EP0942735A1 - Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles schizophreniques - Google Patents

Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles schizophreniques

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Publication number
EP0942735A1
EP0942735A1 EP97953724A EP97953724A EP0942735A1 EP 0942735 A1 EP0942735 A1 EP 0942735A1 EP 97953724 A EP97953724 A EP 97953724A EP 97953724 A EP97953724 A EP 97953724A EP 0942735 A1 EP0942735 A1 EP 0942735A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
methyl
treatment
receptor antagonist
bis
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.)
Withdrawn
Application number
EP97953724A
Other languages
German (de)
English (en)
Inventor
Raymond Bbsrc Baker
Neil Roy Curtis
Jason Matthew Elliott
Timothy Harrison
Gregory John Hollingworth
Philip Stephen Jackson
Janusz Jozef Kulagowski
Nadia Melanie Rupniak
Eileen Mary Seward
Christopher John Swain
Brian John Williams
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.)
Organon Pharma UK Ltd
Original Assignee
Merck Sharp and Dohme 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 GB9625051A external-priority patent/GB9625051D0/en
Priority claimed from GB9701459A external-priority patent/GB9701459D0/en
Priority claimed from GB9713715A external-priority patent/GB9713715D0/en
Priority claimed from GBGB9716491.7A external-priority patent/GB9716491D0/en
Priority claimed from GBGB9721191.6A external-priority patent/GB9721191D0/en
Application filed by Merck Sharp and Dohme Ltd filed Critical Merck Sharp and Dohme Ltd
Publication of EP0942735A1 publication Critical patent/EP0942735A1/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • This invention relates to the treatment or prevention of certain schizophrenic disorders by the administration of a specific class of NK-1 receptor antagonists.
  • the essential features of schizophrenia are a mixture of characteristic signs and symptoms (both positive and negative) which are present in an individual for a significant portion of time over at least one month.
  • the so-called "active-phase" symptoms include delusions, hallucinations, disorganised speech, disorganised or catatonic behaviour and negative symptoms (e.g. affective flattening, alogia and avolition).
  • Some patients have only a single episode of the illness, but most have either recurrent episodes or chronic illness.
  • the care of schizophrenic patients is a major part of the work of psychiatrists.
  • the long-term care of schizophrenic patients is complicated, however, generally symptoms can at least be kept under control if patients with chronic schizophrenia receive long-term treatment with an antipsychotic drug.
  • schizophrenic symptoms cannot be controlled without invoking extrapyramidal side-effects. Consequently, antiparkinsonian drugs may also be prescribed to reduce these side-effects, however, the use of anticholinergic drugs may actually increase the risk of tardive dyskinesia (a late and sometimes irreversible side-effect of prolonged treatment with antipyschotic drugs).
  • Treatment of schizophrenia with antipsychotic (or neuroleptic) agents is typically associated with a number of side-effects, including extrapyramidal symptoms, acute dystonias, tardive dyskinesias, akathesia, tremor, tachycardia, drowsiness, confusion, postural hypotension, blurring of vision, precipitation of glaucoma, dry mouth, constipation, urinary hesitance and impaired sexual function.
  • side-effects are often debilitating and contribute considerably to a patient's non-compliance with prescribed treatment. They may also hinder a patient's social rehabilitation.
  • Neurokinin 1 (NK-1; substance P) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinins, and in particular substance P.
  • Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (see, for instance, International (PCT) patent specification Nos. WO 95/16679, WO 95/18124 and WO 95/23798).
  • European Patent Specification No. 0 286 928 describes inhibitors of the enzyme prolyl-endopeptidase, which enzyme degrades neuropeptides such as substance P, the enzyme inhibitors having an antipsychotic, anxiolytic and antidepressant action.
  • degrading substance P or reducing the action of substance P in some other way might be expected to be detrimental to the treatment of psychoses such as schizophrenic disorders.
  • NK-1 receptor antagonists are described in published European Patent Specification Nos. 0 360 390, 0 394 989, 0 429 366, 0 443 132, 0 482 539, 0 512 901, 0 512 902, 0 514 273, 0 514 275, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 577 394, 0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 714 891, 0 723 959, 0 733 632 and 0 776 893; and in International Patent Specification Nos.
  • the present invention provides the use of a CNS penetrant NK-1 receptor antagonist in an oral, once-a-day medicament for the treatment of schizophrenic disorders.
  • the compounds of this class advantageously exhibit a rapid onset of action and a reduced side-effect profile when compared against conventional antipsychotic agents.
  • the present invention provides a means for the identification of NK-1 receptor antagonists which would be effective in an oral once-a-day medicament for the treatment of schizophrenic disorders.
  • NK-1 receptor antagonists which would be effective in an oral once-a-day medicament for the treatment of schizophrenic disorders.
  • the aforementioned patent specifications which describe NK-1 receptor antagonists provide no reliable method for the identification of such compounds.
  • the exceptional pharmacology of the class of NK-1 receptor antagonists of use in the present invention enables the treatment of schizophrenic disorders, without the need for concomitant therapy and in particular, without the need for concomitant use of a antipsychotic agents. Furthermore, the exceptional pharmacology of the class of NK-1 receptor antagonists of use in the present invention results in a rapid onset of action.
  • the present invention accordingly provides the use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist (as hereinafter defined) for the manufacture of a medicament adapted for oral administration for the treatment or prevention of schizophrenic disorders.
  • the present invention also provides a method for the treatment or prevention of schizophrenic disorders, which method comprises the oral administration to a patient in need of such treatment of an effective amount of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist (as hereinafter defined).
  • an oral pharmaceutical composition for the treatment of schizophrenic disorders which comprises an orally active, long acting, CNS-penetrant NK-1 receptor antagonist (as hereinafter defined), together with a pharmaceutically acceptable carrier or excipient.
  • the present invention accordingly provides the use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist for the manufacture of a medicament adapted for oral administration for the treatment or prevention of schizophrenic disorders in a patient who is non- responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated.
  • the present invention also provides a method for the treatment or prevention of schizophrenic disorders in a patient who is non-responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist.
  • a combination of a conventional antipsychotic drug with a NK-1 receptor antagonist may provide an enhanced effect in the treatment of schizophrenic disorders.
  • Such a combination would be expected to provide for a rapid onset of action to treat schizophrenic symptoms thereby enabling prescription on an "as needed basis".
  • such a combination may enable a lower dose of the CNS agent to be used without compromising the efficacy of the antipsychotic agent, thereby minimising the risk of adverse side- effects.
  • a yet further advantage of such a combination is that, due to the action of the NK-1 receptor antagonist, adverse side-effects caused by the antipsychotic agent such as acute dystonias, dyskinesias, akathesia and tremor may be reduced or prevented.
  • a NK-1 receptor antagonist and an antipsychotic agent for the manufacture of a medicament for the treatment or prevention of schizophrenic disorders.
  • the present invention also provides a method for the treatment or prevention of schizophrenic disorders, which method comprises administration to a patient in need of such treatment of an amount of a NK-1 receptor antagonist and an amount of an antipsychotic agent, such that together they give effective relief.
  • a pharmaceutical composition comprising a NK-1 receptor antagonist and an antipsychotic agent, together with at least one pharmaceutically acceptable carrier or excipient.
  • a NK-1 receptor antagonist and an antipsychotic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of schizophrenic disorders.
  • Such combined preparations may be, for example, in the form of a twin pack.
  • a product comprising a NK-1 receptor antagonist and an antipsychotic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of schizophrenic disorders.
  • the NK-1 receptor antagonist and the antipsychotic agent may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously.
  • the term “combination” also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, the antipsychotic agent may be administered as a tablet and then, within a reasonable period of time, the NK-1 receptor antagonist may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form.
  • a fast-dissolving oral formulation is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds.
  • schizophrenic disorders includes paranoid, disorganised, catatonic, undifferentiated and residual schizophrenia; schizophreniform disorder; schizoaffective disorder; delusional disorder; brief psychotic disorder; shared psychotic disorder; substance-induced psychotic disorder; and psychotic disorder not otherwise specified.
  • treatment refers both to the treatment and to the prevention or prophylactic therapy of the aforementioned conditions.
  • Preferred NK-1 receptor antagonists for use in the present invention are selected from the classes of compounds described in
  • NK-1 receptor antagonists of use in the present invention include:
  • Suitable antipsychotic agents of use in combination with a NK-1 receptor antagonist include the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of antipsychotic agent.
  • Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine.
  • Suitable examples of thioxanthenes include chlorprothixene and thiothixene.
  • An example of a dibenzazepine is clozapine.
  • An example of a butyrophenone is haloperidol.
  • An example of a diphenylbutylpiperidine is pimozide.
  • An example of an indolone is molindolone.
  • Other antipsychotic agents include loxapine, sulpiride and risperidone.
  • the antipsychotic agents when used in combination with a NK-1 receptor antagonist may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride.
  • Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.
  • NK-1 receptor antagonists include dopamine receptor antagonists, especially D2, D3 and D4 dopamine receptor antagonists, and muscarinic ml receptor agonists.
  • D3 dopamine receptor antagonist is the compound PNU-99194A.
  • D4 dopamine receptor antagonist is PNU-101387.
  • a muscarinic ml receptor agonist is xanomeline.
  • Another class of antipsychotic agent of use in combination with a NK-1 receptor antagonist is the 5-HT 2 A receptor antagonists, examples of which include MDL100907 and fananserin.
  • 5-HT 2 A receptor antagonists examples of which include MDL100907 and fananserin.
  • SDAs serotonin dopamine antagonists
  • olanzapine and ziperasidone examples of which include olanzapine and ziperasidone.
  • Suitable pharmaceutically acceptable salts of the NK-1 receptor antagonists of use in the present invention include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid.
  • Salts of amine groups may also comprise the quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group.
  • the present invention also contemplates salts thereof, preferably non-toxic pharmaceutically acceptable salts thereof, such as the sodium, potassium and calcium salts thereof.
  • Suitable pharmaceutically acceptable salts of the antipsychotic agents used in combination with a NK-1 receptor antagonist according to the present invention include those salts described above in relation to the salts of NK-1 receptor antagonists.
  • compositions containing an NK-1 receptor antagonist of use according to the present invention are in unit dosage forms such as tablets, pills, capsules, wafers and the like.
  • the NK-1 receptor antagonists of use according to the present invention may be presented as granules or powders for extemporaneous formulation as volume defined solutions or suspensions.
  • the NK-1 receptor antagonists of use according to the present invention may be presented in ready-prepared volume defined solutions or suspensions. Preferred forms are tablets and capsules.
  • the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • a variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • the liquid forms in which the novel compositions of the present invention may be incorporated for administration orally include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • compositions of the present invention may also be administered via the buccal cavity using conventional technology, for example, absorption wafers.
  • compositions in the form of tablets, pills, capsules or wafers for oral administration are particularly preferred.
  • the present invention further provides a process for the preparation of a pharmaceutical composition comprising a NK-1 receptor antagonist and an antipsychotic agent, which process comprises bringing a NK-1 receptor antagonist and an antipsychotic agent, into association with a pharmaceutically acceptable carrier or excipient.
  • the NK-1 receptor antagonist and an antipsychotic agent are presented in a ratio which is consistent with the manifestation of the desired effect.
  • the ratio by weight of the NK-1 receptor antagonist and the antipsychotic agent will suitably be between 0.001 to 1 and 1000 to 1, and especially between 0.01 to 1 and 100 to 1.
  • a minimum dosage level for the NK-1 receptor antagonist is about lmg per day, preferably about 5mg per day and especially about lOmg per day.
  • a maximum dosage level for the NK-1 receptor antagonist is about 1500mg per day, preferably about lOOOmg per day and especially about 500mg per day.
  • the compounds are administered one to three times daily, preferably once a day.
  • a minimum dosage level for the antipsychotic agent will vary depending upon the choice of agent, but is typically about 0.5mg per day for the most potent compounds or about 20mg per day for less potent compounds.
  • a maximum dosage level for the antipsychotic agent is typically 30mg per day for the most potent compounds or 200mg per day for less potent compounds. The compounds are administered one to three times daily, preferably once a day.
  • the amount of the NK-1 receptor antagonist required for use in the treatment or prevention of schizophrenic diosrders will vary not only with the particular compounds or compositions selected but also with' the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the patient's physician or pharmacist.
  • the amount of the NK-1 receptor antagonist and the antipsychotic agent required for use in the treatment or prevention of schizophrenic disorders will vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the patient's physician or pharmacist.
  • the mixture was stirred at -70 °C for 20 minutes, then allowed to warm to -30°C.
  • the mixture was cooled to -50 °C and triethylamine (55.95ml, 40.45g, 400mmol) was added slowly.
  • the mixture was allowed to warm to 0°C and diluted with ice- cooled dichloromethane (250ml).
  • the mixture was washed with ice cold aqueous citric acid solution (5%, 2x300ml) and water (300ml), dried (MgSO ), and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (42.3g), which was used immediately without further purification.
  • the solution was stirred at -80°C for 30 minutes then at room temperature for 30 minutes before being quenched by addition of saturated ammonium chloride solution and ethyl acetate.
  • the dried (MgSO ) organic phase was purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to 5%). Evaporation of the fractions gave the title compound.
  • Benzyl bromide (66.17ml, 9 ⁇ .3 ⁇ g, O. ⁇ mol) was added to a mixture of 4-(trifluoromethoxy)phenol (90.26g, O. ⁇ lmol) and potassium carbonate (140.97g, 1.2mol) in dimethylformamide (160ml) and the mixture was ⁇ stirred at room temperature for 72 hours. The mixture was poured into water (1.5 1) and extracted with ethyl acetate (3x500ml). The combined organic fractions were washed with aqueous sodium carbonate (saturated, 500ml), dried (MgS0 4 ) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (133. ⁇ g, 99%).
  • Naphthalene 120mg, 0.936mmol was dissolved in THF (1.5ml) under nitrogen and freshly cut lithium metal (7.0mg, 0.94mmol) was 0 added. The mixture was then sonicated at room temperature for 20 minutes to produce a dark green solution of lithium naphthalenide.
  • a further compound and diastereomers thereof of use in the present invention may be prepared according to the following method:
  • Iron(lll)nitrate nonahydrate (1.97 g, 4.87 mmol) was added to a solution of 4-(trifluoromethoxy)phenol (2 g, 11.24 mmol) in ethanol (20 mL) and the mixture was heated under reflux overnight. The mixture was ⁇ allowed to cool to room temperature, acidified to pH 1 with aqueous hydrochloric acid (1M) and extracted with ethyl acetate. The combined organic fractions were dried (MgSO 4 ), and the solvent was evaporated under reduced pressure. The residue was purified by short column chromatography on silica gel, eluting with hexane/EtOAc (70:30), to give 0 the title compound as a yellow oil (2.25 g, 89%).
  • NK-1 receptor antagonists of use in the present invention are compounds which are potent NK-1 receptor antagonists, i.e. compounds with an NK-1 receptor affinity (IC 50 ) of less than lOnM, favourably less than 2nM and preferably less than InM.
  • IC 50 NK-1 receptor affinity
  • NK-1 receptor antagonists of use in the present invention is identified using a ⁇ combination of the following assays:
  • ASSAY 1 NK-1 Receptor binding
  • NK-1 receptor binding assays are performed in intact Chinese
  • CHO hamster ovary
  • ⁇ l- yr 8 - substance P (O.lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in ⁇ l dimethylsulphoxide, DMSO) with ⁇ xlO 4 CHO cells.
  • Ligand binding is performed in 0.2 ⁇ ml of ⁇ OmM Tris-HCl, pH7. ⁇ , containing ⁇ mM MnCl 2 , 0 l ⁇ OmM NaCl, 0.02% bovine serum albumin (Sigma), ⁇ O ⁇ g/ml chymostatin (Peninsula), O.lnM phenylmethylsulphonyl fluoride, 2 ⁇ g/ml pepstatin, 2 ⁇ g/ml leupeptin and 2.8 ⁇ g/ml furoyl saccharine.
  • the incubation proceeds at room temperature until equilibrium is achieved (>40 minutes) and the receptor-ligand complex is harvested by filtration over GF/C filters pre- ⁇ soaked in 0.1% polyethylenimine using a Tomtek 96-well harvester. Nonspecific binding is determined using excess substance P (l ⁇ M) and represents ⁇ 10% of total binding.
  • Gerbil Foot-Tapping 30 CNS-penetrant NK-1 receptor antagonists for use in the present invention can be identified by their ability to inhibit foot tapping in gerbils induced by anxiogenic agents (such as pentagastrin) or central infusion of NK-1 receptor agonists such as GR73632, or caused by aversive stimulation such as foot shock or single housing, based on the method of Rupniak & Williams, Eur. J. Pharmacol, 1994, 265, 179.
  • anxiogenic agents such as pentagastrin
  • NK-1 receptor agonists such as GR73632
  • aversive stimulation such as foot shock or single housing
  • test compounds may be administered orally or by subcutaneous or intraperitoneal routes.
  • stimulation such as foot shock or single housing
  • foot shock or single housing
  • ASSAY 4 Separation-Induced Vocalisation
  • mice Male and female guinea-pigs pups are housed in family groups with their mothers and littermates throughout the study. Experiments are commenced after weaning when the pups are 2 weeks old. Before entering
  • the pups are screened to ensure that a vigorous vocalisation response is reproducibly elicited following maternal separation.
  • the pups are placed individually in an observation cage ( ⁇ cm x 39cm x 19cm) in a room physically isolated from the home cage for l ⁇ minutes and the duration of vocalisation during this baseline period is l ⁇ recorded. Only animals which vocalise for longer than ⁇ minutes are employed for drug challenge studies (approximately ⁇ 0% of available pups may fail to reach this criterion).
  • each pup receives an oral dose or an s.c. or i.p. injection of test compound or vehicle and is then immediately returned to the home cage with its mother and siblings for 30
  • CNS-penetrant refers to NK-1 receptor antagonists which are able to inhibit NK-1 receptor antagonist-induced foot-tapping in the gerbil as hereinafter defined.
  • the NK-1 receptor antagonist is administered orally, 1 hour prior to GR73632 challenge, wherein the foot- tapping over a period of five minutes following recovery from anaesthesia 0 is inhibited with an ID5o ⁇ 30mg/kg, and preferably with an IDso ⁇ lOmg/kg.
  • CNS-penetrant NK-1 receptor antagonists of use in the present ivnention are also effective in the attenuation of separation-induced vocalisations by guinea-pig pups as hereinafter defined.
  • a vocalisation response in guinea-pig pups is induced by ⁇ isolation from their mothers and littermates, which response is attenuated when a CNS-penetrant NK-1 receptor antagonist is administered subcutaneously 30 minutes prior to isolation, wherein vocalisations during the first l ⁇ minutes of isolation are attenuated with an IDso ⁇ 20mg/kg, preferably with an IDso ⁇ lOmg/kg, and especially with an IDso ⁇ mg/kg.
  • the NK-1 receptor antagonist is administered orally, 4 hours prior to isolation, wherein vocalisations during the first l ⁇ minutes of isolation are attenuated with an IDso 20mg/kg, preferably with an IDso ⁇ lOmg/kg, and especially with an IDso ⁇ mg/kg.
  • a suitable selection cascade for NKi antagonists of use according to the present invention is as follows:
  • Yet further preferred compounds of use in the present invention may be selected from those compounds which satisfy the NK-1 receptor binding criteria of step (i) which, in addition, have ⁇ 5-fold shift in affinity when incubated in the presence of human serum albumin (HSA) to show non-specific protein binding.
  • HSA human serum albumin
  • a NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)- ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-( ⁇ -oxo-lH,4H-l,2,4-triazolo)methyl)- morpholine, the preparation of which is described in International Patent Specification No. WO 96/16679. In the aforementioned assays, this compound has the following activity:
  • the active ingredient, cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste.
  • the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
  • the resulting granulation is then compressed into tablets containing 50mg, lOOmg and 300mg of the ⁇ NK-1 receptor antagonist per tablet.
  • compositions comprising a combination of a NK-1 receptor antagonist and an antipsychotic agent may be prepared with separate active ingredients or with a combination of active ingredients in one composition. In such combined preparations, the ratio of the NK-1 receptor antagonist and the antipsychotic agent will depend upon the choice of active ingredients.
  • NK-1 antagonist ⁇ .0 100.0 300.0 chlorpromazine hydrochloride 25.0 2 ⁇ .O 25.0
  • the active ingredients, cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste.
  • the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
  • the resulting granulation is then compressed into tablets containing 50mg, lOOmg and 300mg of the CNS-penetrant NK-1 receptor antagonist per tablet.

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Abstract

La présente invention a pour objet l'utilisation d'un antagoniste du récepteur NK-1, à action prolongée, agissant sur le système nerveux central; et à administration par voie orale, dans la fabrication d'un médicament prévu pour être administré par voie orale permettant de traiter ou de prévenir les troubles schizophréniques. L'invention traite également de procédés de traitement à l'aide d'un antagoniste du récepteur NK-1 et de compositions pharmaceutiques comprenant cet antagoniste.
EP97953724A 1996-12-02 1997-11-25 Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles schizophreniques Withdrawn EP0942735A1 (fr)

Applications Claiming Priority (11)

Application Number Priority Date Filing Date Title
GB9625051 1996-12-02
GB9625051A GB9625051D0 (en) 1996-12-02 1996-12-02 Therapeutic agents
GB9701459 1997-01-24
GB9701459A GB9701459D0 (en) 1997-01-24 1997-01-24 Therapeutic agents
GB9713715 1997-06-27
GB9713715A GB9713715D0 (en) 1997-06-27 1997-06-27 Therapeutic agents
GB9716491 1997-08-04
GBGB9716491.7A GB9716491D0 (en) 1997-08-04 1997-08-04 Therapeutic agents
GBGB9721191.6A GB9721191D0 (en) 1997-10-07 1997-10-07 Therapeutic use
GB9721191 1997-10-07
PCT/EP1997/006691 WO1998024445A1 (fr) 1996-12-02 1997-11-25 Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles schizophreniques

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CA2298777A1 (fr) * 1997-08-04 1999-02-18 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 pour le traitement d'une manie
AU737019B2 (en) * 1997-08-04 2001-08-09 Merck Sharp & Dohme Limited Use of NK-1 receptor antagonists for treating aggressive behaviour disorders
JP2002517448A (ja) * 1998-06-11 2002-06-18 メルク シャープ エンド ドーム リミテッド 精神障害の治療用ｎｋ−１受容体アンタゴニストの使用
ES2150378B1 (es) * 1998-08-07 2001-07-01 Esteve Labor Dr Empleo de derivados de aril(o heteroaril)azolilcarbinoles en la elaboracion de un medicamento para el tratamiento de los trastornos mediados por un exceso de substancia p.
BRPI0412291A (pt) 2003-07-03 2006-09-19 Hoffmann La Roche antagonistas duplos de nka/nk3 para o tratamento de esquizofrenia
EP2117538A1 (fr) 2007-01-24 2009-11-18 Glaxo Group Limited Compositions pharmaceutiques contenant du 2-méthoxy-5- (5-trifluorométhyl-tétrazol-i-yl-benzyl) - (2s-phényl-pipéridin-3s-yl-)

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MY110227A (en) * 1991-08-12 1998-03-31 Ciba Geigy Ag 1-acylpiperindine compounds.
CA2099233A1 (fr) * 1992-06-29 1993-12-30 Conrad P. Dorn Antagonistes du recepteur de la tachykinine a base de morpholine et de thiomorpholine
US5496833A (en) * 1993-04-13 1996-03-05 Merck Sharp & Dohme Limited Piperidine tachykinin receptor antagonists
IL111002A (en) * 1993-09-22 1998-09-24 Glaxo Group Ltd History of piperidine, their preparation and the pharmaceutical preparations containing them
CA2178219C (fr) * 1993-12-29 2005-03-22 Raymond Baker Derives de morpholine substitues et une utilisation en tant qu'agents therapeutiques
ES2157337T3 (es) * 1994-08-15 2001-08-16 Merck Sharp & Dohme Derivados de morfolina y su uso como agentes terapeuticos.

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See references of WO9824445A1 *

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CA2273807A1 (fr) 1998-06-11
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AU732633B2 (en) 2001-04-26
JP2001505881A (ja) 2001-05-08

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