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WO2011151361A1 - Nouveaux composés - Google Patents

Nouveaux composés Download PDF

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Publication number
WO2011151361A1
WO2011151361A1 PCT/EP2011/059011 EP2011059011W WO2011151361A1 WO 2011151361 A1 WO2011151361 A1 WO 2011151361A1 EP 2011059011 W EP2011059011 W EP 2011059011W WO 2011151361 A1 WO2011151361 A1 WO 2011151361A1
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WO
WIPO (PCT)
Prior art keywords
chloro
compound
mmol
carboxamide
pyridinyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2011/059011
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English (en)
Inventor
Barbara Bertani
Susanna Cremonesi
Vincenzo Garzya
Fabrizio Micheli
Renata Rupcic
Fabio Maria Sabbatini
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Group Ltd
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Glaxo Group Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB1009341.7A external-priority patent/GB201009341D0/en
Priority claimed from GBGB1019575.8A external-priority patent/GB201019575D0/en
Priority claimed from GBGB1020622.5A external-priority patent/GB201020622D0/en
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of WO2011151361A1 publication Critical patent/WO2011151361A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the invention relates to tricyclic derivatives, and their use in treating diseases and conditions mediated by antagonism of the mGluRs receptor, in particular substance related disorders.
  • the invention relates to compositions containing the derivatives and processes for their preparation.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • E is -CH2-, -0-, -S-, -(SO)- or -SO2-;
  • ring A is either:
  • ring A is imidazole
  • RY is H, C-
  • n 1 or 2;
  • R1 is phenyl or 5- or 6-membered monocyclic heteroaryl, either of which are
  • R 2 , R3, R and R 5 which may be the same or different, are selected from the list consisting of H, halo, C-
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • E is -CH2-, -0-, -S-, -(SO)- or -SO2-;
  • ring A is either:
  • ring A is imidazole
  • RY is H, C-
  • n 1 or 2;
  • R1 is phenyl or 5- or 6-membered monocyclic heteroaryl, either of which are
  • halo optionally substituted by one or two groups independently selected from halo, C-
  • R 2 , R3, R4 and R 5 which may be the same or different, are selected from the list consisting of H, halo, C-
  • an alkyl substituent is a univalent radical derived by removal of a hydrogen atom from an acyclic alkane.
  • .galkyl refers to such an alkyl substituent containing 1 to 6 carbons.
  • alkyl substituents include methyl and ethyl, may be straight chain (i.e. n-propyl, n-butyl, n- pentyl and n-hexyl) or branched chain (for example, isopropyl, isobutyl, secbutyl, tert- butyl, isopentyl and neopentyl).
  • such an alkyl substituent is methyl, ethyl, n-propyl or isopropyl.
  • a halo substituent refers to fluoro, chloro, bromo and iodo radicals. In an embodiment unless otherwise indicated such a halo substituent is fluoro or chloro.
  • a haloalkyl substituent is an alkyl group substituted by one or more halo substituents, which halo substituents may be the same or different.
  • .ghaloalkyl refers to such a haloalkyl substituent containing 1 to 6 carbons.
  • Such haloalkyl substituents include monofluoromethyl, difluoromethyl, trifluoromethyl and 1-chloro-2-fluoroethyl.
  • such a haloalkyl substituent is monofluoromethyl, difluoromethyl or trifluoromethyl.
  • an alkoxy substituent is a group of formula " -0-" where R is alkyl as defined above.
  • .galkoxy refers to such an alkoxy substituent containing 1 to 6 carbons.
  • alkoxy substituents include methoxy and ethoxy and may be straight chain (i.e. n-propoxy, n-butoxy, n- pentoxy and n-hexyloxy) or branched chain (for example, isopropoxy, isobutoxy, secbutoxy, tert-butoxy, isopentoxy and neopentoxy).
  • such an alkoxy substituent is methoxy, ethoxy, n-propoxy or isopropoxy.
  • an alkylthio substituent is a group of formula "R-S-" where R is alkyl as defined above.
  • R is alkyl as defined above.
  • .galkylthio refers to such an alkylthio substituent containing 1 to 6 carbons.
  • alkylthio substituents include methylthio and ethylthio and may be straight chain or branched chain.
  • such an alkylthio substituent is methylthio, ethylthio, n-propylthio or isopropylthio.
  • an alkylsulfonyl substituent is a group of formula "R-SO2-" where R is alkyl as defined above.
  • R is alkyl as defined above.
  • .galkylsulfonyl refers to such an alkylsulfonyl substituent containing 1 to 6 carbons.
  • alkylsulfonyl substituents include methylsulfonyl and ethylsulfonyl and may be straight chain or branched chain. In an embodiment unless otherwise indicated, such an alkylsulfonyl substituent is methylsulfonyl, ethylsulfonyl, n-propylsulfonyl or isopropylsulfonyl.
  • a haloalkoxy substituent is a group of formula "R-0-" where R is haloalkyl as defined above.
  • R is haloalkyl as defined above.
  • .ghaloalkoxy refers to such a haloalkoxy substituent containing 1 to 6 carbons.
  • Such haloalkoxy substituents include monofluoromethoxy, difluoromethoxy, trifluoromethoxy and 1 - chloro-2-fluoroethoxy and may be straight chain or branched chain.
  • a haloalkylthio substituent is a group of formula "R-S-" where R is haloalkyl as defined above.
  • .ghaloalkylthio refers to such a haloalkylthio substituent containing 1 to 6 carbons.
  • Such haloalkylthio substituents include monofluoromethylthio, difluoromethylthio, trifluoromethylthio and 1-chloro-2-fluoroethylthio and may be straight chain or branched chain.
  • such a haloalkylthio substituent is monofluoromethylthio, difluoromethylthio or trifluoromethylthio.
  • a haloalkylsulfonyl substituent is a group of formula "R-SO2-" where R is haloalkyl as defined above.
  • .ghaloalkylsulfonyl refers to such a haloalkylsulfonyl substituent containing 1 to 6 carbons.
  • Such haloalkylsulphonyl substituents include monofluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl and 1 -chloro-2-fluoroethylsulfonyl and may be straight chain or branched chain.
  • such a haloalkylsulfonyl substituent is monofluoromethylsulfonyl, difluoromethylsulfonyl or trifluoromethylsulfonyl.
  • monocyclic heteroaryl is a univalent radical derived by removal of a hydrogen atom from a monocyclic heteroaromatic ring, which ring comprises ring- carbon atoms and ring-heteroatoms selected from the list nitrogen, oxygen and sulphur, and which ring is aromatic.
  • 5- or 6-membered monocyclic heteroaryl is monocyclic heteroaryl consisting of 5 or 6 ring-atoms, 1 to 3 of which are ring heteroatoms.
  • Examples of monocyclic heteroaryl are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, azepinyl, oxazepinyl, thiazepinyl and diazepinyl.
  • E is -CH2-, -0-, -S- or -SC>2--
  • ring A is:
  • ring A is imidazole, RY is C-
  • ring A is a triazole ring where V is C, W is C, X is N, Y is N and Z is N.
  • ring A is an imidazole ring where V is C, W is C, X is N, Y is -C(RY)- and Z is N; wherein RY is C-
  • R 1 is pyridyl optionally substituted by halo or alkyl.
  • R5 j hich may be the same or different, are selected from the list consisting of H and halo, wherein two or more of R 2 , R3, R4 and R 5 are H.
  • E is -CH2-, -0-, -S- or -SO2-;
  • ring A is a triazole ring where V is C, W is C, X is N, Y is N and Z is N;
  • n 1 or 2;
  • R1 is pyridyl optionally substituted by halo or alkyl
  • R 2 , R3, R4 and R 5 which may be the same or different, are selected from the list consisting of H and halo, wherein two or more of R 2 , R3 j R4 ANC
  • E is -CH 2 -, -0-, -S- or -SO2-;
  • ring A is an imidazole ring where V is C, W is C, X is N, Y is -C(RY)- and Z is N; wherein RY is C-
  • n 1 or 2;
  • R1 is pyridyl optionally substituted by halo or alkyl
  • R5 J w ich may be the same or different, are selected from the list consisting of H and halo, wherein two or more of R ⁇ , R3, R4 ANC
  • the compound of formula (I) is selected from the list:
  • the pharmaceutically acceptable salts of the compounds defined in the first aspect may contain a basic centre and may form non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids.
  • Examples include the HCI, HBr, HI, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts.
  • suitable pharmaceutical salts see Berge et al, J.
  • pro-drugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H.
  • the invention provides a prodrug of a compound defined in the first aspect.
  • the compounds defined in the first aspect may exist in solvated or hydrated form. Therefore, in a further aspect, the invention provides a solvate or hydrate of a compound defined in the first aspect or a pharmaceutically acceptable salt thereof.
  • the compounds defined in the first aspect may exist in one or more polymorphic form.
  • the invention provides a polymorph of a compound defined in the first aspect or their pharmaceutically acceptable salts, or a polymorph of a solvate or hydrate of a compound defined in the first aspect or a
  • the compounds of the invention may possess one or more chiral centres and so exist in a number of stereoisomeric forms. All stereoisomers and mixtures thereof are included in the scope of the present invention. Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to those skilled in the art. In addition, chiral intermediate compounds may be resolved and used to prepare chiral compounds of the invention. In addition, the chiral compounds of the invention may be prepared by chiral synthesis. The compounds of the invention may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included in the scope of the present invention. For example, a claim to 2-hydroxyquinolinyl would also cover its tautomeric form, a- quinolinonyl.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 35 S, 18 F and 36 CI, respectively.
  • isotopic variations of the invention are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Experimental section hereafter using appropriate isotopic variations of suitable reagents.
  • Compound of formula (lib) i.e. compounds of general formula (II) where ring A is an imidazole ring may be prepared according to reaction scheme 3, by reaction compounds of fomula (III) with zinc, followed by reaction with triethylorthoacetate.
  • Compound of general formula (III) can be prepared from compounds of general formula (IV) according to reaction scheme 4.
  • Typical reaction conditions comprise reacting (IV) with Lawesson reagent followed by treatment with base and methyl iodide. The resulting thioether may then be reacted under basic condition with ethyl nitroacetate.
  • Compound of formula (IVb), i.e. compounds of general formula (IVb) where E is - CH 2 -and n is 2, may be prepared according to reaction scheme 6 from compounds of formula (VI). Typical reaction conditions comprise treatment with sodium azide and concentrated sulphuric acid.
  • the compounds of the invention antagonise the mGluR5 receptor and may be used to treat diseases or conditions mediated by antagonism of the mGluR5 receptor. Therefore according to a further aspect, the invention provides a compound of the invention for use in treating a disease or condition.
  • the disease or condition is a human disease or condition.
  • the disease or condition is mediated by antagonism of the mGluR5 receptor.
  • the disease or condition mediated by antagonism of the mGluR5 receptor is selected from the list consisting of: [the numbers in brackets after the listed diseases below refer to the classification code in Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD-10)]: i) Psychotic disorders for example Schizophrenia (including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60)); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) (including the subtypes Bipolar Type and Depressive Type); Delusional Disorder (297.1 ) (including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified
  • 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
  • Depression and mood disorders for example Depressive Episodes (including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode); Depressive Disorders (including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (31 1 )); Bipolar Disorders (including Bipolar I Disorder, Bipolar II Disorder (i.e.
  • Phobia (300.29) (including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type); Social Phobia
  • Substance-related disorders for example Substance Use Disorders (including Substance Dependence, Substance Craving and Substance Abuse); Substance- Induced Disorders (including Substance Intoxication, Substance Withdrawal,
  • Alcohol-Induced Persisting Dementia Alcohol-Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Sexual dysfunction
  • Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks)
  • Inhalant-Related Disorders including Inhalant Dependence (304.60), Inhalant Abuse
  • Phencyclidine (or Phencyclidine-Like)-Related Disorders including Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine Intoxication Delirium, Phencyclidine-lnduced Psychotic Disorder, Phencyclidine-lnduced Mood Disorder, Phencyclidine-lnduced Anxiety Disorder and Phencyclidine-Related Disorder Not Otherwise Specified (292.9)); Sedative-, Hypnotic-, or Anxiolytic-Related Disorders (including Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxio
  • Eating disorders such as Anorexia Nervosa (307.1 ) (including the subtypes Restricting Type and Binge-Eating/Purging Type); Bulimia Nervosa (307.51 )
  • 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).
  • 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.
  • the disease or condition mediated by antagonism of the mGluR5 receptor is selected from the list consisting of: Parkinson's Disease, epilepsy, inflammatory pain, neuropathic pain, migraine, Down's Syndrome, gastroesophageal reflux disease.
  • the invention provides a compound of the invention for use as a neuroprotectant.
  • the disease or condition mediated by antagonism of the mGluR5 receptor is a substance-related disorder.
  • references herein to "treat”, “treating” or “treatment” extend to prophylaxis, prevention of recurrence and suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions.
  • the invention includes the following further aspects. The diseases and conditions described above extend, where appropriate, to these further aspects. i) The use of a compound of the invention in the manufacture of a medicament in treating a disease or condition mediated by antagonism of the mGluR5 receptor.
  • the disease or condition is a substance related disorder.
  • a method of treating a disease or condition mediated by antagonism of the mGluR5 receptor in a mammal (preferably a human) comprising administering an effective amount of a compound of the invention.
  • the disease or condition is a substance related disorder.
  • the compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient by an appropriate route. Accordingly, in another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention and one or more
  • composition or dosage form other than the compound or compounds of the invention.
  • material usually gives form, consistency and performance to the pharmaceutical
  • compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In addition, the pharmaceutical compositions of the invention may comprise one or more additional pharmaceutically active compounds. Such pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be dispensed and then given to the patient such as with powders or syrups.
  • compositions of the invention may be prepared and packaged as dosage forms wherein each physically discrete dosage form contains a safe and effective amount of a compound of the invention. Accordingly, in another aspect, the invention provides dosage forms comprising pharmaceutical
  • compositions of the invention typically contains from 0.1 mg to 100 mg of a compound of the invention.
  • the compositions of the invention will typically be formulated into dosage forms which are adapted for administration to the patient by the desired route of administration.
  • dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration such as sterile solutions, suspensions, implants and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal and vaginal administration such as suppositories, pessaries and foams; (5) inhalation and intranasal such as dry powders, aerosols, suspensions and solutions (sprays and drops); (6) topical administration such as creams, ointments, lotions, solutions, pastes, drops, sprays, foams and gels; (7)
  • Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the release of the compound of the invention at the appropriate rate to treat the condition.
  • Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavouring agents, flavour masking agents, colouring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, rate modifying agents, antioxidants, preservatives, stabilizers, surfactants and buffering agents.
  • excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavouring agents, flavour masking agents, colouring agents, anticaking agents, hume
  • pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
  • Skilled artisans possess the knowledge and skill in the art to enable them to determine suitable pharmaceutically-acceptable excipients in appropriate amounts for use with the compounds of the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically- acceptable excipients and may be useful in selecting suitable pharmaceutically- acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • the pharmaceutical compositions of the invention may be prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include starches, crospovidone, sodium starch glycolate, cros- carmellose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and sodium dodecyl sulphate.
  • the oral solid dosage form may further comprise a glidant such as talc and colloidal silicon dioxide.
  • the oral solid dosage form may further comprise an outer coating which may have cosmetic or functional properties.
  • 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).
  • dopaminergics such as amantadine
  • antidepressants such as amantadine
  • anxiolytics iv
  • 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.
  • Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone and amisulpride).
  • Typical Antipsychotics for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine
  • Atypical Antipsychotics for example clozapine, olanzapine, risperidone, quetiapine,
  • Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine, sertraline femoxetine, fluvoxamine, indalpine and zimeldine); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine and venlafaxine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).
  • Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.
  • Anxiolytics include benzodiazepines such as alprazolam and lorazepam.
  • the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.
  • the starting material may not necessarily have been prepared from the batch referred to.
  • Mass spectra where recorded using a combined high pressure liquid chromatography/ mass spectroscopy (HPLC/MS) apparatus.
  • HPLC part of the apparatus comprised a Sunfire C18 column (30mm x 4.6 mm i.d.35 urn packing diameter) operated at 30 degC.
  • the compounds were eluted using the following solvent gradient where A is 0.1 % v/v solution of formic acid in water and B is a 0.1 % v/v solution of formic acid in acetonitrile.
  • UV detection comprised a summed signal from wavelength 210 to 350 nm.
  • Toluene (20 mL) was sealed and heated in Biotage Initiator at 150 °C for 7 min. After cooling the solvent was filtered off and the residue was triturated in cyclohexane (ca 100 ml) and methanol (ca 2 ml) and filtered. The title product (1 .1 g) was obtained after drying at 40°C and 0 mmHg for 2 hours in the form of pale green powder. The filtrate was evaporated and triturated once more in the same manner and the title compound (0.35 g) was obtained in the form of pale green powder.
  • reaction mixture was stirred at rt for 22h then triethyl orthoacetate (0.094 mL, 0.508 mmol) was added and reaction was stirred for another 2h. Then it was quenched with water (50ml) and extracted with DCM (5x50ml). The organic layer was washed with NaHCC>3(sat.sol.) until evolution of CO2 ceased. Then it was dried over sodium sulphate/magnesium sulphate and passed through an 1ST Phase separator and evaporated to give a crude oil (387 mg).
  • the organic solvent was removed under vacuum and the resulting aqueous residue was extracted with EtOAc (3 ⁇ 100 mL), and dried over Na 2 S0 4 .
  • the solvent was removed under vacuum to obtain the title compound (3.74 g).
  • the filter cake contained significant amounts of the desired compound and therefore it was transfered to a round bottom flask and triturated with EtOAc (150 mL). The mixture was heated for 1 hour at 60 °C, and filtered hot through a Buchner funnel to receive a colourless solution.
  • Reaction mixture was quenched with water (50 mL) and extracted with DCM (3 x 15 ml_). Combined organic extracts were washed with sat NaHC0 3 (3 x 30 mL), brine (50 mL), and dried over Na 2 S0 4 .
  • Reaction mixture was quenched with water (30 mL) and extracted with DCM (3x30 mL). Organic phase was washed with NaHC03 saturated solution (3x20 mL) and water (1 x30 mL), then dried over Na2S04, filtered and evaporated.
  • the mixture was filtered to give a green precipitate which was dried then washed using warm water (2 litres at 35 °C)
  • the washings were basified with 25 % aqueous ammonia solution to pH 1 1-12 (during base addition the mixture was cooled with ice added to the mixture).
  • 6-Chloro-1 ,3-benzothiazol-2-amine (intermediate 39, 8.7 g, 47.1 mmol) was suspended in 50 % aqueous sodium hydroxide solution (120 mL) and stirred at reflux for 18 hours. Water (50 ml) was added and the mixture was filtered through a Buchner funnel. Adding ice in the mixture and cooling it in the ice bath, the mixture was vigorously stirred and pH of the mixture was adjusted to 6.5 to 7 using glacial acetic acid.
  • the mixture was stirred at room temperature for 2 hours then the reaction mixture was poured into 50 ml of water.
  • the organic substances were extracted using phase separator cartridge using 60 ml of DCM in total.
  • the DCM layer was then washed twice with 100 ml of NaHCC>3 (in total).
  • the precipitate was dissolved in warm water (1 litre) and basified with 25 % aqueous ammonium hydroxide solution to pH 1 1 to 12 with cooling. The resulting precipitate was filtered, washed with aqueous ammonium hydroxide to pH 1 1 to 12) and dried in a vacuum oven at 40 °C to give the title mixture of two regioisomers, 5-chloro-6-fluoro-1 ,3-benzothiazol-2-amine (6.32 g) and 7-chloro-6-fluoro-1 ,3-benzothiazol-2-amine (3.16 g);
  • the mixture was extracted with DCM (200 ml was used in total) and the DCM layer was dried using a phase separator cartridge. The solvent was evaporated and the residue was dissolved in dimethyl sulfoxide (200 mL) and heated at 70 °C for 16 hours. The mixture was cooled to room temperature, poured in 200 ml of water and the resulting precipitate was filtered and dried in a vacuum oven at 40 °C.
  • 6-Chloro-7-fluoro-3-(methylthio)-2H-1 ,4-benzothiazine (intermediate 52, 1.25 g, 5.05 mmol) was dissolved in ethyl nitroacetate (6 ml, 54.2 mmol) under an argon atmosphere.
  • Benzyltrimethylammonium hydroxide in 40 % methanol solution (2.316 ml, 5.10 mmol) was added and the resulting mixture was stirred for 48 hours at 40 °C.
  • the mixture was diluted with water (approximately 100 ml).
  • Organic substances were extracted with 3x50 ml of DCM and the combined DCM layers were washed with 2x50 ml of 10 % aqueous potassium carbonate solution.
  • 6-Fluoro-1 ,3-benzothiazol-2-amine (intermediate 57, 12 g, 71.3 mmol) was suspended in 50 % aquous sodium hydroxide soluiton (200 mL) and heated under reflux for 24 hours. The mixture was cooled, diluted with water (70 mL) and extracted with ethyl acetate (3x). The organic phase was washed with water and all aqueous layers (3 L in total) were combined, filtered and the filtrate was acidified with glacial acetic acid to pH 6). This aqueous mixture was extracted with ethyl-acetate (3x) and the combined extracts were washed with water and dried over IS ⁇ SC ⁇ . The solvent was evaporated to give the title compound (6.2 g); 1 H NMR (500 MHz,
  • the second reaction vessel also containing 7-fluoro-2H-1 ,4-benzothiazin-3(4H)-one (1 ,7 g, 9,28 mmol) and Lawesson's reagent (2,252 g, 5,57 mmol) suspended in toluene (18 mL) was sealed and heated in Biotage Initiator at 150 °C for 7 minutes. After cooling, the two reaction mixtures were gathered and triturated with
  • Triethyl orthoacetate (1 .3 mL, 7.05 mmol) was added followed by p-toluenesulfonic acid monohydrate (14.0 mg, 0.074 mmol) and the mixture was heated at 70 °C with stirring for 2 hours. The reaction was quenched with water and extracted with DCM (2x). Organic phase was washed with saturated aqueous sodium bicarbonate solution, dried using a phase separator filter tube and concentrated under reduced pressure.
  • the reaction was quenched with dioxane/water (30/1 )and the reaction mixture was evaporated to dryness.
  • DCM 50 ml was added and stirred for 0.5 h.
  • the layers were separated by passing through an 1ST Phase separator, and the aqueous layer was extracted three times with DCM (3x50ml). The combined organic layers were then washed with water (100 ml) and brine (100ml), dried over sodium sulphate and passed through an 1ST phase separator.
  • the reaction was then cooled to room temperature and then to 0°C and quenched with dioxane/water (30/1 ). The entire reaction mixture was evaporated to dryness. DCM (50 ml) was added and stirred for 0.5 h. NaHC0 3 (sat. sol.) (20 ml) was added and stirring continued for 15 min. The layers were separated by passing the mixture through an 1ST Phase separator. The aqueous layer was extracted three times with DCM (3x50ml) and the combined organic layers were washed with water (100 ml) and brine (100ml), dried over sodium sulphate and passed through an 1ST phase separator.
  • the combined organic extracts were diluted with water (30 mL) and the pH adjusted to 2 with 0.1 M HCI. The layers were separated and the aqueous layer was extracted with DCM (25 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (30 mL), brine (30 mL) and dried over Na 2 S0 4 .
  • the reaction mixture was cooled to room temperature and carefully quenched with water (3 mL), stirred for 10 minutes and concentrated under vacuum.
  • the residue was diluted with DCM (50 mL) and washed with 0.5 M NaOH (3x30 mL).
  • the combined organic extracts were diluted with water (50 mL) and the pH adjusted to 2.0 with 5 M HCI.
  • the layers were separated and the aqueous layer extracted with DCM (50 mL). Combined organic extracts were washed with brine (50 mL) and dried over Na 2 S0 4 .
  • reaction mixture was diluted with DCM (20 mL) and washed with water (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The combined water aqueous layers were extracted with DCM (4x20 mL) and the combined organic extracts were dried over Na2SC> , filtered and evaporated.
  • reaction mixture was cooled to 0 °C and quenched with dioxane/water (30ml_/1 mL) and stirred for 10 min.
  • the reaction mixture was concentrated, dissolved in water (25 mL) and extracted with DCM (4x25 ml). The combined organic extracts were washed with brine (25 ml) and dried over anhydrous Na2SC>4. The solvent was filtered through a phase separator filter tube and removed in vacuo.
  • the mixture was cooled to 0 °C and quenched with dioxane/water (30 mL/1 mL) and stirred for 10 min.
  • the mixture was concentrated and dissolved in water (25 mL) and extracted with DCM (4 x 35 ml).
  • the combined organic extracts were washed with 1 N HCI (3x25 ml), then with brine (25 ml) and dried over anhydrous Na2SC> .
  • the solvent was filtered through a phase separator filter tube and removed in vacuo.
  • reaction mixture was cooled to room temperature, quenched with dioxane/water (2.0/0.5 mL) and stirred for 10 min. 1 M NaOH (15 mL) was added and the mixture was extracted with DCM (4x15 ml). The combined organic extracts were washed with 1 N HCI (4x10 mL) then brine (15 ml), and dried over anhydrous Na2SC> . The mixture was filtered through a phase separator filter tube and the solvent removed in vacuo.
  • the mixture was extracted with DCM (4 x 30 ml) and the combined organic extracts were washed with 1 N HCI (4x25 mL), then brine (20 ml) and dried over anhydrous IS ⁇ SC ⁇ .
  • the mixture was filtered through a phase separator filter tube and the solvent removed in vacuo.
  • the residue was purified using a Biotage SP1 purification system using a Normal phase Silica SNAP 10 g column, eluting with a gradient of EtOAc in Cyclohexane (8 % in 1 CV, 8-66 % in 15 CV, 66 % in 5 CV), followed by precipitation from
  • the retained aqueous phase was basified with 1 M NaOH and extracted with DCM.
  • the organic layer was dried using a phase separator filter tube and concentrated under reduced pressure to give a residue containing the title compound together with some impurities.
  • This residue was dissolved in DCM, 1 M HCI was added and mixture stirred vigorously for 1 hour.
  • the layers were separated and the water layer basified with 1 M NaOH.
  • the mixture was was extracted with DCM and the organic layer dried using a phase separator filter tube and concentrated under reduced pressure to give the title compound of >90% purity (by NMR). This 90% pure material was further purified.
  • the residue was dissolved in DCM, water was added and mixture stirred vigorously for 1 hour.
  • the compounds of the invention may be tested in the following mGluR5 aequorin assay.
  • CHO cells containing human mGluR5 receptors with Tet On expression control technology (supplied by Clontech) were prepared. These cells were grown in cell factories, induced with 10ng/ml doxycycline to enable expression, harvested and then cryo-preserved at -140°C in 1 ml aliquots for future use. On the afternoon prior to the assay, the cells were thawed, suspended in growth media and centrifuged at l OOOrpm for 5 min. The growth media consisted of F12 Hams Nutrient mix (supplied by Gibco - catalogue number 21765) and 10% Tet approved FBS (supplied by Clontech - catalogue number 631 106).
  • the cells were then re-suspended in growth media and incubated at 37°C for 1 hour in a spinner flask. After this post thaw recovery period, the cell suspension was centrifuged once more and resuspended at 2.5 x 10 ⁇ cells/ml in loading buffer consisting of HBSS, 0.1 % BSA (supplied by CalBiochem - catalogue number 126609) and 0.1 % Pluronic F68 (supplied by Gibco - catalogue number 24040-032). The cells were loaded with coelentrazine (supplied by Invitrogen C - catalogue number 6780) to a concentration of 5 ⁇ , wrapped in foil and loaded overnight with mixing. Immediately prior to the assay, the cells were diluted to 15 x 10 ⁇ cells/ml in dilution buffer consisting of HBSS and 0.1 % Pluronic F68.
  • Coelentrazine is the chromophore co-factor which activates the apo-protein, aequorin.
  • the protein has three high affinity binding sites for calcium.
  • agonism of the mGluR5 receptor binding of calcium to the aequorin protein induces a conformational change resulting in an oxidative decarboxylation reaction producing coelenteramide and a flash luminescence signal. This signal was measured using the Lumilux (supplied by Perkin Elmer).
  • test compounds were prepared in DMSO at a concentration of 3mM. These solutions are serially diluted with DMSO to 1 in 4 using a Biomek FX liquid handling device (supplied by Beckman Coulter) in a 384-well compound plate (supplied by Greiner). Daughter plates of 0.5 ⁇ / ⁇ were stamped-out from this master plate for use in the assay. Glutamate Dose Response Curve Preparation
  • a 100mM solution of glutamic acid was prepared in water. This was further diluted with DMSO to a concentration of 10mM. 16 x 1 1 point concentration response curves (CRC) were prepared in DMSO, making the final assay concentration 1.66 x10 " ⁇ M, with 1 in 3 serial dilutions using the Biomek FX. 0.5 ⁇ stamp-outs of this plate were generated for use in the assay.
  • CRC concentration response curves
  • the glutamate CRC plate was placed on the Lumilux where 20 ⁇ / ⁇ of dilution buffer was added, followed by 10 ⁇ /well of loaded cell suspension and a
  • luminescence read was made.
  • An EC80 concentration of glutamate was calculated by using 4X EC50 generated.
  • the EC80 solution was prepared in dilution buffer and added to a reservoir within the Lumilux.

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Abstract

L'invention concerne des dérivés tricycliques et leur utilisation dans le traitement de maladies et d'états à médiation par un antagonisme du récepteur mGluR5, en particulier de troubles liés à l'usage de substances. De plus, l'invention concerne des compositions contenant les dérivés et des procédés pour leur préparation.
PCT/EP2011/059011 2010-06-03 2011-06-01 Nouveaux composés Ceased WO2011151361A1 (fr)

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WO2014209978A1 (fr) * 2013-06-24 2014-12-31 Merck Patent Gmbh Composés imidazole servant de modulateurs des récepteurs de la fshr et leurs utilisations
CN104788474A (zh) * 2015-03-28 2015-07-22 陈定奔 一种三氮唑苯并噻嗪酮稠杂环的合成方法
WO2015177646A1 (fr) 2014-05-14 2015-11-26 Novartis Ag Dérivés de carboxamide
US9403810B2 (en) 2014-05-14 2016-08-02 Novartis Ag Carboxamide derivatives
CN111454229A (zh) * 2020-04-10 2020-07-28 颜建发 二氢萘并异噁唑类衍生物及其在抗肿瘤药物中的应用
CN113045557A (zh) * 2021-03-08 2021-06-29 宁夏一帆生物科技有限公司 一种丙炔氟草胺除草剂的生产工艺

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JP2016523864A (ja) * 2013-06-24 2016-08-12 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ Ｆｓｈｒの調節剤としてのイミダゾール化合物及びその使用
WO2014209978A1 (fr) * 2013-06-24 2014-12-31 Merck Patent Gmbh Composés imidazole servant de modulateurs des récepteurs de la fshr et leurs utilisations
US10138233B2 (en) 2013-06-24 2018-11-27 Merck Patent Gmbh Imidazole compounds as modulators of FSHR and uses thereof
AU2014302710B2 (en) * 2013-06-24 2018-10-04 Merck Patent Gmbh Imidazole compounds as modulators of FSHR and uses thereof
CN106536512B (zh) * 2014-05-14 2019-06-07 诺华股份有限公司 甲酰胺衍生物
WO2015177646A1 (fr) 2014-05-14 2015-11-26 Novartis Ag Dérivés de carboxamide
CN106536512A (zh) * 2014-05-14 2017-03-22 诺华股份有限公司 甲酰胺衍生物
CN106661012A (zh) * 2014-05-14 2017-05-10 诺华股份有限公司 甲酰胺衍生物
JP2017515845A (ja) * 2014-05-14 2017-06-15 ノバルティス アーゲー カルボキサミド誘導体
AU2015263049B2 (en) * 2014-05-14 2017-09-28 Novartis Ag Carboxamide derivatives
US11672782B2 (en) 2014-05-14 2023-06-13 Novartis Ag Carboxamide derivatives
US9931319B2 (en) 2014-05-14 2018-04-03 Novartis Ag Carboxamide derivatives
US9403810B2 (en) 2014-05-14 2016-08-02 Novartis Ag Carboxamide derivatives
US9403833B2 (en) 2014-05-14 2016-08-02 Novartis Ag Carboxamide derivatives
US10195181B2 (en) 2014-05-14 2019-02-05 Novartis Ag Carboxamide derivatives
CN106661012B (zh) * 2014-05-14 2019-12-20 诺华股份有限公司 甲酰胺衍生物
CN104788474A (zh) * 2015-03-28 2015-07-22 陈定奔 一种三氮唑苯并噻嗪酮稠杂环的合成方法
CN104788474B (zh) * 2015-03-28 2017-10-10 陈定奔 一种三氮唑苯并噻嗪酮稠杂环的合成方法
CN111454229A (zh) * 2020-04-10 2020-07-28 颜建发 二氢萘并异噁唑类衍生物及其在抗肿瘤药物中的应用
CN111454229B (zh) * 2020-04-10 2022-07-19 徐瑛 二氢萘并异噁唑类衍生物及其在抗肿瘤药物中的应用
CN113045557A (zh) * 2021-03-08 2021-06-29 宁夏一帆生物科技有限公司 一种丙炔氟草胺除草剂的生产工艺

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