WO2007129111A1 - Dérivés de diazépine en tant qu'antagonistes de 5-ht2a - Google Patents

Dérivés de diazépine en tant qu'antagonistes de 5-ht2a Download PDF

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WO2007129111A1
WO2007129111A1 PCT/GB2007/050224 GB2007050224W WO2007129111A1 WO 2007129111 A1 WO2007129111 A1 WO 2007129111A1 GB 2007050224 W GB2007050224 W GB 2007050224W WO 2007129111 A1 WO2007129111 A1 WO 2007129111A1
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compound according
carbon atoms
pharmaceutically acceptable
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formula
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Christopher Swain
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Organon Pharma UK Ltd
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Merck Sharp and Dohme Ltd
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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones

Definitions

  • the present invention relates to a class of diazepine derivatives which act on serotonin receptors (also known as 5-hydroxytryptamine or 5 -HT receptors). More particularly, the invention concerns a class of 5-amino-7-aryl-2,3-dihydro- IH- 1 ,4-diazepines and benzo-fused analogues thereof. These compounds are potent and selective antagonists of the human 5-HT 2 A receptor and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of adverse conditions of the central nervous system, including sleep disorders such as insomnia, psychotic disorders such as schizophrenia and psychiatric disorders such as anxiety.
  • sleep disorders such as insomnia
  • psychotic disorders such as schizophrenia and psychiatric disorders such as anxiety.
  • Compounds of the invention typically display more effective binding to the human 5-HT 2 A receptor than to other human receptors such as D 2 and IKr receptors. They can therefore be expected to manifest fewer side-effects than compounds which do not discriminate in their binding affinity between such receptors. In particular these compounds have lower effects on the IKr receptors and there is a separation of the desired effect from side effects such as cardiac effects.
  • the compounds of the present invention are effective in the treatment of neurological conditions including sleep disorders such as insomnia, psychotic disorders such as schizophrenia, and also depression, anxiety, panic disorder, obsessive-compulsive disorder, pain, eating disorders such as anorexia nervosa, and dependency or acute toxicity associated with narcotic agents such as LSD or MDMA; and moreover are beneficial in controlling the extrapyramidal symptoms associated with the administration of neuroleptic agents. They are also effective in the lowering of intraocular pressure and hence in treating glaucoma, and may also be effective in treating menopausal symptoms, in particular hot flushes (see Waldinger et al, Maturitas, 2000, 36, 165-8).
  • 5-HT 2A receptor antagonists many containing inter alia a sulphonyl moiety as described in WO 2005/047246, WO 2005/047247, WO 03/099786, WO 2004/101518, WO 01/74797, WO 00/43362, WO 96/35666, EP-A- 0261688, EP-0304888, and US Patents 4,218,455 and 4,128,552, DE-A-3901735 and Fletcher et al, J. Med. Chem., 2002, 45, 492-503. None of these publications, however, discloses or suggests the class of compounds provided by the present invention.
  • US 4,096,140 discloses certain 5-amino-7-aryl-2,3-dihydro-lH-l,4-diazepines as anti- obesity or anti-diabetic agents, but there is no disclosure of activity towards the 5-HT 2A receptor or of utility in treating conditions known to be mediated by 5-HT 2A receptor activity.
  • the compounds according to the present invention are potent and selective 5-HT 2A receptor antagonists, suitably having a human 5-HT 2A receptor binding affinity (K 1 ) of 1000 nM or less, typically of 500 nM or less and preferably of 100 nM or less.
  • K 1 human 5-HT 2A receptor binding affinity
  • the compounds of the invention may possess at least a 10-fold selective affinity, suitably at least a 20-fold selective affinity and preferably at least a 50-fold selective affinity, for the human 5-HT 2A receptor relative to the human dopamine D 2 receptor and/or the human IKr receptors. Many compounds also show selectivity relative to the human 5-HT 2c receptor.
  • each A represents CR 2 where each R is independently H or or the moiety A-A represents 1 ,2-phenylene;
  • Ar represents phenyl or pyridyl which bears 0 - 3 substituents selected from halogen, Ci- 4alkyl, CN and CF 3 ;
  • R 1 represents a hydrocarbon group of up to 12 carbon atoms.
  • the invention further provides a method of treatment of a subject suffering from or prone to a condition mediated by 5-HT 2A receptor activity which comprises administering to that subject an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof.
  • the condition mediated by 5-HT 2A receptor activity is sleep disorder, in particular insomnia.
  • the condition mediated by 5- HT 2 A receptor activity is selected from psychotic disorders (such as schizophrenia), depression, anxiety, panic disorder, obsessive-compulsive disorder, pain, glaucoma, eating disorders (such as anorexia nervosa), dependency or acute toxicity associated with narcotic agents such as LSD or MDMA, and hot flushes associated with the menopause.
  • hydrocarbon group refers to groups consisting solely of carbon and hydrogen atoms. Such groups may comprise linear, branched or cyclic structures, singly or in any combination consistent with the indicated maximum number of carbon atoms, and may be saturated or unsaturated, including aromatic when the indicated maximum number of carbon atoms so permits unless otherwise indicated.
  • Ci_ x alkyl where x is an integer greater than 1 refers to straight-chained and branched alkyl groups wherein the number of constituent carbon atoms is in the range 1 to x. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl. Derived expressions such as are to be construed in an analogous manner.
  • halogen as used herein includes fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred and fluorine particularly preferred.
  • C3-6cycloalkyl refers to nonaromatic monocyclic hydrocarbon ring systems comprising from 3 to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexenyl.
  • the compounds of formula I may be in the form of pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds of formula I or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, benzenesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, benzenesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tart
  • the compounds according to the invention may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
  • each A in formula I represents CR 2 where each R is independently H or Ci- 4 alkyl (such as methyl).
  • the moiety A - A represents 1,2- phenylene (i.e. A - A completes a fused benzene ring).
  • a - A represents CH 2 -CH 2 or 1 ,2-phenylene, most suitably CH 2 -CH 2 .
  • Ar represents phenyl or pyridyl which optionally bears up to 3 substituents selected from halogen, CN and CF 3 .
  • Ar represents optionally substituted phenyl.
  • Ar bears not more than 2 substituents.
  • Preferred substituents include halogen (especially Cl and F) and (such as methyl).
  • groups represented by Ar include phenyl, 4-methoxyphenyl, 2-methylphenyl, 4-methylphenyl, 2,4- dimethylphenyl, 3-(trifluoromethyl)phenyl, 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2-fluoro-4-methylphenyl, 2-chlorophenyl, 4-chlorophenyl, 4-cyanophenyl and 2-pyridyl.
  • R 1 represents a hydrocarbon group of up to 12 carbon atoms, preferably of 3 to 10 carbon atoms.
  • Suitable hydrocarbon groups include alkyl groups, in particular branched alkyl groups such as t-butyl, 2,2-dimethylpropyl, 3-methyl-3-pentyl, 3-ethyl-3-pentyl and 2,3-dimethyl-2-butyl; cycloalkyl groups such as cyclohexyl; alkylcycloalkyl groups such as 1-methylcyclohexyl and 1- ethylcyclopentyl; cycloalkylalkyl groups such as 2-cyclobutyl-2-propyl; and arylalkyl groups such as benzyl, 2-phenylethyl and 2-methyl-3-phenyl-2-propyl.
  • R 11 has the same definition and particular identities as described for R 1 with the proviso that if R 11 represents an alkyl group said alkyl group is branched and comprises at least 5 carbon atoms;
  • compositions comprising one or more compounds of formula II or pharmaceutically acceptable salts or hydrates thereof and a pharmaceutically acceptable carrier.
  • the present invention also provides a compound of formula II or a pharmaceutically acceptable salt or hydrate thereof for use in a method of treatment of the human body.
  • the treatment is for a condition mediated by 5-HT 2 A receptor activity.
  • Specific compounds useful in this invention include those compounds exemplified hereinafter and their pharmaceutically acceptable salts.
  • the compounds of formula I have an activity as antagonists of the human 5-HT 2 A receptor and hence find use in the treatment or prevention of disorders mediated by 5-HT 2A receptor activity.
  • compositions comprising one or more compounds of formula I and a pharmaceutically acceptable carrier.
  • these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, transdermal patches, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the principal active ingredient typically is mixed with a pharmaceutical carrier, e.g.
  • a tableting ingredient such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate and dicalcium phosphate, or gums, dispersing agents, suspending agents or surfactants such as sorbitan monooleate and polyethylene glycol, and other pharmaceutical diluents, e.g. water, to form a homogeneous preformulation composition containing a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This 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.
  • Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient.
  • 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.
  • 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.
  • suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, poly(ethylene glycol), polyvinylpyrrolidone) or gelatin.
  • a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day but preferably once per day, for example before going to bed.
  • the compounds according to this invention may be co-administered with another sleep inducing or anti-schizophrenic or anxiolytic medicament.
  • Such co-administration may be desirable where a patient is already established on sleep inducing or anti-schizophrenic or anxiolytic treatment regime involving other conventional medicaments.
  • the compounds of the invention may be co-administered with a GABA A receptor agonist such as gaboxadol, or with a short term and/or rapid-onset hypnotic such as Zolpidem, or a benzodiazepine, a barbiturate, a prokineticin modulator, an antihistamine, trazodone, or derivative of trazodone as disclosed in WO 03/068148.
  • a GABA A receptor agonist such as gaboxadol
  • a short term and/or rapid-onset hypnotic such as Zolpidem, or a benzodiazepine
  • a barbiturate such as a benzodiazepine
  • a barbiturate such as a benzodiazepine
  • a barbiturate such as a benzodiazepine
  • a barbiturate such as a benzodiazepine
  • a barbiturate such as a benzodiazepin
  • a method of treatment or prevention of sleep disorders, schizophrenia or depression comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof in combination with gaboxadol.
  • the expression "in combination with” requires that therapeutically effective amounts of both a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof and gaboxadol are administered to the subject, but places no restriction on the manner in which this is achieved.
  • the two species may be combined in a single dosage form for simultaneous administration to the subject, or may be provided in separate dosage forms for simultaneous or sequential administration to the subject. Sequential administration may be close in time or remote in time, e.g.
  • the separate species may be administered at the same frequency or at different frequencies, e.g. one species once a day and the other two or more times a day.
  • the separate species may be administered by the same route or by different routes, e.g. one species orally and the other parenterally, although oral administration of both species is preferred, where possible.
  • a pharmaceutical composition comprising, in a pharmaceutically acceptable carrier, a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof and gaboxadol.
  • the invention further provides the use, for the manufacture of a medicament for treatment or prevention of sleep disorders, schizophrenia or depression, of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof and gaboxadol.
  • the invention further provides a kit comprising a first medicament comprising a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof and a second medicament comprising gaboxadol together with instructions for administering said medicaments sequentially or simultaneously to a patient suffering from a sleep disorder, schizophrenia or depression.
  • gaboxadol is inclusive of 4,5,6,7-tetrahydroisoxazolo[5,4- c]pyridin-3-ol in free base or zwitterionic form and also of pharmaceutically acceptable acid addition salts thereof such as the hydrochloride salt. Most suitably, gaboxadol is in the form of a crystalline monohydrate of the zwitterionic form.
  • R 1 , Ar and A have the same meanings as before.
  • the reaction takes place at ambient temperature using neat reagents.
  • Chlorides (1) are available by reaction of POCI3 with lactams (2):
  • reaction may be carried out by heating at about 12O 0 C for 12 hours.
  • Lactams (2) maybe obtained by cyclisation of enamine derivatives (3) in which R 1 is t- butyl:
  • compounds of formula I are conveniently obtained by cyclising compounds (3) under dehydrating conditions, e.g. in the presence of anhydrous CaCl2 (especially when A-A is 1 ,2-phenylene) or of strong acid such as perchloric acid or methanesulfonic acid.
  • anhydrous CaCl2 especially when A-A is 1 ,2-phenylene
  • strong acid such as perchloric acid or methanesulfonic acid.
  • the starting materials and reagents described above may be obtained from commercially available precursors by means of well known synthetic procedures and/or the methods disclosed in the Examples section herein.
  • any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further desired compound of formula I using techniques known from the art.
  • a bromo substituent present on Ar may be replaced by cyano by treatment with copper(I) cyanide in the presence of 1- methyl-2-pyrrolidinone (NMP).
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
  • it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • Step 3 The product of Step 3 (1 mmol) was dissolved in 5 ml of absolute ethanol. The solution was acidified to a pH of about 1 with methanesulfonic acid, refluxed under nitrogen for one hour, allowed to cool to room temperature and evaporated. The residue was purified by preparative TLC to give the target compound.
  • the resulting solid was purified by preparative TLC to give the target compound.
  • the lactam from Step 1 (1.2 g) was dissolved in 15 ml of POCI3 and heated at 12O 0 C for 12h. The reaction mixture was allowed to cool and the POCI3 was removed at reduced pressure to give the product (1-2 g) in the form of white crystals.
  • step 1 The product of step 1 (1.0 mmol) was dissolved in 5 ml of absolute ethanol. 1.0 g of anhydrous CaCl2, was added and the solution was stirred under nitrogen for 24 hours. Solid was filtered off and the filtrate concerntrated. The residue was recrystallized from DCM/ether to give off-red crystals.

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Abstract

L'invention concerne des composés de formule I : qui sont des antagonistes sélectifs de 5HT2A et trouvent ainsi des applications dans le traitement prophylactique ou thérapeutique de divers troubles du SNC.
PCT/GB2007/050224 2006-05-03 2007-04-30 Dérivés de diazépine en tant qu'antagonistes de 5-ht2a Ceased WO2007129111A1 (fr)

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GBGB0608655.7A GB0608655D0 (en) 2006-05-03 2006-05-03 Therapeutic Treatment
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Cited By (14)

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WO2009105507A3 (fr) * 2008-02-19 2010-01-14 Adolor Corporation Béloxépine, ses énantiomères et certains de leurs analogues convenant au traitement de la douleur
US8148417B2 (en) 2006-05-18 2012-04-03 Arena Pharmaceuticals, Inc. Primary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US8148418B2 (en) 2006-05-18 2012-04-03 Arena Pharmaceuticals, Inc. Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US8785441B2 (en) 2004-11-19 2014-07-22 Arena Pharmaceuticals, Inc. 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US8871797B2 (en) 2003-07-22 2014-10-28 Arena Pharmaceuticals, Inc. Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto
US8980891B2 (en) 2009-12-18 2015-03-17 Arena Pharmaceuticals, Inc. Crystalline forms of certain 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9034911B2 (en) 2008-10-28 2015-05-19 Arena Pharmaceuticals, Inc. Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto
US9126946B2 (en) 2008-10-28 2015-09-08 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)urea and crystalline forms related thereto
US9199940B2 (en) 2006-05-18 2015-12-01 Arena Pharmaceuticals, Inc. Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor
US9434692B2 (en) 2006-10-03 2016-09-06 Arena Pharmaceuticals, Inc. Pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US9556149B2 (en) 2008-04-02 2017-01-31 Arena Pharmaceuticals, Inc. Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor
US9567327B2 (en) 2007-08-15 2017-02-14 Arena Pharmaceuticals, Inc. Imidazo[1,2-a]pyridine derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US10022355B2 (en) 2015-06-12 2018-07-17 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder
US10034859B2 (en) 2015-07-15 2018-07-31 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease

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Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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