes of formula (Vl) or ketones of formula (VII) in the presence of a reducing agent, such as NaBH(0Ac)3, in an organic solvent such as DCE at room temperature.
  • a reducing agent such as NaBH(0Ac)3
  • an organic solvent such as DCE
  • Aldehydes of formula (Vl) and ketones of formula (VII) are either commercially available or may be prepared by procedures known to the skilled person.
  • Compounds of formula (III) may be prepared from compounds of formula (VIII) according to reaction scheme 5 by reaction with a piperazine of formula (IX) in the presence of trimethylsilyl trifluoromethylsulphonate at a temperature of 130 0 C.
  • Piperazines of formula (IX) are either commercially available or may be prepared by procedures known to the skilled person.
  • Compounds of formula (VIII) may be prepared from compounds of formula (X) according to reaction scheme 6 by intramolecular cyclisation with a strong base such as lithium diisopropylamide in an aprotic organic solvent, such as THF, at low temperature (eg. -78°C).
  • a strong base such as lithium diisopropylamide in an aprotic organic solvent, such as THF, at low temperature (eg. -78°C).
  • Compounds of formula (X) may be prepared from compounds of formula (Xl) according to reaction scheme 7 by reaction with an imidizole of formula (XII) in the presence of a suitable base, such as potassium carbonate, 2,8,9-triisobutyl-2,5,8,9-tetraaza-1- phosphabicyclo[3.3.3]undecane or an excess of imidazole (XII), at room temperature in an aprotic organic solvent such as THF or DMF.
  • a suitable base such as potassium carbonate, 2,8,9-triisobutyl-2,5,8,9-tetraaza-1- phosphabicyclo[3.3.3]undecane or an excess of imidazole (XII)
  • Imidazoles of formula (XII) and compounds of formula (Xl) are either commercially available or may be prepared by procedures known to the skilled person.
  • the compounds of the invention are antagonists of the H-
  • the compounds of the invention are useful for the treatment of diseases and conditions mediated by antagonism of the H-
  • the compounds of the invention may treat diseases or conditions selected from the list consisting of: [the numbers in brackets after the listed diseases below refer to the classification code in Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD-10)]:
  • i) Psychotic disorders for example 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 for example Depressive Episodes (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 Il Disorder (i.e. 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 for example Social Anxiety Disorder; Panic Attack; Agoraphobia,
  • Panic Disorder; Agoraphobia Without History of Panic Disorder 300.22
  • Specific Phobia (300.29) (including the subtypes Animal Type, Natural Environment Type, Blood-lnjection- Injury Type, Situational Type and Other Type); Social Phobia (300.23); Obsessive- Compulsive Disorder (300.3); Posttraumatic Stress Disorder (309.81 ); Acute Stress Disorder (308.3); Generalized Anxiety Disorder (300.02); Anxiety Disorder Due to a General Medical Condition (293.84); Substance-Induced Anxiety Disorder; and Anxiety Disorder Not Otherwise Specified (300.00).
  • Substance-related disorders for example Substance Use Disorders (including Substance Dependence, Substance Craving and Substance Abuse); Substance-Induced Disorders (including 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 (including 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
  • Amphetamine or Amphetamine-I_ike-Related Disorders (for example Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,
  • Amphetamine-Induced Sexual Dysfunction Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9)
  • Caffeine Related Disorders including Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9)
  • Cannabis-Related Disorders including Cannabis Dependence (304.30),
  • Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-lnduced Psychotic Disorder, Cannabis-lnduced Anxiety Disorder and Cannabis- Related Disorder Not Otherwise Specified (292.9)); Cocaine-Related Disorders (including Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine- Induced sexual Dysfunction, Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Specified (292.9)); Hallucinogen-Related Disorders (including Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292.89), Hall
  • Sexual dysfunction for example sexual Desire Disorders (including Hypoactive Sexual Desire Disorder (302.71 ) and Sexual Aversion Disorder (302.79)); sexual arousal disorders (including Female sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72)); orgasmic disorders (including Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75)); sexual pain disorder (including Dyspareunia (302.76) and Vaginismus (306.51 )); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias (including 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 (including Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.9)
  • Sleep disorder for example primary sleep disorders such as Dyssomnias (including 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 (including 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 (including Insomnia Related to
  • 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; Binge Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50).
  • Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder, Rett's Disorder, Childhood Disintegrative Disorder and Pervasive Developmental Disorder Not Otherwise Specified.
  • 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 Onset (312.89), Oppositional Defiant Disorder (313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23).
  • 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).
  • 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
  • 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.
  • the invention provides the use of the compounds of the invention in the manufacture of a medicament for treating or preventing sleep disorders.
  • the sleep disorder is selected from the list consisting of: primary sleep disorders such as Dyssomnias (including 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 (including 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 (including 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).
  • primary sleep disorders such as Dyssomnias (including Primary Insomnia (307.42), Primary Hypers
  • the compounds of the invention may be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics; ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).
  • anticholinergics such as benztropine, biperiden, procyclidine and trihexyphenidyl
  • antihistamines such as diphenhydramine
  • dopaminergics such as amantadine
  • antidepressants such as amantadine
  • iv) anxiolytics such as anxio
  • the compounds of the invention may be used in combination with antidepressants to treat or prevent depression and mood disorders.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilisers; ii) antipsychotics; and iii) antidepressants.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil and sildenafil; ii) dopamine agonists/dopamine antagonists/dopamine transport inhibitors for example apomorphine and buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) androgen receptor modulators such as testosterone; vi) serotonin agonists/antagonists/modulators/serotonin transporter inhibitors for example serotonin reuptake inhibitors; vii) noradrenaline transport inhibitors for example reboxetine; viii) oxytocin receptor antagonists; (ix) sodium and calcium channel inhibitors/blockers; and (x) opioid receptor antagonists.
  • phosphodiesterase V inhibitors for example vardenafil and silden
  • the compounds of the invention may be used in combination with the same agents specified for male sexual dysfunction to treat or prevent female sexual dysfunction, and in addition an estrogen agonist such as estradiol.
  • Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone and amisulpride).
  • Typical Antipsychotics for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine
  • Atypical Antipsychotics for example clozapine, olanzapine, risperidone, quetiapine,
  • Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine, sertraline femoxetine, fluvoxamine, indalpine and zimeldine); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine and venlafaxine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).
  • Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.
  • Anxiolytics include benzodiazepines such as alprazolam and lorazepam.
  • the compound of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.
  • references herein to "treatment” extend to prophylaxis, prevention of recurrence and suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions.
  • the compound of the invention may be administered as the raw chemical but is suitably presented as a pharmaceutical formulation.
  • the compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient by an appropriate route. Accordingly, in another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically-acceptable excipients.
  • pharmaceutically-acceptable excipient means any pharmaceutically acceptable material present in the pharmaceutical composition or dosage form other than the compound or compounds of the invention. Typically the material gives form, consistency and performance to the pharmaceutical composition.
  • the pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In addition, the pharmaceutical compositions of the invention may comprise one or more additional pharmaceutically active compounds.
  • compositions of the invention may be prepared and packaged in bulk form wherein a safe and therapeutically effective amount of a compound of the invention can be dispensed and then given to the patient such as with powders or syrups.
  • the pharmaceutical compositions of the invention may be prepared and packaged as dosage forms wherein each physically discrete dosage form contains a safe and effective amount of a compound of the invention. Accordingly, in another aspect, the invention provides dosage forms comprising pharmaceutical compositions of the invention.
  • a therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the composition, and the route of administration, and will ultimately be at the discretion of the attendant physician.
  • antagonist activity will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day.
  • the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a pharmaceutically acceptable salt thereof may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.
  • the optimal quantity and spacing of individual dosages of compounds of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of compounds of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • compositions of the invention will typically be formulated into dosage forms which are adapted for administration to the patient by the desired route of administration.
  • dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration such as sterile solutions, suspensions, implants and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal and vaginal administration such as suppositories, pessaries and foams; (5) inhalation and intranasal such as dry powders, aerosols, suspensions and solutions (sprays and drops); (6) topical administration such as creams, ointments, lotions, solutions, pastes, drops, sprays, foams and gels; (7) ocular administration such as drops, ointment, sprays, suspensions and inserts; (8) buccal and sub
  • Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the release of the compound of the invention at the appropriate rate to treat the condition.
  • Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavouring agents, flavour masking agents, colouring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, rate modifying agents, antioxidants, preservatives, stabilizers, surfactants and buffering agents.
  • excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavouring agents, flavour masking agents, colouring agents, anticaking agents, hume
  • Skilled artisans possess the knowledge and skill in the art to enable them to determine suitable pharmaceutically-acceptable excipients in appropriate amounts for use with the compounds of the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • the pharmaceutical compositions of the invention may be prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include starches, crospovidone, sodium starch glycolate, cros-carmellose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and sodium dodecyl sulphate.
  • the oral solid dosage form may further comprise a glidant such as talc and colloidal silicon dioxide.
  • the oral solid dosage form may further comprise an outer coating which may have cosmetic or functional properties. It will be appreciated that the invention includes the following further aspects. The diseases and conditions described above extend, where appropriate, to these further aspects.
  • a compound of the invention for use in treating or preventing sleep disorders.
  • a method of treatment or prevention of sleep disorders in a mammal comprising administering an effective amount of a compound of the invention.
  • a compound of the invention for use in the treatment of sleep disorders.
  • Reagents were obtained from commercial suppliers (for example Sigma-Aldrich and Lancaster) and used without further purification. Solvents were obtained in dry form or were dried according to standard procedures. For example, DCM and DCE were dried over calcium hydride; THF, toluene and diethyl ether were dried over Na/benzophenone; and EtOH was dried over Mg/I 2 . Anhydrous reactions were run under a positive pressure of dry N 2 or argon.
  • Proton Nuclear Magnetic Resonance ( 1 H NMR) spectra were recorded either on Varian instruments at 300, 400, 500 or 600 MHz, or on Bruker instruments at 300, 400 or 500 MHz. Chemical shifts are reported in ppm ( ⁇ ) using the residual solvent line as internal standard. Splitting patterns are designated as: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad.
  • the NMR spectra were recorded at a temperature ranging from 25 to 9O 0 C.
  • MS Mass spectra
  • mass directed analytical HPLC (Agilent technology HP1 100) was carried out using a 19 mm x 100 mm or 30 mm x 100 mm, 5 ⁇ m, reversed phase Waters Atlantis column as the stationary phase and a gradient from water + 0.1% formic acid to acetonitrile + 0.1% formic acid as the eluent.
  • the HPLC system was monitored by DAD array detector and an Agilent 110MSD mass spectrometer.
  • the LC elution method (using Zorbax Eclipse XDB, 4.6 x 150 mm, 5 ⁇ m C8 column) was the following: 15 min method at 25 0 C, mobile phase composed of different CH3CN/H2O-HCOOH 0.1% mixtures at a flow rate of 1 mL/min (all solvent were HPLC grade, Fluka).
  • HPLC spectra were performed using a reversed-phase liquid chromatography (ProStar 210/215 PrepStar218) and UV-Vis Detector (ProStar 325).
  • the LC elution method (using Varian Polaris 5 C-18, 150 x 4.6 mm) was the following: 15 min method at 25 0 C, mobile phase composed of different CH 3 CN/H 2 O-HCOOH 0.1% mixtures at a flow rate of 1 mL/min (all solvent were HPLC grade, Fluka).
  • HPLC spectra were performed using a Waters 2690 apparatus at 25°C using a 3 mm x 100 mm, 3.5 ⁇ m, reversed phase X-Terra C-18 column as the stationary phase and a gradient from water + 0.1% formic acid 5% to acetonitrile + 0.1% formic acid 90% during 19.5 min or water + 0.1% formic acid 20% to acetonitrile + 0.1% formic 95% during 19 min as the eluent. Flow rate was 0.5 mL/min (all solvents were HPLC grade, Merck). The HPLC system was monitored by DAD array detector at 254 nm and a Micromass Quattromicro mass spectrometer.
  • TIC Total ion current
  • DAD UV chromatographic traces together with MS and UV spectra associated with the peaks were taken also on a UPLC/MS AcquityTM system equipped with 2996 PDA detector and coupled to a Waters Micromass ZQTM mass spectrometer operating in positive or negative electrospray ionisation mode.
  • Flash silica gel chromatography was carried out on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany) or over Varian Mega Be-Si pre-packed cartridges or over pre-packed Biotage or lsolute FlashTM silica cartridges. Alternatively chromatographic purifications were performed on columns packed with Merck 60 silica gel, 23-400 mesh, for flash technique. Flash modified silica gel chromatography was carried out over Biotage KP-NH (NH) or Varian Mega BE-NH2 (NH2) pre-packed aminoalkyl functionalised silica gel cartridges.
  • SCX cartridges are ion exchange solid phase extraction columns by supplied by Varian or Phenomenex.
  • the eluent used with SCX cartridges is methanol followed by 2N ammonia solution in methanol.
  • Mega BE-C18 (C18) cartridges are reverse phase extraction columns supplied by Varian.
  • the eluent used with C18 columns is water followed by MeOH.
  • purification was performed using either Biotage manual flash chromatography (Flash+) or automatic flash chromatography (Horizon) systems. All these instruments work with standard Biotage Silica cartridges.
  • MDAP Multipurification
  • Fraction lynxTM equipped with Waters 2996 PDA detector and coupled with a ZQTM mass spectrometer (Waters) operating in positive and negative electrospray ionisation mode ES+, ES- (mass range 100-1000).
  • METHOD B Chromatographic Acidic conditions for up to 100 mq of crude: Column: 150 x 30 mm XTerra Prep MS C18 (10 ⁇ m particle size) Mobile phase: A[water + 0.1% formic acid] / B [acetonitrile + 0.1% formic acid] Flow rate: 40 mL/min Gradient: 1 % B to 100%B in 7 min lasting for 7.5 min.
  • the reaction mixture was stirred for further 2 hours and the temperature was allowed to reach O 0 C, then the reaction was quenched with saturated NH4CI solution, extracted with DCM, the combined organic layers were dried (Na2SC>4) and concentrated in vacuo.
  • the crude product was purified by flash chromatography on silica gel eluting with a gradient of MeOH in DCM from 0 to 2%, and then by trituration using diethyl ether, to afford the title compound (314 mg, 1.376 mmol) as an -1 :1 mixture with unreacted methyl (2- ⁇ [5-(methyloxy)-1 H-imidazol-1-yl]methyl ⁇ phenyl)acetate.
  • the temperature was allowed to reach -55 0 C in 1 hour then cooled down to -78 0 C and dimethylsulfamoyl chloride (8.33 ml_, 78 mmol) was slowly added and the mixture was stirred at -78 0 C for 30min and at 2O 0 C for 2 hours.
  • the solvents were removed by evaporation and the residue was stirred with 2M HCI solution (100ml) for 12 hour at room temperature. Complete deprotection of the nitrogen was achieved while partial TBDMS deprotection was observed.
  • the aqueous acid solution was basified with KOH pellets and the aqueous phase was extracted with EtOAc. The organic phases were dried over Na2SO4 and evaporated under reduced pressure.
  • reaction mixture was cooled to -78 0 C and a 1.6M solution of butyllithium in hexanes (37.5 ml_, 59.9 mmol) was added.
  • the reaction was stirred for 1 hour then a solution of N- fluorobenzenesulfonimide (18.00 g, 57.1 mmol) in THF (50 ml) was added.
  • the reaction was stirred at -78 0 C for 1 hour then allowed to warm to room temperature and stirred for another 1 hour.
  • the reaction was quenched with 1 M HCI solution (100 ml) and stirred for 1 hour.
  • the reaction mixture was quenched with saturated NH4CI solution (50 ml), diluted with brine (100 ml) and extracted with EtOAc (3 x 100 ml). The combined organic phases were dried (Na2SC>4) and evaporated under reduced pressure to give a yellow solid.
  • the crude was triturated with EtOAc (10 ml) and EtOAc/cyclohexane (1 :1 , 3 x 10 ml). The supernatants were loaded sequentially onto a preconditioned silica gel column (10Og), which was then eluted with 30-70% EtOAc in cyclohexane.
  • Trimethylsilyl trifluoromethanesulfonate (2467 ⁇ l, 13.65 mmol) was added to a mixture of 2-fluoro-5,10-dihydro-1 1 H-imidazo[1 ,2-b][2]benzazepin-1 1-one (Intermediate 37, 984 mg, 4.55 mmol) and piperazine (1960 mg, 22.76 mmol) in a screw-topped vial at room temperature. The mixture was heated to 13O 0 C with shaking in a PLS reaction station for 17 hours. The mixture was cooled and partitioned between dichloromethane (100 ml) and saturated Na2CO3 solution (50 ml).
  • Methyl 4-[4-(5H-imidazo[1 ,2-b][2]benzazepin-1 i-yO-i-piperazinyOcyclohexanecarboxylate isomer 2 (Intermediate 8, 7.0 mg, 0.017 mmol) was dissolved in methanol (1 ml) and water (1 ml) and lithium hydroxide (5 mg, 0.209 mmol) was added to the reaction. The mixture was heated at 40 0 C for 4 hours.
  • the residue was twice dissolved in water (10 ml) and then evaporated to dryness under reduced pressure to remove all traces of methanol.
  • the residue was dissolved in water (10 ml) and the pH was adjusted to pH6 by addition of 1 M HCI (-4.5 ml required).
  • the reaction mixture was loaded onto a pre-conditioned C18 column and eluted with water to remove salts and then with MeOH to elute the product.
  • Antagonist Assay a) Adherent Chinese Hamster Ovary (CHO) cells stably expressing the recombinant human H 1 receptor were maintained in culture at 37°C under 5% CO 2 in Alpha Minimum Essential Medium without ribonucleosides (Gibco Invitrogen), supplemented with 10% dialysed foetal calf serum and 20OmM Glutamine. These cells, expressing the human H-
  • Supporting compounds 1-14 were tested and gave a pKi against H-
  • 5HT2A Antagonist Assay a) Adherent SH-SY5Y cells stably expressing recombinant human 5-HT 2A were maintained in culture at 37°C under 5% CO 2 in Alpha Minimum Essential Medium + ribonucleosides (Gibco Invitrogen,) supplemented with 10% dialysed foetal calf serum and 400 micrograms geneticin. SH-SY5Y cells are neuroblastoma and are commercially available from the American Type Culture Collection (ATCC). The SH-SY5Y cells, expressing 5-HT 2A receptors, were seeded into black-walled clear-based 384-well plates at a density of 16,000 cells per well and cultured overnight at 37°C under 5% CO 2 .
  • ATCC American Type Culture Collection
  • HBSS medium (CaCI 2 .2H 2 O 1.26Mm, Glucose 5.55mM, KCI 5.36mM MgSO 4 (anhyd) 0.81 mM, NaCI 136.89mM, KH 2 PO 4 (anhyd) 0.41 mM, HEPES 2OmM, NaHCO 3 4.16mM) containing cytoplasmic calcium indicator, Fluo-4 in the acetylmethyl form (4 mM), 2.5mM Probenecid and 250 ⁇ M Brilliant Black (Molecular Devices) at 37°C for 60 min. The loaded cells were then incubated with test compound for 30 min at 37°C.
  • the plates were then placed into a FLIPR (Molecular Devices, UK) for testing in antagonist mode, where a pre-determined concentration of 5-HT (approximately 4xEC50) was added while cell fluorescence ( ⁇ ex 488nm, ⁇ em 540nm) was monitored.
  • 5-HT approximately 4xEC50
  • cell fluorescence ⁇ ex 488nm, ⁇ em 540nm
  • Supporting compounds 1 and 8-14 were tested and gave a pKi against 5HT 2 A i n the range 5.0-9.0. Compound 1 gave a pKi against 5HT 2 A of 6.6.
  • HEK Frozen Human Embryonic Kidney cells stably expressing the human 5-HT 2A serotonin receptor and aequorin apo-protein were thawed and added drop wise to an appropriate volume of warm DMEM media (Gibco Invitrogen 41965-039) containing 10% dialysed foetal bovine serum (FBS) (Invitrogen; 05-4011 DK). Cells were then spun down at IOOOrpm for 5 minutes at room temperature.
  • DMEM media Gibco Invitrogen 41965-039
  • FBS dialysed foetal bovine serum

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Abstract

La présente invention a pour objet de nouveaux dérivés d'imidazobenzazépine de formule (I) ou un sel pharmaceutiquement acceptable de ceux-ci, pour le traitement de maladies et d'états du système nerveux central (SNC), en particulier des troubles du sommeil.
PCT/EP2010/057948 2009-06-10 2010-06-08 Composés imidazobenzazépine pour le traitement des maladies du système nerveux central (snc) Ceased WO2010142652A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8314092B2 (en) 2011-02-07 2012-11-20 Eli Lilly And Company Substituted [(5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoic acid compounds as dual activity H1 inverse agonists/5-HT2A antagonists
JP2014518280A (ja) * 2011-07-08 2014-07-28 イーライ リリー アンド カンパニー 二重作用Ｈ１インバースアゴニスト／５−ＨＴ２Ａアンタゴニストとしての（チエノ［２，３−ｂ］［１，５］ベンゾオキサゼピン−４−イル）ピペラジン−１−イル化合物

Citations (1)

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EP0357043A2 (fr) * 1988-08-31 1990-03-07 F. Hoffmann-La Roche Ag Dérivés d'imidazodiazépine

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HINO KATSUHIKO ET AL: "Agents acting on the central nervous system. Synthesis of 3-phenyl-2-piperazinyl-1-benzazocines, 3-substituted-2-piperazinyl-1- benzazepines and related compounds", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, TOKYO, JP, vol. 36, 1 January 1988 (1988-01-01), pages 2386 - 2400, XP002217345, ISSN: 0009-2363 *
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KHANNA J M ET AL: "Agents acting on the central nervous system. X. 1-Substituted 3-phenyl-2,3,4,5-tetrahydro-1H-1benzazepines", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US LNKD- DOI:10.1021/JM00317A043, vol. 395, no. 10, 1 January 1967 (1967-01-01), pages 944 - 945, XP002968897, ISSN: 0022-2623 *
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8314092B2 (en) 2011-02-07 2012-11-20 Eli Lilly And Company Substituted [(5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoic acid compounds as dual activity H1 inverse agonists/5-HT2A antagonists
JP2014504637A (ja) * 2011-02-07 2014-02-24 イーライ リリー アンド カンパニー 二重活性Ｈ１逆アゴニスト／５−ＨＴ２Ａアンタゴニストとしての置換［（５Ｈ−ピロロ［２，１−ｃ］［１，４］ベンゾジアゼピン−１１−イル）ピペラジン−１−イル］−２，２−ジメチルプロパン酸化合物
JP2014518280A (ja) * 2011-07-08 2014-07-28 イーライ リリー アンド カンパニー 二重作用Ｈ１インバースアゴニスト／５−ＨＴ２Ａアンタゴニストとしての（チエノ［２，３−ｂ］［１，５］ベンゾオキサゼピン−４−イル）ピペラジン−１−イル化合物

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