EP0968190A1 - Substituted isoquinoline derivatives and their use as anticonvulsants - Google Patents

Substituted isoquinoline derivatives and their use as anticonvulsants

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Publication number
EP0968190A1
EP0968190A1 EP98909647A EP98909647A EP0968190A1 EP 0968190 A1 EP0968190 A1 EP 0968190A1 EP 98909647 A EP98909647 A EP 98909647A EP 98909647 A EP98909647 A EP 98909647A EP 0968190 A1 EP0968190 A1 EP 0968190A1
Authority
EP
European Patent Office
Prior art keywords
tetrahydroisoquinolin
methyl
bromo
methoxybenzamide
hydrochloride
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Withdrawn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
EP98909647A
Other languages
German (de)
English (en)
French (fr)
Inventor
Mervyn Smithkline Beecham Pharm. Thompson
Robert William Smithkline Beecham Pharm. Ward
Peter David SmithKline Beecham Pharm. EDWARDS
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
Original Assignee
SmithKline Beecham 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 GBGB9705619.6A external-priority patent/GB9705619D0/en
Priority claimed from GBGB9726695.1A external-priority patent/GB9726695D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0968190A1 publication Critical patent/EP0968190A1/en
Withdrawn legal-status Critical Current

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D217/00Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/12Heterocyclic 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/472Non-condensed isoquinolines, e.g. papaverine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/472Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02Muscle relaxants, e.g. for tetanus or cramps
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/06Antimigraine agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/08Antiepileptics; Anticonvulsants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16Anti-Parkinson drugs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/18Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/20Hypnotics; Sedatives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/22Anxiolytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/24Antidepressants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D217/00Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D217/00Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02Heterocyclic 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
    • C07D217/04Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D217/00Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02Heterocyclic 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
    • C07D217/06Heterocyclic 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 the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/38Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic 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
    • C07D413/12Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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.
  • WO97/48683 discloses tetrahydroisoquinolinyl benzamides in which the benzamide moiety has a 2- alkoxy substituent, including the compounds: N-(7-iodo-2-methy 1-1, 2,3,4- tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide, N-(7-iodo- 1 ,23,4- tet ⁇ ydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide, N-(5-iodo- 1 ,23,4- tetrahydroisoquinolin-7-yl)-5-benzoyl-2-methoxybenzamide, N-(5-iodo-l,2,3,4- tet_ahydroisoquinolin-7-yl)-2-me ⁇ oxy- t_iflu
  • carboxamide 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 ***e, 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 Orcadian 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,
  • 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, C ⁇ _ 6 alkyl (optionally substituted by hydroxy or C j .
  • R is hydrogen, hydroxy, or up to three substituents selected from halogen,
  • C3_6cycloalkyl-C ⁇ _4alkylCO- acetoxy, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C ⁇ _ alkyl-, C ⁇ galkylS-, C ⁇ _6alkylSO 2 -, (Cj. 4alkyl) 2 NSO 2 -, (C 1 . 4 alkyl)NHSO 2 -, (C 1 . 4 alkyl) 2 NCO- , (C j.
  • R 4 is hydrogen, C ⁇ alkyl, formyl, -CO 2 C ⁇ _4alkyl or -COC ⁇ alkyl;
  • X is hydrogen, halogen, C ⁇ _6 alkoxy, C ⁇ _6 alkyl, ammo or trifluoroacetylamino;
  • the compounds of this invention are typically, (tetrahydroisoquinolin-7-yl) carboxamides, especially (tetrahydroisoquinolin-7-yl)benzamides.
  • substituent X is not hydrogen it may be at the 5, 6, or 8 position of the tetrahydroisoquinoline moiety, especially position 5.
  • the ring system Q is typically optionally substituted phenyl or optionally substituted
  • heteroaryl typically thiophenyl or 3-isoxazolyl.
  • R groups typically a 5-7 membered ring
  • Q may be a naphthalene or an indane or indanone ring system or a bicyclic heteroaryl such as 5-dihydrobenzofuranyl.
  • alkyl groups including alkyl groups that arc part of other moieties, such as alkoxy or acyl, may be straight chain or branched.
  • Phenyl groups, including phenyl groups that are part of other moieties, in R may optionally be substituted with one or more independently selected from halogen or C j .g alkyl, C j .g alkoxy or C g alkylcarbonyl.
  • Suitable C ⁇ cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Suitable halo substituents include fluoro, chloro, iodo and bromo.
  • Ri as hydrogen, methyl, ethyl, propyl, hydroxyethyl, methoxyethyl, formyl, acetyl, trifluoroacetyl or methanesulfonyl
  • R ⁇ as hydrogen or one or more of methyl, ethyl, n-butyl, isopropyl, wo-butyl, t- butyl, phenyl, methoxy, ethoxy, is ⁇ -propoxy, ⁇ -butoxy, cyclopropylmethoxy, phenoxy, benzyloxy, , amino, acetylamino, nitro, azido, cyano, bromo, chloro, fluoro, iodo, acetyl, pivaloyl, iso-butyroyl, benzoyl, iodobenzoyl, trifluoromethyl, perfluoroethyl, trifluoromethoxy, trifluoroace
  • X as hydrogen, chloro, bromo, iodo, fluoro, amino, trifluoroacetylamino.
  • a preferred group of compounds of formula (I) have R 1 as hydrogen, methyl, methoxyethyl,
  • R as hydrogen or one or more of methyl, n-butyl, t-butyl, wo-propyl, phenyl, methoxy, ethoxy, tso-propoxy, phenoxy, acetyl, nitro, cyano, bromo, chloro, fluoro, iodo, pivaloyl, trifluoromethyl, azido, trifluoromethoxy.
  • X as hydrogen, iodo, chloro, bromo or trifluoroacetylamino.
  • these compounds When synthesised, these compounds are often 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.
  • administration of such compounds to a mammal may be by way of oral, parenteral, sub-lingual, nasal, rectal, topical or transdermal administration.
  • 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, rectal, topical or parenteral (especially intravenous) composition.
  • a unit-dose composition such as a unit dose oral, including sub-lingual, rectal, topical or parenteral (especially intravenous) composition.
  • Such 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, colorants, 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 p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • 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 further 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 ***e, 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 Orcadian 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 compul
  • 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 ***e, 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 Orcadian 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 ***e, 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 Orcadian 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 ***e, 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 Orcadian 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 is a process for the preparation of compounds of formula (I), which comprises reacting a compound of formula (H)
  • R 1A is R 1 as defined for formula (I) or a group convertible to R 1 and X is as defined in claim 1 with a compound of formula (HI)
  • R 2A groups are independently R 2 as defined for formula (I) or groups convertible to R 2 , and where required converting an R ⁇ or R 2A group to a R* or R 2 group, converting one R 1 or R 2 group to another R* or R 2 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
  • Suitable solvents include ethyl acetate or dichloromethane, optionally in the presence of a base such as triethylamine.
  • a base such as triethylamine.
  • conventional conditions for condensation of such acids with amines may be used, for example reacting the components in a mixture of (dimethylaminopropyl)-ethyl- carbodiimide/hydroxybenzotriazole in a suitable solvent such as dimethyl formamide.
  • Conversions of an R 1 0 r R 2 ⁇ group to a R* or R 2 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 2 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 (IV) may also be reacted with formic acid and formaldehyde to introduce the N-methyl group.
  • the nitro-tetrahydroisoquinoline of formula (TV) may be prepared by hydrolysis of 2- trifluoroacetyl-nitro-tetrahydroisoquinoline obtained by reaction of an N- (nitrophenyl)ethyl-trifluoroacetamide and paraformaldehyde in acidic conditions using the procedure of Stokker, TeLLett.,1996, 37, 5453.
  • N-(nitrophenyl)ethyl-trifluoroacetamides can be prepared from readily available materials by reaction of trifluoracetic anhydride with lutidine and nitrophenethylamine hydrochloride, as illustrated in the Descriptions below.
  • R N is NH 2 or NO 2 by reaction with a compound R 1A Z where Z is a leaving group such as halogen, especially iodo, or tosylate to obtain an intermediate of formula (VH)
  • the N of the tetrahydroisoquinoline or isoquinoline is preferably protected conventionally, prior to the coupling step that forms the carboxamide of formula (I), for example by tert.-butoxycarbonyl or trifluoroacetyl.
  • the compound can be deprotected under standard conditions, for example using trifluoroacetic acid/methylene chloride.
  • Amino/nitro-isoquinolines of formulae (VI) and the reagents used are commercially available, or can be prepared from commercially available materials using conventional procedures described in the literature.
  • substituent X is other than hydrogen it may be introduced during any of the procedures above, for example by conventional substitution of the aromatic ring of compounds of formula (IV), (V) or (VH) or may be present on commercially available starting materials usable in the above described procedures.
  • the substituent X is introduced to a compound of formula (H) in which X is hydrogen.
  • X as halogen may be incorporated via an amino group using Sandmeyer chemistry as illustrated in the descriptions below.
  • Compounds of formula (HI) may be prepared by further substitution of commercially available benzoic acid or thiophene carboxylic acid derivatives using conventional procedures, or by oxidation of corresponding substituted benzyl alcohols.
  • benzoic acids can be prepared from co repondingly substituted phenols, for example by formation of the acetate, conversion to an acetophenone and then to the desired acid.
  • nitro compound D8 (0.73g, 3.32mmol) in ethanol (100ml) was heated to 50°C and treated with a solution of tin (H) chloride (2.52g, 13.27mmol) in cone. HCl (10ml) and stirring continued for 3h. The mixture was basified with 40% NaOH and the product extracted into dichloromethane. Work-up and chromatography on Kieselgel 60 in 10% methanol:dichloromethane gave the title compound as a viscous yellow oil (0.26g; 41%).
  • the title compound was prepared in 14% overall yield from D3 and acetaldehyde using a method similar to that described in Descriptions 5 and 8.
  • Triethylamine (0.112ml; 0.81mmol) and 3-bromo-4-ethoxybenzoyl chloride (193mg; 0.73mmol) were dissolved in dichloromethane (100ml) with stirring. To this mixture was added the compound of D15 (204mg; 0.67mmol). The mixture was stirred overnight and then evaporated in vacuo. The resultant residue was purified by chromatography on silica with 10% methanol:dichloromethane to give the title compound (123mg; 35%).
  • the 5-amino compound D23 (1.6g, 7.7mmol) in 5MHC1 (25ml) at 0°C was treated with a solution of sodium nitrite (0.55g, 8.0mmol) in water (3ml) over 5min. The cold solution was then added gradually to a solution of copper(I)chloride (l.Og, lOmmol) in 5MHC1 (25ml). The mixture was stirred at 25°C for 30min and then basified with 40% NaOH. Work-up with dichloromethane (300ml) followed by flash chromatography on Kieselgel 60 (5% methanol:dichloromethane) gave the title compound (l.lg, 62%) as a yellow solid.
  • the title compound was prepared from diethyl trifluoroacetamide and 3-bromobenzyl TBDMS ether using a method similar to that described in Preparations 1, 2, 3 and 4.
  • the title compound was prepared from 4-ethylbenzoic acid.
  • Methyl 3-bromo-4-w ⁇ -propyloxybenzoate (828mg; 3.03 mmol) in DMF (25ml) was treated with potassium trifluoroacetate (922mg; 6.06 mmol), copper (I) iodide (1.15g; 6.06 mmol) and toluene (50ml).
  • the resulting mixture was heated at reflux for 1.5h (Dean and Stark with removal of ca 50ml of distillate) followed by reflux for 18h then cooled.
  • the mixture was poured into Et,O (100ml) and H j O (100ml).
  • the two-phase mixture was stirred at room temperature for 0.5h then filtered through Celite. The two phases were separated, the aq. phase further extracted with Et (50ml) and the organic extracts combined, washed with saturated, aq. Na,S 2 O 3 , H,O, saturated brine, dried
  • Ethyl 2-ethoxy-4-i_ ⁇ -propyl-5-cyanobenzoate (l-2g, 3*8mmol) was treated witii copper (I) cyanide (682mg, 7-6 m.mol) in N-methyl-2-pyrrolidinone (40ml) as described in Procedure 5 to give the title compound as an oil (400mg).
  • Example 1 The compound of Example 1 (200mg; 0.5 mmol), 98% formic acid (0.4ml) and aqueous formaldehyde (0.6ml) were treated according to the procedure of Description 4. Chromatography on Kieselgel 60 in methanol - ethyl acetate followed by crystallisation from ethyl acetate - ether gave the title compound as an off-white powder, m.p. 138- 40°C.
  • the compound D16 (115mg; 0.22 mmol) was dissolved in THF with stirring and tetra- butylammonium fluoride (1 M in THF; 0.216 mmol) added. The reaction was stirred overnight and the mixture purified by column chromatography through SiO, eluting with 10% methanohdichloromethane. Trituration with petroleum ether, gave the title compound (48mg; 49%).
  • the title compound was prepared in 40% overall yield from D15 in a manner similar to that of Descriptions 16 and Example 106.
  • the title compound was prepared in 81% yield from the acid Preparation 28 and amine D6.
  • the tide compound (0.66g) was prepared from D25 (0.50g) and 3-bromo-4- methoxybenzoic acid (0.63g) using a procedure similar to that of Description 7.
  • WO 92/22293 discloses compounds having anti-convulsant activity, including inter alia the compound tr ⁇ ns-(+)-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 96718650 (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.
  • To carry out the radioligand binding assay aliquots of tissue prepared as above (usually at a concentration of l-2mg )rotein/ml) are mixed with aliquots of [3H]-Compound A dissolved in buffer.
  • the final concentration of [3H]-Compound A in the mixture is usually 20nM.
  • the mixture is incubated at room temperature for 1 hour.
  • [3H]-Compound A bound to the tissue is then separated from unbound [3H]-Compound A by filtration through Whatman GF/B glass fibre filters.
  • the filters arc then washed rapidly with ice-cold buffer.
  • the amount of radioactivity bound to the tissue trapped on the filters is measured by addition of liquid scintillation cocktail to the filters followed by counting in a liquid scintillation counter.
  • the affinity of the binding of test compounds to die 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 die level of specific [3H]- Compound A binding as a result of competition by increasing concentrations of die 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 1 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 die 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 threshold for maximal (tonic hindlimb extension) electroshock seizures in male rats was determined by a Hugo Sachs Electronik stimulator which delivered a constant current (0.3 sec duration; from 1 -300mA in steps of 5-20mA). The procedure is similar to that outlined above for mouse and full details are as published by Upton et al,.4
  • the percentage increase or decrease in CC50 for each group compared to the control is calculated.
  • Drugs are suspended in 1% methyl cellulose.
  • the compounds of Examples 48, 49, 51 and 67 show increases of 389%, 325%, 545% and 303% increases respectively.

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EP98909647A 1997-03-18 1998-03-16 Substituted isoquinoline derivatives and their use as anticonvulsants Withdrawn EP0968190A1 (en)

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GB9726695 1997-12-17
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GB9726695D0 (en) 1997-12-17 1998-02-18 Smithkline Beecham Plc Novel compounds
WO1999021836A1 (en) * 1997-10-24 1999-05-06 Smithkline Beecham Plc Substituted isoquinoline derivatives and their use as anticonvulsants
GB9817424D0 (en) 1998-08-11 1998-10-07 Smithkline Beecham Plc Novel compounds
US20020006908A1 (en) * 1998-12-03 2002-01-17 Daniel P. Van Kammen Anticonvulsant derivatives useful in treating schizophrenia
ATE306481T1 (de) * 1999-05-12 2005-10-15 Ortho Mcneil Pharm Inc Pyrazolecarboxamide zur behandlung von fettleibigkeit und anderen erkrankungen
FR2795724B1 (fr) * 1999-07-02 2002-12-13 Sanofi Synthelabo Nouveaux derives du benzene, un procede pour leur preparation et les compositions pharmaceutiques les contenant
GB9915589D0 (en) * 1999-07-02 1999-09-01 Smithkline Beecham Plc Novel compounds
ES2316777T3 (es) 2002-02-15 2009-04-16 Glaxo Group Limited Moduladores de receptores vainilloides.
GB0210762D0 (en) * 2002-05-10 2002-06-19 Glaxo Group Ltd Compounds
WO2004014388A1 (en) * 2002-08-13 2004-02-19 Warner-Lambert Company Llc 6,6-fused heteroaryl derivatives as matrix metalloproteinase inhibitors
GB0226724D0 (en) 2002-11-15 2002-12-24 Merck Sharp & Dohme Therapeutic agents
MXPA05013434A (es) 2003-06-12 2006-03-17 Astellas Pharma Inc Derivados de benzamida o sal del mismo.
BRPI0415167A (pt) * 2003-10-07 2006-11-28 Renovis Inc composto de amina como ligandos de canal de ìon e usos dos mesmos
GB2413129A (en) * 2003-10-07 2005-10-19 Renovis Inc Aromatic amide compounds as ion channel ligands and uses thereof
CA2553968A1 (en) * 2004-01-23 2005-08-11 Amgen Inc. Vanilloid receptor ligands and their use in treatments of inflammatory and neuropathic pain
JP2008513426A (ja) * 2004-09-20 2008-05-01 バイオリポックス エービー 炎症の治療に有用なピラゾール化合物
SE0403117D0 (sv) * 2004-12-21 2004-12-21 Astrazeneca Ab New compounds 1
CA2659539A1 (en) 2006-08-01 2008-02-07 Glaxo Group Limited Pyrazolo[3,4-b]pyridine compounds, and their use as pde4 inhibitors
CN106608901B (zh) * 2015-10-22 2020-10-16 彭莉 二羟基二甲基四氢异喹啉-3-甲酰-Lys(Lys-Ala),其合成,活性及应用
CN111138359A (zh) * 2020-01-19 2020-05-12 浙江农林大学暨阳学院 制备3-羰基-4-叠氮基-n-苯磺酰基-1,2,3,4-四氢异喹啉类化合物的方法

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CZ416498A3 (cs) * 1996-06-17 1999-06-16 Smithkline Beecham Plc Substituovaný benzamidový derivát a jeho použití jako antikonvulsantu

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