WO2007147836A1 - Composés inhibant le transporteur de la glycine et utilisations en médecine - Google Patents

Composés inhibant le transporteur de la glycine et utilisations en médecine Download PDF

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Publication number
WO2007147836A1
WO2007147836A1 PCT/EP2007/056115 EP2007056115W WO2007147836A1 WO 2007147836 A1 WO2007147836 A1 WO 2007147836A1 EP 2007056115 W EP2007056115 W EP 2007056115W WO 2007147836 A1 WO2007147836 A1 WO 2007147836A1
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disorder
methyl
disorders
compound
solvate
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PCT/EP2007/056115
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English (en)
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Steven Coulton
Martin Leonard Gilpin
Roderick Alan Porter
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Glaxo Group Limited
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Publication of WO2007147836A1 publication Critical patent/WO2007147836A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to glycine transporter inhibiting compounds, their use in the manufacture of medicaments for treating neurological and neuropsychiatric disorders, in particular psychoses, dementia or attention deficit disorder.
  • the invention further comprises processes to make these compounds and pharmaceutical formulations thereof.
  • GIyTI is found predominantly in the forebrain and its distribution corresponds to that of glutamatergic pathways and NMDA receptors (Smith, et al., Neuron, 8, 1992: 927-935).
  • GIyT-Ia three variants of GIyTI , termed GIyT-Ia, GIyT-I b and GIyT-I c (Kim et al., Molecular Pharmacol ogy, 45, 1994: 608-617), each of which displays a unique distribution in the brain and peripheral tissues.
  • GlyT2 in contrast, is found predominantly in the brain stem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors (Liu et al., J. Biological Chemistry, 268, 1993: 22802-22808; Jursky and Nelson, J. Neurochemistry, 64, 1995 : 1026-1033).
  • Another distinguishing feature of glycine transport mediated by GlyT2 is that it is not inhibited by sarcosine as is the case for glycine transport mediated by GIyTI .
  • NMDA receptors are critically involved in memory and learning (Rison and Staunton, Neurosci. Biobehav. Rev., T9 533-552 (1995); Danysz et al, Behavioral Pharmacol., 6 455-474 (1995)); and, furthermore, decreased function of NMDA-mediated neurotransmission appears to underlie, or contribute to, the symptoms of schizophrenia (Olney and Farber, Archives General Psychiatry. 52, 998-1007 (1996).
  • agents that inhibit GIyTI and thereby increase glycine activation of NMDA receptors can be used as novel antipsychotics and anti-dementia agents, and to treat other diseases in which cognitive processes are impaired, such as attention deficit disorders and organic brain syndromes.
  • NMDA receptors have been implicated in a number of disease states, in particular the neuronal death associated with stroke and possibly neurodegenerative diseases, such as Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or other conditions in which neuronal cell death occurs, such as stroke or head trauma.
  • neurodegenerative diseases such as Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or other conditions in which neuronal cell death occurs, such as stroke or head trauma.
  • Coyle & Puttfarcken Science, 262, 689-695 (1993); Lipton and Rosenberg, New Engl. J. of Medicine. 330, 613-622 (1993); Choi, Neuron, 1 , 623-634 (1988).
  • pharmacological agents that increase the activity of GIyTI will result in decreased glycine- activation of NMDA receptors, which activity can be used to treat these and related disease states.
  • drugs that directly block the glycine site of the NMDA receptors can be used to treat these and related disease states.
  • Glycine transport inhibitors are already known in the art, for example as disclosed in published international patent application WO03/055478 (SmithKline Beecham).
  • the present invention provides a novel compound which inhibit the glycine transporter, and is thus useful in the treatment of neurological and neuropsychiatric disorders.
  • salt refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts.
  • Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a pharmaceutically acceptable anion or cation.
  • salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example naphthalene-1 ,
  • Salts having a non-pharmaceutically acceptable anion or cation are within the scope of the invention as useful intermediates for the preparation of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.
  • the salts may have any suitable stoichiometry.
  • a salt may have 1 :1 or 2:1 stoichiometry.
  • Non- integral stoichiometry ratios are also possible.
  • ⁇ /-[[1-(dimethylamino)cyclopentyl](phenyl)methyl]-4-fluoro-2-methyl- 6-(methyloxy)benzamide hydrochloride or a solvate thereof is provided.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, ⁇ /-[[1-(dimethylamino)cyclopentyl](phenyl)methyl]-4-fluoro-2- methyl-6-(methyloxy)benzamide 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, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid.
  • the solvent used is water.
  • the compound of the present invention or a salt or solvate thereof may have the ability to crystallise in more than one form.
  • This is a characteristic known as polymorphism, and it is understood that such polymorphic forms (“polymorphs”) are within the scope of the present invention.
  • Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallisation process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
  • Enantiomers may be separated by chiral high-performance liquid chromatography or other appropriate means. When a single enantiomer is desired, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. ENeI, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
  • individual enantiomers of the compound of the present invention may be prepared.
  • an optically pure enantiomer is provided.
  • the term "optically pure enantiomer” means that the compound contains greater than about 90 % of the desired isomer by weight, such as greater than about 95 % of the desired isomer by weight, or greater than about 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound.
  • one enantiomer of a particular structure may have a significantly higher activity than the other enantiomer of the same structure.
  • Chirally pure, or chirally enriched compounds may be prepared by chirally selective synthesis or by separation of enantiomers. The separation of enantiomers may be carried out on the final product or, alternatively on a suitable intermediate.
  • the compounds of the present invention may be prepared by methods known in the art of organic synthesis, and/or by the methods described below.
  • the present invention provides a method of preparing ⁇ /- [[i ⁇ dimethylaminoJcyclopenty ⁇ phenyOmethylJ- ⁇ fluoro ⁇ -methyl- ⁇ methyloxy ⁇ enzamide or a salt or solvate thereof, comprising reacting ⁇ 1- [amino(phenyl)methyl]cyclopentyl ⁇ dimethylamine and a compound of formula (II):
  • L may be halogen and the acylation reaction may be carried out in an inert solvent such as dichloromethane, in the presence of a base such as triethylamine.
  • L represents hydroxy
  • the reaction may take place in an inert solvent such as dichloromethane in the presence of a coupling reagent, for example a diimide reagent such as N 1 N dicyclohexylcarbodiimide (DCC), N-(3-(dimethylamino)propyl)-N- ethylcarbodiimide hydrochloride (EDC), polymer-supported EDC, polymer-supported DCC or 0-(7-azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluoro phosphate (HATU).
  • a coupling reagent for example a diimide reagent such as N 1 N dicyclohexylcarbodiimide (DCC), N-(3-(dimethylamino)propyl)-N- ethylcarbodiimide hydrochloride (EDC), polymer-supported EDC, polymer-supported
  • Salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • the compounds of the present invention inhibit the GIyTI transporter.
  • the compounds may selectively inhibit the GIyTI transporter over the GlyT2 transporter.
  • Such compounds would be suitable for the treatment of certain neurological and neuropsychiatric disorders.
  • treatment and “treating” refer to the alleviation and/or cure of established symptoms as well as prophylaxis.
  • affinities of the compounds of this invention for the GIyTI transporter can be determined by the following assay:
  • HEK293 cells expressing the Glycine (Type 1 ) transporter were grown in cell culture medium [DMEM/NUT mix F12 containing 2mM L-Glutamine, 0.8mg/mL G418 and 10% heat inactivated fetal calf serum] at 37 0 C and 5% CO 2 .
  • Cells grown to 70-80% confluency in T175 flasks were harvested and resuspended at 1.32x10 6 cells/mL in assay buffer [14OmM NaCI, 5.4mM KCI, 1.8mM CaCI 2 , O. ⁇ mM MgSO 4 , 2OmM HEPES, 5mM glucose and 5mM alanine, pH 7.4].
  • the following assay may also be used:
  • HEK293 cells expressing the Glycine (Type 1 ) transporter are grown in cell medium
  • DMEM/NUT mix F12 containing 2 mM L-Glutamine, 0.8 mg/mL G418 and 10% heat inactivated fetal calf serum (Gibco BRL) at 37 0 C in 5% CO2.
  • Cells grown to 70-80% confluency in T175 flasks are harvested and resuspended at 4x10 5 cells/ml in assay buffer [NaCI (140 mM), KCI (5.4 mM), CaCI 2 (1.8 mM), MgSO 4 (0.8 mM), HEPES (2OmM), glucose (5 mM) and alanine (5 mM), pH 7.4].
  • ElectrodeTM SPA beads (12.5mg/ml suspended in assay buffer) is added to the cell suspension.
  • Compounds are prepared as 1OmM stocks in DMSO. 2.5 fold serial dilutions of the compounds are made in DMSO from a top cone of 2.5 mM. 100 nL of compound at each concentration is added to the assay plate (384-well white solid bottom plate) using the hummingbird dispenser. 5uL of the cell/bead mix is then added on top of the compound using a multidrop dispenser.
  • Substrate (5uL) is then added to each well (1 :100 dilution of H3-glycine in assay buffer containing 2.5 uM glycine) Data is collected using a PerkinElmer Viewlux as 5 minute exposures. plC50 data values are determined using Activity Base.
  • Compounds may be assayed in their free base form or in the form of a salt, for example the hydrochloride salt or the formate salt.
  • a disorder mediated by GIyTI refers to a disorder that may be treated by the administration of a medicament that alters the activity of the GIyTI transporter.
  • the action of GIyTI transporters affects the local concentration of glycine around NMDA receptors. As a certain amount of glycine is needed for the efficient functioning of NMDA receptors, any change to that local concentration can affect NMDA-mediated neurotransmission.
  • changes in NMDA-mediated neurotransmission have been implicated in certain neuropsychiatric disorders such as dementia, depression and psychoses, for example schizophrenia, and learning and memory disorders, for example attention deficit disorders and autism.
  • alterations in the activity of the GIyTI transporter are expected to influence such disorders.
  • the disorders mediated by GIyTI referred to herein include neurological and neuropsychiatric disorders, including psychoses such as schizophrenia, dementia and other forms of impaired cognition such as attention deficit disorders and organic brain syndromes.
  • Other neuropsychiatric disorders include drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants and cocaine) psychosis, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, and psychosis NOS, "schizophrenia-spectrum” disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), and MMDA receptor-related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury.
  • MMDA receptor-related disorders such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury.
  • the compounds of the present invention are of use as antipsychotic agents for example in the treatment of schizophrenia, schizo-affective disorders, schizophreniform diseases, psychotic depression, mania, acute mania, paranoid and delusional disorders.
  • DSM-IV Diagnostic and Statistical Manual of Mental Disorders
  • ICD-10 International Classification of Diseases
  • the compounds of the present invention are of use in the treatment of 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).
  • the compounds of the present invention are also of use in the treatment of mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and
  • Bipolar I Disorder Bipolar I Disorder
  • Bipolar Il Disorder Recurrent Major Depressive
  • Substance-Induced Mood Disorder including the subtypes with
  • the compounds of the present invention are also of use in the treatment of anxiety disorders including 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-lnjury 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).
  • the compounds of the present invention are also of use in the treatment of substance- related disorders including Substance Use Disorders such as Substance Dependence 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-
  • the compounds of the present invention are also of use in the treatment of sleep disorders including primary sleep disorders such as Dyssomnias such as Primary
  • 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.
  • the compounds of the present invention are also of use in the treatment of 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).
  • 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).
  • the compounds of the present invention are also of use in the treatment of 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 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).
  • Attention-Deficit /Hyperactivity Disorder including the subtypes Attention
  • the compounds of the present invention are also of use in the treatment of 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
  • the compounds of the present invention are also of use in the 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.
  • cognition impairment includes for example the treatment of impairment of cognitive functions including attention, orientation, learning disorders, memory (i.e.
  • Alzheimer's disease Huntington's disease, Pick disease, Aids-related dementia or other dementia states
  • Multiinfarct dementia alcoholic dementia, hypotiroidism- related dementia, and dementia associated to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis
  • other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, head trauma, age related cognitive decline, stroke, neurodegeneration, drug- induced states, neurotoxic agents, mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, and post-electroconvulsive treatment related cognitive disorders
  • dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism, and tardive dyskinesias.
  • the compounds of the present invention are also of use in the treatment of 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
  • the invention also provides a ⁇ /-[[1-(dimethylamino)cyclopentyl](phenyl)methyl]-4-fluoro- 2-methyl-6-(methyloxy)benzamide or a salt or solvate thereof for use in the treatment of schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention-deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive- compulsive disorders, amnesia, aggression, vertigo, dementia and circadian rhythm disorders.
  • the invention also provides ⁇ /-[[1-(dimethylamino)cyclopentyl](phenyl)methyl]-4-fluoro-2- methyl-6-(methyloxy)benzamide or a salt or solvate thereof for use in the treatment of psychotic disorders, substance abuse, cognitive impairment, obesity, and gastric motility disorders.
  • a method of treating a mammal including a human, suffering from or susceptible to a disorder mediated by GIyTI , which comprises administering an effective amount of ⁇ /-[[1- (dimethylamino)cyclopentyl](phenyl)methyl]-4-fluoro-2-methyl-6-(methyloxy)benzamide or a salt or solvate thereof.
  • the invention also provides a method of treating schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention-deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, Parkinson's disease, dyskinetic disorders, depression, bipolar disorder, cognitive impairment, obesity, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, vertigo, dementia and circadian rhythm disorders which comprises administering to a mammal in need thereof an effective amount of ⁇ /-[[1- (dimethylaminoJcyclopenty ⁇ phenyOmethyll- ⁇ fluoro ⁇ -methyl- ⁇ -CmethyloxyJbenzamide or a salt or solvate thereof.
  • the invention also provides a method of treating psychotic disorders, substance abuse, cognitive impairment, obesity and gastric motility disorders which comprises administering to a mammal in need thereof an effective amount of ⁇ /-[[1- (dimethylamino)cyclopenty
  • the compounds of the present invention are also of use as anticonvulsants.
  • the compounds are thus useful in the treatment of convulsions in mammals, and particularly epilepsy in humans.
  • "Epilepsy” is intended to include the following seizures: simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures.
  • the invention also provides a method of treating convulsions, which comprises administering to a mammal in need thereof an effective amount of ⁇ -[[I ⁇ dimethylaminojcyclopenty ⁇ phenyljmethyll- ⁇ fluoro ⁇ -methyl- ⁇ - (methyloxy)benzamide or a salt or solvate thereof.
  • the compounds of the present invention also find use in the treatment of neuropathic pain, for example in diabetic neuropathy, sciatica, non-specific lower back pain, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, neuralgia such as post-herpetic neuralgia and trigeminal neuralgia and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions.
  • neuropathic pain for example in diabetic neuropathy, sciatica, non-specific lower back pain, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, neuralgia such as post-herpetic neuralgia and trigeminal neuralgia and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions.
  • the disorder mediated by GIyTI to be treated by the use or method as hereinbefore described is a psychosis, including schizophrenia, dementia and attention deficit disorders, particularly schizophrenia.
  • the invention also provides the use of ⁇ /-[[1-(dimethylamino)cyclopenty
  • the invention also provides the use of ⁇ /-[[1-(dimethylamino)cyclopentyl](phenyl)methyl]- 4-fluoro-2-methyl-6-(methyloxy)benzamide or a salt or solvate thereof in the manufacture of a medicament for the treatment of psychotic disorders, substance abuse, cognitive impairment, obesity and gastric motility disorders.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • compositions for use according to the invention may be administered as the raw material.
  • the active ingredients are provided in the form of pharmaceutical compositions.
  • a pharmaceutical composition comprising ⁇ /-[[1-(dimethylamino)cyclopenty
  • compositions may be used in the treatment of clinical conditions for which a GIyTI inhibitor is indicated such as, for example, schizophrenia.
  • the carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition.
  • the carrier may be a solid or a liquid and may be formulated with at least ⁇ /-[[1-
  • the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5HT1 B antagonists, 5HT1 D antagonists, D1 agonists, M1 agonists and/or anticonvulsant agents, as well as atypical antipsychotic drugs and cognitive enhancers.
  • different antidepressant agents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, H3 antagonists, 5HT1A antagonists, 5
  • Suitable 5HT3 antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide.
  • Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metoclopramide.
  • Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.
  • Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.
  • Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chlomipramine and nortriptyline.
  • Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.
  • Suitable anticonvulsant agents which may be used in combination of the compounds of the invention include for example divalproex, carbamazepine and diazepam.
  • the compound of the present invention and its salts and solvates thereof are also suitable for combination with typical and atypical antipsychotics to provide improved treatment of psychotic disorders.
  • adjunctive 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 add-on therapeutic administration.
  • Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of /V- ⁇ i ⁇ dimethylaminoJcyclopentylKphenyOmethylj- ⁇ fluoro ⁇ -methyl- ⁇ - (methyloxy)benzamide or a salt or solvate thereof and at least one neuroleptic 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 receives administration of another component.
  • the compound of the present invention or a salt or solvate thereof may be administered as adjunctive therapeutic treatment to patients who are receiving administration of at least one neuroleptic agent, but the scope of the invention also includes the adjunctive therapeutic administration of at least one neuroleptic agent to patients who are receiving administration of the compound of the present invention or a salt or solvate thereof.
  • 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 ⁇ /-[[1- (dimethylaminoJcyclopentylKphenylJmethyO- ⁇ fluoro ⁇ -methyl- ⁇ methyloxyJbenzamide or a salt or solvate thereof to a patient receiving therapeutic administration of at least one neuroleptic agent.
  • the invention provides the use of ⁇ /-[[1- (dimethylamino)cyclopentyl](phenyl)methyl]-4-fluoro-2-methyl-6-(methyloxy)benzamide or a 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 neuroleptic agent.
  • the invention further provides ⁇ /-[[1- (dimethylamino)cyclopentyl](phenyl)methyl]-4-fluoro-2-methyl-6-(methyloxy)benzamide or a 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 neuroleptic agent.
  • the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of at least one neuroleptic agent to a patient receiving therapeutic administration of ⁇ /-[[1-(dimethylamino)cyclopenty
  • the invention provides the use of at least one neuroleptic 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 ⁇ /-[[1- (dimethylamino)cyclopentyl](phenyl)methyl]-4-fluoro-2-methyl-6-(methyloxy)benzamide or a salt or solvate thereof.
  • the invention further provides at least one neuroleptic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of ⁇ /-[[1-(dimethylamino)cyclopentyl](phenyl)methyl]- 4-fluoro-2-methyl-6-(methyloxy)benzamide or a salt or solvate thereof.
  • the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of ⁇ /-[[1-
  • the invention further provides the use of a combination of ⁇ /-[[1- (dimethylamino)cyclopentyl](phenyl)methyl]-4-fluoro-2-methyl-6-(methyloxy)benzamide or a salt or solvate thereof and at least one neuroleptic 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 /V-[[1- (dimethylamino)cyclopenty
  • the invention further provides ⁇ /-[[1-(dimethylamino)cyclopentyl](phenyl)methyl]-4-fluoro- 2-methyl-6-(methyloxy)benzamide or a salt or solvate thereof for use for simultaneous therapeutic administration with at least one neuroleptic agent in the treatment of a psychotic disorder.
  • the invention further provides the use of at least one neuroleptic agent in the manufacture of a medicament for simultaneous therapeutic administration with ⁇ /-[[1-(dimethylamino)cyclopentyl](phenyl)methy
  • the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of a pharmaceutical composition comprising ⁇ /-[[1-(dimethylamino)cyclopentyl](phenyl)methyl]-4-fluoro-2-methyl-6- (methyloxy)benzamide or a salt or solvate thereof and at least one mood stabilising or antimanic agent, a pharmaceutical composition comprising ⁇ /-[[1- (dimethylamino)cyclopentyl](phenyl)methyl]-4-fluoro-2-methyl-6-(methyloxy)benzamide or a salt or solvate thereof and at least one mood stabilising or antimanic agent, the use of a pharmaceutical composition comprising ⁇ /-[[1-(dimethylamino)cyclopentyl](phenyl)methyl]- 4-fluoro-2-methyl-6-(methyloxy)benzamide or a salt or solvate thereof and at least one mood stabilising or antimanic agent in the manufacture of a medicament for the treatment of
  • the invention provides a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising ⁇ /-[[1- (dimethylamino)cyclopentyl](phenyl)methyl]-4-fluoro-2-methyl-6-(methyloxy)benzamide or a salt or solvate thereof and one or more further dosage forms each comprising a neuroleptic agent for simultaneous therapeutic administration.
  • psychiatric disorder includes those disorders mentioned above, such as schizophrenia, mood disorders, anxiety disorders, substance-related disorders, sleep disorders, eating disorders, autistic disorder, attention- deficit/hyperactivity disorder, disruptive behaviour disorder, tic disorders, personality disorders, cognition impairment in other diseases, sexual dysfunction, dyskinetic disorders, depression, bipolar disorder, cognitive impairment and obsessive-compulsive disorders and all the various forms of the disorders as mentioned herein, which are contemplated as part of the present invention.
  • neuroleptic/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; aripipra
  • clozapine available under the tradename CLOZARIL®, from Mylan, Zenith Goldline, UDL, Novartis
  • olanzapine available under the tradename ZYPREX®, 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
  • haloperidol available under the tradename HALDOL®, from Ortho-McNeil
  • chlorpromazine available under the tradename THORAZINE®, from SmithKline Beecham (GSK); fluphenazine (available under the tradename PROLIXIN®, from Apothecon, Copley, Schering, Teva, and American Pharmaceutical Partners, Pasadena); thiothixene (available under
  • neuroleptic 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
  • the neuroleptic agents for use in the invention are selected from the group consisting of olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.
  • the compounds of the present invention are usually administered as a standard pharmaceutical composition.
  • the present invention therefore provides in a further aspect a pharmaceutical composition comprising ⁇ /-[[1- (dimethylaminoJcyclopenty ⁇ phenyOmethylJ ⁇ -fluoro ⁇ -methyl- ⁇ methyloxyJbenzamide or a salt or solvate thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be for use in the treatment of any of the conditions described herein.
  • Possible formulations include those suitable for oral, sub-lingual, buccal, parenteral (for example, subcutaneous, intramuscular, or intravenous), rectal, topical and intranasal administration and in forms suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • parenteral for example, subcutaneous, intramuscular, or intravenous
  • rectal topical and intranasal administration and in forms suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • inhalation or insufflation either through the mouth or nose.
  • oral administration is provided.
  • Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, or lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions.
  • a compound of the invention may be prepared as a formulation with a controlled release profile. This may be in any of the above mentioned pharmaceutical forms.
  • it may be a gel formulation in a non aqueous oily vehicle, for example Miglyol, with a suitable gelling agent if required, for example methyl cellulose or hydrophobic colloidal silica.
  • Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically, a flavoured base, such as sugar and acacia or tragacanth and pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.
  • a flavoured base such as sugar and acacia or tragacanth
  • pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.
  • Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution may be isotonic with the blood of the intended recipient. Although such solutions may be administered intraveneously, they may also be administered by subcutaneous or intramuscular injection. Formulations suitable for rectal administration may be provided as unit-dose suppositories comprising the active ingredient and one or more solid carriers forming the suppository base, for example, cocoa butter.
  • Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils.
  • Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof.
  • Formulations of compounds of the invention may, for example, be composed so as to improve the exposure profile of the compound of the invention.
  • compositions suitable for transdermal administration include ointments, gels and patches.
  • the composition is in unit dose form such as a tablet, capsule or ampoule.
  • the formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.
  • a tablet may be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • one or more optional ingredients such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in sufficient water to give the desired concentration and then rendering the resulting solution sterile and isotonic.
  • the compound may be administered in single or divided doses and may be administered one or more times, for example 1 to 4 times per day.
  • PET shall mean: positron emission tomography
  • SPECT shall mean: single photon emission (computed) tomography
  • Ci 4 H 22 N 2 requires 218; and enantiomer 2 (0.28g); Chiral HPLC: 98% ee; 1 H NMR (CDCI3) ⁇ : 0.42 (1 H, m), 1.32 (3H, m), 1.49 (I H, m), 1.63 (I H, m), 1.76 (1 H, m), 1.95 (3H, m), 2.29 (6H 1 s), 4.39 (1 H, s), 7.28 (3H, m), 7.50 (2H, d); Mass spectrum (Electrospray LC/MS): Found 219 (MH + ). Ci 4 H 22 N 2 requires 218.
  • UV wavelength range 225nm
  • Dry THF (6ml) was stirred under argon at -80° and treated with sec-butyl lithium (4.6ml of a 1.4M solution in cyclohexane, 6.5mmol) and N,N,N',N'-tetramethylethylenediamine (1.00ml, 6.5mmol).
  • a solution of 4-fluoro-2-methoxybenzoic acid (0.5Og, 2.94mmol) in dry THF (2ml) was now added dropwise over 30 minutes and allowed to stir for a further 30 minutes at -80°.
  • lodomethane (732ul, 11.76mmol) was now added dropwise over 5 minutes and the reaction stirred at -70° for a further 20 minutes and allowed to warm to room temperature.
  • Example compound above is convertable to the corresponding hydrochloride salt by dissolving the parent free base in DCM or DCM/methanol mixtures and adding 1 M hydrogen chloride in ether, followed by evaporation and drying in vacuo.

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Abstract

La présente invention concerne le N-[[1-diméthylamino[cyclopentyl](phényl)méthyl]-4-fluoro-2-méthyl-6-(méthyloxy)benzamide, et les sels et solvates de ce composé. L'invention concerne également les utilisations pour la fabrication de médicaments destinés au traitement de troubles neurologiques et neuropsychiatriques, tels que des psychoses, des démences ou des troubles du déficit de l'attention, ainsi que des procédés de fabrication de ces composés et de leurs formulations pharmaceutiques.
PCT/EP2007/056115 2006-06-22 2007-06-20 Composés inhibant le transporteur de la glycine et utilisations en médecine WO2007147836A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010035026A1 (fr) * 2008-09-23 2010-04-01 Merck Sharp & Dohme Ltd Utilisation d'amplificateurs d'activité de nmda pour traiter l’hypersomnie, un état de veille réduit ou une vigilance réduite
US9045445B2 (en) 2010-06-04 2015-06-02 Albany Molecular Research, Inc. Glycine transporter-1 inhibitors, methods of making them, and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003055478A1 (fr) * 2001-12-21 2003-07-10 Smithkline Beecham P.L.C. Inhibiteurs de transporteurs glyt1 et utilisatons de ceux-ci dans le traitement de troubles neurologiques et neuropsychiatriques
WO2006067414A2 (fr) * 2004-12-23 2006-06-29 Glaxo Group Limited Composes
WO2006067423A1 (fr) * 2004-12-23 2006-06-29 Glaxo Group Limited Inhibiteurs de transport de la glycine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003055478A1 (fr) * 2001-12-21 2003-07-10 Smithkline Beecham P.L.C. Inhibiteurs de transporteurs glyt1 et utilisatons de ceux-ci dans le traitement de troubles neurologiques et neuropsychiatriques
WO2006067414A2 (fr) * 2004-12-23 2006-06-29 Glaxo Group Limited Composes
WO2006067423A1 (fr) * 2004-12-23 2006-06-29 Glaxo Group Limited Inhibiteurs de transport de la glycine

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010035026A1 (fr) * 2008-09-23 2010-04-01 Merck Sharp & Dohme Ltd Utilisation d'amplificateurs d'activité de nmda pour traiter l’hypersomnie, un état de veille réduit ou une vigilance réduite
US20110269782A1 (en) * 2008-09-23 2011-11-03 Magnus Ivarsson Use of nmda activity enhancers to treat hypersomnia, reduced wakefulness or reduced vigilance
US9045445B2 (en) 2010-06-04 2015-06-02 Albany Molecular Research, Inc. Glycine transporter-1 inhibitors, methods of making them, and uses thereof

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