WO1998041508A1 - Substituted isoquinoline derivatives and their use as anticonvulsants - Google Patents

Substituted isoquinoline derivatives and their use as anticonvulsants Download PDF

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Publication number
WO1998041508A1
WO1998041508A1 PCT/GB1998/000782 GB9800782W WO9841508A1 WO 1998041508 A1 WO1998041508 A1 WO 1998041508A1 GB 9800782 W GB9800782 W GB 9800782W WO 9841508 A1 WO9841508 A1 WO 9841508A1
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WO
WIPO (PCT)
Prior art keywords
tetrahydroisoquinolin
methyl
bromo
methoxybenzamide
hydrochloride
Prior art date
Application number
PCT/GB1998/000782
Other languages
French (fr)
Inventor
Mervyn Thompson
Robert William Ward
Peter David Edwards
Original Assignee
Smithkline Beecham Plc
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
Priority to BR9809047-0A priority Critical patent/BR9809047A/en
Priority to PL335676A priority patent/PL192116B1/en
Priority to AU64128/98A priority patent/AU737955B2/en
Priority to EP98909647A priority patent/EP0968190A1/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to CA002284218A priority patent/CA2284218A1/en
Priority to KR1019997008443A priority patent/KR100568654B1/en
Priority to NZ337424A priority patent/NZ337424A/en
Priority to IL13175698A priority patent/IL131756A0/en
Priority to JP54024898A priority patent/JP3690423B2/en
Priority to HU0000987A priority patent/HUP0000987A3/en
Publication of WO1998041508A1 publication Critical patent/WO1998041508A1/en
Priority to NO19994510A priority patent/NO314081B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • 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
    • C07D217/06—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 the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic 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
    • C07D333/26—Heterocyclic 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic 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
    • C07D405/02—Heterocyclic 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
    • C07D405/12—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic 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
    • C07D417/02—Heterocyclic 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
    • C07D417/12—Heterocyclic 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 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 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 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 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 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 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 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 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 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 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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Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof; where Q is a monocyclic or bicyclic aryl or heteroaryl ring, R1 is hydrogen, C¿1-6?alkyl (optionally substituted by hydroxy or C1-4alkoxy), C1-6alkenyl, C1-6alkynyl, C1-6alkylCO-, formyl, CF3CO- or C1-6alkylSO2-, R?2¿ is hydrogen or up to three substituents selected from halogen, NO¿2?, CN, N3, CF3O-, CF3S-, CF3CO-, trifluoromethyldiazirinyl, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C1-6perfluoroalkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl-, C1-6alkylO-, C1-6alkylCO-, C3-6cycloalkylO-, C3-6cycloalkylCO-, C3-6cycloalkyl-C1-4alkylO-, C3-6cycloalkyl-C1-4alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl-, C1-6alkylS-, C1-6alkylSO2-, (C1-4alkyl)2NSO2-, (C1-4alkyl)NHSO2-, (C1-4alkyl)2NCO-, (C1-4alkyl)NHCO- or CONH2; or -NR?3R4¿ where R3 is hydroven or C¿1-4?alkyl, and R?4¿ is hydrogen, C¿1-4?alkyl, formyl, -CO2C1-4alkyl or -COC1-4alkyl; or two R?2¿ groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by -OH or =O; and X is hydrogen, halogen, C¿1-6?alkoxy, C1-6alkyl, amino or trifluoroacetylamino, but when X is hydrogen excluding compounds in which R?2¿ is 2-alkoxy and when X is hydrogen excluding the compounds N-(7-iodo-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl) -5-benzoyl-2-methoxybenzamide, N-(7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl) -5-benzoyl-2-methoxybenzamide, N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl) -5-benzoyl-2-methoxybenzamide, N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-methoxy-4-trifluoromethyldiazirinylbenzamide, N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-methoxy-5-trifluoromethyldiazirinylbenzamide, N-(7-iodo-1,2,3,4,-tetrahydroisoquinolin-5-yl) -2-methoxy-5-trifluoromethyldiazirinylbenzamide et N-(8-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl) -4-t-butyl-2-methoxybenzamide, are useful inter alia in the treatment and prophylaxis of epilepsy.

Description

SUBSTITUTED ISOQUINOLINE DERIVATIVES AND THEIR USE AS ANTICONVULSANTS
This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.
WO97/48683 (SmithKline Beecham), unpublished at the filing date of this application, 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- tetι^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-meΛoxy- t_ifluoromemyldiaziιinylbenzamide, N-(5-iodo- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-5-trifluoromemyldia_±inyl- benzamide, N-(7-iodo-l,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5- trifluoromethyldiazirinyl-benzamide and N-(8-fluoro-2-methyl- 1 ,2,3,4- tetrahydroisoquinolin-5-yl)-4-t-butyl-2-methoxybenzamide.
It has now been surprisingly found that 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 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 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).
Accordingly, the present invention provides a compound of formula (I) or pharmaceutically acceptable salt thereof:
Figure imgf000004_0001
where Q is a monocyclic or bicyclic aryl or heteroaryl ring, R is hydrogen, Cι_6alkyl (optionally substituted by hydroxy or Cj.
4alkoxy), Cj.galkenyl, C^galkynyl, C^alkylCO-, formyl, CF3CO- or
C1.6alkylSO2-,
R is hydrogen, hydroxy, or up to three substituents selected from halogen,
NO2, CN, N3,CF3O-, CF3S-, CF3CO-, trifluoromethyldiazirinyl, Cχ_
Figure imgf000004_0002
C 1.galkynyl, C _6perfluoroalkyl, C3_6Cycloalkyl,
C3_6Cycloalkyl-C1.4alkyl-, C galkylO-, C galkylCO-,
C3_6cycloal ylO-, C3_6cycloalkylCO-, C3_6cycloalkyl-Cμ4alkylO-,
C3_6cycloalkyl-Cι_4alkylCO-, acetoxy, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-Cι_ alkyl-, C^galkylS-, Cι_6alkylSO2-, (Cj. 4alkyl)2NSO2-, (C 1.4alkyl)NHSO2-, (C 1.4alkyl)2NCO- , (C j.
4alkyl)NHCO- or CONH2; or -NR-'R4 where R-* is hydrogen or C 1.4 alkyl, and
R4 is hydrogen, C^alkyl, formyl, -CO2Cι_4alkyl or -COC^alkyl;
2 or two R groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by -OH or =O; and
X is hydrogen, halogen, Cι_6 alkoxy, Cι_6 alkyl, ammo or trifluoroacetylamino;
2 but when X is hydrogen excluding compounds in which R is 2-alkoxy and when X is halogen excluding the compounds N-(7-iodo-2-methyl- 1,2,3,4- tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide, N-(7-iodo- 1 ,2,3,4- tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide, N-(5-iodo- 1 ,2,3,4- tetrahydroisoquinolin-7-yl)-5-benzoyl-2-methoxybenzamide, N-(5-iodo- 1,2,3,4- tetr_dιydroisoqdnoUn-7-yl)-2-memoxy-4-trifluoromemyldiazirinylbenzamide, N-(5-iodo- l,2,3,4-tetrahydroi_κκιuinolin-7-yl)-2-meΛoxy-5-trifluoromemyldi__z nylbenzamide, N-(7-iodo-l,23,4-tetrahydroisoquino_in-5-yl)-2-memoxy-5-trifluoromemyldiazirinyl benzamide and N-(8-fluoro-2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-5-yl)-4-t-butyl-2- methoxybenzamide.
The compounds of this invention are typically, (tetrahydroisoquinolin-7-yl) carboxamides, especially (tetrahydroisoquinolin-7-yl)benzamides. When the 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
2 heteroaryl, typically thiophenyl or 3-isoxazolyl. When two R groups form a carbocyclic ring, this is typically a 5-7 membered ring, and Q may be a naphthalene or an indane or indanone ring system or a bicyclic heteroaryl such as 5-dihydrobenzofuranyl.
In the formula (I), 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 Cj.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.
One suitable group of compounds of this invention are of formula (IA)
Figure imgf000005_0001
and another suitable group are of formula (IB)
Figure imgf000005_0002
A suitable group of compounds of formula (I) have
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, isø-propoxy, π-butoxy, cyclopropylmethoxy, phenoxy, benzyloxy, , amino, acetylamino, nitro, azido, cyano, bromo, chloro, fluoro, iodo, acetyl, pivaloyl, iso-butyroyl, benzoyl, iodobenzoyl, trifluoromethyl, perfluoroethyl, trifluoromethoxy, trifluoroacetyl, trifluoromeftyldiazirinyl, methanesulfonyl, n-propylsulfonyl, isopropylsulfonyl, dimethylsulfamoyl; 2 or two groups R form a benzene, cyclopentane or cyclopentanone ring;
X as hydrogen, chloro, bromo, iodo, fluoro, amino, trifluoroacetylamino.
A preferred group of compounds of formula (I) have R1 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.
Examples of compounds of formula (I) are:
N-(l,2,3,4-tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-carboxamide
N-(2-methyl-l, 2, 3, 4-tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-carboxamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)benzamide N-(2-methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-chlorobenzamide N-(2-methyl- 1 ,2,3,4-tet_rahydroisoquinolin-7-yl)-4-t-butylbenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-£so-propoxybenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-phenoxybenzamide N-(2-methyl- 1 ,2,3 ,4-tetrahydroisoquinolin-7-yl)-4-nitrobenzamide N-(2-me yl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-phenylbenzamide N-(2-methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylbenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluorobenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyanobenzamide N-(2-methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dichlorobenzamide N-(2-methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-iodobenzamide N-(2-methyl-l,23,4-tetrahydroisoquinolin-7-yl)-4-bromobenzamide N-(2-methyl- l,2,3,4-tetrahydroisoquinolin-7-yl)-4-memylbenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-nitrobenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinol_n-7-yl)-4-ethoxybenzamide N-(2-methyl-l,23,4-tetrahydroisoquinolin-7-yl)-4-/ι-butylbenzamide N-(2-meΛyl-1^3,4-tetrahydroisoquinolin-7-yl)-2-acetoxybenzamide N-(2-methyl- 1 A3,4-tet_ahydroisoquinolin-7-yl)-3-trifluoromemylbenz_unide N-(2-methyl-13,3,4-tetrahydroisoquinolin-7-yl 2,4-difluoiObenzaιnide N-(2-meΛyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3,4-dimethoxybenzamide N-(2-memyl-l,2,3,4-tetrahydroisoquinolin-7-yl 2-fluoro-4-trifluoromethyl benzamide N-(2-memyl-133,4-tetr__bιyd_x)isoquinolin-7-yl)-4-c__loro-3-_dtrobenzamide N-(2-methyl- 1 ,2,3,4-tetrahydrois»quinolin-7-yl)-3^-di-trifluoromel_hylbenzamide N-(2-meΛyl-l,2,3,4-tetι^ydro_soquinolin-7-yl)-2,4-dicMoro-5-fluorobenzamide N-(2-methyl- l,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluoro-5-trifluoromethyl benzamide N-(2-methyl- l,23,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methoxybenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3,4,5-trimethoxybenzamide N-(2-methyl- 1 ,2,3,4-tet_^ydroisoquinoUn-7-yl)-4-trifluoromethoxybenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-pivaloylbenzamide N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-i.o-propoxybenzamide N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-acetoxybenzamide
N-(2-Methyl- 13,3,4-tetrahydroisoquinolin-7-yl)-4-cyclopentyloxybenzamide N-(2-Methyl-l,23,4-tetrahydroisoquinolin-7-yl)-4-cyclopropylmethoxybenzamide N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-methoxybenzamide N-(2-Methyl- 133,4-tetrahydroisoquinolin-7-yl)-2-naphthamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methybenzamide N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-naphthalene-l-carboxamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-methoxybenzamide N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-tert-butoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4- i-propoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl) benzotriazole-5-carboxamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)benzothiazole-6-carboxamide N-(2-Methyl-l,23,4-tetrahydroisoquinolin-7-yl)-2,3-dihydrobenzofuran-5-carboxamide N-(2-Methyl-l,23,4-tetr__hydroisoquinolin-7-yl)-2-methylbenzimidazole-5-carboxamide N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-i_O-propoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide N-(2-Methyl-l,23,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethyl benzamide N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dichloro-4-methoxybenzamide N-(2-Methyl)- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dichloro-4-ethoxybenzamide
N-(2-Methyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dichloro-4-iso-propoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylsulfonylbenzamide N-(2-methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-tert-butylbenzamide N-(2-Methyl-l,2,3,4-tetr_Lhydroisoquinol__ι-7-yl)-2-bromo-5-methoxybenzamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-fluoro-3-methoxybenzamide, hydrochloride
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)- 1 -methylpyrazole-4-carboxamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-trifluoromethylpyrazole-3- carboxamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylthiazole-4-carboxamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-5-methylisoxazole-3-carboxamide
N-(2-Methyl- 1 ,23,4-tetrahydroisoquinolin-7-yl)-5-te/ -butylisoxa__ole-3-carboxamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-methoxyisoxazole-5-carboxamide hydrochloride
N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)indole-2-carboxamide.
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-wo-propylbenzamide, hydrochloride N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-£so-propylbenzamide, hydrochloride
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluoro-4-methoxybenzamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-π-propoxybenzamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-/ι-propoxybenzamide
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-iodo-4-methoxybenzamide
N-(2-Methyl-l,2,3,4-tetrahydroisoqumolin-7-yl)-4-iso-propoxy-3-trifluoromethyl benzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-chloro-3-methoxybenzamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoqu_nolin-7-yl)-4-/ι-propoxy-3-trifluoromethyl benzamide
N-(2-Methyl-l,2,3,4-tetr__hydroisoquinolin-7-yl)-3-chloro-4-terr-butylbenzamide, hydrochloride N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxybenzamide hydrochloride.
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-fluoro-3-methylbenzamide, hydrochloride
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-wo-propylbenzamide
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethylbenzamide hydrochloride
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-wo-propyl-3-trifluoromethyl- benzamide hydrochloride N-(2-Methyl- 1 ,2,3,4-tetrahydroisoqumolin-7-yl)^ethyl-3-_rifluoromethylbenzainide hydrochloride
N-(2-Methyl-l,2,3,4-tetrahydroiscκιuinolin-7-yl)-3-cyano-4-i_'o-propoxybenzamide hydrochloride N-(l ,23,4-Tet_ hydroisoquinolin-7-yl)-4-methoxy-3-t_ifluoromethylbenzamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methyl-3-methylsulf onyl-benzamide
N-(2-Methyl- 1 ,2,3,4-tet_ahydroisoquinolin-7-yl)-4-ethyl-3-methylsulfonylbenzamide
N-(2-Methyl- 1 ,23,4-tetrahydroisoquinolin-7-yl)-3-methylsulfonyl-4-wo- propylbenzamide N-(2-Methyl-l,2,3,4-te _hydroisoquinolin-7-yl -3-memylsulfonyl-4-meΛoxybenzamide
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-trifluoroacetylbenzamide, hydrochloride
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-pentafluoroethyl- benzamide hydrochloride N-(2-n-Propyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
N-(2-/ι-Propyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3- trifluoromethylbenzamide
N-(2-n-Propyl-l,2,3,4-tetrahydroisquinolin-7-yl)-3-chloro-4-i5o-propoxybenzamide
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-wo-butylbenzamide hydrochloride
N-(2-Methyl- 1 ,23,4-tetrahydroisoquinol_n-7-yl)-4-wo-butyl-3-trifluoromethyl- benzamide hydrochloride
N-(2-Ethyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
N-(2-Ethyl- 1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-4-methoxy-3-trifluoromethyl benzamide N-(2-wo-Propyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
N-(2-wo-Propyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-meΛoxy-3-trifluoromethyl benzamide
N-(2-Methyl-l,2,3,4-tetι^ydroisoquinolin-7-yl)-4-ethoxy-3-methylsulfonyl-benzamide
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-oxochroman-6-carboxamide hydrochloride
N-(2-Formyl~l,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3- trifluoromethylbenzamide
N-(2-Hydroxyethyl-l,2,3,4-tetrahydroisoqumolin-7-yl)-3-bromo-4-eΛoxybenzamide
N-(2-Hydroxyethyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-emylben_amide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-phenylmethoxy-3-trifluoromethyl benzamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-hydroxy-3-trifluoromethyl benzamide N-(2-Methoxyethyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-i_σ- propoxybenzamide
N-(2-Methoxyethyl- 1 ,2 ^-tetr_d_ydroisoquinolin-7-yl)-3-cMoro-4- iso- propoxybenzamide N-(2-Methoxyethyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3- trifluoromethylbenzamide
N-(5-Iodo- 1,2,3 ,4-tetrahydroisoquinolin-7-yl)-4-azidobenzamide, trifluoroacetate N-(2-Methyl-5-trifluoroacetylamino- 1 ,23,4-tetrahydroisoquinolin-7-yl)-3-bromo-4- methoxybenzamide N-(2-Methyl-5-cWoro-l^,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide N-(2-Methyl-5-chloro- 1 ,2,3 ,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide
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.
The above compounds and pharmaceutically acceptable salts thereof, especially the hydrochloride, and pharmaceutically acceptable solvates, especially hydrates, form a preferred aspect of the present invention.
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. However, 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.
It is greatly preferred that 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. 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.
These 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.
For parenteral administration, 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. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, 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. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
Accordingly, 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 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 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) which comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
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 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.
In a further aspect 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 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).
In a further aspect 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 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).
Another aspect of the invention is a process for the preparation of compounds of formula (I), which comprises reacting a compound of formula (H)
Figure imgf000014_0001
where R1A is R1 as defined for formula (I) or a group convertible to R1 and X is as defined in claim 1 with a compound of formula (HI)
Figure imgf000014_0002
where Q is as defined in formula (I), Y is Cl or OH, and R2A groups are independently R2 as defined for formula (I) or groups convertible to R2, and where required converting an R^ or R2A group to a R* or R2 group, converting one R1 or R2 group to another R* or R2 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
Reaction of a compound of formula (HI) which is an acid chloride (Y=C1) will lead directly to the hydrochloride salt Suitable solvents include ethyl acetate or dichloromethane, optionally in the presence of a base such as triethylamine. When the compound of formula (IE) is an aromatic acid (Y=OH), 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 R1 0r R2^ group to a R* or R2 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 R2 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.
Compounds of formula (H) in which X is hydrogen may be prepared from a nitro- tetrahydroisoquinoline of formula (IV).
Figure imgf000015_0001
by reaction with a compound R1AZ where Z is a leaving group such as halogen, especially iodo, or tosylate to obtain an intermediate of formula (V)
Figure imgf000015_0002
which can be reduced, for example using either tin (II) chloride and HCL or hydrogen and a palladium/activated carbon catalyst, to obtain an amino-tetrahydroisoquinoline of formula (II).
When the intended R!A group is methyl, 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.
Compounds of formula (LI) may also be prepared from the corresponding amino- isoquinoline (or its nitro-analogue)of formula (VI)
Figure imgf000016_0001
where RN is NH2 or NO2 by reaction with a compound R1AZ where Z is a leaving group such as halogen, especially iodo, or tosylate to obtain an intermediate of formula (VH)
Figure imgf000016_0002
which can be reduced, for example using sodium borohydride, or hydrogenated, for example using hydrogen and a palladium/activated carbon catalyst, to obtain a tetrahydroisoquinoline of formula (II). When the compound of formula (VH) is replaced by a nitro-isoquinoline, the nitro group is converted to an amino group in the hydrogenation step.
When the intended R1 is hydrogen, 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. When the 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. Most suitably the substituent X is introduced to a compound of formula (H) in which X is hydrogen. For example 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. Alternatively 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.
Where the above described intermediates are novel compounds, they also form part of this invention.
The preparation of compounds of this invention is further illustrated by the following Descriptions and Examples. The utility of compounds of this invention is shown by the Pharmacological Data that follow the Examples.
Description 1 N-2-(4-Nitrophenyl)ethyl-triπuoroacetamide
A solution of trifluoroacetic anhydride (10.6ml) in dichloromethane (100ml) was added dropwise to a stirred solution of 2,6- lutidine (17.44ml) and 4-nitrophenethylamine hydrochloride (15.2g; 75 mmol) at 0°C. The mixture was stirred at 25°C overnight under argon and then washed with dilute citric acid (x2), brine and dried over Na2SO The material in the organic phase gave the title compound as a pale yellow solid (19.04g).
Description 2
7-Nitro-l^_3.4-tetrahydro-2-trifluoroacetylisoquinoline
The nitro compound Dl (2.26g; 9.15 mmol) and paraformaldehyde (0.45g; 14.4 mmol) in acetic acid (10ml) and cone. H2SO4 (15ml) were stirred at 25°C for 20h according to the procedure of G.E. Stokker., TeL Lett, 1996, 37, 5453. Work up afforded the title compound as a white solid (2.17g).
*H NMR (CDC13) δ: 3.10 (2H, m), 3.92 (2H, m), 4.85 + 4.92 (2H, 2xs), 7.38 (1H, t), 8.10 (2H, m); m/z (El): 274 (M+) Description 3 7-Nitro-l,23>4-te_ra_ιydro_soquinoline
The trifluoroacetamide D2 (17.22g; 63 mmol) was hydrolysed at room temperature using a solution of potassium carbonate (46.6g) in 10% aqueous methanol (660ml). Work-up with dichloromethane gave the title compound (llg).
Description 4 2-Methyl-7-nJtro-l,23>4-tetrahydroisoquinoline 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).
m/z (CI): 193 (MH+).
Description 5 7-Amino-2-methyl-l,23>4-tetrahydroisoquinoline
The 7-nitro compound D4 (0.25g; 1.3 mmol) in methanol (40ml) was hydrogenated over 10% palladium on carbon (lOOmg) at atmospheric pressure overnight. The catalyst was removed by filtration through a pad of Kieselguhr and evaporation in vacuo gave the title compound as a white solid (213mg).
m/z (CI): 163 (MH+)
Description 6
7-A_nino-2-(t-butyloxycarbonyI)-1^3.4- tetrahydroisoquinoline 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. Description 7
N-(2-/-Butyloxycaτbonyl-l,23.4-tetrahydroisoquinoline-7-yl)-5-chlorothiophene-2- carboxamide
5-Chlorothiophene-2-carboxylic acid (214mg; 1.3mmol), ethyldimethylaminopropyl carbodiimide (250mg; 1.3mmol) and 1-hydroxybenzotriazole (176mg; 1.3 mmol) in dry DMF (25ml) was stirred at room temperature for 30 min. A solution of the N-boc amine D6 (300mg; 1.21 mmol) in dichloromethane (5ml) was added and the mixture kept at room temperature overnight Work-up gave a pink gum which was chromatographed on Kieselgel 60 in 30% ethyl acetate-hexane. Combination of appropriate fractions gave the title compound as an off white solid (0.5g).
l NMR (400MHz, CDC13) δ: 1.51 (9H, s), 2.82 (2H, t), 3.65 (2H, t), 4.56 (2H, s), 6.95 and 7.37 (2H, ABq), 7.12 (1H, d), 7.28 (1H, s), 7.46 (1H, br).
Description 8
7-Nitro-2-«-propyl-1^3»4-tetrahydroisoquinoline
Nitro compound D3 (1.55g, 8.7mmol) and propionaldehyde (2.52g, 43.5mmol) in 1,2- dichloroethane (50ml) were treated with sodium triacetoxyborohydride (0.28g, 13.1 mmol) and glacial acetic acid (0.6ml, 9.0mmol). The mixture was stirred at 25°C over the weekend and then diluted with dichloromethane (50ml). The mixture was washed with saturated NaHCO3, dried (Na2SO4) and evaporated in vacuo. Chromatography on Kieselgel 60 in ethyl acetate gave the title compound.
Description 9 7-Amino-2-ιι-propyl-1^3>4-tetrahydroisoquinoline
The 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%).
m/z (API+): 191 (MH+; 80%).
Description 10 7-Amino-2-isø-propyl-l,23.4-tetrahydroisoquinoIine
The title compound was prepared from D3 and acetone in 10% overall yield using a method similar to that described in Descriptions 8 and 9. Description 11 7-An_ino-2-ethyl-1^3>4-tetrahydroisoquinoline
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.
Description 12
2-FormyI-7-nitro-l^_3>4-tetrahydroisoquinotine
A mixture of acetic anhydride (1.4ml) and formic acid (0.7ml) was stirred at 50°C for 15 min. After cooling to 0°C, a solution of D3 (1.78g) and 4-dimethylaminopyridine (O.lg) in dichloromethane (30ml) was added and stirring continued at 25°C for 2h. The reaction mixture was washed with aq. potassium carbonate, water, brine and dried (MgSO ). Evaporation in vacuo gave the title compound (2.4g).
*H NMR (250 MHz, CDCI3) δ: 3.0 (2H, m), 3.72(t) and 3.88 (t) (together 2H), 4.68 (t) and 4.80 (t) (together 2H), 7.28-7.40 (IH, m), 8.04 (2H, m), 8.22 (s) and 8.30 (s) (together IH), m/z (API+): 207 (MH+; 80%).
Description 13 7-Amino-2-formyl-1^3»4-tetrahydroisoquinoline The compound D12 (2.3g) was dissolved in ethanol (50ml) and shaken at room temperature and 50psi with hydrogen in the presence of 5% Pd C catalyst (0.8g). Filtration and evaporation then provided the title compound as a white solid (1.6g).
*H NMR (250 MHz, dg-DMSO) δ: 2.55(t) and 2.59(t) (together 2H), 3.56 (2H, t), 3.39 (s) and 3.41(s) (together 2H), 6.35-6.45 (2H, m), 6.79 (IH, d), 8.15 (s) and 8.18 (s) (together IH), m/z(API+): 177 (MH+).
Description 14 2-(2-tert-Butyldimethylsilyloxyethyl)-7-nitro-1^.3>4-tetrahydrodisoqι_inoIine 7-Nitro-tetrahydroisoquinoline (5.0g; 28.0mmol) was dissolved in DMF (150ml). This solution was treated with (2-bromoethoxy)-ter_-butyl-d_methylsilane (12.0ml; 56.0mmol), and stirred at 80°C overnight The mixture was cooled to room temperature and the solvent removed in vacuo. Purification by column chromatography through SiO2, eluting with 50% diethyl ether/petroleum ether gave the title compound (4.2g, 44%). iH NMR (250 MHz; CDCI3) δ: 0.00 (6H, s), 0.83 (9H, s), 2.66 (2H, t, J = 6 Hz), 2.79 (2H, t J = 6 Hz), 2.90 (2H, t J = 6 Hz), 3.71 (2H, s), 3.77 (2H, t J = 6 Hz), 7.16 (IH, d, J = 9 Hz), 7.82 (IH, d, J = 2 Hz), 7.89 (IH, dd, J = 9, 2 Hz).
Description 15 7-Amino-2-(2-tert-butyldimethylsilyloxyethyl)-1^3.4-tetrahydroisoquinoline
2-(2-te/ -Butyldimethylsilyloxyethyl) compound D14 (2.88g; 8.57mmol) and 10% Pd/C (0.5g, 60% paste in water) in methanol (100ml) was hydrogenated in a manner similar to that of Description 5 to give the title compound (2.62g).
lH NMR (250 MHz, CDCI3) δ: 0.00 (6H, s), 0.83 (9H, s), 2.61 (2H, t, J = 6 Hz), 2.71 (4H, s, overlapping signals), 3.55 (2H, s), 3.77 (2H, t J = 6 Hz), 6.27 (IH, d, J = 2 Hz), 6.43 (IH, d, J = 8 Hz), 6.80 (IH, d, J = 8 Hz).
Description 16
2-(_ tert-ButyIdimethylsilyloxyethyl)-l^,3>4-tetrahydro-isoquinolin-7-yl)-3-broino- 4-ethoxy benzamide
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%).
AH NMR (250 MHz; CDCI3) δ: 0.0 (6H, s), 0.82 (9H, s), 1.42 (3H, t, J = 7 Hz), 2.80
(2H, t J = 5 Hz), 2.91 (2H, t J = 5 Hz), 2.95 (2H, t J = 4 Hz), 3.81 (2H, s), 3.87 (2H, t J = 6 Hz), 4.08 (2H, q, J = 7 Hz), 6.84 (IH, d, J = 9 Hz), 7.00 (IH, d, J = 8 Hz), 7.29 (2H, d, J = 8 Hz), 7.33 (IH, s), 7.77 (IH, dd, J = 9, 2 Hz), 8.00 (IH, d, J = 2 Hz).
Description 17 7-Amino-2-(2-methoxyethyl)-l,23,4-tetrahydroisoquinoline
*H NMR (250 MHz; CDCI3) δ: 2.74 (6H, m), 3.38 (3H, s,), 3.60 (4H, m), 3.20 - 3.70 (2H, br), 6.37 (IH, s), 6.50 (IH, dd, J = 8, 2 Hz), 6.88 (IH, d, J = 8 Hz). Description 18 5-Iodo-7-nitro-l,23,4-tetrahydroisoqiiinoline
The nitro compound of Description 3 (750mg; 3.9mmol) and N-iodosuccinimide (1.13g) in triflic acid (5ml) was stirred at 25°C overnight The mixture was poured cautiously into saturated NaHCO3 and then extracted into ether (2x). The combined organic extracts were washed with aqueous sodium thiosulfate, dried (MgSO ) and evaporation in vacuo gave a residue. Chromatography on Kieselgel 60 in 2% methanol - dichloromethane gave the title compound (650mg).
Description 19
7-Aπύno-5-iodo-l,23>4-tetrahydroisoquinoline
A solution of the nitro compound D18 (650mg, 2.14mmol) in ethanol (20ml) at 50°C was treated with a solution of tin (H) chloride (1.42g) in c. HCl (3ml). The resultant yellow solution was basified with 10% aqueous sodium hydroxide and the product extracted into dichloromethane. Flash chromatography on Kieselgel 60 (5% methanol - dichloromethane) gave the title compound (428mg; 73%).
Description 20 7-Amino-5-iodo-2-(_ert-butoxycarbonyl)-l,23,4-tetrahydroisoquinoline The iodoamine D 19 (580mg, 2.12mmol) in DMF (30ml) was treated with DMAP (20mg) and di-terr-butyl-dicarbonate (466mg, 2.13mmol) and the solution was stirred at room temperature overnight The reaction mixture was evaporated to dryness in vacuo. Chromatography on Kieselgel 60 (2% methanol - dichloromethane) gave the title compound (745mg; 94%).
Description 21
5,7-Dinitr o-l,23.4- tetrahydroisoquinoline
5-Nitro-13.3,4-tetrahydroisoquinoline (l.Og, 5.6mmol) in cone, sulfuric acid (3ml) was treated with cone, nitric acid (1ml) and the mixture stirred at room temperature for lh. The mixture was cooled, basified with 40% aqueous NaOH and work-up with dichloromethane gave the title compound (1.14g).
Description 22
5,7-Dinitro-2-methyl-1^3>4- tetrahydroisoquinoline The amine D21 (1.8g) in formic acid (5ml) and paraformaldehyde (7ml) were reacted in a similar manner to that of Description 2 to give the title compound (1.74g, 91%). *H NMR (CDCl3)δ: 2.51 (3H, s), 2.75 (2H, t), 3.27 (2H, t), 3.75(2H, s), 8.16 (IH, d, J = 2Hz), 8.66 (IH, d, J = 2Hz); /z (Cl): 238.1(MH+; 100%).
Description 23 5-Amino-7-nitro-2-methyl-1^3»4-tetrahydroisoquinoline
The dinitro compound D22 (1.7g) was reduced with tin(H)chloride (5.42g) in a manner similar to that of Description 19 to give the title compound (0.6g).
Description 24 5-Trifluoroacetylamino-7-nitro-2-methyl-1^3.4-tetrahydroisoquino_ine
The amine D23 (0.5g) in dichloromethane (10ml) and triethylamine (1.5eq) was treated with trifluoroacetic anhydride (l.leq) and the mixture stirred at 25°C for 3h. Work-up with dichloromethane followed by chromatography on Kieselgel 60 in 3%- methanol:dichloromethane gave the title compound (0.7g, 96%).
/z (Cl): 304 (MH+; 80%).
Description 25 7-Amino-5-trifluoroacetylamino-2-methyl-1^3.4-tetrahydroisoquinoline The nitro compound D24 (0.7g, 2.28mmol) in ethanol (20ml) was hydrogenated over 10% Pd/C (70mg). The catalyst was removed by filtration through Celite and evaporation in vacuo gave the title compound as a pale solid (0.6g, 93%).
Description 26 5-Chloro-7-nitro-2-methyl-l,23,4-tetrahydroisoquinoline
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.
!H NMR (CDCl3)δ: 2.32 (3H, s), 2.61 (2H, t), 2.79 (2H, t), 3.57(2H, s), 7.96 (IH, d, J = 2Hz), 8.08 (IH, d, J = 2Hz). Description 27 7-Amino-5-chloro-2-methyl-1^3.4-tetrahydroisoquinoline
The nitro D26 (0.80g, 3.5mmol) in ethanol (70ml) and cone. HCl (7ml) was heated to 50°C and tin(H)chloride (2.66g, 14mmol) was added. The mixture was heated for 15min and allowed to cool; work-up similar to that described in Description 19 gave the title compound as a yellow oil (0.48g).
iH NMR (CDCl3)δ: 2.42 (3H, s), 2.64 (2H, m), 2.77 (2H, m), 3.45(2H, d), 6.27 (IH, d, J = 2Hz), 6.59 (IH, d, J = 2Hz).
Preparation 1 3-Bromobenzyl TBMS ether
To a solution of 3-bromobenzyl alcohol (5.00g, 0.027mole) in dichloromethane (30ml) and Et3N (4.2ml, 0.03 mole) was added a 1M solution tert-butyldimethylsilyl chloride in dichloromethane (28.0ml) dropwise. The mixture was allowed to stir at room temperature overnight then water (30ml) was added. The organic layer was washed with brine, dried (Na2SO4) and evaporated to give a red oil which was purified by flash chromatography on silica gel using 20% ether in hexane to give a colourless oil (8.0g).
Preparation 2
3-PivaloyIbenzylaIcohoI TBDMS Ether n-Butyllithium (2.80ml, 7.00mmol, 2.5M in hexane) was slowly added to a solution of Preparation 1 TBDMS ether (1.80g, ό.Ommol) in dry THF (10ml) over 5 min at -78°C. The reaction mixture was maintained under argon at -78°C for lh. and N,O-dimethyl- hydroxy pivaloyl amide (0.86g, 6.60mmol) in THF (2ml) was added dropwise with stirring at -78°C. The resulting mixture was allowed to stir at -78°C for 2.5h, quenched with NH4CI solution and allowed to warm to room temperature. The mixture was extracted with ether (2x50ml), the combined organics were dried (Na2SO4) and concentrated in vacuo to give the title compound as a colourless oil (1.75g
m/z (API+): 307 (MH+; 8%).
Preparation 3 3-PivaIoylbenzylalcohol The ether of Preparation 2 (1.47g, 4.80mmol) was dissolved in methanol (25ml); cone. HCl (20 drops) was added and the whole allowed to stir at room temperature for 4h. Saturated NaHCO3 solution was added and the mixture extracted with ether (2x50ml). The organic layer was dried over sodium sulfate and evaporation in vacuo gave title compound as a colourless oil (0.80g).
m/z (API+): 193 (MH+; 17%).
Preparation 4 3-Pivaloyl benzoic acid
3-Pivaloylbenzyl alcohol (0.80g, 4.16mmol) was dissolved in dioxane (20ml). A solution of KOH (0.35g, 6.30mmol) in water (5ml) was added followed by KMnθ4 (1.45g, 9.17 mmol). The mixture was stirred at room temperature over the weekend. The solution was filtered through Celite and extracted with ether. The aqueous phase was acidified with dil. HCl and extracted with ether (3x50ml). The organic layer was dried over magnesium sulphate and concentrated in vacuo to afford the title compound as a white solid (0.80g).
lH NMR (250MHz, CDCl3)δ: 1.38 (9H, s), 7.55 (IH, t), 7.92 (IH, d, J = 6.5Hz), 8.20 (IH, d, J = 6.5Hz), 8.44 (IH, s).
Preparation 5 3-Trifluoroacetylbenzoic acid
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.
m/z (API-): 217 (M-H+; 20%).
Preparation 6
Methyl 3-Chloro-4-i.ø-propo__ybenzoate
Methyl 3-chloro-4-hydroxybenzoate (5g, 26.8mmol) in DMF (45ml) was treated with potassium carbonate (7.41g, 53.6mmol), 2-iodopropane (3.85ml, 40.2mmol) and then stirred at 25°C for 18h. Work-up with ethyl acetate gave the title compound (6.1g).
Preparation 7 3-Chloro-4-£sø-propoxybenzoic acid
Methyl 3-chloro-4-irø-propoxybenzoate (5.5g, 24.1mmol) was hydrolysed using 1M NaOH (36ml) in methanol (80ml). Extraction and work-up with ethyl acetate gave the title compound (4.3g).
'H NMR (DMSO-D6) δ: 1.33 (6H, d), 4.79 (IH, m), 7.24 (IH, d), 7.87 (2H, m). Preparation 8 3-Bromo-4-ethoxybenzoic acid
The title compound was prepared from 4-ethoxybenzoic acid in a manner similar to that of Procedure 1.
Η NMR (DMSO-D6) δ: 1.45 (3H, t J = 7 Hz), 4.26 (2H, q, J = 7 Hz), 7.26 (IH, d, J = 9 Hz), 7.98 (IH, dd, J = 2, 9 Hz), 8.12 (IH, d, J = 2 Hz)
Preparation 9
3-Bromo-4-ethylbenzoic acid
The title compound was prepared from 4-ethylbenzoic acid.
!H NMR (DMSO-D6) δ: 1.20 (3H, t, J = 7 Hz), 2.78 (2H, q, J = 7Hz), 7.50 (IH, d, J = 8 Hz), 7.90 (IH, dd, J = 2, 8 Hz), 8.07 (IH, d, J = 8 Hz
Preparation 10 3-Cyano-4-isø-propylbenzoic acid
The title compound was prepared from 4-wo-propylbenzoic acid similar to that described in Procedure 5.
Η NMR (DMSO-D6) δ: 1.07 (6H, d, J = 7 Hz), 3.13 (lH,m, overlapped), 7.48 (IH, d, J = 7 Hz), 7.96 (IH, dd, J = 2, 8 Hz)), 8.00 (IH, d, J = 2 Hz).
Preparation 11 4-Metho__y-3-trifluoroπ_ethylbenzoic acid
The title compound was prepared from 3-bromo-4-methoxybenzoic acid and potassium trifluoroacetate in a manner similat to that of Procedures 3 and 4.
Η NMR (DMSO-D6) δ: 3.78 (3H, s), 7.18 (IH, d, J = 9 Hz), 7.90 (IH, d, J = 2 Hz), 8.00 (IH, dd, J = 2, 9 Hz), 12.70 - 13.10 (IH, br.exchangeable)
Preparation 12 4-Methoxy-3-trifluoromethylbenzoyl chloride
The title compound was prepared from 4-methoxy-3-trifluoromethylbenzoic acid with oxalyl chloride and DMF in chloroform at room temperature [D. Levin, Chem. Br., 1977, 20] followed by evaporation in vacuo. Preparation 13
Methyl 3-Bromo-4-_sø-propoxybenzoate
Methyl 3-bromo-4-hydtOxybenzoate (2.5g, 10.8mmol) in DMF (35ml) was treated with potassium carbonate (3.0g, 21.6mmol), 2-iodopropane (2.76, 21.6mmol) and then stirred at 25°C for 48h. Work-up with ethyl acetate gave the title compound (3.0g).
1H NMR (250MHz, CDCI3) δ: 1-41 (6H, d, J=7 Hz), 3-89 (3H, s), 4.66 (IH, m), 6-90 (IH, d, J = 8 Hz), 7.93 (IH, dd, J = 8, 2 Hz), 8-22 (IH, d, J = 2 Hz)
Preparation 14
Methyl 3-Cyano-4-isø-propoxybenzoate
Methyl 3-bromo-4-wø-propoxybenzoate (2.0g, 7.3mmol) and copper(I)cyanide in N- methyl pyrrolidone (50ml) were heated under vigorous reflux for 4h. Work-up with ethyl acetate gave the title compound (l.Og).
1H NMR (250MHz, CDCI3) δ: 1-56 (6H, d, J=7 Hz), 4.05 (3H, s), 4.88 (IH, m), 7.13 (IH, d, J = 8 Hz), 8.31 (IH, dd, J = 8, 2 Hz), 8-38 (IH, d, J = 2 Hz)
Preparation 15
Methyl 3,5 Dichloro-4-ethoxybenzoate
The title compound was prepared in 69% yield from methyl 3,5-dichloro-4- hydroxybenzoic acid and iodoethane in a manner similar to that of Preparation 6.
1H NMR (250MHz, CDCI3) δ: 1-47 (3H, t J=7 Hz), 3.91 (3H, s), 4.16 (2H, q, J = 7 Hz), 7.96 (2H, s).
Preparation 16 3-Methanesulfony_-4-£_ø-propylbenzoic acid 3-Chlorosulfonyl-4-tsø-propylbenzoic acid (2.62g, lOmmol) [made from 4-iso-propyl benzoic acid in a manner similar to that described in Procedures 7 and 8] was added slowly to a slurry of NaHCO3 (2.52g, 30mmol) and Na2SO3 (1.26g lOmmol) in water (9ml) at 75°C. The mixture was stirred for lh and tiien treated with bromoacetic acid (2.08g, 15mmol) and NaOH (0.60g, 15mmol). The temperature was raised to 105°C and the mixture heated at reflux for 24h. The mixture was cooled, acidified to pH 1 and die resultant precipitate collected, washed and dried to give the title compound (1.43g, 59%). 1H NMR (250MHz, acetone-D6) δ: 1-24 (6H, d, J=7 Hz), 3.13 (3H, s), 3.88 (IH, m), 7.72 (IH, d, J = 7 Hz), 8.15 (IH, dd, J = 7 Hz), 8.52 (IH, d, J = 2 Hz).
Preparation 17 Methyl-3-rnethanesulfonylbenzoic acid
Prepared in 30% overall yield in a manner similar to that of Preparation 16.
1H NMR (250MHz, acetone-D6) δ: 2.57 (3H, s), 2.99 (3H, s), 7.39 (IH, d, J = 7 Hz), 7.97 (IH, dd, J = 7, 2 Hz), 8.39 (IH, d, J = 2 Hz).
Preparation 18
4-Ethyl-3-methanesulfonylbenzoic acid
Prepared in 44% overall yield in a manner similar to that of Preparation 16.
1H NMR (250MHz, acetone-D6) δ: 1.22 (3H, t, J = 7 Hz), (3H, s), 3.05 (2H, q, J = 7 Hz), 3.12 (3H, s), 7.57 (IH, d, J = 7 Hz), 8.13 (IH, dd, J = 7, 2 Hz), 8.51 (IH, d, J = 2 Hz).
Preparation 19 3-Met_ιanesulfonyl-4-metho__ybenzoic acid Prepared in 20% overall yield in a manner similar to that of Preparation 16.
1H NMR (250MHz, acetone-D6) δ: 3.00 (3H, s), 3.89 (3H, s), 7.17 (IH, d, J = 7 Hz), 8.06 (IH, dd, J = 7, 2 Hz), 8.31 (IH, d, J = 2 Hz).
Preparation 20
4-Ethoxy-3-methanesulfonylbenzoic acid
Prepared in 20% overall yield in a manner similar to that of Preparation 16.
1H NMR (250MHz, acetone-D6) δ: 1.44 (3H, J = 7 Hz), (3H, s), 3.30 (3H, s), 4.35 (2H, q, J = 7 Hz), 7.40 (IH, d, J = 7 Hz), 8.20 (IH, dd, J = 7, 2 Hz), 8.37 (IH, d, J = 2 Hz).
Preparation 21 3-Chloro-4-ethoxybenzoic acid
!H NMR (DMSO-D6) δ: 1.39 (3H, t J = 7 Hz), 4.20 (2H, q, J = 7 Hz), 7.22 (IH, d, J = 7 Hz), 7.87 (2H, m). Preparation 22 4-isø-Propylθ-_y-3-trifluoromethylbenzoic acid
Methyl 3-bromo-4-wø-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 HjO (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,S2O3, H,O, saturated brine, dried
(MgSO4) and evaporated in vacuo to give a brown oil. This was dissolved in MeOH (ca 20ml) and treated with 2M NaOH (2ml; 4 mmol) and the resulting solution heated at reflux for 3h. The volatiles were removed in vacuo and the residue partitioned between EtOAc and I O. The phases were separated, the aq. phase acidified to pHl with 2M HCl in the presence of EtOAc and the phases separated. The aq. phase was further extracted with EtOAc, the extracts combined, washed with HjO, saturated brine, dried (MgSO ) and evaporated to dryness in vacuo to give the title compound as a white solid (671mg; 89%).
*H NMR (250MHz; (CD3)2CO) δ: 1.02 (6H, d, J = 6 Hz), 4.53 - 4.63 (IH, m), 7.01 (IH, d, J = 9 Hz), 7.85 - 7.88 (2H, m); . (API): 205.0 [M-Pr1].
Preparation 23 4-Ethyl-3-trifluoromethylbenzoic acid Prepared as described in Preparation 22 from methyl 4-ethyl-3-bromobenzoate (1.10g; 4.52 mmol) and isolated as a white solid (923mg; 93%).
*H NMR (250MHz; (CD3)2CO) δ: 0.98 (3H, t J = 7 Hz), 2.60 (2H, q, J = 7 Hz), 7.36 (IH, d, J = 8 Hz), 7.89 and 7.93 (IH, m), 7.96 (IH, br s); . (API): 217.1 [M-H].
Preparation 24
4-«-Propy_o__y-3-trifluoromethylbenzoic acid
Prepared as described in Preparation 22 from methyl 3-bromo-4-/ι-ρropyloxybenzoate (1.43g; 5.23 mmol) and isolated as a white solid (1.18g; 91%).
'H NMR (250MHz; (CD3)2SO) δ: 1.09 (3H, t J = 7 Hz), 1.79 - 1.93 (2H, m), 4.26 (2H, t J = 6 Hz), 7.45 (IH, d, J = 9 Hz), 8.19 (IH, d, J = 2 Hz), 8.25 and 8.28 (IH, dd, J = 9, 2 Hz); , (API): 203.1 [M-COJEfl. Preparation 25 4-/-ButyI-3-trifluoromethylbenzoic acid
Prepared as described in Preparation 22 from methyl 3-bromo-4-t-butylbenzoate (2.46g; 9.1 mmol) and isolated as a white solid (1.55g; 69%).
'H NMR (250MHz; (CD3)2SO) δ: 1.42 (9H, s), 7.86 - 7.90 (IH, m), 8.09 - 8.13 (IH, m), 8.23 (IH, d, J = 2 Hz); 7, (API): 245.1 [M-H].
Preparation 26 4-Oxochroman-6-carboxylic acid
3-(4-Carboxyphenoxy)propionic acid (2.5g) [prepared according to the procedure of J. Lichtenberger and R. Geyer. Bull. Soc. Chim. Fr., 1963275] in cone, sulfuric acid (20ml) was heated to 100°C for 4h and then poured onto crushed ice. The resultant precipitate was filtered and dried in vacuo to give the title compound (1.6g).
Η NMR (DMSO-D6) δ: 2.99 (2H, t J = 7 Hz), 4.77 (2H, J = 7 Hz), 7.28 (IH, d, J = 8 Hz), 8.21 (lH,dd, J = 8, 2 Hz), 8.46 (IH, d, J = 2 Hz).
Preparation 27 3-Bromo-4-£sø-propoxybenzoic acid
The title compound was prepared using a method similar to that of Preparation 7.
*H NMR (DMSO-D6) δ: 1.29 (6H, d, J = 7 Hz), 4.77 (IH, sep, J = 7 Hz), 7.20 (IH, d, J =
8 Hz), 7.87 (IH, dd, J = 8, 2 Hz), 8.02 (IH, d, J = 2 Hz), 12.92 (IH, brs).
Preparation 28
4-Azidobenzoic acid
To a solution of 4-aminobenzoic acid (2.00g, 14.00mmol) in trifluoroacetic acid (10ml) at
5°C, was added sodium nitrite (3.50g) portionwise, and the mixture allowed to stir for 30 min. Sodium azide (3.79g,) was then added portionwise and the mixture stirred for a further 30 min at 0°C. The mixture was diluted with water, and a white solid precipitated.
The solid was filtered, washed with cold water and dried, to afford the title compound
(1.66g, 73%).
Procedure 1
5-Bron_o-2,4-dimethoxybenzoic acid
To a solution of 2,4-dimethoxybenzoic acid (4.0g, 0.022mol) in chloroform (60ml) was added bromine (1.13ml, 0.022mol) in chloroform (20ml) dropwise. After stirring overnight at room temperature the precipitate was filtered off and dried to afford the title compound as a white solid (2.87g).
Procedure 2 5-Bromo-4-£sø-propyl-2-methoxybenzoic acid
To a solution of 2-methoxy-4-£_ø-propyl benzoic acid (7.0g, 36.0 mmol) in chloroform (100 ml) was added bromine (1.86 ml) in chloroform (20 ml) dropwise. The reaction was stirred at room temperature overnight Evaporation in vacuo afforded an oil (9.27g).
7Z (Cl): 275, 273 (MH+; 70%).
Procedure 3
Methyl 5-bromo-4-i_ø-propyl-2-methoxy benzoate
5-Bromo-4-wø-propyl-2-methoxybenzoic acid (9.268g 34.0 mmol) was dissolved in methanol (250 ml) and cone. H2SO4 (2 ∞l added. The mixture was refluxed for 5h and concentrated in vacuo. Residual material was taken up into ethyl acetate and water, and the organic layer, dried (MgSO4). Concentration in vacuo afforded an oil, which was purified by Biotage Column Chromatography on silica gel using 10% ether in hexane to give an oil (5.5g).
Procedure 4
2,4-Dimethoxy-5-trifluoromethy_benzoic acid
2,4-Dimethoxy-5-bromobenzoic acid methyl ester (1.5g; 5.4 mmol) in DMF (25ml) and toluene (8ml) under argon was treated with potassium trifluoroacetate (1.53g; 10.1 mmol) and copper (I) iodide (2.1g, 10.9 mmol). The mixture was heated to 170°C witii removal of water (Dean/Stark), and then at 155°C overnight The mixture was allowed to cool, poured into ether and water and filtered through Kieselguhr. The organic layer was dried (Na2SO4) and concentrated in vacuo to give a brown solid. Chromatography on Kieselgel 60 with 1:1 ether/petrol gave a solid (1.03g) which was hydrolysed in 1:1 methanolic: aqueous NaOH (50ml) at 50°C. Work-up gave the title compound as a white solid (lg).
Procedure 5a
Methyl 2-methoxy-5-cyano-4-i_ø-propylbenzoate
Copper (I) cyanide (550mg, όmmol) was added to a solution of methyl 2-methoxy-5- bromo-4-isø-propylbenzoate (861mg) in N-methyl-2-pyrrolidinone (30ml). The mixture was stirred under argon and boiled under reflux for 4h. The mixture was cooled, poured into excess ice/water and ethyl acetate and filtered. The organic phase was separated, washed with water, brine and dried(MgSO4). Evaporation gave a crude brown solid which was purified by chromatography on silica gel eluting with ethyl acetate/ n-hexane (1:4). The product was obtained as a white solid (523 mg).
Η NMR (250MHz, CDCI3) δ: 1-33 (6H, d, J=7Hz), 3-38 (IH, sep, J=7Hz), 3-89 (3H, s), 3-98 (3H, s), 6-91 (IH, s), 8-08 (IH, s); m/z (API+): 234 (MH+, 30%).
Procedure 5b 2-Methoxy-5-c ano-4-isø-propyIbenzoic acid
2N NaOH (l-25ml) was added to a solution of the methyl ester P5a (490mg) in methanol (10ml). The solution was stirred overnight at room temperature. The solution was then diluted with water, concentrated in vacuo and washed with ethyl acetate. The aqueous phase was then acidified with 2N HCl and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4) and evaporated to dryness giving the product as a white solid (418mg). Η NMR (250MHz, CDCI3) δ: 1-35 (6H, d, J=7Hz), 3-43 (IH, sep, J=7Hz), 4- 14 (3H,s), 7-00 (IH, s), 8-41 (IH, s); m/z (API+): 220 (MH+, 100%).
Procedure 6a
Ethyl 2-ethoxy-4-i_ø-propyl-5-cyanobenzoate Ethyl 2-ethoxy-4-wσ-propyl-5-bromobenzoate (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).
Η NMR (250MHz, CDCI3) δ: 1.12 (6H, d, J=7Hz), 1.30 (3H, t J=7Hz), 1.84 (3H, t J=7Hz), 3.17 (IH, sep, J=7Hz), 3.99 (2H, q, J=9Hz), 4.16 (2H, q, J=7Hz), 6.69 (IH, s), 7.86 (IH, s); m/z (API+): 262 (MH+, 100%).
Procedure 6b 2-Ethoxy-4-£_ø-propyl-5-cyanobenzoic acid The ester P6a (370mg, 1.41mmol) was dissolved in methanol (5ml) and over a 24 h period IN NaOH (2.1ml, 2.1mmol) was added. The solution was concentrated under vacuum, diluted with water and washed with ethyl acetate. The aqueous phase was acidified with 2N HCl and extracted with ethyl acetate. The extract was washed with brine, dried (Mg SO4) and evaporated to give die title acid (306 mg).
Η NMR (250MHz CDCI3) δ: 1.39 (3H, d, J=7Hz), 1.66 (3H, t J=7Hz), 3.47 (IH, sep, J=7Hz), 4.46 (2H, q, J=7Hz), 7.03 (IH, s), 8.47 (IH, s); /z (API+): 234 (MH+, 100%). Procedure ? 4-Ethoxy-2-methoxy-5-methyIsulfonylbenzoic acid
4-Ethoxy-2-methoxy-5-chlorosulfonyl benzoic acid was prepared in 49% yield using the procedure of M.W. Harrold et al., J. Med. Chem., 1989, 32874. This was used according to the method of R.W. Brown, J. Org. Chem., 1991, 56, 4974, to the title compound in 19% yield.
Η NMR (DMSO-D6) δ: 1.30 (3H, t), 3.10 (3H, s), 3.83 (3H, s), 4.24 (2H, q), 6.73 (IH, s), 8.07 (IH, s).
Procedure 8
4-isø-Propyl-2-methoxy-5-methylsulfonylbenzoic acid
This was prepared in a similar manner to the procedure of C. Hansch, B. Schmidhalter,
F. Reiter, W. Saltonstall . J. Org. Chem., 1956, 21, 265 to afford the intermediate 5- chlorosulfonyl-4-isopropyl-2-methoxybenzoic acid which was converted into the title compound using the method of Procedure 7.
'H NMR (DMSO-D6) δ: 1.30 (6H, d), 3.21 (3H, s), 3.80 (IH, m), 3.94 (3H, s), 7.26 (IH, s), 8.19 (lH, s).
Example 1
N-(1^3»4-Tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-carboxaniide, monotrifluoroacetate
The N-boc amine D7 (0.48g; 1.22 mmol) in dichloromethane (25ml) containing trifluoroacetic acid (2ml) was kept at 25°C for 18h. Evaporation in vacuo followed by crystallisation of the residue from ethyl acetate - ether gave the title compound as off- white crystals (0.46g; 92%), m.p. 153-5°C.
l NMR (400MHz, DMSO-d δ: 2.96 (2H, t), 3.38 (2H, t), 4.29 (2H, s), 7.23 (IH, d), 7.28 (IH, d, ABq), 7.51 (IH, dd), 7.63 (IH, d), 7.90 (IH, d, ABq), 9.01 (2H, br, s), 10.33 (IH, s); m/z (Cl): 293 (MH+; 100%).
Example 2 N-(2-MethyI-tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-carboxanιide
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.
H NMR (250MHz, CDCl3)δ: 2.46 (3H, s), 2.69 (2H, t), 2.89 (2H, t), 3.54 (2H, s), 6.93 and 7.37 (2H, ABq), 7.07 (IH, d), 7.25 (IH, dd), 7.34 (IH, d), 7.63 (IH, br, s); /z (Cl): 307 (MH+; 100%).
Example 3 N-(2-Methyl-l,23>4-tetrahydroisoquinolin-7-yl)benzamide
The N-methyl amine D5 in dichloromethane (25ml) containing triethylamine (0.5ml) was treated with benzoyl chloride and the mixture kept at 25°C for 18h. Normal work-up gave the product which was chromatographed on Kieselgel 60 by gradient elution in ethyl acetate±exane. Combination of appropriate fractions gave the title compound.
H NMR (250MHz, CDCtyδ: 2.46 (3H, s), 2.69 (2H, t), 2.91 (2H, t), 3.58 (2H, s), 7.10 (IH, d), 7.30 (IH, dd), 7.40 - 7.60 (4H, overlapping m), 7.75 (IH, br s), 7.87 (2H, m).
The following Examples were made using procedures similar to the methods described earlier.
Example 4 N-(2-MethyM^3.4-tetrahydroisoquinoIin-7-yl)-3-chlorobenzamide
!H NMR (250MHz, CDCtyδ: 2.46 (3H, s), 2.68 (2H, t), 2.90 (2H, t), 3.57 (2H, s), 7.10 (IH, d), 7.29 (IH, dd, overlapping with CHCI3), 7.39 (IH, s), 7.42 (IH, d), 7.52 (IH, m), 7.73 (IH, m), 7.83 (2H, m).
Example 5
N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yI)-4-t-butylbenzamide
iH NMR (250MHz, CDCl3)δ: 1.34 (9H, s), 2.44 (3H, s), 2.68 (2H, t), 2.89 (2H, t), 3.55 (2H, s), 7.07 (IH, d), 7.29 (IH, dd overlapping with CHCI3 signal), 7.38 - 7.53 (3H, m, overlapping signals), 7.75 - 7.90 (3H, m, overlapping signals). Example 6 N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yI)-4-i$ø-propoxybenzan_ide
iH NMR (250MHz, CDCl3)δ: 1.38 (6H, d), 2.46 (3H, s), 2.69 (2H, t), 2.90 (2H, t), 3.58 (2H, s), 4.64 (IH, septet), 6.94 (2H, m), 7.09 (IH, d), 7.23 - 7.34 (IH, m, overlapping CHC13), 7.42 (IH, s), 7.70 (IH, br s), 7.81 (2H, m); m/z (Cl): 325 (MH+, 100%).
Example 7 N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-4-phenoxybenzamide
iH NMR (250MHz, CDCl3)δ: 2.46 (3H, s), 2.69 (2H, t), 2.91 (2H, t), 3.59 (2H, s), 7.00 - 7.50 (10H, overlapping m), 7.72 (IH, br s), 7.83 (2H, m).
Example 8 N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-4-nitrobenzamide
!H NMR (CDCl3)δ: 2.45 (3H, s), 2.70 (2H, m), 2.90 (2H, m), 3.60 (2H, s), 7.10 (2H, dd), 7.25 (IH, dd), 7.40 (IH, d), 8.00 (2H, dd), 8.35 (2H, dd), 7.80 (IH, s). m/z (CI): 312 (MH+, 70%).
Example 9 N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-4-phenylbenzaπιide
!H NMR (CDCl3)δ: 2.45 (3H, s), 2.70 (2H, m), 2.90 (2H, m), 3.60 (2H, s), 6.30 (IH, d), 6.50 (IH, dd), 6.90 (IH, dd), 7.10 (IH, d), 7.40 (2H, m), 7.60 (IH, dd), 7.70 (IH, dd), 7.80 (IH, s), 7.90 (IH, d), 8.05 (IH, s); m/z (Cl): 343 (MH+; 90%).
Example 10 N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-3-methylbenzamide
*H NMR (CDCl )δ: 2.43 (3H, s), 2.47 (3H, s), 2.70 (2H, t), 2.90 (2H, t), 3.60 (2H, s), 7.05 (IH, dd), 7.30 (IH, m), 7.35 (2H, m), 7.45 (IH, s), 7.65 (3H, m). /z (CI): 281 (MH+; 90%). Example 11 N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-3-fluorobenzamide
iH NMR (CDCl )δ: 2.50 (3H, s), 2.75 (2H, t), 2.90 (2H, t), 3.65 (2H, s), 7.10 (IH, dd), 7.28 (2H, m), 7.40 (2H, m), 7.60 (2H, m), 7.75 (IH, s); m/z (Cl): 285 (MH+; 100%).
Example 12 N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-3-cyanobenzamide
*H NMR (CDCl )δ: 2.47 (3H, s), 2.70 (2H, t), 2.90 (2H, t), 3.60 (2H, s), 7.12 (IH, dd), 7.30 (IH, m), 7.40 (IH, s), 7.65 (IH, dt), 7.80 (2H, m), 8.10 (IH, d), 8.15 (IH, s). /z (Cl): 292 (MH+).
Example 13 N-(2-MethyI-l^_3»4-tetrahydroisoquinolin-7-yI)-3,4-dichlorobenzamide
iH NMR (CDCl )δ: 2.50 (3H, s), 2.80 (2H, t), 2.90 (2H, t), 3.70 (2H, s), 7.10 (IH, d), 7.30 (IH, dd), 7.40 (IH, s), 7.55 (IH, d), 7.70 (IH, dd), 8.00 (2H, m). /z (Cl): 335 (MH+).
Example 14 N-(2-MethyM^3.4-tetrahydroisoquinolin-7-yl)-4-iodobenzamide
*H NMR (CDCl3)δ: 2.47 (3H, s), 2.71 (2H, t), 2.89 (2H, t), 3.58 (2H, s), 7.10 (IH, d), 7.30 (IH, m), 7.43 (IH, s), 7.60 and 7.85 (4H, ABq), 7.82 (IH, s). m/z (Cl): 393 (MH+; 100%).
Example 15 N-(2-MethyI-1^3.4-tetrahydroisoquinolin-7-yl)-4-bromobenzanιide
iH NMR (CDCl3)δ: 2.47 (3H, s), 2.71 (2H, t), 2.89 (2H, t), 3.60 (2H, s), 7.10 (IH, d), 7.30 (IH, m), 7.43 (IH, s), 7.64 and 7.74 (4H, ABq), 7.70 (IH, s). m/z (Cl): 347, 345 (MH+; 100%). Example 16 N-(2-Methyl-1^3,4-tetrahydroisoquinolin-7-yl)-4-methylbenzamide
H NMR (CDCl3)δ: 2.44 (3H, s), 2.48 (3H, s), 2.75 (2H, t), 2.90 (2H, t), 3.63 (2H, s), 7.10 (IH, d), 7.28 and 7.78 (4H, ABq), 7.30 (IH, m), 7.44 (IH, s), 7.74 (IH, m). m/z (Cl): 281.2 (MH+; 100%).
Example 17 N-(2-Methyl-1^3,4-tetrahydroisoquino_in-7-yl)-3-ιιitrobenzamide
lH NMR (CDCl3)δ: 2.48 (3H, s), 2.71 (2H, t), 2.92 (2H, t), 3.61 (2H, s), 7.13 (IH, d), 7.34 (IH, dd), 7.42 (IH, s), 7.71 (IH, t), 8.00 (IH, d), 8.26 (IH, d), 8.40 (IH, d), 8.70 (IH, t); m/z (CI): 312.1 (MH+; 100%).
Example 18
N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-4-ethoxybenzamide
*H NMR (CDCl3)δ: 1.46 (3H, m), 2.47 (3H, s), 2.71 (2H, t), 2.90 (2H, t), 3.61 (2H, s), 4.11 (2H, m), 7.14 (IH, d), 7.30 (IH, m), 7.49 (IH, s), 7.68 (IH, s), 7.82 (2H, d), 8.10 (3H, m); «VZ (Cl): 311.2 (MH+; 100%).
Example 19 N-(2-Methyl-1^3>4-tetrahydroisoquinolin-7-yl)-4-n-butylbenzamide
l NMR (CDCl3)δ: 0.93 (3H, t), 1.25 - 1.48 (2H, m), 1.52 - 1.70 (2H, m), 2.51 (3H, s), 2.66 (2H, m), 2.80 (2H, t), 2.95 (2H, t), 3.69 (2H, s), 7.12 (IH, d), 7.20 (IH, d), 7.29 (2H, d), 7.32 (IH, m), 7.47 (IH, s), 7.78 (2H, d), 7.93 (IH, d); m/z (CI): 323.2 (MH+; 100%).
Example 20
N-(2-Methyl-1^3»4-tetrahydroisoquinolin-7-yl)-2-acetoxybenazmide
iH NMR (CDC_3)δ: 2.33 (3H, s), 2.48 (3H, s), 2.71 (2H, t), 2.91 (2H, t), 3.61 (2H, s), 7.10 (IH, d), 7.16 (IH, d), 7.23 (IH, m), 7.32 - 7.45 (2H, m), 7.52 (IH, t), 7.83 (IH, d), 7.94 (IH, s); m/z (CI): 325.2 (MH+; 100%). Example 21 N-(2-Methyl-l^t3.4-tetrahydroisoquinolin-7-yI)-3-trifluoromethylbeιιzamide
lH NMR (CDCl3)δ: 2.48 (3H, s), 2.73 (2H, t), 2.92 (2H, t), 3.62 (2H, s), 7.11(1H, d), 7.32 (IH, d), 7.42 (IH, s), 7.63 (IH, t), 7.75 - 7.91 (2H, m), 8.07 (IH, t), 8.12 (IH, s). m/z (CI): 335.1 (MH+; 100%)
Example 22 N-(2-Methyl-1^3,4-tetrahydroisoquinolin-7-yl)-2,4-difluorobenzamide
!H NMR (CDCl3)δ: 2.47 (3H, s), 2.71 (2H, t), 2.92 (2H, t), 3.61 (2H, s), 6.95 (IH, m), 7.00 - 7.18 (2H, m), 7.32 (IH, dd), 7.44 (IH, s), 8.14 - 8.36 (2H, m). m/z (CI): 303.1 (MH+; 100%).
Example 23
N-(2-Methyl-1^3>4-tetrahydroisoqιιinolin-7-yl)-3,4-dimethoxybeι_zamide
m/z (CI): 327.2 (MH+; 100%).
Example 24
N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-2-fluoro-4-trifluoromethyl benzamide
1H NMR (CDCl3)δ: 2.47 (3H, s), 2.70 (2H, t), 2.92 (2H, t), 3.61 (2H, s), 7.11 (IH, d), 7.35 (IH, dd), 7.45 (2H, s), 7.50 (IH, s), 7.59 (IH, d), 8.20 - 8.40 (2H, br m). m/z (CI): 353.1 (MH+; 100%).
Example 25 N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-4-chloro-3-nitrobenzamide
l NMR (CDCl3)δ: 2.48 (3H, s), 2.72 (2H, t), 2.94 (2H, t), 3.60 (2H, s), 7.10 (IH, d), 7.32 (IH, d), 7.38 (IH, s), 7.67 (IH, d), 7.95 - 8.13 (2H, br m), 8.38 (IH, d). m/z (CI): 348 (MH+; 33%), 346.1 (MH+; 100%). Example 26 N-(2-Methyl-1^3.4-tetι^ydroisoqι noUn-7-yl)-3^-di-trifluoromethylbeι_zamide
*H NMR (CDCl3)δ: 2.52 (3H, s), 2.78 (2H, t), 2.94 (2H, t), 3.66 (2H, s), 7.14 (IH, d), 7.36 (IH, d), 7.42 (IH, s), 7.94 (IH, m), 8.04 (IH, s), 8.32 (2H, s). m/z (CI): 403.1 (MH+; 100%).
Example 27 N-(2-Methyl-1^3,4-tetrahydroisoquinolin-7-yl)-2,4-dichloro-5-fluorobenzamide
l NMR (CDCl3)δ: 2.47 (3H, s), 2.70 (2H, t), 2.91 (2H, t), 3.60 (2H, s), 7.11 (IH, d), 7.25 (IH, d), 7.38 (IH, s), 7.52 (IH, dd), 7.62 (IH, dd), 7.90 (IH, brs). m/z (CD: 353.0 (MH+; 100%).
Example 28
N-(2-Methyl-l 2 >4-tetrahydroisoquinolin-7-yI)-3-fluoro-5-trifluoromethyl benzamide
!H NMR (CDCl3)δ: 2.49 (3H, s), 2.73 (2H, t), 2.91 (2H, t), 3.62 (2H, s), 7.13 (IH, d), 7.32 (IH, dd), 7.40 (IH, s), 7.50 (IH, d), 7.80 (IH, m), 7.90 (IH, s), 8.02 (IH, s). m/z (CD: 353.1 (MH+; 100%).
Example 29 N-(2-Methyl-1^3>4-tetrahydroisoquinoIin-7-yl)-3-bromo-4-methoxybeι_zamide
!H NMR (CDCl3)δ: 2.47 (3H, s), 2.71 (2H, t), 2.91 (2H, t), 3.60 (2H, s), 3.97 (3H, s), 6.96 (IH, d), 7.10 (IH, d), 7.29 (IH, m), 7.40 (IH, s), 7.67 (IH, s), 7.84 (IH, dd), 8.02 (IH, s), 8.05 (IH, d); m/z (CI): 377, 375 (MH+; 30%).
Example 30
N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-3,4,5-trimethoxybenzamide
!H NMR (CDCl3)δ: 2.42 (3H, s), 2.66 (2H, t), 2.88 (2H, t), 3.55 (2H, s), 3.83 (3H, s), 3.86 (6H, s), 7.00 (IH, s), 7.05 (IH, d), 7.19 (IH, s), 7.26 (IH, d), 7.34 (IH, s), 7.68 (IH, s), 7.94 (IH, s); m/z (CI): 357.2 (MH+; 100%). Example 31 N-(2-MethyI-1^3,4-tetrahydroisoquino_in-7-yl)-4-trifluoromethoxybenzamide
iH NMR (CDCl3)δ: 2.47 (3H, s), 2.70 (2H, t), 2.91 (2H, t), 3.60 (2H,s), 7.10 (IH, d), 7.25 (IH, m), 7.32 (2H, d), 7.40 (IH, s), 7.74 (IH, s), 7.90 (2H, d); m/z (CI): 351.1 (MH+; 100%).
Example 32
N-(2-Methyl-1^3,4-tetrahydroisoquinolin-7-yI)-3-pivaloylbenzamide, hydrochloride
The acid of Preparation 5 (200mg, Ommol) and oxalyl chloride (140mg, l.lmmol) in dichloromethane (10ml) containing DMF (5 drops) was stirred at 25°C for lh and then evaporated to dryness in vacuo. The residue in dichloromethane was treated with the amine D5 (162mg, Ommol) and kept at 25°C overnight Work-up similar to that of Example 2 gave the title compound (HOmg), m.p. 197 - 201°C (from methanokether).
!H NMR (free base; 250 MHz; CDCl3)δ: 1.38 (9H, s), 2.45 (3H, s), 2.68 (2H, t), 2.89 (2H, t), 3.55 (2H, s), 7.08 (IH, d), 7.30 (IH, d), 7.40 (IH, s), 7.49 (IH, t), 7.83 (IH, d), 7.95 (IH, d), 8.08 (IH, s), 8.14 (IH, s); m/z (CI): 351.2 (MH+; 100%).
Example 33 N-(2-Methyl-l,23.4-tetrahydroisoquinolin-7-yI)-3-bromo-4-isø-propoxybenzamide
AH NMR (CDCI3) δ: 1.42 (6H, d, J = 6 Hz), 2.47 (3H, s), 2.71 (2H, t, J = 6 Hz), 2.91 (2H, J = 6 Hz), 3.60 (2H, s), 4.67 (IH, dt J = 6 Hz), 6.96 (IH, d, J = 9 Hz), 7.10 (IH, d, J = 8 Hz), 7.30 (IH, m), 7.40 (IH, d, J = 2 Hz), 7.71 (IH, s), 7.80 (IH, dd, J = 2 and 9 Hz), 8.05 (IH, d, J = 2 Hz).
Example 34
N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-4-acetoxybenzamide
lU NMR (CDCI3) δ: 2.34 (3H, s), 2.48 (3H, s), 2.73 (2H, t, J = 6 Hz), 2.92 (2H, J = 6 HZ), 3.62 (2H, s), 7.11 (IH, d, J = 8 Hz), 7.21 (2H, m), 7.31 (IH, m), 7.43 (IH, s), 7.75 (IH, s), 7.88 (2H, m); m/z (CI: 325 (MH+; 100%) Example 35 N-(2-Methyl-l^J3>4-tetrahydroisoquinolin-7-yl)-4-cyclopentyloxybenzamide
H NMR (CDCI3) δ: 1.56 - 1.68 (2H, bm), 1.74 - 1.97 (6H, bm), 2.61 (3H, s), 2.95 (4H, m), 3.79 (2H, s), 4.81 (IH, m), 6.38 (IH, s), 6.54 (IH, dd, J = 2 and 8 Hz), 6.85 (2H, m), 6.93 (2H, d, J = 8 Hz), 7.95 (2H, d, J = 8 Hz); ∞/z (CD: 349 (MH+; 20%)
Example 36 N-(2-Methyl-l 23.4-tetrahydroisoquinolin-7-yl 4-cyclopropylmethoxybenzamide
!H NMR (CDCI3) δ: 0.36 (2H, m), 0.66 (2H, m), 1.28 (IH, m), 2.44 (3H, s), 2.81 (2H, t J = 6 Hz), 2.89 (2H, t J = 6 Hz), 3.51 (2H, s), 3.86 (2H, m), 6.34 (IH, d, J = 2 Hz), 6.50 (IH, dd, J = 2 and 8 Hz), 6.92 (2H, m), 7.06 (IH, d, J = 8 Hz), 7.31 (IH, dd, J = 2 and 8 Hz), 7.82 (IH, m), 8.00 (IH, m); ° Z (CD: 337 (MH+; 100%).
Example 37 N-(2-Methyl-1^3>4-tetrahydroisoquinolin-7-yl)-3-cyano-4-methoxybenzamide
!H NMR (CDCI3) δ: 2.47 (3H, s), 2.70 (2H, J = 6 Hz), 2.91 (2H, t, J = 6 Hz), 3.59 (2H, s), 4.02 (3H, s), 7.09 (2H, t, J = 8 Hz), 7.29 (IH, dd, J = 2 and 8 Hz), 7.39 (IH, d, J = 2 Hz), 7.80 (IH, s), 8.10 (2H, m); m/z (CI): 322 (MH+; 100%)
Example 38
N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yI __-naphthamide
!H NMR (CDCI3) δ: 2.50 (3H, s), 2.75 (2H, t, J = 6 Hz), 2.94 (2H, t J = 6 Hz), 3.65 (2H, s), 7.13 (IH, d, J = 8 Hz), 7.38 (IH, dd, J = 2 and 8 Hz), 7.50 (IH, d, J = 2 Hz), 7.56 - 7.22 (3H, bm), 7.88 - 8.07 (4H, bm), 8.38 (IH, s); /z (CI): 317 (MH+; 100%)
Example 39
N-(2-Methyl-1^3>4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methybenzamide
lH NMR (CDCI3) δ: 2.47 (6H, bs), 2.71 (2H, t J = 6 Hz), 2.91 (2H, t J = 6 Hz), 3.60 (2H, s), 7.10 (IH, d, J = 8 Hz), 7.23 - 7.39 (2H, bm), 7.42 (IH, s), 7.70 (2H, dd, J = 2 and 8 Hz), 8.02 (IH, d, J = 2 Hz); /z (CI): 359, 361 (MH+; 100%) Example 40 N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-naphthalene-l-carbo__amide
iH NMR (CDCI3) δ: 2.50 (3H, s), 2.75 (2H, t, J = 6 Hz), 2.92 (2H, t J = 6 Hz), 3.66 (2H, s), 7.12 (IH, d, J = 8 Hz), 7.35 (IH, d, J = 8 Hz), 7.45 - 7.70 (5H, m), 7.75 (IH, d, J = 8 Hz), 7.90 (IH, m), 7.96 (IH, d, J = 7 Hz), 8.36 (IH, d, J = 8 Hz). m/z (API+): 317.2 (MH+; 100%).
Example 41 N-(2-Methyl-1^3>4-tetrahydroisoquinolin-7-yl)-3-chloro-4-methoxybenzamide
iH NMR (CDCI3) δ: 2.47 (3H, s), 2.70 (2H, t, J = 6 Hz), 2.91 (2H, t J = 6 Hz), 3.59 (2H, s), 3.97 (3H, s), 6.99 (IH, d, J = 9 Hz), 7.09 (IH, d, J = 8 Hz), 7.32 (IH, dd, J = 2 and 8 Hz), 7.40 (IH, s), 7.79 (2H, m), 7.90 (IH, d, J = 2 Hz).
Example 42 N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-4-teιt-butoxybenzamide
iH NMR (CDCI3) δ: 1.41 (9H, s), 2.47 (3H, s), 2.71 (2H, t, J = 6 Hz), 2.91 (2H, J = 6 Hz), 3.61 (2H, s), 7.03 - 7.12 (3H, b m), 7.30 (IH, dd, J = 2 and 8 Hz), 7.43 (IH, d, J = 2 Hz), 7.68 (IH, s), 7.79 (2H, d, J = 9 Hz); m/z (CD: 339 (MH+; 100%).
Example 43 N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-4-n-propoxybenzamide
iH NMR (CDCI3) δ: 1.01 (3H, t, J = 7 Hz), 1.83 (2H, m), 2.87 (3H, s), 3.19 (2H, m), 3.44 (2H, t, J = 7 Hz), 3.61 (2H, s), 3.87 (2H, m), 4.40 (2H, s), 6.93 (2H, d), 7.09 (IH, d), 7.51 (IH, dd, J = 8, 2 Hz), 7.61 (IH, d,), 7.92 (2H, d), 8.39 (IH, s).
Example 44
N-(2-Methyl-1^23>4-tetrahydroisoquinolin-7-yl) benzotriazole-5-carboxamide
m/z (CI): 308 (MH+; 65%) Example 45 N-(2-Methyl-1^3»4-tetrahydroisoqιdnoUn-7-yI)beι_zot_ azole-6-carboxaπ-ide
*H NMR (CDCI3) δ: 2.48 (3H, s), 2.72 (2H, t, J = 6 Hz), 2.93 (2H, t J = 6 Hz), 3.62 (2H, s), 7.13 (IH, d, J = 8 Hz), 7.34 (IH, dd, J = 2 and 8 Hz), 7.45 (IH, d, J = 2 Hz), 7.88 (IH, s), 7.97 (IH, dd, J = 2 and 8 Hz), 8.22 (IH, d, J = 8 Hz), 8.56 (IH, d, J = 2 Hz), 9.15 (IH, s); ∞/z (CI): 322 (MH": 100%)
Example 46 N-(2-Methyl-1^3,4-tetrahydroisoquinolin-7-yl)-23-dihydrobenzofuran-5- carboxamide
!H NMr (CDCI3) δ: 2.48 (3H, s), 2.73 (2H, t J = 6 Hz), 2.91 (2H, t J = 6 Hz), 3.27 (2H, t J = 9 Hz), 3.62 (2H, s), 4.66 (2H, t J = 9 Hz), 6.83 (IH, d, J = 8 Hz), 7.08 (IH, d, J = 8 Hz), 7.28 (IH, dd, J = 2 and 8 Hz), 7.42 (IH, s), 7.64 (IH, d, J = 8 Hz), 7.76 (2H, m). m/z (CI): 309 (MH+; 100%).
Example 47
N-(2-Methyl-1^3»4-tetrahydroisoquinolin-7-yl)-2-methylbenzimidazole-5- carboxamide
!H NMR (d MeOH) δ: 2.51 (3H, s), 2.61 (3H, s), 2.92 (2H, t, J = 6 Hz), 2.96 (2H, t J = 6 Hz), 3.69 (2H, s), 7.14 (IH, d, J = 9 Hz), 7.47 (3H, m), 7.56 (IH, d, J = 8 Hz), 7.80 (IH, dd, J = 2 and 8 Hz), 8.10 (IH, s); m/z (CI): 321 (MH+; 100%).
Example 48 N-(2-Methyl-1^3>4-tetrahydroisoquinolin-7-yl)-3-chloro-4-isø-propoxybenzamide
*H NMR (CDCI3) δ: 1.42 (6H, d, J = 6 Hz), 2.49 (3H, s), 2.74 (2H, t J = 6 Hz), 2.92 (2H, J = 6 Hz), 3.63 (2H, s), 4.67 (IH, quintet J = 6 Hz), 6.98 (IH, d, J = 9 Hz), 7. .09 (IH, d, J = 8 Hz), 7.28 (IH, dd, J = 2 and 8 Hz), 7.40 (IH, d, J = 2 Hz), 7.67 - 7.81 (2H, bm), 7.88 (IH, d, J = 2 Hz); « Z (CI): 359 (MH+; 100%).
Example 49 N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
*H NMR (CDCI3) δ: 1.51 (3H, t J = 7 Hz), 2.49 (3H, s), 2.74 (2H, t, J = 6 Hz), 2.92 (2H, t J = 6 Hz), 3.62 (2H, s), 4.17 (2H, q, J = 7 Hz), 6.93 (IH, d, J = 9 Hz), 7.09 (IH, d, J = 8 Hz), 7.28 (IH, dd, J = 2 and 8 Hz), 7.39 (IH, d, J = 2 Hz), 7.71 (IH, s), 7.80 (IH, dd, J = 2 and 9 Hz), 8.05 (IH, d, J = 2 Hz); "Vz (CI): 389, 391 (MH+; 100%)
Example 50 N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide
*H NMR (CDCI3) δ: 1.51 (3H, t J = 7 Hz), 2.49 (3H, s), 2.74 (2H, t J = 6 Hz), 2.92 (2H, t J = 6 Hz), 3.62 (2H, s), 4.18 (2H, q, J = 7 Hz), 6.96 (IH, d, J = 9 Hz), 7.09 (IH, d, J = 8 Hz), 7.31 (IH, dd, J = 2 and 8 Hz), 7.39 (IH, d, J = 2 Hz), 7.76 (2H, m), 7.89 (IH, d, J = 2 Hz); m/z (CI): 345 (MH+; 100%).
Example 51
N-(2-Methyl-1^3>4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethyl benzamide
!H NMR (CDCI3) δ: 2.48 (3H, s), 2.72 (2H, t, J = 6 Hz), 2.92 (2H, t J = 6 Hz), 3.60 (2H, s), 3.98 (3H, s), 7.09 (2H, m), 7.32 (IH, dd, J = 2 and 8 Hz), 7.41 (IH, d, J = 2 Hz), 7.83 (IH, s), 8.07 (2H, m); /z (CI): 365 (MH+; 100%)
Example 52
N-(2-Methyl-1^3,4-tetrahydroisoquinolin-7-yl)-3,5-dichloro-4-methoxybenzamide
iH NMR (CDCI3) δ: 2.46 (3H, s), 2.69 (2H, t, J = 6 Hz), 2.90 (2H, t, J = 6 Hz), 3.57 (2H, s), 3.96 (3H, s), 7.09 (IH, d, J = 8 Hz), 7.30 (IH, dd, J = 2 and 8 Hz), 7.34 (IH, d, J = 2 Hz), 7.81 (2H, s), 7.89 (IH, s); m/z (CI): 365 (MH+; 100%)
Example 53 N-(2-Methyl)-1^3>4-tetrahydroisoquinolin-7-yl)-3,5-dichloro-4-ethoxybenzamide
l NMR (CDCI3) δ: 1.49 (3H, t J = 7 Hz), 2.46 (3H, s), 2.69 (2H, t J = 7 Hz), 2.90 (2H, t J = 6 Hz), 3.56 (2H, s), 4.17 (2H, q, J = 7 Hz), 7.09 (IH, d, J = 8 Hz), 7.29 (IH, dd, J = 2 and 8 Hz), 7.32 (IH, s), 7.80 (2H, s), 7.86 (IH, s); m/z (CI): 379 (MH+; 100%) Example 54 N-(2-Methyl)-1^3,4-tetrahydroisoquinolin-7-yl)-3^-dichloro-4-wø- propoxybenzamide iH NMR (CDCI3) δ: 1.39 (6H, d, J = 6 Hz), 2.47 (3H, s), 2.70 (2H, t J = 6 Hz), 2.91 (2H, t J = 6 Hz), 3.59 (2H, s), 4.72 (IH, quintet J = 6 Hz), 7.10 (IH, d, J = 8 Hz), 7.30 (IH, dd, J = 2 and 8 Hz), 7.36 (IH, s), 7.76 (d, J = 2 Hz), 7.80 (2H, s). m/z (CD: 393 (MH+, 100%)
Example 55 N-(2-Methyl-1^3»4-tetrahydroisoquinolin-7-yl)-3-methylsulfonylbenzanιide
*H NMR (CDCI3) δ: 2.48 (3H, s), 2.71 (2H, J = 6 Hz), 2.92 (2H, t J = 6 Hz), 3.12 (3H, s), 3.60 (2H, s), 7.12 (IH, d, J = 8 Hz), 7.35 (IH, dd, J = 2 and 8 Hz), 7.42 (IH, s), 7.73 (IH, t J = 8 Hz), 8.05 (IH, s), 8.11 (IH, d, J = 8 Hz), 8.22 (IH, d, J = 8 Hz), 8.40 (IH, s); m/z (CI): 345 (MH+; 100%)
Example 56 N-(2-methyl-1^3>4-tetrahydroisoquinolin-7-yl)-3-bromo-4-tert-butylbenzamide
A solution of the amine D5 (162mg; 1.0 mmol) and 3-bromo-4-terr-butylbenzoic acid (257mg; 1.0 mmol) in anhydrous N,N-dimethylformamide (7ml), was treated with 1- hydroxybenzotriazole (135mg; 1.0 mmol) and l-(3-Dimethylaminopropyl)-3- ethylcarbodϋmide (192mg; 1.0 mmol) at 25°C. The mixture was shaken for 48h before extracting the product into dichloromethane and washing with 10% aqueous NaHCO3, water and finally brine. The organic layer was dried over MgSO4 and evaporated in vacuo to afford 373mg of the title compound in 93% yield.
H NMR (CDCI3) δ: 1.54 (9H, s), 2.47 (3H, s), 2.71 (2H, t J = 6 Hz), 2.91 (2H, t, J = 6 Hz), 3.60 (2H, s), 7.10 (IH, d, J = 8 Hz), 7.31 (IH, dd, J = 2 and 8 Hz), 7.41 (IH, d, J = 2 Hz), 7.54 (IH, d, J = 8 Hz), 7.72 (2H, m), 8.06 (IH, d, J = 2 Hz).
Example 57 N-(2-Methyl-1^23-4-tetrahydroisoquinolin-7-yl)-2-bromo-5-methoxybenzamide
*H NMR (CDCI3) δ: 2.47 (3H, s), 2.70 (2H, t, J = 6 Hz), 2.91 (2H, t J = 6 Hz), 3.61 (2H, s), 3.83 (3H, s), 6.88 (IH, dd), 7.11 (IH, d, J = 8 Hz), 7.21 (IH, d), 7.31 (IH, dd, J = 8, 2 Hz), 7.44 (IH, d,), 7.50 (IH, d), 7.71 (IH, s); m/z (API+): 375.0 (MH+; 100%) Example 58
N-(2-Methyl-1^3»4-tetrahydroisoquinolin-7-yl)-4-fluoro-3-methoxybenzamide, hydrochloride
!H NMR (free base CDCI3) δ: 2.53 (3H, s), 2.76 (2H, t J = 6 Hz), 2.97 (2H, t J = 6 Hz),
3.63 (2H, s), 4.01 (3H, s), 7.16 (IH, dd, J = 6, 2Hz), 7.21 (IH, d), 7.32 - 7.50 (3H, m),
7.64 (IH, dd, J = 6, 2Hz), 8.00 (IH, brs); m/z (API+): 315.1 (MH+; 100%)
Example 59 N-(2-MethyI-1^3.4-tetrahydroisoquinolin-7-yI)-l-methylpyrazole-4-carboxamide
iH NMR (250 MHz, CDCI3) δ: 2.30 (3H, s), 2.53 (2H, m), 3.40 (2H, s), 3.78 (3H, s), 6.91 (IH, d, J = 8 Hz), 7.11 (IH, m), 7.21 (IH, d), 7.20 (IH, brs), 7.46 (IH, br), 7.68 (IH, s), 7.76 (IH, s); m/z (API+): 271 (MH+; 100%)
Example 60
N-(2-Methyl-1^23.4-tetrahydroisoquinolin-7-yl)-4-trifluoromethylpyrazole-3- carboxamide
*H NMR (250 MHz, D6 DMSO) δ: 2.41 (3H, s), 2.81 - 2.85 (4H, m), 7.13 (IH, d, J = 8 Hz), 7.46 (2H, m), 8.64 (IH, s); /z (API+): 325 (MH+; 100%)
Example 61 N-(2-Methyl-1^3,4-tetrahydroisoquinolin-7-yl)-2-methylthiazole-4-carboxamide
!H NMR (250 MHz, CDCI3) δ: 2.47 (3H, s), 2.67 - 2.76 (5H, m), 2.89 (2H, m), 3.60 (2H, s), 7.10 (IH, d, J = 8 Hz), 7.40 (IH, dd, J = 8, 2 Hz), 7.49 (IH, brs), 8.02 (IH, br), 9.12 (IH, br); m/z (API+): 288 (MH+; 100%)
Example 62
N-(2-MethyI-1^3>4-tetrahydroisoquinolin-7-yl)-5-methylisoxazole-3-carboxamide
iH NMR (250 MHz, CDCI3) δ: 2.46 (3H, s), 2.51 (3H, s), 2.68 (2H, m), 2.90 (2H, ra), 3.58 (2H, s), 6.51 (IH, s), 7.10 (IH, d, J = 8 Hz), 7.33 (IH, dd, J = 8, 2 Hz), 7.41 (IH, brs), 8.47 (IH, brs); /z (API+): 272 (MH+; 100%) Example 63
N-(2-Me yl-1^ .4-tetrahydroisoquinolin-7-yl)-5-terr-butylisoxazole-3- carboxamide
*H NMR (250 MHz, CDC13) δ: 1.38 (9H, s), 2.46 (3H, s), 2.66 - 2.71 (2H, m), 2.89 (2H, m), 3.59 (2H, s), 6.48 (IH, s), 7.10 (IH, d, J = 8 Hz), 7.30 (2H, brd, J = 8 Hz), 7.41 (IH, brs), 8.43 (IH, brs); m/z (API+): 314 (MH+; 100%)
Example 64 N-(2-Methyl-1^3>4-tetrahydroisoquinolin-7-yl)-3-methoxyisoxazole-5-carboxamide hydrochloride
*H NMR (250 MHz, DMSO-d6) δ: inter alia 2.81 (3H, brs), 3.88 (3H, s), 7.00 (IH, s), 7.16 (2H, d, J = 8 Hz), 7.52 (2H, m); m/z (API+): 288 (MH+; 100%)
Example 65 N-(2-methyI-1^3>4-tetrahydroisoquinolin-7-yl)indole-2-carboxamide.
D5 was converted into the title compound by reaction witii indole-2-carboxylic acid, in a similar manner to the procedure of Description 7.
lH NMR (D6 DMSO) δ: 2.84 (3H, s), 3.07 (2H, t J = 6 Hz), 3.29 (2H,t J = 6 Hz), 3.97 (2H, s), 5.01 (IH, m), 7.53 (2H, m), 7.70 (2H, m), 8.08 (4H, m), 9.90 ( IH, brs). m/z (API+): 306 (MH+; 100%)
Example 66
N-(2-Methyl-l,23>4-tetrahydroisoquinolin-7-yl)-3-bromo-4-isø-propylbenzaπιide, hydrochloride
lU NMR (free base, CDCI3) δ: 1.26 (6H, d, J = 7 Hz), 2.48 (3H, s), 2.75 (2H, m), 2.90 (2H, m), 3.41 (IH, sep, J = 7 Hz), 3.62 (2H, s), 7.09 (IH, d, J = 8 Hz), 7.31 (2H, dd, J = 8, 2 Hz), 7.37 (2H, m), 7.76 (IH, dd, J = 8, 2 Hz), 7.90 (IH, brs), 8.02 (IH, d, J = 2 Hz); m/z (API+): 387, 389 (MH+; 100%) Example 67
N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-3-cyano^t-iso-propylbenzamide> hydrochloride
lU NMR (free base, CDCI3) δ: 1.25 (6H, d, J = 7 Hz), 2.37 (3H, s), 2.60 (2H, m), 2.80 (2H, m), 3.45 (IH, sep, J = 7 Hz), 3.62 (2H, s), 7.00 (IH, d, J = 8 Hz), 7.25 (2H, m), 7.41 (IH, d), 7.97 (IH, dd, J = 8, 2 Hz), 8.03 (IH, d, J = 2 Hz), 8.10 (IH, brs); /z (API+): 334 (MH+; 100%)
Example 68
N-(2-Methyl-1^3,4-tetrahydroisoquinolin-7-yl)-3-fluoro-4-methoxybenzamide
iH NMR (250 MHz CDCI3) δ: 2.48 (3H, s), 2.73 (2H, t, J = 6 Hz), 2.92 (2H, t J = 6 Hz), 3.61 (2H, s), 3.96 (3H, s), 7.05 (2H, m), 7.30 (IH, dd, J = 6, 2Hz), 7.40 (IH, s), 7.63 (2H, d), 7.80 (IH, d); m/z (API+): 315.2 (MH+; 100%)
Example 69 N-(2-Methyl-1^3»4-tetrahydroisoquinolin-7-yl)-3-cyano-4-n-propoxybenzamide
*H NMR (250 MHz CDCI3) δ: 1.10 (3H, t J = 8 Hz), 1.92 (2H, m), 2.47 (3H, s), 2.70 (2H, t J = 6 Hz), 2.90 (2H, t J = 6 Hz), 3.58 (2H, s), 4.10 (2H, , J = 8 Hz), 7.02 (IH, d,), 7.09 (IH, d), 7.33 (IH, dd, J = 6, 2Hz), 7.38 (IH, s), 8.02 (IH, s), 8.08 (2H, m); m/z (API+): 350.2 (MH+; 100%)
Example 70
N-(2-Methyl-1^3>4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethoxybenzamide
iH NMR (250 MHz CDCI3) δ: 1.53 (3H, t J = 8 Hz), 2.49 (3H, s), 2.74 (2H, t J = 6 Hz), 2.92 (2H, t, J = 6 Hz), 3.62 (2H, s), 4.23 (2H, q, J = 8 Hz), 7.04 (IH, d), 7.10 (IH, d), 7.32 (IH, dd, J = 6, 2Hz), 7.40 (IH, d), 7.92 (IH, s), 8.09 (2H, m); m/z (API+): 336.2 (MH+; 100%)
Example 71 N-(2-Methyl-l,23»4-tetrahydroisoquinolin-7-yl)-3-bromo-4-fi-propoxybenzamide
!H NMR (250 MHz CDCI3) δ: 1.10 (3H, t J = 8 Hz), 1.90 (2H, m), 2.46 (3H, s), 2.69 (2H, t J = 6 Hz), 2.90 (2H, t, J = 6 Hz), 3.58 (2H, s), 4.05 (2H, t J = 8 Hz), 6.93 (IH, d), „„,i< rft0 98/41508
7.09 (IH, d), 7.30 (IH, dd, J = 6, 2Hz), 7.39 (IH, d), 7.72 (IH, s), 7.80 (IH, dd, J = 6, 2Hz), 8.05 (IH, d); /z (API+): 403.1 (MH+; 90%)
Example 72 N-(2-MethyI-1^3.4-tetr_ιhydroisoquinolin-7-yl)-3-bromo-4-ethylbeι_zamide
iH NMR (250 MHz CDCI3) δ: 1.26 (3H, t J = 8 Hz), 2.46 (3H, s), 2.69 (2H, t J = 6 Hz), 2.82 (2H, q, J = 8 Hz), 2.90 (2H, J = 6.Hz), 3.59 (2H, s), 7.10 (IH, d), 7.28 (IH, dd, J = 6, 2 Hz), 7.34 (IH, d), 7.41 (IH, d), 7.74 (2H, dd), 8.03 (lH,s); m/z (API+): 373.1 (MH+; 100%)
Example 73 N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-3-iodo-4-methoxybenzamide
H NMR (250 MHz CDCI3) δ: 2.50 (3H, s), 2.79 (2H, t, J = 6 Hz), 2.93 (2H, t J = 6 Hz), 3.64 (2H, s), 3.94 (3H, s), 6.85 (IH, d), 7.21 (IH, d), 7.08 (IH, d), 7.34 (IH, dd, J = 6, 2Hz), 7.38 (IH, d), 7.89 (IH, dd), 8.12 (IH, s), 8.29 (IH, d); m/z (API+): 423.0 (MH+; 100%)
Example 74
N-(2-Methyl-1^3>4- etrahydroisoquinolin-7-yl)-4-i$ø-propoxy-3- trifluoromethyl benzamide
!H NMR (250 MHz CDCI3) δ: 1.39 (6H, d, J = 8 Hz), 2.48 (3H, s), 2.70 (2H, t J = 6 Hz), 2.87 (2H, t, J = 6 Hz), 3.54 (2H, s), 4.72 (IH, m), 7.06 (2H, t), 7.30 (IH, dd, J = 6, 2Hz), 7.37 (IH, s), 8.03 (3H, m); m/z (API+): 393.2 (MH+; 100%)
Example 75 N-(2-Methyl>l^,3.4-tetrahydroisoquinolin-7-yl)-4-chloro-3-methoxybenzamide
*H NMR (250 MHz CDCI3) δ: 2.47 (3H, s), 2.70 (2H, t J = 6 Hz), 2.88 (2H, t J = 6 Hz), 3.59 (2H, s), 3.98 (3H, s), 7.11 (IH, d), 7.21 (IH, d), 7.30 (2H, m), 7.40 (IH, d), 7.45 (IH, d), 7.75 (IH, s); m/z (API+): 331.1 (MH+; 100%) Example 76
N-(2-Methyl-1^3>4-tetrahydroisoquinolin-7-yl)-4-Λ-propoxy-3- trifluoromethyl benzamide
iH NMR (250 MHz CDC13) δ: 1.08 (3H, t J = 8 Hz), 1.86 (2H, m), 2.46 (3H, s), 2.70 (2H, t J = 6 Hz), 2.90 (2H, t J = 6 Hz), 3.58 (2H, s), 4.08 (2H, J = 8 Hz), 7.07 (2H, m), 7.29 (IH, dd, J = 6, 2Hz), 7.41 (IH, d), 7.97 (IH, s), 8.03 (IH, d), 8.07 (IH, s); ∞/z (API+): 393.2 (MH+; 100%)
Example 77
N-(2-MethyI-1^3»4-tetrahydroisoquinolin-7-yl)-3-chloro-4-tert-butylbenzamide, hydrochloride
iH NMR (250 MHz, DMSO-dg) δ: inter alia 1.68 (9H, s), 7.36 (IH, d, J = 8 Hz), 7.77 (3H, m), 8.00 (IH, dd, J = 8, 2 Hz), 8.11 (IH, d, J = 2 Hz); m/z (API+): 357 (MH+; 100%)
Example 78
N-(2-Methyl-1^3>4-tetrahydroisoquinolin-7-yl)-4-methoxybenzamide hydrochloride.
D5 was converted into the title compound in 95% yield by reaction with 4- methoxybenzoyl chloride in a manner similar to that described in Example 3.
*H NMR (D2O) δ: 3.13 (3H, s), 3.25 (2H, brs), 3.68 (2H, brs), 3.96 (3H, s), 4.48 (2H, brs), 7.15 (2H, d, J = 9 Hz), 7.35-7.50 (3H, m), 7.90 (2H, d, J = 9 Hz).
Example 79
N-(2-Methyl-1^3,4-tetrahydroisoquinolin-7-yl)-4-fluoro-3-methylbenzamide, hydrochloride
!H NMR (free base CDCI3) δ: 2.34 (3H, s), 2.46 (3H, s) 2.69 (2H, t, J = 6 Hz), 2.90 (2H, t J = 6 Hz), 3.58 (2H, s), 7.08 (2H, m), 7.30 (IH, dd), 7.40 (IH, d, ), 7.60 - 7.80 (2H, m), 7.74 (IH, s); m/z (API+): 299.2 (MH+; 100%) Example 80 N-(2-Methyl-1^3>4-tetrahydroisoquinolin-7-yl)-3-chloro-4-i$ø-propylbenzamide
*H NMR (free base 250 MHz CDC13) δ: 1.40 (6H, d, J = 7 Hz), 2.59 (3H, s), 2.82 (2H, m), 3.03 (2H, m), 3.58 (IH, sep, J = 7 Hz), 3.71 (2H, s), 7.23 (IH, d, J = 8 Hz), 7.42 (IH, dd, J = 8, 2 Hz), 7.53 (2H, m), 7.82 (2H, m), 7.96 (IH, d, J = 2 Hz); m/z (API+): 343, 345 (MH+; 100, 50%)
Example 81 N-(2-Methyl-1^3>4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethylbenzamide hydrochloride
H NMR (free base 250 MHz, CDCI3) δ: 1.31 (3H, t, J = 8 Hz), 2.43 (3H, s), 2.66 (2H, m), 2.90 (4H, m), 3.55 (2H, s), 7.09 (IH, d, J = 8 Hz), 7.28 (2H, dd, J = 8, 2 Hz), 7.36 (IH, brs), 7.44 (IH, d, J = 8 Hz), 7.86 (IH, brs), 8.00 (IH, dd, J = 8, 2 Hz), 8.09 (IH, d, J = 2 Hz); m/z (API+): 320 (MH+; 100%)
Example 82
N-(2-Methyl-1^3,4-tetrahydroisoquinolin-7-yl)-4-isø-propyl-3-trifluoromethyl- benzamide hydrochloride
H NMR (free base 250 MHz, CDCI3) δ: inter alia 1.38 (6H, d, J = 6 Hz), 2.32 (3H, s), 2.57 (2H, m), 2.76 (2H, m), 3.25 (IH, m), 3.45 (2H, s), 6.95 (IH, d, J = 8 Hz), 7.16 (IH, brd, J = 8 Hz), 7.26 (IH, brs), 7.43 (IH, d, J = 8 Hz), 7.72 (IH, brs), 7.84 (IH, d, J = 8 Hz), 7.93 (IH, brs); /z (API+): 377 (MH+; 100%)
Example 83
N-(2-Methyl-1^23,4-tetrahydroisoquinolin-7-yl)-4-ethyl-3- trifluoromethylbenzamide hydrochloride
*H NMR (free base 250 MHz, CDCI3) δ: inter alia 1.25 (3H, t, J = 8 Hz), 2.46 (3H, s), 2.68 (2H, m), 2.90 (2H, m), 3.58 (2H, brs), 7.10 (IH, d, J = 8 Hz), 7.30 (IH, dd, J = 8, 2 Hz), 7.47 (IH, d, J = 8 Hz), 7.40 (IH, brs), 7.78 (IH, brs), 7.97 (IH, dd), 8.08 (IH, brs); m/z (API-): 361 (MH"; 100%) Example 84
N-(2-Methyl-1^3»4-tetrahydroisoquinoUn-7-yI)-3-cyano-4-isø-propoxybenzamide hydrochloride
H NMR (250 MHz CDCI3) δ: 1.45 (6H, d, J = 8 Hz), 2.47 (3H, s), 2.70 (2H, t J = 6 Hz), 2.91 (2H, t J = 6 Hz), 3.59 (2H, s), 4.75 (IH, m), 7.04 (IH, d), 7.10 (IH, d), 7.29 (IH, dd, J - 6, 2Hz), 7.37 (IH, d), 7.71 (IH, s), 8.05 (2H, m); m/z (API+): 350.2 (MH+; 100%)
Example 85
N-(1^3>4-Tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide
*H NMR (250 MHz CDCI3) δ: 2.65 (2H, t, J = 6 Hz), 3.00 (2H, t J = 6 Hz), 3.85 (3H, s), 3.89 (2H, s), 6.95 (2H, d), 7.17 (IH, dd, J = 6, 2Hz), 7.25 (IH, s), 7.57 (IH, s), 7.93 (2H, m); m/z (API+): 351.1 (MH+; 100%)
Example 86
N-(2-Methyl-1^3>4-tetrahydroisoquinolin-7-yl)-4-methyl-3-methylsulfonyl- benzamide
lU NMR (CDCI3) δ: 2.48 (3H, s), 2.71 (2H, t J = 7 Hz), 2.80 (3H, s), 2.92 (2H, t, J = 7 Hz), 3.15 (3H, s), 3.61 (2H, s), 7.13 (2H, d), 7.35 (IH, dd), 7.43 (IH, s), 7.52 (IH, d), 7.93 (IH, s), 8.14 (IH, dd), 8.45 (IH, d); /z (API+): 359.2 (MH+; 100%)
Example 87
N-(2-Methyl-lA3.4-tetrahydroisoquinoIin-7-yl)-4-ethyl-3-methylsulfonylbenzamide
JH NMR (CDCI3) δ: 1.49 (3H, t J = 8 Hz), 2.59 (3H, s), 2.81 (2H, t J = 7 Hz), 3.03 (2H, t J = 7 Hz), 3.27 (5H, m), 3.71 (2H, s), 7.23 (2H, d), 7.46 (IH, dd), 7.54 (IH, d), 7.69 (IH, d), 8.04 (IH, s), 8.29 (IH, dd), 8.55 (IH, d); m/z (API+): 373.2 (MH+; 100%)
Example 88
N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-3-methylsulfonyl-4-isø- propylbenzamide
!H NMR (CDCI3) δ: 1.27 (6H, d, J = 8 Hz), 2.37 (3H, s), 2.60 (2H, t J = 7 Hz), 2.81 (2H, t J = 7 Hz), 3.06 (3H, s), 3.46 (2H, s), 3.85 (IH, m), 7.00 (2H, d), 7.26 (IH, dd), 7.31 (IH, d), 7.57 (IH, d), 8.10 (IH, dd), 8.21 (IH, s), 8.37 (IH, d); /z (API+): 387.2 (MH+; 100%)
Example 89
N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-3-methylsulfonyl-4- methoxybenzamide
iH NMR (CDC13) δ: 2.31 (3H, s), 2.54 (2H, t, J = 7 Hz), 2.75 (2H, t J = 7 Hz), 3.09 (3H, s), 3.42 (2H, s), 3.87 (3H, s), 6.95 (2H, m), 7.12 (IH, s), 7.21 (IH, d), 8.08 (2H, m), 8.23 (IH, d); /z (API+): 375.2 (MH+; 75%)
Example 90
N-(2-Methyl-1^3>4-tetrahydroisoquinolin-7-yl)-3-trifluoroacetylbenzamide, hydrochloride
XH NMR (free base CDCI3) δ: 2.47 (3H, s), 2.46 (3H, s) 2.77 (2H, t J = 6 Hz), 2.94 (2H, t J = 6 Hz), 3.63 (2H, s), 7.13 (IH, d, J = 6 Hz), 7.45 (IH, d, J = 6 Hz), 7.54 (IH, t, J = 6 Hz), 7.81 (IH, d, J = 6 Hz), 7.97 (IH, d, J = 6 Hz); 8.20 (IH, s); /z (API+): 363.2 (MH+; 60%)
Example 91
N-(2-Methyl-1^3>4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-pentafluoroethyl- benzamide hydrochloride
iH NMR (free base 250 MHz, CDCI3) δ: 2.46 (3H, s), 2.70 (2H, m), 2.90 (2H, m), 3.59 (2H, s), 3.94 (3H, s), 7.10 (2H, m), 7.30 (IH, dd, J = 8, 2 Hz), 7.39 (IH, brs), 7.73 (IH, brs), 8.01 (IH, d, J = 2 Hz), 8.06 (IH, dd, J = 9, 2 Hz); m/z (API+): 415 (MH+; 100%)
Example 92 N-(2-ιι-PropyM^3>4- etrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
!H NMR (CDCI3) δ: 0.95 (3H, t J = 7 Hz), 1.51 (3H, t J = 7 Hz), 1.62 (2H, m), 2.47 (2H, J = 8 Hz), 2.72 (2H, t J = 6 Hz), 2.88 (2H, t, J = 6 Hz), 3.61 (2H, s), 4.17 (2H, q, J = 7 Hz), 6.92 (IH, d, J = 9 Hz), 7.07 (IH, d, J = 8 Hz), 7.26 (IH, dd, J = 8, 2 Hz), 7.39 (IH, d, J = 2 Hz), 7.72 (IH, brs), 7.79 (IH, dd, J = 9, 2 Hz), 8.04 (IH, d, J = 2 Hz). m/z (API+): 417, 419 (MH+; 95%) Example 93
N-(2-«-Propyl-1^3»4-tetrahydroisoquinolin-7-yl)-4-methoxy-3- trifluoromethylbenzamide
lH NMR (CDCI3) δ: 0.96 (3H, t J = 7 Hz), 1.61 (2H, m), 2.47 (2H, t, J = 8 Hz), 2.73 (2H, t J = 6 Hz), 2.88 (2H, t J = 6 Hz), 3.62 (2H, s), 3.98 (3H, s), 7.08 (2H, m), 7.30 (IH, m), 7.41 (IH, d, J = 2 Hz), 7.76 (IH, brs), 8.05 (2H, m); m/z (API+): 393 (MH+; 100%)
Example 94 N-(_Un-Propyl-1^3.4-tetι^ahydroisquinolin-7-yl)-3-chloro-4-κø-propoxy benzamide
*H NMR (CDCI3) δ: 0.95 (3H, t J = 7 Hz), 1.42 (6H, d, J = 6 Hz), 1.62 (2H, m), 2.48 (2H, t J = 8 Hz), 2.73 (2H, t J = 6 Hz), 2.88 (2H, t, J = 6 Hz), 3.63 (2H, s), 4.66 (IH, sept, J = 6 Hz), 6.98 (IH, d, J = 9 Hz), 7.08 (IH, d, J = 8 Hz), 7.26 (IH, m), 7.41 (IH, d, J = 2 Hz), 7.65 (IH, brs), 7.73 (IH, dd, J = 9, 2 Hz), 7.87 (IH, d, J = 2 Hz). /z (API+): 387 (MH+; 90%)
Example 95 N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-3-cyano-4-i_ø-butylbenzamide hydrochloride
!H NMR (250 MHz, DMSO-dό) δ: inter alia 0.95 (6H, d, J = 7 Hz), 1.99 (IH, sep, J = 7 Hz), 2.77 (2H, brs), 7.26 (IH, d, J = 8 Hz), 7.65 (3H, m), 8.21 (IH, dd, J = 8, 2 Hz), 8.41 (IH, d, J = 8 Hz); m/z (API+): 348 (MH+; 100%)
Example 96
N-(2-Methyl-1^.3»4-tetrahydroisoquinolin-7-yl)-4-isø-butyl-3-trifluoromethyl- benzamide hydrochloride
*H NMR (250 MHz, DMSO-dό) δ: 'nter <*lia l-01 (6H, < = 6-5 Hz), 2.09 (IH, sep, J = 6.5 Hz), 7.35 (IH, d, J = 8 Hz), 7.75 (3H, m), 8.32 (IH, d, J = 8 Hz); m/z (API+): 391 (MH+; 100%) Example 97 N-(2-Ethyl-1^3>4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
iH NMR (CDCI3) δ: 1.20 (3H, t J = 7 Hz), 1.51 (3H, J = 7 Hz), 2.61 (2H, q, J = 7 Hz), 2.76 (2H, m), 2.90 (2H, m), 3.64 (2H, s), 4.16 (2H, q, J = 7 Hz), 6.91 (IH, d, J = 9 Hz), 7.07 (IH, d, J = 8 Hz), 7.26 (IH, m), 7.40 (IH, d, J = 2 Hz), 7.79 (2H, m), 8.05 (IH, d, J = 2 Hz); m/z (API+): 403, 405 (MH+; 65%)
Example 98 N-(2-Ethyl-1^3»4-tetrahydro-isoquinolin-7-yI)-4-metiιoxy-3-trifluoromethyl benzamide
!H NMR (CDCI3) δ: 1.21 (3H, t J = 7 Hz), 2.65 (2H, q, J = 7 Hz), 2.80 (2H, d, J = 6 Hz), 2.92 (2H, t J = 6 Hz), 3.67 (2H, s), 3.97 (3H, s), 7.07 (2H, m), 7.30 (IH, m), 7.41 (IH, d, J = 2 Hz), 7.89 (IH, brs), 8.06 (2H, m); /z (API+): 379 (MH+; 100%)
Example 99 N-(2-_sø-Propyl-1^3.4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
XH NMR (CDCI3) δ: 1.13 (6H, d, J = 7 Hz), 1.51 (3H, t J = 7 Hz), 2.84 (5H, m), 3.71 (2H, s), 4.16 (2H, q, J = 7 Hz), 6.91 (IH, d, J = 9 Hz), 7.06 (IH, d, J = 8 Hz), 7.25 (IH, m), 7.42 (IH, d, J = 2 Hz), 7.78 (2H, m), 8.04 (IH, d, J = 2 Hz). m/z (API+): 419 (MH+; 90%)
Example 100
N-(2-faø-Propyl-1^3.4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethyl benzamide
iH NMR (CDCI3) δ: 1.13 (6H, d, J = 7 Hz), 2.84 (5H, m), 3.72 (2H, s), 3.97 (3H, s), 7.07 (2H, m), 7.26 (IH, m), 7.43 (IH, d, J = 2 Hz), 7.83 (IH, brs), 8.04 (2H, m) «VZ (API+): 393 (MH+; 100%) Example 101
N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-4-ethoxy-3-methylsulfonyl- benzamide
*H NMR (CDCI3) δ: 1.52 (3H, t J = 8 Hz), 2.46 (3H, s), 2.69 (2H, t J = 7 Hz), 2.90 (2H, J = 7 Hz), 3.26 (3H, s), 3.57 (2H, s), 4.27 (2H, q, J = 7 Hz), 7.09 (2H, dd), 7.36 (IH, dd), 7.42 (IH, s), 7.83 (IH, brs), 8.12 (IH, s), 8.20 (IH, dd), 8.37 (IH, d); m/z (API+): 389.2 (MH+; 100%)
Example 102
N-(2-MethyI-1^3>4-tetrahydroisoquinolin-7-yI)-4-oxochroman-6-carboxamide hydrochloride
lU NMR (D6 DMSO) δ: 2.63 (3H, narrow d), 3.02 (2H, t, J = 7Hz), 3.14 (2H, brm), 3.60 (2H, brm), 4.54 (2h, brs), 4.77 (2H, d, J = 7 Hz), 7.25 (IH, m), 7.31 (IH, d, J = 8 Hz), 7.44 (2H, d, J = 6 Hz), 8.20 (IH, dd, J = 8, 2 Hz), 8.59 (IH, d, J = 2 Hz), 10.31 (IH, s), 10.95 (IH, brs); m/z (API+): 337.4 (MH+; 100%)
Example 103 N-(2-Formyl-1^3>4-tetrahydroisoquinolin-7-yl)-4-methoxy-3- trifluoromethylbenzamide
7-Amino-2-formyl-l,2,3,4-tetrahydroisoquinoline (0.176g) was converted into the title compound by reaction with 4-methoxy-3-trifluoromethylbenzoyl chloride, following the procedure of Example 3. The product was isolated as a white solid (0.035g).
lH NMR (dβ-DMSO) δ: 2.80 (2H, m), 3.65 (2H, broad t), 4.00 (3H, s), 4.59 (2H, d), 7.17 (IH, d, J = 8 Hz), 7.45 (IH, d, J = 8 Hz), 7.60 (2H, m), 8.26 (3H, m), 10.30 (IH, s). m/z (API+): 379 (MH+).
Example 104 N-(2-Hydroxyethyl-1^3.4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
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%). iH NMR (250 MHz, CDCI3) δ: 1.51 (3H, t J = 7 Hz), 2.77 (2H, t J = 5 Hz), 2.90 (4H, m, overlapping signal), 3.74 (4H, m, overlapping signal), 4.17 (2H, q, J = 7 Hz), 6.93 (IH, d, J = 10 Hz), 7.10 (IH, d, J = 8 Hz), 7.36 (IH, dd, J = 8, 2 Hz), 7.48 (IH, d, J = 2 Hz), 7.87 (IH, dd, J = 9, 2 Hz), 7.97 (IH, s), 8.08 (IH, d, J = 2 Hz)
Example 105 N-(2-Hydroxyethyl-1^3»4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide
The title compound was prepared in 40% overall yield from D15 in a manner similar to that of Descriptions 16 and Example 106.
*H NMR (250 MHz, CDCI3) δ: 2.77 (10H, m, overlapping signals), 3.68 (5H, m, overlapping signals), 7.08 (IH, d, J = 8 Hz), 7.30 (2H, m, overlapping signals), 7.48 (IH, d, J = 2 Hz), 7.75 (H, dd, J = 8, 2 Hz), 8.02 (IH, d, J = 2 Hz), 8.17 (IH, s).
Example 106
N-(2-Methyl-1^3>4-tetrahydroisoquinolin-7-yl)-4-phenylmethoxy-3- trifluoromethyl benzamide
!H NMR (CDCI3) δ: 2.50 (3H, s), 2.75 (2H, t, J = 6 Hz), 2.94 (2H, t J = 6 Hz), 3.64 (2H, s), 7.10 (2H, d, J = 8 Hz), 7.30 - 7.60 (7H, m, overlapping), 7.70 (IH, brs), 8.04 (IH, dd, J = 8, 2 Hz), 8.10 (IH, d, J = 2 Hz); m/z (CD: 441.2 (MH+; 100%)
Example 107
N-(2-Methyl-1^3.4-tetrahydroisoquinolin-7-yl)-4-hydroxy-3-trifluoromethyl benzamide
m/z (CI): 351.1 (MH+; 100%)
Example 108
N-(2-Methoxyethyl-l^_3>4-tetrahydroisoquinolin-7-yl)-3-bromo-4-faø- propoxybenzamide
*H NMR (250 MHz, CDCI3) δ: 1.41 (6H, d, J = 6 Hz), 2.75 (4H, t, overlapping, J = 6 Hz), 2.83 (2H, d, J = 5 Hz), 3.39 (3H, s), 3.61 (4H, t overlapping, J = 6 Hz), 4.64 (lH,m), 6.91 (IH, d, J = 9 Hz), 7.01 (IH, d, J = 8 Hz), 7.20 (IH, dd, J = 8, 2 Hz), 7.29 (IH, d, J = 2 Hz), 7.80 (IH, dd, J = 9, 2 Hz), 8.07 (IH, d, J = 2 Hz), 8.10 (IH, s); m/z (API+): 447, 449 (MH+, 90%)
Example 109
N-(2-Methoxyethyl-1^3»4-tetrahydroisoquinolin-7-yl)-3-chloro-4-i_ø- propoxybenzamide
!H NMR (250 MHz, CDCI3) δ: 1.41 (6H, d, J = 6 Hz), 2.75 (4H, t overlapping, J = 6 Hz), 2.83 (2H, d, J = 5 Hz), 3.39 (3H, s), 3.61 (4H, t overlapping, J = 5 Hz), 4.64 (IH, m), 6.94 (IH, d, J = 9 Hz), 7.01 (IH, d, J = 8 Hz), 7.20 (IH, d, J = 8 Hz), 7.30 (IH, s), 7.75 (IH, dd, J = 9, 2 Hz), 7.90 (IH, d, J = 2 Hz); m z (API+): 403, 405 (MH+)
Example 110 N-(2-Methoxyethyl-l,23,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3- trifluoromethylbenzamide
!H NMR (250 MHz, CDCI3) δ: 2.75 (4H, m), 2.85 (2H, d, J = 5 Hz), 3.39 (3H, s), 3.61 (4H, t overlapping), 3.96 (3H, s), 7.04 (2H, m), 7.25 (IH, d, J = 10Hz), 7.35 (IH, s), 8.07 (3H, m); m/z (API+): 409 (MH+, 100%)
Example 111
(a) N-(2-f-Butyloxycarbonyl-5-iodo-1^3>4-tetrahydroisoquinolin-7-yl)-4- azidobenzamide
The title compound was prepared in 81% yield from the acid Preparation 28 and amine D6.
(b) N-(5-Iodo-1^3>4-tetrahydroisoquinolin-7-yl)-4-azidobenzamide, trifluoroacetate.
The title compound was prepared in 91% yield from using a method similar to that of Example 1.
/z (CI): 420 (MH+; 100%). Example 112
N-(2-Methyl-5-trifluoroacetylan_ino-lA3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4- methoxy benzamide
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.
nyz (CI): 486, 488 (MH+; 90%).
Example 113 N-(2-Methyl-5-chloro- l,23,4-tetrahydroisoquinolin-7-yl)-3-bromo-4- ethoxybenzamide
m/z (CI): 425 (MH+; expected isotope pattern).
Example 114
N-(2-Methyl-5- _doro-1^3>4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide
!H NMR (CDCl3)δ: 1.25 (3H, t J = 7Hz), 2.48 (3H, s), 2.70-3.00 (6H, m, overlapping signals), 3.59 (2H, s), 7.29 (IH, d, J = 2Hz), 7.33 (IH, d, J = 7Hz), 7.51 (IH, d, J = 2Hz), 7.71 (IH, dd, J = 7,2Hz), 7.83 (lH.brs), 8.01 (lH,dJ = 2Hz); m/z (CD: 409 (MH+; expected isotope pattern).
PHARMACOLOGICAL DATA
1. Binding Assay Method
WO 92/22293 (SmithKline Beecham) discloses compounds having anti-convulsant activity, including inter alia the compound trαns-(+)-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.
Method
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.
In order to determine the amount of "specific" binding of [3H]-Compound A, parallel assays are carried out as above in which [3H]-Compound A and tissue are incubated together in the presence of unlabelled Compound A (usually 3 μM). The amount of binding of [3H]-Compound A remaining in the presence of this unlabelled compound is defined as "non-specific" binding. This amount is subtracted from the total amount of [3H]-Compound A binding (i.e. that present in the absence of unlabelled compound) to obtain the amount of "specific" binding of [3H]-Compound A to die novel site.
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.
Results
Compounds of this invention were active in this test For example, compounds of Examples 1, 4, 5, 6, 7, 10 and 13 gave pKi values greater than 7.
2. MEST Test
The maximal electroshock seizure (MEST) threshold test in rodents is particularly sensitive for detecting potential anticonvulsant properties 1. In this model, anticonvulsant agents elevate the threshold to electrically-induced seizures whilst proconvulsants lower the seizure threshold. Method for mouse model
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 down1 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.
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.
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.
Results
Compounds of tiiis invention dosed at 10 mg kg by the oral route as a suspension in methyl cellulose and tested one hour post dosing showed an increase in seizure threshold. For example, the compounds of Examples 4, 5, 6 and 7 show increases of 24%, 36%, 90% and 23% respectively.
Method for rat model
The threshold for maximal (tonic hindlimb extension) electroshock seizures in male rats (Sprague Dawley, 80 - 150g, 6 weeks old) 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.
Results
At a dosage of 2 mg/kg p.o. at 2h, the compounds of Examples 48, 49, 51 and 67 show increases of 389%, 325%, 545% and 303% increases respectively.
References
1. Loscher, W. and Schmidt D. (1988). Epilepsy Res., 2, 145-181
2. Dixon, W.J. and Mood, A.M. (1948). J. Amer. Stat Assn., 43, 109-126
3. Litchfield, J.T. and Wilcoxon, F.Q949). J. Pharmacol, exp. Ther., 96, 99-113
4. N.Upton, T.P.Blackburn, C.A.Campbell, D.Cooper, M.L.Evans, H.J.Herdon, P.D.King, A.M.Ray, T.O.Stean, W.N.Chan, J.M.Evans and M.Thompson. (1997). B. J. Pharmacol, 121, 1679-1686

Claims

Claims
1. A compound of formula (D or a pharmaceutically acceptable salt thereof:
Figure imgf000063_0001
where Q is a monocyclic or bicyclic aryl or heteroaryl ring, R is hydrogen, , Cι_6 lkyl (optionally substituted by hydroxy or Cχ_
4alkoxy), C ^alkenyl, C ^alkynyl, C^alkylCO-, formyl, CF3CO- or
Figure imgf000063_0002
R s hydrogen, ydroxy or up to three substituents selected from halogen, NO2,
CN, N3, CF3O-, CF3S-, CF3CO-, trifluoromethyldiazirinyl, C i.galkyl, C ^alkenyl,
Cι_6alkynyl, Cx.gperfluoroalkyl, C3_6cycloalkyl, C3_6cycloa__kyl-C1_ alkyl-, C^galkylO-, C^galkylCO-, C3_6cycloalkylO-, C3.6Cycloal_.ylCO-, C3_6cycloalkyl-Cχ.4alkylO-, C3.6cycloalkyl-Cχ.4alkylCO-, acetoxy, phenyl, phenoxy, benzyloxy,
Figure imgf000063_0003
(C 1.4alkyl)2NSO2-,
(C1.4alkyl)NHSO2-, (C^alkyl^NCO- , (C^alkyDNHCO- or CONH2; or -NR^R4 where R^ is hydrogen or Cχ.4 alkyl, and
R4 is hydrogen, C^alkyl, formyl, -CO2Cχ_4alkyl or -COC^alkyl;
2 or two R groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by -OH or =O; and
X is hydrogen, halogen, C χ_6 alkoxy, C χ_6 alkyl, amino or trifluoroacetylamino;
2 but when X is hydrogen excluding compounds in which R is 2-alkoxy and when X is halogen excluding the compounds N-(7-iodo-2-methyl- 1,2,3,4- tetπdιydroisc)quinolin-5-yl)-5-benzoyl-2-methoxybenzamide, N-(7-iodo- 1,2,3,4- tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide, N-(5-iodo- 1,2,3,4- tetrahydroisoquinolin-7-yl)-5-benzoyl-2-methoxybenzamide, N-(5-iodo- 1^,3,4- tetr__hydroisoquinotin-7-yl)-2-memoxy-4-t_ifluoromethyldiazirinylbenzamide, N-(5-iodo- l,2,3,4-tetrahydroisoquinolin-7-yl)-2-memoxy-5-trifluoromemyldiazirinylber__ _unide^ N-(7-iodo- 1 ,2,3,4-tetrahydro_soquinolin-5-yl)-2-methoxy-5-trifluorome thyldiazirinyl benzamide and N-(8-fluoro-2-medιyl-l,2,3,4-tetrahydroisoquinolin-5-yl)-4-t-butyl-2- methoxybenzamide.
2. A compound of formula (LA) or (IB):
Figure imgf000064_0001
Figure imgf000064_0002
wherein R1, R2 and X are as defined in claim 1.
3. A compound selected from the group consisting of:
N-( 1 ,23,4-tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-carboxamide N-(2-methyl-l, 2, 3, 4-tetrahydroisoquinolin-7-yl)-5-chlorothiophene-2-carboxamide N-(2-methyl- 1 ,2,3,4-tetrahydro_soquinolin-7-yl)benzamide N-(2-methyl- 1 ,2,3 ,4-tetrahydroisoquino_in-7-yl)-3-chlorobenzamide N-(2-me yl-l,2,3,4-tetrahydroisoquinoUn-7-yl)-4-^utylbenzamide
N-(2-meΛyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-isø-propoxybenzamide N-(2-methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-phenoxybenzamide N-(2-methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-nitrobenzamide N-(2-meΛyl-l,2,3,4-tettahydroisoquinolin-7-yl)-4-phenylbenzamide N-(2-methyl- l,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylbenzamide N-(2-methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluorobenzamide N-(2-memyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyanobenzamide N-(2-memyl-l,2,3,4-tettahydroisoqmnolin-7-yl)-3,4-dicUoroben__amide N-(2-memyl-l,23,4-tetrahydroisoquinolin-7-yl)-4-iodobenzamide N-(2-memyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-bromobenzamide N-(2-memyl-l,2,3,4-tetrt_hydro_soquinolin-7-yl)-4-memylbert_amide N-(2-methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-nitrobenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethoxybenzamide N-(2-methyl-l,2,3,4-tetr^ydroisoquinolin-7-yl)-4-n-butylben_amide N-(2-memyl-l,2,3,4-tettahydroi_»quinolin-7-yl)-2-acetoxyber_zamide N-(2-memyl-l,2,3,4-tetπιhydiO_soquinol_n-7-yl)-3-trifluoromemylber__aιm N-(2-memyl-l,2,3,4-tettahydroisoquinolin-7-yl)-2,4-difluorobenzamide N-(2-methyl- 1 ,23,4-tetrahydroisoquinolin-7-yl)-3,4-dimethoxybenzamide
N-(2-methyl- l,2,3,4-tetι^ydro_soquinolin-7-yl)-2-fluoro-4-trifluoromethyl benzamide N-(2-memyl-l,2,3,4-teti^ydroisoquinolin-7-yl)-4^hloiO-3-nitroben__arnide N-(2-methyl- 1 ,2,3,4-tetrahydroisoqt_inolin-7-yl)-3,5-di-trifluoromethylbenzamide N-(2-methyl- 1 ^,3,4-tetrahydroisoquinolin-7-yl)-2,4-dichloro-5-fluorobenzamide N-(2-memyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluoro-5-trifluoromethyl benzamide N-(2-methyl- 1 ,2,3 ,4-tet_^ydroisoquino_in-7-yl)-3-bromo-4-methoxybenzamide N-(2-memyl-l,2,3,4-tetiahydroisoqmnolin-7-yl)-3,4,5-trimethoxybenzamide N-(2-methyl- 1 ,2,3,4-tetrahydroisc>quinoUn-7-yl)-4-trifluoromethoxybenzamide N-(2-methyl- 1 ,2,3,4-tet_^ydroisoquinolin-7-yl)-3-pivaloylbenzamide N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-wø-propoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-acetoxybenzamide N-(2-Medιyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-cyclopentyloxybenzamide N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-cyclopropylmethoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-methoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-2-naphthamide
N-(2-Methyl- 1 ,23,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-methybenzamide N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-naphthalene-l-carboxamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-methoxybenzamide N-(2-Methyl- 1 ,2,3,4- tetrahydroisoquinolin-7-yl)-4-terf-butoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-n-propoxybenzamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl) benzotriazole-5-carboxamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)benzothiazole-6-carboxamide N-(2-Methyl-l,2,3,4-tefr__hydroisoquinolin-7-yl)-2,3-dihydrobenzofuran-5-carboxamide N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylbenzimidazole-5-carboxamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-i. ø-propoxybenzamide N-(2-Memyl-l,2,3,4-tefrahydroisoquino_in-7-yl)-3-bromo-4-emoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-ethoxybenzamide N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-medιoxy-3-trifluoromethyl benzamide N-(2-Medιyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dichloro-4-methoxybenzamide N-(2-Methyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dichloro-4-edιoxybenzamide N-(2-Methyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)-3,5-dichloro-4-wø-propoxybenzamide N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylsulfonylbenzamide N-(2-methyl- 1 ,2,3,4-tettahydroisoquinolin-7-yl)-3-bromo-4-t -buty_benzamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-2-bromo-5-methoxybenzamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-fluoro-3-methoxybenzamide, hydrochloride N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-l-methylpyrazole-4-carboxamide
N-(2-Methyl- 1 ,23,4-tettahydroisoquinolin-7-yl)-4-trifluoromethylpyrazole-3- carboxamide
N-(2-Medιyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-2-methylthiazole-4-carboxamide
N-(2-Methyl-l,2,3,4-tettahydroisoquinolin-7-yl)-5-methylisoxazole-3-carboxamide N-(2-Medιyl-l,2,3,4-tefrahydroisoquino_in-7-yl)-5-terf-butylisoxazole-3-carboxamide
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-methoxyisoxazole-5-carboxamide hydrochloride
N-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)indole-2-carboxamide.
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-wø-propylbenzamide, hydrochloride
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-wø-propylbenzamide, hydrochloride
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-fluoro-4-methoxybenzamide
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-/ι-propoxybenzamide N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethoxybenzamide
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-n-propoxybenzamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-iodo-4-medιoxybenzamide
N-(2-Methyl-l,2,3,4-tett_Λydroisoquinolin-7-yl)-4-i.ø-propoxy-3-trifluoromethyl benzamide
N-(2-Medιyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-chloro-3-methoxybenzamide
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-_ι-propoxy-3-trifluoromethyl benzamide
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-terr-butylbenzamide, hydrochloride
N-(2-Medιyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxybenzamide hydrochloride.
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-fluoro-3-methylbenzamide, hydrochloride
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-wø-propylbenzamide N-(2-Methyl- 1 ,23,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-ethylbenzamide hydrochloride
N-(2-Medιyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-i_O-propyl-3-trifluoromethyl- benzamide hydrochloride N-(2-Medιyl- 1 ,2,3,4-tetiahydroisoquinolin-7-yl)-4-ethyl-3-trifluoromethylbenzamide hydrochloride
N-(2-Medιyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-isø-propoxybenzamide hydrochloride N-(l,2,3,4-Tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-me yl-3-methylsulfonyl-benzamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethyl-3-methylsulfonylbenzamide
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-methylsulfonyl-4-wø- propylbenzamide N-(2-Methyl-l,23,4-tetrahydroisoquinolin-7-yl)-3-methylsulfonyl-4-methoxybenzamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-trifluoroacetylbenzamide, hydrochloride
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-pentafluoroethyl- benzamide hydrochloride N-(2-/i-Propyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
N-(2-/ι-Propyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3- trifluoromethylbenzamide
N-(2-n-Propyl-l,2,3,4-tetrahydroisquinolin-7-yl)-3-chloro-4-i.ø-propoxybenzamide
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-cyano-4-wø-butylbenzamide hydrochloride
N-(2-Methyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-i.ø-butyl-3-trifluoromethyl- benzamide hydrochloride
N-(2-Ethyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
N-(2-Ethyl- 1 ,2,3,4-tetrahydro-isoquinolin-7-yl)-4-methoxy-3-trifluoromethyl benzamide N-(2-isø-Propyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
N-(2-isø-Propyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-medιoxy-3-trifluoromethyl benzamide
N-(2-Medιyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-ethoxy-3-methylsulfonyl-benzamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-oxochroman-6-carboxamide hydrochloride
N-(2-Formyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3- trifluoromethylbenzamide
N-(2-Hydroxyedιyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
N-(2-Hydroxyethyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide N-(2-Methyl- 1 ,2,3,4-tefrahydroisoquinolin-7-yl)-4-phenylmethoxy-3-trifluoromethyl benzamide
N-(2-Methyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-hydroxy-3-trifluoromethyl benzamide N-(2-Methoxyethyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-i.ø- propoxybenzamide
N-(2-Methoxyethyl-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-iyø- propoxybenzamide N-(2-Medιoxyethyl- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3- trifluoromethylbenzamide
N-(5-Iodo- l,23,4-tetrahydroisoquinolin-7-yl)-4-azidobenzamide, trifluoroacetate
N-(2-Methyl-5-trifluoroacetylamino- 1 ,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4- methoxybenzamide N-(2-Medιyl-5-chloro-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethoxybenzamide
N-(2-Medιyl-5-chloro-l,2,3,4-tetrahydroisoquinolin-7-yl)-3-bromo-4-ethylbenzamide
4. A pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated witii 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 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) which comprises a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
5. A method of treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated witii 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 according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof.
6. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for me 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 neurodystiiesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction and amyotrophic lateral sclerosis (ALS)
7. A process for the preparation of a compound according to any one of claims 1 to 3, which comprises reacting a compound of formula (ID
Figure imgf000069_0001
where R1^ is Ri as defined for formula (I) or a group convertible to R* and X is as defined in claim 1 with a compound of formula (IH)
Figure imgf000070_0001
where Q is as defined in formula (D, Y is Cl or OH, and R2^ groups are independenύy R2 as defined for formula (I) or groups convertible to R2, and where required converting an R^ or R ^ group to a R* or R2 group, converting one R* or R2 group to another R or R2 group, converting a salt product to die free base or another pharmaceutically acceptable salt or converting a free base product to a pharmaceutically acceptable salt
PCT/GB1998/000782 1997-03-18 1998-03-16 Substituted isoquinoline derivatives and their use as anticonvulsants WO1998041508A1 (en)

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PL335676A PL192116B1 (en) 1997-03-18 1998-03-16 Substitution derivatives of isoquinoline and their applications as anticonvulsants
AU64128/98A AU737955B2 (en) 1997-03-18 1998-03-16 Substituted isoquinoline derivatives and their use as anticonvulsants
EP98909647A EP0968190A1 (en) 1997-03-18 1998-03-16 Substituted isoquinoline derivatives and their use as anticonvulsants
BR9809047-0A BR9809047A (en) 1997-03-18 1998-03-16 Substituted isoquinoline derivatives and their use as anticonvulsants
CA002284218A CA2284218A1 (en) 1997-03-18 1998-03-16 Substituted isoquinoline derivatives and their use as anticonvulsants
KR1019997008443A KR100568654B1 (en) 1997-03-18 1998-03-16 Substituted Isoquinoline Derivatives and Their Use as Anticonvulsants
NZ337424A NZ337424A (en) 1997-03-18 1998-03-16 Substituted isoquinoline derivatives and their use as anticonvulsants and in the treatment and/or prophylaxis of other neurological disorders
IL13175698A IL131756A0 (en) 1997-03-18 1998-03-16 Substituted isoquinoline derivatives and their use as anticonvulsants
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WO1999021836A1 (en) * 1997-10-24 1999-05-06 Smithkline Beecham Plc Substituted isoquinoline derivatives and their use as anticonvulsants
WO1999031068A1 (en) * 1997-12-17 1999-06-24 Smithkline Beecham Plc Substituted isoquinoline derivatives and their use as anticonvulsants
WO2000009486A1 (en) * 1998-08-11 2000-02-24 Smithkline Beecham P.L.C. Substituted isoquinoline derivatives and their use as anticonvulsivants
WO2000032183A1 (en) * 1998-12-03 2000-06-08 Ortho-Mcneil Pharmaceutical, Inc. Topiramate and related derivatives for treating schizophrenia
WO2001002366A2 (en) * 1999-07-02 2001-01-11 Smithkline Beecham P.L.C. Substituted isoquinoline derivatives and their use as inticonvulsants
US6291476B1 (en) * 1999-05-12 2001-09-18 Ortho-Mcneil Pharmaceutical, Inc. Pyrazole carboxamides useful for the treatment of obesity and other disorders
WO2003068749A1 (en) * 2002-02-15 2003-08-21 Glaxo Group Limited Vanilloid receptor modulators
WO2003095428A1 (en) * 2002-05-10 2003-11-20 Glaxo Group Limited Dopamine receptor modulators as antipsychotic agents
WO2004014388A1 (en) * 2002-08-13 2004-02-19 Warner-Lambert Company Llc 6,6-fused heteroaryl derivatives as matrix metalloproteinase inhibitors
WO2004046133A1 (en) * 2002-11-15 2004-06-03 Merck Sharp & Dohme Limited Amino-heterocycles as vr-1 antagonists for treating pain
GB2406856A (en) * 2003-10-07 2005-04-13 Renovis Inc Novel amide compounds as ion channel ligands and uses thereof
WO2005072681A2 (en) * 2004-01-23 2005-08-11 Amgen Inc. Vanilloid receptor ligands and their use in treatments of inflammatory and neurotic pain.
GB2413129A (en) * 2003-10-07 2005-10-19 Renovis Inc Aromatic amide compounds as ion channel ligands and uses thereof
WO2006032851A1 (en) * 2004-09-20 2006-03-30 Biolipox Ab Pyrazole compounds useful in the treatment of inflammation
WO2006068592A1 (en) * 2004-12-21 2006-06-29 Astrazeneca Ab New benzothiazolecarboxamides
KR100760446B1 (en) * 1999-07-02 2007-10-04 사노피-아벤티스 Antipsychotic Cyclic ?-Aralkyl Amines
US7585878B2 (en) 2003-06-12 2009-09-08 Astellas Pharma Inc. Benzamide derivative or salt thereof
US8003663B2 (en) 2006-08-01 2011-08-23 Glaxo Group Limited Pyrazolo[3,4-b]pyridine compounds, and their use as PDE4 inhibitors

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CN106608901B (en) * 2015-10-22 2020-10-16 彭莉 Dihydroxydimethyltetrahydroisoquinoline-3-formyl-Lys (Lys-Ala), and synthesis, activity and application thereof
CN111138359A (en) * 2020-01-19 2020-05-12 浙江农林大学暨阳学院 Method for preparing 3-carbonyl-4-azido-N-benzenesulfonyl-1, 2,3, 4-tetrahydroisoquinoline compounds

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Cited By (33)

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Publication number Priority date Publication date Assignee Title
WO1999021836A1 (en) * 1997-10-24 1999-05-06 Smithkline Beecham Plc Substituted isoquinoline derivatives and their use as anticonvulsants
WO1999031068A1 (en) * 1997-12-17 1999-06-24 Smithkline Beecham Plc Substituted isoquinoline derivatives and their use as anticonvulsants
US6248754B1 (en) 1997-12-17 2001-06-19 Smithkline Beecham, P.L.C. Substituted isoquinoline derivatives and their use as anticonvulsants
WO2000009486A1 (en) * 1998-08-11 2000-02-24 Smithkline Beecham P.L.C. Substituted isoquinoline derivatives and their use as anticonvulsivants
US6492378B1 (en) 1998-08-11 2002-12-10 Smithkline Beecham P.L.C. Substituted isoquinoline derivatives and their use as anticonvulsivants
WO2000032183A1 (en) * 1998-12-03 2000-06-08 Ortho-Mcneil Pharmaceutical, Inc. Topiramate and related derivatives for treating schizophrenia
US6291476B1 (en) * 1999-05-12 2001-09-18 Ortho-Mcneil Pharmaceutical, Inc. Pyrazole carboxamides useful for the treatment of obesity and other disorders
US6770657B2 (en) 1999-07-02 2004-08-03 Smithkline Beecham P.L.C. Compounds
US6492388B1 (en) 1999-07-02 2002-12-10 Smithkline Beecham P.L.C. Substituted isoquinoline derivatives and their use as inticonvulsants
WO2001002366A3 (en) * 1999-07-02 2001-04-19 Smithkline Beecham Plc Substituted isoquinoline derivatives and their use as inticonvulsants
AU762716B2 (en) * 1999-07-02 2003-07-03 Smithkline Beecham Plc Novel compounds
KR100760446B1 (en) * 1999-07-02 2007-10-04 사노피-아벤티스 Antipsychotic Cyclic ?-Aralkyl Amines
US7105536B2 (en) 1999-07-02 2006-09-12 Smithkline Beecham Plc Compounds
EP1367055A1 (en) * 1999-07-02 2003-12-03 Smithkline Beecham Plc Isoquinolinyl carboxamides and their use as anticonvulsants
WO2001002366A2 (en) * 1999-07-02 2001-01-11 Smithkline Beecham P.L.C. Substituted isoquinoline derivatives and their use as inticonvulsants
US7538121B2 (en) 2002-02-15 2009-05-26 Glaxo Group Limited Vanilloid receptor modulators
EP2033953A1 (en) * 2002-02-15 2009-03-11 Glaxo Group Limited Vanilloid receptor modulators
WO2003068749A1 (en) * 2002-02-15 2003-08-21 Glaxo Group Limited Vanilloid receptor modulators
WO2003095428A1 (en) * 2002-05-10 2003-11-20 Glaxo Group Limited Dopamine receptor modulators as antipsychotic agents
WO2004014388A1 (en) * 2002-08-13 2004-02-19 Warner-Lambert Company Llc 6,6-fused heteroaryl derivatives as matrix metalloproteinase inhibitors
WO2004046133A1 (en) * 2002-11-15 2004-06-03 Merck Sharp & Dohme Limited Amino-heterocycles as vr-1 antagonists for treating pain
US7442701B2 (en) 2002-11-15 2008-10-28 Merck Sharp & Dohme Ltd. Amino-heterocycles as VR-1 antagonists for treating pain
US7855198B2 (en) 2003-06-12 2010-12-21 Astellas Pharma Inc. Benzamide derivative or salt thereof
US7585878B2 (en) 2003-06-12 2009-09-08 Astellas Pharma Inc. Benzamide derivative or salt thereof
GB2413129A (en) * 2003-10-07 2005-10-19 Renovis Inc Aromatic amide compounds as ion channel ligands and uses thereof
US7338950B2 (en) 2003-10-07 2008-03-04 Renovis, Inc. Amide compounds as ion channel ligands and uses thereof
GB2406856B (en) * 2003-10-07 2005-10-19 Renovis Inc Amide compounds as ion channel ligands and uses thereof
GB2406856A (en) * 2003-10-07 2005-04-13 Renovis Inc Novel amide compounds as ion channel ligands and uses thereof
WO2005072681A3 (en) * 2004-01-23 2005-09-22 Amgen Inc Vanilloid receptor ligands and their use in treatments of inflammatory and neurotic pain.
WO2005072681A2 (en) * 2004-01-23 2005-08-11 Amgen Inc. Vanilloid receptor ligands and their use in treatments of inflammatory and neurotic pain.
WO2006032851A1 (en) * 2004-09-20 2006-03-30 Biolipox Ab Pyrazole compounds useful in the treatment of inflammation
WO2006068592A1 (en) * 2004-12-21 2006-06-29 Astrazeneca Ab New benzothiazolecarboxamides
US8003663B2 (en) 2006-08-01 2011-08-23 Glaxo Group Limited Pyrazolo[3,4-b]pyridine compounds, and their use as PDE4 inhibitors

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PL192116B1 (en) 2006-08-31
NZ337424A (en) 2001-08-31
AR012092A1 (en) 2000-09-27
BR9809047A (en) 2000-08-01
TR199902283T2 (en) 1999-12-21
IL131756A0 (en) 2001-03-19
EP0968190A1 (en) 2000-01-05
CN1183116C (en) 2005-01-05
CO4950553A1 (en) 2000-09-01
CA2284218A1 (en) 1998-09-24
TW555694B (en) 2003-10-01
CN1255124A (en) 2000-05-31
KR20000076342A (en) 2000-12-26
JP3690423B2 (en) 2005-08-31
AU737955B2 (en) 2001-09-06
JP2001515504A (en) 2001-09-18
NO994510D0 (en) 1999-09-17

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