EP1005459A1 - Isoquinoleines substituees en tant qu'anticonvulsifs - Google Patents

Isoquinoleines substituees en tant qu'anticonvulsifs

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Publication number
EP1005459A1
EP1005459A1 EP98942869A EP98942869A EP1005459A1 EP 1005459 A1 EP1005459 A1 EP 1005459A1 EP 98942869 A EP98942869 A EP 98942869A EP 98942869 A EP98942869 A EP 98942869A EP 1005459 A1 EP1005459 A1 EP 1005459A1
Authority
EP
European Patent Office
Prior art keywords
methyl
tetrahydroisoquinolin
urea
disorders
alkyl
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Withdrawn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
EP98942869A
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German (de)
English (en)
Inventor
Mervyn Smithkline Beecham Pharma. Thompson
Roderick A. SmithKline Beecham Pharma. PORTER
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.)
SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Publication date
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP1005459A1 publication Critical patent/EP1005459A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/34—Tobacco-abuse
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.
  • WO96/39382 discloses the preparation of N-heterocycyl-ureas as 5-HT antagonists, including the compound N-(l -methyl- lH-indol-5-yl)-N'-( 1,2, 3,4-tetrahydro-7- isoquinolinyl)-urea.
  • urea compounds of formula (I) below possess anti- convulsant activity and are therefore believed to be useful in the treatment and/or prevention of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • Giles de la Tourette's syndrome traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • the present invention provides a compound of formula (I) or pharmaceutically acceptable salt thereof:
  • R is hydrogen, phenylC ⁇ _6 alkyl or C1.5 alkyl
  • R is hydrogen or up to three substituents independently selected from halogen, NO 2 , CN, N 3 , C ⁇ _ 6 alkylO-, C ⁇ _ 6 alkylS-, C ⁇ _ 6 alkyl, Cj ⁇ haloalkyl, C3_5cycloalkyl, C3_gcycloalkyl-C 4alkyl-, C j .galkenyl, C ⁇ .galkynyl, C ⁇ _6haloalkylCO-, C ⁇ _ 6 alkylCO-, C 3.6 cycloalkylCO-, C3_ cycloalkyl-C ⁇ 4alkylCO-.
  • the compounds of this invention are typically N-(tetrahydroisoquinolinyl)-N' -optionally substituted phenyl-ureas/thioureas.
  • the compounds of the invention may be
  • the phenyl moiety may be substituted by up to three, preferably 2 or 1, groups.
  • alkyl groups including alkyl groups that are part of another moiety, may be straight chain or branched.
  • Alkyl groups are typically C g alkyl, especially C 4 alkyl, such as methyl, ethyl, «-propyl, wo-propyl, n-butyl, t-butyl.
  • Aromatic rings such as the aromatic ring in the bicyclic heterocyclic moiety in formula (I)
  • R may optionally be substituted with one or more independently selected substituents such as halogen or C ⁇ _g alkyl, C g alkoxy or C ⁇ _ alkylcarbonyl groups, or other optional subtituents indicated below.
  • Suitable C 3 _g cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Suitable halo substituents include fluoro, chloro, iodo and bromo, which may also appear in haloalkyl, haloalkyloxy and haloalkyl carbonyl groups mentioned above, examples of which are trifluoromethyl, trifluoromethoxy and trifluoroacetyl.
  • R " represents heterocyclyl
  • this group is preferably a 5- to 10-membered monocyclic or bicyclic ring, which may be saturated or unsaturated. for example containing 1 , 2 or 3 heteroatoms selected from oxygen, nitrogen or sulphur, for example oxazolyl, thienyl or piperidinyl.
  • the heterocyclyl group may contain up to 5, more preferably 1, 2 or 3 optional substituents.
  • a substituent for a heterocyclyl group is selected from halogen, (C ⁇ _5)alkyl, aryl(C ⁇ _6)alkyl, (C ⁇ _6)alkoxy, (C ⁇ _6)alkoxy(C ⁇ _6)alkyl, halo(C 6)alkyl, hydroxy, amino, mono- and di-N-(C ⁇ _6)alkyl-amino, acylamino, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-(C 6)alkylcarbonyl, aryloxycarbonyl, (C ⁇ .
  • an adjacent pair of R ⁇ together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring, it is preferably a 5- to 7-membered ring, which may be aromatic or non-aromatic.
  • Heterocyclic rings preferably contain 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulphur; for example, pyrrole or pyrrolidine.
  • a carbocyclic or heterocyclic ring formed by an adjacent pair of R ⁇ together with the carbon atoms to which they are attached may be optionally substituted on carbon or nitrogen by one or more substituents, e.g. up to 3 substituents.
  • substituents for the carbocyclic or heterocyclic ring include; halogen, (C ⁇ _6)alkyl, aryl(C 6)alkyl, (C ⁇ _ 6)alkoxy, (C ⁇ _6)alkoxy(C ⁇ _6)alkyl, halo(C ⁇ _g)alkyl, hydroxy, amino, mono- and di-N- (C ⁇ _6)alkyl-amino, acylamino, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-(C ⁇ _g)alkylcarbonyl, aryloxycarbonyl, (C ⁇ _6)alkoxycarbonyl(C 6)alkyl, aryl, oxy groups, ureido, guanidino, sulphonylamino, aminosulphonyl, (C ⁇ _6)alkylthio, (C ⁇ _6)alkylsulphinyl, (C ⁇ _6)alkylsulf
  • R as hydrogen, benzyl, methyl, ethyl, wo-propyl or t-butyl
  • R2 as hydrogen, methyl, ethyl, n-butyl, wo-propyl, t-butyl, phenyl, benzyl, methoxy, ethoxy, n-propoxy, /.r ⁇ -propoxy, n-butoxy, phenoxy, benzyloxy, bromo, chloro, iodo, fluoro, nitro, cyano, acetyl, pivaloyl, wo-butyroyl, benzoyl, trifluoromethyl, trifluoromethoxy, trifluoroacetyl, carbomethoxy, carboethoxy, methylthio, n-propylsulfonyl, isopropylsulfonyl, dimethylsulfamoyl or oxazolyl, R° and R ⁇ are hydrogen, acetyl or methanesulfonyl, or two R groups linked to form naphthyl, indolyl
  • R! is hydrogen or methyl
  • R ⁇ is hydrogen, methyl, ethyl, t-butyl, methoxy, ethoxy, w ⁇ -propoxy, phenoxy, benzyloxy, methylthio, bromo, chloro, fluoro, nitro, cyano, acetyl, benzoyl, trifluoromethyl, trifluoromethoxy, carbomethoxy, carboethoxy, amino, acetylamino, methanesulphonylamino or oxazolyl, or two R2 groups form methylindolyl or acetylindolinyl or naphthyl.
  • these compounds When synthesised, these compounds may be in salt form, such as the hydrochloride or trifluoroacetate, and such salts also form part of this invention. Such salts may be used in preparing pharmaceutically acceptable salts.
  • the compounds and their salts may be obtained as solvates, such as hydrates, and these also form part of this invention.
  • the compounds of this invention possess anti-convulsant activity and are therefore believed to be useful for adminstration to mammals in the treatment and/or prevention of the disorders mentioned above, especially for humans, but also as a veterinary treatment.
  • the administration of such compounds to a mammal may be by way of oral, parenteral, sub-lingual, nasal, rectal, topical or transdermal administration.
  • An amount effective to treat the disorders hereinbefore described depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal.
  • a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active compound.
  • Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range of approximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, for example 1 to 6 mg/kg/day.
  • the compound of formula (I) is administered in the form of a unit-dose composition, such as a unit dose oral, including sub-lingual, nasal, rectal, topical or parenteral (especially intravenous) composition.
  • compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories.
  • Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl -hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate,
  • Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
  • fluid unit dose forms are prepared containing the compound and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
  • compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
  • the present invention provides a pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with ADDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive
  • Giles de la Tourette's syndrome traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS) which comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • the present invention also provides a method of treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post- traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • Giles de la Tourette's syndrome traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS) comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other
  • Giles de la Tourette's syndrome traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate, thereof as a therapeutic agent, in particular for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • Giles de la Tourette's syndrome traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • Another aspect of the invention provides a process for the preparation of compounds of formula (I), which comprises reacting a compound of formula (H)
  • R 1 A is R* as defined for formula (I) or a group convertible to R 1
  • P is NH2 or NCX, X being as defmed for formula (I), with a compound of formula (III)
  • R ⁇ A is R ⁇ as defined for formula (I) or a group or groups convertible to R ⁇ , and where required converting a R ⁇ or R- ⁇ A group to a R' or R ⁇ group, converting one R! or R2 group to another R* or R ⁇ group, converting a salt product to the free base or another pharmaceutically acceptable salt, or converting a free base product to a pharmaceutically acceptable salt.
  • Conversions of an R ⁇ or R ⁇ A group to a R or R ⁇ group typically arise when a protecting group is needed during the above coupling reaction or during the preparation of the reactants by the procedures described below.
  • Interconversion of one R* or R ⁇ group to another typically arises when one compound of formula (I) is used as the immediate precursor of another compound of formula (I), or when it is easier to introduce a more complex or reactive substituent at the end of a synthetic sequence.
  • the compound of formula (H) which can be reduced, for example using sodium borohydride, to the compound of formula (H).
  • the compound of formula (V) can be hydrogenated, for example using hydrogen at 50psi in a solution of acetic/sulphuric acid with a platinum oxide catalyst.
  • a compound of formula (H) in which P is NH2 may be prepared directly from the corresponding nitro compound by catalytic hydrogenation. More specifically 7-amino- tetrahydroisoquinolines may be prepared by the procedure of G E Stokker, Tet. Lett. 1996, 37, 5453.
  • the compound of formula (LI) can be obtained by direct hydrogenation of the compounds of formula (IV) or (VI), using the reagents already described.
  • the NH may be protected conventionally, for example by making R t-butoxycarbonyl, prior to formation of the urea, and then deprotected under standard conditions, for example using trifluoroacetic acid/methylene chloride.
  • Compounds of formula (IH) in which Q is iso(thio)cyanate are commercially available or may be prepared by formation of iso(thio)cyanates from commercially available substituted phenyl compounds using conventional procedures such as described by I T Forbes et al , J.Med.Chem., 1993, 36, 1104, and in Fieser and Fieser, Reagents for Organic Synthesis Vol I.
  • an isocyanate may be prepared by stirring a relevant amine with one equivalent of carboxyl diimidazole in a suitable solvent such as dichloromethane at room temperature, and then evaporated to dryness in vacuo.
  • Isothiocyanates may be prepared by reaction of the relevant amine with carbon disulphide in pyridine in the presence of dicyclohexylcarbodiimide.
  • Compounds of formula (LT) in which P is iso(thio)cyanate may be similarly prepared starting from the amines of formula (LT) described above.
  • Compounds of formula (HI) in which Q is amino are commercially available or may be prepared by formation of amines on commercially available substituted phenyl compounds using conventional procedures.
  • the compounds of the present invention may contain a chiral centre, and therefore the above processes may produce a mixture of diastereoisomers.
  • a single diastereoisomer may be prepared by separating such a mixture of diastereoisomers which has been synthesised using a racemic starting material, or by synthesis using an optically pure starting material.
  • the compounds of this invention may be in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated.
  • solvent of crystallisation may be present in the crystalline product.
  • some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be present in the crystalline product. Crystallisation procedures will usually produce stoichiometric hydrates. Compounds containing variable amounts of water may be produced by processes such as lyophilisation.
  • the compounds according to the invention are suitably provided in substantially pure form, for example at least 50% pure, suitable at least 60% pure, advantageously at least 75% pure, preferably at least 85% pure, more preferably at least 95% pure, especially at least 98% pure, all percentages being calculated as weight/weight.
  • An impure or less pure form of a compound according to the invention may, for example, be used in the preparation of a more pure form of the same compound or of a related compound (for example a corresponding derivative) suitable for pharmaceutical use.
  • the present invention also includes pharmaceutically acceptable salts and derivatives of the compounds of the invention.
  • Salt formation may be possible when one of the substituents carries an acidic or basic group.
  • Salts may be prepared by salt exchange in conventional manner.
  • Acid-addition salts may be pharmaceutically acceptable or non-pharmaceutically acceptable. In the latter case, such salts may be useful for isolation and purification of the compound of the invention, or intermediates thereto, and will subsequently be converted into a pharmaceutically acceptable salt or the free base.
  • the amine D3 (2.08g; 11.7 mmol) was treated with 88% formic acid (3.45ml) and 37% aqueous formaldehyde (5.88ml) at 80°C for 2h according to the procedure of G.M. Carrera and D.S. Garvey, J. Het. Chem., 1992, 29, 847. Basification with 10% sodium hydroxide followed by work-up with ethyl acetate afforded an orange gum (2.3g). Chromatography on Kiesegel 60 in 0-3% methanol - ethyl acetate gave the title compound as an orange solid (1.7g).
  • the title compound was prepared from the compound of Description D3 using di t-butyl dicarbonate in 10% aqueous hydroxide in dioxan at 25°C followed by catalytic hydrogenation according to the procedure described for D5.
  • urea (a) (540mg; 1.32 mmol) in 10% aqueous methanol(80ml) and potassium carbonate (lg) was stirred at room temperature overnight. The mixture was partitioned between chloroform and water and the organic phase dried over magnesium sulfate. Evaporation in vacuo gave a pale yellow solid which was recrystallised from chloroforrmhexane (300mg, 72%). m.p. 232-5 °C.
  • N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(2-cyano-3-methylphenyl) urea The isocyanate D10 (160mg) was dissolved in dimethylformamide (10ml), 6-methyl-2- aminobenzonitrile (0.13g) added and the mixture heated at 100°C for 3h. Dimethylformamide was removed at reduced pressure and the residue partitioned between dichloromethane and water. The organic phase was washed with water, dried MgSO4) and solvent removed at reduced pressure.
  • the title compound was prepared in 42% yield from 3-isopropoxyaniline and the isocyanate D10 using the method of Example 43.
  • the title compound was prepared in 72% yield from 3-(l,3-oxazol-5-yl)aniline and the isocyanate D10 using the method of Example 43.
  • the title compound was prepared in 24% yield from amine D9 and 3, 5-dinitroaniline using a method similar to that of Example 69.
  • the title compound was prepared in 20% yield from amine D9 and 3-bromo-4- methoxyaniline using a method similar to that of Example 69.
  • N- ⁇ 3-[3-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)ureido]phenyl ⁇ acetamide hydrochloride A solution of N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-N'-(3-aminophenyl) urea E74 (0.296g) and triethylamine (0.151g) in dichloromethane was treated with acetyl chloride (0.078g) and stirred for 6h. Aqueous sodium hydrogen carbonate was added with vigorous stirring and the precipitated solid collected by filtration. The material was dissolved in methanol and treated with an excess of ethereal HC1. The precipitated title compond (0.145g) was collected by filtration and dried in vacuo.
  • WO 92/22293 discloses compounds having anti-convulsant activity, including ter alia the compound tr ⁇ nO+)-6-acetyl-4S-(4-fluorobenzoylamino)- 3,4-dihydro-2,2-dimethyl-2H-l-benzopyran-3R-ol (hereinafter referred to as Compound A). It has been found that the compounds of WO 92/22293 bind to a novel receptor obtainable from rat forebrain tissue, as described in WO 96/18650 (SmithKline Beecham). The affinity of test compounds to the novel receptor site is assessed as follows.
  • Whole forebrain tissue is obtained from rats.
  • the tissue is first homogenised in buffer (usually 50mM Tris/HCl, pH 7.4).
  • the homogenised tissue is washed by centrifugation and resuspension in the same buffer, then stored at -70°C until used.
  • the affinity of the binding of test compounds to the novel site can be estimated by incubating together [3H]-Compound A and tissue in the presence of a range of concentrations of the compound to be tested.
  • the decrease in the level of specific [3H]- Compound A binding as a result of competition by increasing concentrations of the compound under test is plotted graphically, and non-linear regression analysis of the resultant curve is used to provide an estimate of compound affinity in terms of pKi value.
  • the maximal electroshock seizure (MEST) threshold test in rodents is particularly sensitive for detecting potential anticonvulsant properties 1.
  • anticonvulsant agents elevate the threshold to electrically-induced seizures whilst proconvulsants lower the seizure threshold.
  • mice (naive male, Charles River, U.K. CD-I strain, 25 - 30g) are randomly assigned to groups of 10 - 20 and dosed orally or intraperitoneally at a dose volume of 10 ml/kg with various doses of compound (0.3 - 300 mg/kg) or vehicle. Mice are then subjected at 30 or 60 min post dose to a single electroshock (0.1 sec, 50Hz, sine wave form) administered via corneal electrodes. The mean current and standard error required to induce a tonic seizure in 50% (CC50) of the mice in a particular treatment group is determined by the 'up and down' method of Dixon and Mood (1948)2. Statistical comparisons between vehicle- and drug-treated groups are made using the method of Litchfield and Wilcoxon (1949)3.
  • the CC50 In control animals the CC50 is usually 14 - 18 mA. Hence the first animal in the control group is subjected to a current of 16 mA. If a tonic seizure does not ensue, the current is increased for a subsequent mouse. If a tonic convulsion does occur, then the current is decreased, and so on until all the animals in the group have been tested.
  • the percentage increase or decrease in CC50 for each group compared to the control is calculated. Studies are carried out using a Hugo Sachs Electronik Constant Current Shock Generator with totally variable control of shock level from 0 to 300 mA and steps of 2 mA are usually used.
  • Drugs are suspended in 1 % methyl cellulose.

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Abstract

N-(tétrahydroisoquinoléinyl)-N'-phénylurées/thiourées représentés par la formule suivante (I) utiles pour le traitement ou la prophylaxie de l'anxiété, de la manie, de la dépression ou de l'agression, de maladies associées à une hémorragie subarachnoïde ou à un choc nerveux, des effets associés à l'arrêt de la consommation de substances toxiques, telles que la cocaïne, la nicotine, l'alcool et les benzodiazépines, de maladies pouvant être traitées ou prévenues par des agents anticonvulsifs, telles que l'épilepsie, y compris l'épilepsie post-traumatique, la maladie de Parkinson, la psychose, la migraine, l'ischémie cérébrale, la maladie d'Alzheimer et d'autres maladies dégénératives, telles que la chorée d'Huntingdon, la schizophrénie, les maladies compulsives obsessionnelles (OCD), les déficiences neurologiques associées au SIDA, les troubles du sommeil (y compris les problèmes du rythme circadien, l'insomnie et la narcolepsie), les tics (par exemple, le syndrome de Gilles de la Tourette), la lésion cérébrale traumatique, l'acouphène, la névralgie, particulièrement, la névralgie faciale, la douleur névropathique, la douleur dentaire, la douleur provoquée par le cancer, l'activité neuronale inadéquate conduisant vers des neurodysthésies dans des maladies, telles que le diabète, la sclérose en plaques (MS) et les troubles moteurs neuronaux, les ataxies, la rigidité musculaire (hypertonie spastique), le syndrome de Costen et la sclérose latérale amyotrophique (ALS).
EP98942869A 1997-09-12 1998-09-09 Isoquinoleines substituees en tant qu'anticonvulsifs Withdrawn EP1005459A1 (fr)

Applications Claiming Priority (3)

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GB9719530 1997-09-12
GBGB9719530.9A GB9719530D0 (en) 1997-09-12 1997-09-12 Novel compounds
PCT/GB1998/002728 WO1999014197A1 (fr) 1997-09-12 1998-09-09 Isoquinoleines substituees en tant qu'anticonvulsifs

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GB9816982D0 (en) * 1998-08-05 1998-09-30 Smithkline Beecham Plc Novel compounds
PL373970A1 (en) * 2002-02-08 2005-09-19 Bristol-Myers Squibb Company (oxime)carbamoyl fatty acid amide hydrolase inhibitors
WO2004085433A2 (fr) * 2003-03-28 2004-10-07 Pharmacia & Upjohn Company Llc Modulateurs allosteriques positifs du recepteur nicotinique de l'acetylcholine
KR20110137941A (ko) * 2010-06-18 2011-12-26 (주) 에빅스젠 신규한 티오우레아 또는 우레아 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 ａｉｄｓ 예방 또는 치료용 약학 조성물

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JPH07504429A (ja) * 1992-03-12 1995-05-18 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー ５ＨＴ↓１ｃアンタゴニストとしてのインドール誘導体
WO1994014801A1 (fr) * 1992-12-29 1994-07-07 Smithkline Beecham Plc Derives heterocycliques de l'uree antagonistes de 5ht2c et 5h¿2b?
TW397812B (en) * 1995-02-11 2000-07-11 Astra Ab Bicyclic isothiourea derivatives useful in therapy
GB9511355D0 (en) * 1995-06-06 1995-08-02 Fujisawa Pharmaceutical Co Urea derivatives

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JP2001516745A (ja) 2001-10-02
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CA2303777A1 (fr) 1999-03-25

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