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WO2011054773A1 - Nouveaux composes lactame - Google Patents

Nouveaux composes lactame Download PDF

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Publication number
WO2011054773A1
WO2011054773A1 PCT/EP2010/066545 EP2010066545W WO2011054773A1 WO 2011054773 A1 WO2011054773 A1 WO 2011054773A1 EP 2010066545 W EP2010066545 W EP 2010066545W WO 2011054773 A1 WO2011054773 A1 WO 2011054773A1
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Prior art keywords
bis
methylphenyl
trifluoromethyl
fluoro
pyridinyl
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PCT/EP2010/066545
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English (en)
Inventor
Steven Mark Bromidge
Maria Pia Catalani
Jag Paul Heer
Christian Alan Paul Smethurst
Simona Tommasi
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GlaxoSmithKline LLC
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GlaxoSmithKline LLC
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Publication of WO2011054773A1 publication Critical patent/WO2011054773A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present invention relates to novel lactam compounds having pharmacological activity, to processes for their preparation, to compositions containing them and to their medical uses.
  • WO 2005/002577 (F. Hoffmann-La Roche AG), WO 2006/013050 (F. Hoffmann-La Roche AG) and WO 2007/028654 (SmithKline Beecham Corporation) describe series of pyridine derivatives which are claimed to be dual NK1/NK3 antagonists for treating schizophrenia.
  • WO 2002/16324 (F. Hoffmann-La Roche AG) describes 4-phenyl pyridine derivatives as NK1 receptor antagonists.
  • the present invention provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • R is halogen, C 1.4 alkyl or trifluoromethyl
  • Rl 0' Rl 1 ar, d R12 are independently hydrogen, halogen, C(0)NH2, C(0)NHC i_6 alkyl , C(0)N(C i_g alkyl) 2 , C 3.8 cycloalkyl, haloC-
  • R3 is hydrogen, C -
  • R4 and R5 are independently hydrogen or C 1.4 alkyl
  • Rg is trifluoromethyl, halogen, trifluoromethoxy, C -
  • n is an integer from 0 to 2;
  • q 1 or 2;
  • n 1 and p is 0 or n is 0 and p is 1.
  • Compounds of formula (I) may form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, sulphate, citric, lactic, mandelic, tartaric, p- toluenesulfonic, benzoic and methanesulphonic.
  • acids such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, sulphate, citric, lactic, mandelic, tartaric, p- toluenesulfonic, benzoic and methanesulphonic.
  • Some of the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed.
  • This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.
  • Salts, solvates and hydrates of compounds of formula (I) therefore form an aspect of the invention.
  • 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.
  • Suitable pharmaceutically acceptable salts of the compound 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 benzenesul
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).
  • the subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention or pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as ⁇ H, 3H, H e, 13C, 14 C , 15N, 17 0 , 18 0 , 31 P , 32 Pj 35 Sj 18 f , 36 C
  • Isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as ⁇ H, 1 ⁇ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 ⁇ , and carbon-14, i.e., 1 ⁇ C, isotopes are particularly preferred for their ease of preparation and detectability.
  • H e and 1 ⁇ F isotopes are particularly useful in PET (positron emission tomography), and 125
  • substitution with heavier isotopes such as deuterium, i.e., ⁇ H can 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.
  • Isotopically labelled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • 'halogen' refers to a fluorine, chlorine, bromine or iodine atom.
  • .g alkyl' as used herein as a group or a part of the group refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms.
  • examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like.
  • .g alkoxy' refers to an -0-C1-6 alkyl group wherein C1-6 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like.
  • 3.3 cycloalkyl' refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like.
  • .g alkyl' refers to a C-
  • examples of such groups include fluoroethyl, trifluoromethyl or trifluoroethyl and the like.
  • the wedge shaped bond indicates that the bond is above the plane of the paper and it is referred to as ⁇ configuration.
  • the broken bond indicates that the bond is below the plane of the paper and is in the a configuration.
  • p is 0 and n is 1.
  • p is 1 and n is 0.
  • R4 and R5 are methyl. In a further embodiment R3 is methyl.
  • Rg is trifluoromethyl or halogen and q is 2.
  • R is halogen or C 1.4 alkyl and m is 2.
  • Rg is hydrogen
  • R-12 is hydrogen or methyl.
  • p is 0 and n is 1
  • is hydrogen or methyl optionally substituted by a hydroxyl group
  • R2 is hydrogen, C -
  • Rg is hydrogen
  • Q is hydrogen or methyl optionally substituted by a hydroxyl group
  • i is hydrogen, C -
  • R-12 is hydrogen or methyl
  • R3,R4 and R5 are methyl
  • Rg is trifluoromethyl or halogen and q is 2
  • R is halogen or methyl and m is 2.
  • and R2 are hydrogen, R7 is hydrogen, RQ is C -
  • Q is hydrogen or methyl optionally substituted by a hydroxyl group , -12 ' s hydrogen or methyl, R3,R4 and R5 are methyl, Rg is trifluoromethyl or halogen and q is 2, R is halogen or methyl and m is 2.
  • CH 2 OH may be obtained in accordance with the following Scheme 1 .
  • Step (i) typically comprises reacting a chlorine of formula (I), with 2-ethenyl-4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolane, Pd(PPh 3 ) 4 , in the presence of a suitable solvent such as dioxane/ water and a suitable base such as Na 2 C0 3 at reflux temperature.
  • a suitable solvent such as dioxane/ water
  • a suitable base such as Na 2 C0 3 at reflux temperature.
  • Step (ii) typically comprises oxidation with osmium tetroxide in the presence of sodium periodate in a suitable solvent such as tetrahydrofuran and water.
  • a suitable solvent such as tetrahydrofuran and water.
  • the oxidation reaction may be carried out by ozonolysis in the presence of a suitable solvent such an alcohol i.e. methanol.
  • Step (iii) typically comprises reacting an aldehyde (III) with a phosphorus ylide ethyl
  • compounds of formula (IV), wherein R2 a is hydrogen may be obtained by Suzuki reaction (step(vii)) reacting a compound of formula (I) with ethyl-3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-propenoate in the presence of bis(triphenylphosphine)palladium(ll) chloride and sodium carbonate, in a suitable solvent such as mixture of dimethoxyethane, water and ethanol at temperature of 140-150°C with microwave irradiation for 20 min.
  • a suitable solvent such as mixture of dimethoxyethane, water and ethanol at temperature of 140-150°C with microwave irradiation for 20 min.
  • Step (iv) typically comprises reacting (IV) with nitro CHR-
  • Step (v) typically comprises cyclisation of (V), wherein R2 a is hydrogen, in the presence of Raney-Ni, in a suitable solvent such as ethanol under H2 atmosphere to obtain compounds of formula (I), wherein p is 0 and n is 1 , R-12 is hydrogen, R-
  • Step (vi) typically comprises cyclisation of (V), wherein R2 a is C(0)OEt, in the presence of Raney-Ni, in a suitable solvent such as ethanol under H2 atmosphere, followed by reduction reaction with Sodium borohydride in the presence of calcium chloride in a suitable solvent such as methanol, to obtain compounds of formula(l), wherein p is 0 and n is 1 , R-12 is hydrogen, R-
  • R3 Step (i) typically comprises reacting an aldehyde (III) with nitroCH2R"i o > wherein R-
  • Step (ii) typically comprises reacting compounds (VI) with diethylmalonate in the presence of T1CI4 and pyridine in a suitable solvent such as a mixture of tetrahydrofuran and tetrachloromethane at room temperature to obtain compounds (Va) wherein R2a is C(0)OEt.
  • Compounds(Va) may be converted into compounds (I), wherein p is 0 and n is 1 , R-
  • are hydrogen, and R-
  • and R2 are CH2OH, may be obtained from a compound of formula (I) wherein p is 0 and n is 1 , R-12, R9, Ri and R2 are hydrogen, R-
  • Step (i) typically comprises protecting a compound of formula (I) with a suitable nitrogen protecting group P, such as tertbutyloxycarbonyl (Boc) by reaction of (I) with di-tert- butyldicarbonate in the presence of triethylamine and 4-dimethylaminopyridine in a suitable solvent such as dichloromethane, followed by reaction with Lithium bis(trimethylsilyl)amide then methyl chloroformate in a suitable solvent such as tetrahydrofuran at -78°C to obtain compounds (VII) wherein R-
  • a suitable nitrogen protecting group P such as tertbutyloxycarbonyl (Boc)
  • Step (ii) typically comprises reduction of compounds (VII) with sodium borohydride in the presence of calcium chloride in a suitable solvent such as methanol followed by deprotection of the amine to obtain compounds (I), wherein R-
  • Step (iii) typically comprises the reaction of a compound of formula (I) with methylchloroformate in the presence of a suitable organic base such as n-butyl lithium in a suitable solvent such as tetrahydrofuran.
  • Step (iv) typically comprises deprotection of the amine group of (VIII) and the reduction to alcohol as described in Scheme 1 step (vi) to obtain compounds of formula (I), wherein R-
  • Step (v) typically comprises a reaction of a compound of formula (I) with acetone in the presence of a base such lithium bis(trimethylsilyl)amide in a suitable solvent such as tetrahydrofuran at temperature of -78°C to obtain compounds of formula (I) wherein R-
  • Step (vi) typically comprises a reaction of a compound of formula (VII) with C(1 -6)alkylL wherein L is a leaving group such as halogen (i.e iodine, chlorine) in the presence of a base such as sodium hydride in a suitable solvent such tetrahydrofuran to obtain compounds of formula(VI la) wherein R-
  • L is a leaving group such as halogen (i.e iodine, chlorine) in the presence of a base such as sodium hydride in a suitable solvent such tetrahydrofuran
  • Step (vii) typically comprises a reduction of the ethyl ester group in (Vila) to CH2O H as described in step (ii) above to obtain compounds of formula (I) wherein R-
  • Step (i) typically comprises reacting compound (IV) with diethyl(acetylamino)propanedioate in the presence of a base such as NaOEt in a suitable solvents such as ethanol, dimethylsulfoxide or a mixture thereof to obtain compounds (IX), wherein R-
  • C(0)OEt and R2 a is hydrogen or C(0)OEt.
  • Step (ii) typically comprises reduction of compounds (IX) with sodium borohydride in a suitable solvent such as methanol to obtain compounds of formula (I) wherein R"i i ,R"io are CH2OH and R2 is hydrogen or CH2OH.
  • Step (iii) typically comprises reaction of compounds (IX), with a base such as sodium hydroxide in a solvent such as a mixture of water and methanol, followed by addition of methanol and hydrochloride to obtain compounds (X), wherein R 10 is hydrogen and R-
  • Step (iv) typically comprises reduction as described above in step (ii) to obtain compounds of formula (I) wherein R2 is CH2OH or hydrogen, R-
  • Step (v) typically comprises reducing a compound of formula (X), wherein R 2 is hydrogen with lithium hydroxide in a solvents such as methanol, water or tetrahydrofuran or a mixture thereof, to the compounds of formula (X) wherein R"i i aa is carboxylic acid and R-
  • Step (vi) typically comprises a reaction of compound of formula (X), wherein R-
  • Step (vii) typically comprises a reaction of compounds of formula (X), wherein R-
  • 2 an d R9 are hydrogen and Re is CH2OH may be obtained in accordance with the following Scheme 5.
  • Step (i) typically comprises oxidation of compounds (II) with osmium tetroxide in the presence of sodium periodate in a suitable solvent such as tetrahydrofuran and water, following by esterification reaction with methanol in the presence of hydrochloric acid.
  • Step (ii) typically comprises reaction of compounds (XI) in ethyl acetate in the presence of a suitable base such as for example potassium tert-butoxide at temperature of 75°C.
  • Step (iii) typically comprises reaction of compounds (XII) with ethyl choloroacetate in the presence of a base such as potassium carbonate and sodium iodide in a suitable solvent such as acetone, dimethoxyethane or mixture thereof.
  • a base such as potassium carbonate and sodium iodide
  • a suitable solvent such as acetone, dimethoxyethane or mixture thereof.
  • Step (iv) typically comprises reductive amination of compounds (XIII) with sodium cyanoborohydride in methanol and in the presence of ammonium acetate, followed by in situ cyclisation.
  • Step (v) typically comprises reduction of compounds (XIV) with lithium borohydride in the presence of calcium chloride in a suitable solvent such as tetrahydrofuran.
  • 2 is C-
  • 2 is hydrogen
  • .g alkylL wherein L is a suitable leaving group such as halogen i.e chlorine and iodine.
  • Compounds of formula (I) and its pharmaceutically acceptable salts have affinity for and are specific antagonists of tachykinins, including substance P and other neurokinins.
  • Tachykinins are a family of peptides that share a common carboxyl-terminal sequence (Phe- X-Gly-Leu-Met-NH2). They are actively involved in the physiology of both lower and advanced life forms. In mammalian life forms, the main tachykinins are substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB) which act as neurotransmitters and neuromodulators. Mammalian tachykinins may contribute to the pathophysiology of a number of human diseases.
  • SP substance P
  • NAA Neurokinin A
  • NKB Neurokinin B
  • NK1 SP-preferring
  • NK2 NKA-preferring
  • NK3 NKB-preferring
  • compounds of formula (I) and their pharmaceutically acceptable salts have affinity for and are antagonists of the NK1 and NK3 receptor and thus may be of use in the treatment of psychotic disorders.
  • the term "psychotic disorder” includes: Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81 ) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9)
  • Compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may also be of use in the treatment of the following disorders: Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (31 1 ); Bipolar Disorders including Bipolar I Disorder, Bipolar II Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301 .13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90):
  • Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance- Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance- Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced sexual Dysfunction, Substance-Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder,
  • Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; sleep apnea and jet-lag
  • 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 (299.80), Rett's Disorder (299.80), Childhood Disintegrative Disorder (299.10) and Pervasive Disorder Not Otherwise Specified (299.80, including Atypical Autism).
  • 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):
  • 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.
  • 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), Voy
  • Skin disorders including psoriasis, pruriginous diseases, urticaria, herpes, photodermatosis, atopic dermatitis, contact dermatitis, lichen, prurigo, pruritus, erythema, in particular solar erythema, insect bites, in fibrosis and other collagen maturation disorders such as for example scleroderma, in hair disorders such as alopecia areata, alopecia totalis and alopecia universalis.
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance in the treatment of skin disorders.
  • the invention furthermore provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance in the treatment of hair disorders.
  • the invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance in the treatment or prophylaxis of the above psychotic disorders, in particular schizophrenia and Alcohol-Related Disorders such as Alcohol Dependence, Alcohol Abuse, Alcohol Intoxication.
  • the invention further provides a method of treating schizophrenia and Alcohol-Related Disorders such as Alcohol Dependence, Alcohol Abuse, Alcohol Intoxication which comprises administering to a host in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention further provides a method of treating skin disorders.
  • the invention further provides a method of treating hair disorders.
  • the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of schizophrenia and Alcohol-Related Disorders such as Alcohol Dependence, Alcohol Abuse, Alcohol Intoxication.
  • the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of skin disorders.
  • the invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of the above disorders.
  • the compounds of formula (I) are usually formulated in a standard pharmaceutical composition. Such compositions can be prepared using standard procedures.
  • the present invention further provides a pharmaceutical composition for use in the treatment of the above disorders which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention further provides a pharmaceutical composition which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • 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).
  • 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 improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches; and ii) bupropion.
  • the compounds of the invention may be used in combination with the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists for example acamprosate; ii) GABA receptor agonists for example tetrabamate; and iii) Opioid receptor antagonists for example naltrexone.
  • the compounds of the invention may be used in combination with the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; and iii) vasodilatory antihypertensives for example lofexidine.
  • opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine
  • opioid receptor antagonists for example naltrexone
  • vasodilatory antihypertensives for example lofexidine.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita and phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate and chlormethiazole.
  • benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam
  • non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon
  • barbiturates for example
  • the compounds of the invention may be used in combination with the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; and v) premenstral agents for example pyridoxine and progesterones.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; and vii) premenstral agents.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; and iv) stimulants for example methylphenidate, amphetamine formulations and pemoline.
  • the compounds of the invention may be used in combination with the following agents to treat or prevent ADHD: i) stimulants for example methylphenidate, amphetamine formulations and pemoline; and ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).
  • stimulants for example methylphenidate, amphetamine formulations and pemoline
  • non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).
  • the compounds of the invention may be used in combination with the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; and iv) anxiolytics.
  • 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 transport inhibitors for example apomorphine and buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibitors for example serotonin reuptake inhibitors; v) noradrenaline transport inhibitors for example reboxetine and vii) 5-HT1A agonists, for example flibanserine.
  • phosphodiesterase V inhibitors for example vardenafil and sildenafil
  • dopamine agonists/dopamine transport inhibitors for example apomorphine and buproprion
  • alpha adrenoceptor antagonists
  • 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 and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine); 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).
  • serotonin reuptake inhibitors such as citalopram, escitalopram, fluoxetine, parox
  • 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 invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent or agents.
  • the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound in preparing solutions, can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions suitable for transdermal administration include ointments, gels and patches.
  • the composition may contain from 0.1 % to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • the dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1 .0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.
  • NMR Nuclear Magnetic Resonance
  • Agilent LC/MSD 1 100 Mass Spectrometer coupled with HPLC instrument Agilent 1 100 Series, operating in positive or negative electrospray ionization mode and in both acidic and basic gradient conditions
  • Acidic gradient LC/MS - ES (+ or -) analyses performed on a Sunfire C18 column (30 x 4.6 mm, 3.5 ⁇ ).
  • Mobile phase A - water + 0.1 % HC0 2 H / B - CH 3 CN + 0.1 % HC0 2 H.
  • Gradient: t 0 min 0% (B), from 0% (B) to 100% (B) in 3 min lasting for 1 min, from 100% (B) to 0% (B) in 0.1 min, stop time 4.10 min.
  • Column T rt.
  • Flash chromatography was carried out on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany), Varian Mega Be-Si pre-packed cartridges, pre-packed Biotage silica cartridges (e.g. Biotage SNAP cartridge), KP-NH pre-packed flash cartridges or ISCO RediSep Silica cartridges.
  • SPE-SCX cartridges are ion exchange solid phase extraction columns supplied by Varian.
  • the eluent used with SPE-SCX cartridges is methanol followed by 2N ammonia solution in methanol.
  • SPE-Si cartridges are silica solid phase extraction columns supplied by Varian.
  • Enantiomer 1 or 2 means a compound of the invention or an intermediate thereof as a single enantiomer whose absolute configuration was not determined either R or S stereochemistry. "Anti isomer” indicates that the two substituents on two distinct carbon atoms of the lactam ring are on the opposite side respect to the plane.
  • Syn isomer indicates that the two substituents on two distinct carbon atoms of the lactam ring are on the same side respect to the plane.
  • reaction mixture was purged with nitrogen at -65°C for 30 min and dimethyl sulfide (7.55 ml, 103 mmol) was then added at -65°C. The temperature was allowed to rise gradually to 20°C over 3 h.
  • reaction was concentrated to dryness and purified by column chromatography on a silica gel column using EtOAc in iso-hexane, 0%-20% (3CV), 20%- 50% (10CV) to yield the title compound as a white crystalline solid (Intermediate 26, 928 mg, 1.334 mmol, 76% yield).
  • Methylmagnesium bromide (3M in Et 2 0) (0.2 ml, 0.600 mmol) was added and the mixture was stirred at 0°C for 2 h. The reaction was allowed to warm to r.t. and stirred overnight. Additional methylmagnesium bromide (3M in Et 2 0) (0.2 ml, 0.600 mmol) was added and the reaction stirred at r.t. for a further 4 h before the reaction was quenched by addition of saturated aqueous NH 4 CI (1 ml). Water (20 ml) was added and the mixture was extracted into EtOAc (2 x 50 ml).
  • Example 6 9.6 mg (0.016 mmol): Chiral analysis Rt 2.71 min.; chromatographic conditions: [Column: Chiralcel OD-H (25 x 0.46 cm); ChiralPak AD-H (25 x 4.6 cm); Modifier: 12% (EtOH+0.1 % isopropylamine), 15% from 7 min.; Flow Rate 2.5 ml/min; DAD: 210-340 nm; CD: - nm].
  • Example 7 1 1 .2 mg (0.018 mmol): Chiral analysis Rt 3.16 min.; chromatographic conditions: [Column: Chiralcel OD-H (25 x 0.46 cm); ChiralPak AD-H (25 x 4.6 cm); Modifier: 12% (EtOH+0.1 % isopropylamine), 15% from 7 min.; Flow Rate 2.5 ml/min; DAD: 210-340 nm; CD: - nm].
  • Example 8 9.5 mg (0.016 mmol): Chiral analysis Rt 5.69 min.; chromatographic conditions: [Column: Chiralcel OD-H (25 x 0.46 cm); ChiralPak AD-H (25 x 4.6 cm); Modifier: 12% (EtOH+0.1 % isopropylamine), 15% from 7 min.; Flow Rate 2.5 ml/min; DAD: 210-340 nm; CD: - nm].
  • Example 9 1 1 .2 mg (0.018 mmol): Chiral analysis Rt 10.72 min.; chromatographic conditions: [Column: Chiralcel OD-H (25 x 0.46 cm); ChiralPak AD-H (25 x 4.6 cm); Modifier: 12% (EtOH+0.1 % isopropylamine), 15% from 7 min.; Flow Rate 2.5 ml/min; DAD: 210-340 nm; CD: - nm].
  • Example 1 1 and 12 were subsequently separated (in order of elution) using the following preparative chiral hplc conditions:
  • Example 11 25 mg (0.040 mmol) isolated.
  • Example 14a (420 mg) was separated using the following preparative HPLC conditions to give Examples 15 and 16:
  • reaction mixture was concentrated to dryness, re-dissolved in DCM (75 ml) and washed with aqueous saturated NaHC0 3 solution (75 ml). The organic layer was then dried (Na 2 S0 4 ) and concentrated to dryness to yield the desired material as a yellow crystalline solid which was purified by MDAP to yield the title compound as a white crystalline solid (156 mg, 0.239 mmol, 81 % yield).
  • U20S cells were harvested from tissue culture flasks, re-suspended to a cell density of 200-300K/ml and mixed with recombinant BacMam virus carrying NKR gene in a virus/cell ratio of 1 % (v/v). 10K-15K cells/well were then seeded in 384-well Greiner bio-one plate in culture medium (DMEM with 10% FBS), incubated overnight in 5% C0 2 at 37°C. After aspirating the medium, cells were loaded 18-24 hr later with cytoplasmic calcium indicator Fluo-4 Calcium (Invitrogen)
  • IC 50 values of each compound were determined by an 1 1 -point 3X-dilution inhibition curve.
  • the potency each antagonist (fpK,) was calculated from plC 50 by the Cheng-Prusoff equation using EC 50 of ligand determined in a separate experiment.

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Abstract

L'invention concerne de nouveaux composés lactame représentés par la formule (I) ou un sel pharmaceutiquement acceptable de ceux-ci. Dans la formule (I) (CH2)p R8 O N N R5 R3 N (CH2)n O R12 R10 R7R1 R2 R11 R9 R4 (R6)q (R)m 5, R représente halogène, C 1-4 alkyle ou trifluorométhyle; R1, R2, R7, R8, R9, R10, R11 et R12 représentent indépendamment hydrogène, halogène, C(O)NH2, C(O)NHC 1-6 alkyle, C(O)N(C 1-6 alkyl)2, C 3-8 cycloalkyle, haloC1-6 alkyle ou C 1-6 alkyle éventuellement substitué par un ou plusieurs groupes hydroxyle, C 3-8 cycloalkyle ou C 1-6 alcoxy; R3 représente hydrogène, C 1-6 alkyle ou haloC 1-6 alkyle; R4 et R5 représentent indépendamment hydrogène ou C 1-4 alkyle; R6 représente trifluorométhyle, halogène, trifluoromethoxy, C 1-6 alcoxy ou C 1-4 alkyle; m est un nombre entier compris entre 0 et 2; q est égal à 1 ou 2; et n est égal à 1 et p est égal à 0 ou n est égal à 0 et p est égal à 1.
PCT/EP2010/066545 2009-11-03 2010-10-29 Nouveaux composes lactame Ceased WO2011054773A1 (fr)

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WO2015068744A1 (fr) 2013-11-08 2015-05-14 キッセイ薬品工業株式会社 Dérivé de carboxyméthylpipéridine
WO2015170693A1 (fr) * 2014-05-07 2015-11-12 キッセイ薬品工業株式会社 Dérivé de cyclohexyl-pyridine
WO2016021562A1 (fr) * 2014-08-06 2016-02-11 キッセイ薬品工業株式会社 Dérivé de cyanothiophène
WO2017157885A1 (fr) 2016-03-16 2017-09-21 Bayer Cropscience Aktiengesellschaft Dérivés de n-(cyanobenzyl)-6-(cyclopropylcarbonylamino)-4-(phényl)-pyridine-2-carboxamide et composes apparentés utilisés comme agents phytosanitaires pesticides

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Cited By (14)

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US10100030B2 (en) 2013-11-08 2018-10-16 Kissei Pharmaceutical Co., Ltd. Carboxymethyl piperidine derivative
WO2015068744A1 (fr) 2013-11-08 2015-05-14 キッセイ薬品工業株式会社 Dérivé de carboxyméthylpipéridine
KR20160078997A (ko) 2013-11-08 2016-07-05 깃세이 야쿠힌 고교 가부시키가이샤 카복시메틸피페리딘 유도체
WO2015170693A1 (fr) * 2014-05-07 2015-11-12 キッセイ薬品工業株式会社 Dérivé de cyclohexyl-pyridine
JP5847362B1 (ja) * 2014-05-07 2016-01-20 キッセイ薬品工業株式会社 シクロヘキシルピリジン誘導体
KR20170002474A (ko) 2014-05-07 2017-01-06 깃세이 야쿠힌 고교 가부시키가이샤 사이클로헥실피리딘 유도체
CN106414406A (zh) * 2014-05-07 2017-02-15 橘生药品工业株式会社 环己基吡啶衍生物
CN106414406B (zh) * 2014-05-07 2019-04-16 橘生药品工业株式会社 环己基吡啶衍生物
US9708266B2 (en) 2014-05-07 2017-07-18 Kissei Pharmaceutical Co., Ltd. Cyclohexyl pyridine derivative
RU2681316C2 (ru) * 2014-05-07 2019-03-06 Киссеи Фармасьютикал Ко., Лтд. Производные циклогексилпиридина
US10011568B2 (en) 2014-05-07 2018-07-03 Kissei Pharmaceutical Co., Ltd. Cyclohexyl pyridine derivative
WO2016021562A1 (fr) * 2014-08-06 2016-02-11 キッセイ薬品工業株式会社 Dérivé de cyanothiophène
JPWO2016021562A1 (ja) * 2014-08-06 2017-06-15 キッセイ薬品工業株式会社 シアノチオフェン誘導体
WO2017157885A1 (fr) 2016-03-16 2017-09-21 Bayer Cropscience Aktiengesellschaft Dérivés de n-(cyanobenzyl)-6-(cyclopropylcarbonylamino)-4-(phényl)-pyridine-2-carboxamide et composes apparentés utilisés comme agents phytosanitaires pesticides

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