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WO1999052857A1 - Nouveaux composes - Google Patents

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Publication number
WO1999052857A1
WO1999052857A1 PCT/GB1999/001135 GB9901135W WO9952857A1 WO 1999052857 A1 WO1999052857 A1 WO 1999052857A1 GB 9901135 W GB9901135 W GB 9901135W WO 9952857 A1 WO9952857 A1 WO 9952857A1
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WIPO (PCT)
Prior art keywords
alkyl
hydrogen
compound
formula
butyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB1999/001135
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English (en)
Inventor
Barry Sidney Orlek
Mervyn Thompson
Robert William Ward
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Publication of WO1999052857A1 publication Critical patent/WO1999052857A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.
  • benzamide compounds of formula (I) and (la) 10 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 15 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, 20 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) (hereinafter "the Disorders”).
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • a first aspect of the present invention provides a compound of formula (I) or pharmaceutically acceptable salt thereof:
  • n and p are independently integers from 1 to 4 and (n+p) is from 2 to 5;
  • R is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3O-, CF3S-, CF3CO-, trifluoromethyldiazirinyl, C 1 . 6 alkyl, C ⁇ galkenyl, Ci .galkynyl, Ci.gperfluoroalkyl, C3_6cycloalkyl, C 3 . 6 cycloalkyl-C 1 _ 4 alkyl-, C 1 _ 6 alkylO-, C j . 6 alkylCO-,
  • R 4 is hydrogen or C ⁇ g alkyl, R is hydrogen or C ⁇ 6 alkyl.
  • the ring system represented by a broken circle is typically optionally substituted phenyl or optionally substituted thiophenyl.
  • phenyl When two R groups form a carbocyclic ring, this is typically a 5-7 membered ring, so that the broken circle may be a naphthalene or an indane or indanone ring system.
  • a second aspect of the present invention provides a compound of formula (la) or pharmaceutically acceptable salt thereof:
  • n and p are independently integers from 1 to 4 and (n+p) is from 2 to 5;
  • R 1 is C ⁇ alkylO-;
  • R 2 is hydrogen, halogen, CN, N 3 , CF 3 , CF 3 O-, CF3S-, CF 3 CO-, C ⁇ _ 6 alkyl, C3.6 c y loa ⁇ ylC3.
  • R 3 is hydrogen, halogen, NO 2 , CN, N 3 ,
  • R 7 is hydrogen, C ⁇ _ alkyl, -CHO,
  • R 4 is hydrogen or C ⁇ _g alkyl
  • R 5 is hydrogen or C,. 6 alkyl.
  • the compounds of this invention are typically amino-indanyl-benzamides, such as amino- (indan-4-yl)-benzamides, amino-(indan-5-yl)-benzamides or amino-(indan- ⁇ -yl)- benzamides, or amino-tetralinyl-benzamides, such as amino-(tetralin-5-yl)-benzamides or amino-(tetralin-7-yl)-benzamides.
  • amino-indanyl-benzamides such as amino- (indan-4-yl)-benzamides, amino-(indan-5-yl)-benzamides or amino-(indan- ⁇ -yl)- benzamides
  • amino-tetralinyl-benzamides such as amino-(tetralin-5-yl)-benzamides or amino-(tetralin-7-yl)-benzamides.
  • R 1 alkoxy groups are typically based on straight chain alkyl groups, but in general alkyl groups, including alkyl groups that are part of another moiety, may be straight chain or branched.
  • Aromatic rings, including rings that are part of another moiety, may optionally be substituted with one or more independently selected halogen or C ⁇ g alkyl, C j _g alkoxy or C j _g alkylcarbonyl.
  • Suitable C ⁇ cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Suitable halo substituents include fluoro, chloro, iodo and bromo.
  • a suitable group of compounds of formula (la) have R' as methoxy, ethoxy or n-propoxy
  • R 2 as hydrogen, methoxy, bromo, chloro, iodo, acetyl, pivaloyl, wo-butyroyl, benzoyl, trifluoromethyl, trifluoroacetyl, n-propylsulfonyl, wo-propylsulfonyl or dimethylsulfamoyl
  • R 3 as hydrogen, methyl, ethyl, w-butyl, t-butyl, methoxy, ethoxy, w ⁇ -propoxy, «-butoxy, benzyloxy, amino, acetylamino, nitro, benzoyl, iodobenzoyl, chloro or azido
  • R 4 as hydrogen, methyl, ethyl or propyl R-> as hydrogen, methyl, ethyl or propyl.
  • N-(2-dimethylaminoindan-5-yl)-5-bromo-2,4-dimethoxybenzamide N-( 1 -amino- 1 ,2,3 ,4-tetrahydronaphthalen-7-yl)-5-bromo-2,4-dimethoxybenzamide
  • these compounds When synthesised, these compounds are often in salt form, typically the hydrochloride or trifiuoroacetate, 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 administration of such compounds to a mammal may be by way of oral, parenteral, sub-lingual 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) or (la) 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.
  • 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, i ⁇ jectable and infusable solutions or suspensions or suppositories.
  • Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl />-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monoole
  • Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
  • fluid unit dose forms are prepared containing the compound and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
  • compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
  • the present invention provides a pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive
  • Giles de la Tourette's syndrome traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and/or amyotrophic lateral sclerosis (ALS), which comprises a compound of formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • the present invention also provides a method of treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post- traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • Giles de la Tourette's syndrome traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and/or amyotrophic lateral sclerosis (ALS) comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (I) or (la), 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 (la), or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • 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/or amyotrophic lateral sclerosis (ALS).
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • the invention provides the use of a compound of formula (I) or (la), or a pharmaceutically acceptable salt or solvate, thereof as a therapeutic agent, in particular for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • Giles de la Tourette's syndrome traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and/or amyotrophic lateral sclerosis (ALS).
  • MS multiple sclerosis
  • ALS amyotrophic lateral sclerosis
  • Another aspect of the invention provides a process for the preparation of compounds of formula (la), which comprises reacting a compound of formula (II)
  • n and p are as defined for formula (la) and R ⁇ and R ⁇ are R 4 and R 5 as defined for formula (la) or a group convertible to R 4 and R- 1
  • Rl A , R 2A ' and R 3A are respectively R , R 2 ' and R 3 as defined for formula (la) or groups convertible to R , R > and R 3 , and where required converting a R A , R 2A ' R 3A , R 4A or R ⁇ A group to a R 1 , R 2 ' R 3 , R 4 or R 5 group, converting one R , R 2 ' R 3 , R 4 or R 5 group to another R 1 , R 2 ' R 3 , R 4 or R 5 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.
  • conventional conditions for condensation of aromatic 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.
  • the NH 2 group is converted to NR 4A R ⁇ , where R 4A and R ⁇ are preferably protecting groups convertible to the intended R and R , especially when R and R are intended to be hydrogen.
  • R 4A and R ⁇ are preferably protecting groups convertible to the intended R and R , especially when R and R are intended to be hydrogen.
  • a suitable procedure is to convert the amine to a carbamic acid ester, for example by reaction with di-t-butyl carbonate to form the t-butyl carbamate, typically in a suitable solvent such as tetrahydrofuran or dioxan in the presence of a suitable base such as triethylamine and dimethylaminopyridine.
  • the nitro group is hydrogenated to obtain the compound of formula (II).
  • this is carried out in an ethanolic solution using a palladium/carbon catalyst, typically at ambient pressure and temperature.
  • any protecting group can be removed under conventional conditions.
  • the t-butyl carbamic acid ester can be returned to the amine group by treatment
  • Compounds of formula (IV) can be prepared by introducing the nitro group into the corresponding amine, for example reacting the amine hydrochloride with potassium nitrate in sulphuric acid.
  • a nitro compound such as indanone or tetralone, can be reacted with methoxylamine hydrochloride to introduce a methoximino group, which can be converted into amino by treatment with a borane-tetrahydrofuran complex.
  • the nitro compound D2 (0.47g, 1.62 mmol) in ethanol (40ml) was hydrogenated over 10% palladium on carbon (60mg) at atmospheric pressure and room temperature. After 3h. the
  • the title compound D10 was prepared from l-amino-5-nitroindane and di-t- butyldicarbonate similar to that method used in Description 2.
  • the title compound Dl 1 was prepared from the nitro compound D10 using a method similar to that of Description 3.
  • 4-Amino-2-methoxy benzoic acid methyl ester (15g, 82.7mmol) was dissolved in sulfuric acid ( 80ml of a 25% solution). The solution was cooled in an ice bath and diazotized with saturated sodium nitrite solution (8.57g, 124mmol) maintaining the temperature below 5°C. The diazonium solution was poured slowly into boiling sulphuric acid (1L of a 3% solution) and the mixture was heated for an additional 5 mins. The mixture was then allowed to cool before being extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate and concentration in vacuo gave a brown solid (9.7g).
  • Trifluoroacetic acid 35ml was cooled in an ice bath. 4-Ethoxy-2-methoxy- benzoic acid methyl ester (4.85g, 23mmol) was then added slowly. N-chloromorpholine (3.64g, 29.9mmol) was then added dropwise maintaining the reaction mixture temperature below 10°C. The ice bath was removed and the mixture stirred under argon for 12h at room temperature. The solvent was then removed in vacuo and the residue taken up in ethyl acetate and washed wth water. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford a brown oil which was triturated with ether and 60/80 petrol.
  • the title compound was prepared in an analogous manner to Preparation 19 from 2- ⁇ tert- butyldimethylsilanyloxymethyl)-4-bromoanisole (500 mg, 1.51 mmol).
  • the crude product was purified by chromatography (SiO 2 , 50% ether/petrol) to give the title compound as a colourless oil (63%).
  • the acetophenone of Preparation 25 (1 l.Og, 53 mmol) was added to a solution of sodium hydroxide (28.68g), sodium hypochlorite (182ml, 12% w/w) and water (70ml) at 80°C with stirring. After heating for 1.25h, the mixture was cooled to 0°C and a solution of sodium metabisulphite (41.1 g) in water (170ml) was added. The mixture was stirred for 15 min and then acidified (pHl) with cone. HCl (45ml). Extraction with ethyl acetate gave the title compound as a white solid (8.9g).
  • n-Butyllithium (11.43ml, 0.0183 mole, 1.6M in hexane) was slowly added to a solution of 5-bromo-2-methoxy benzyl TBDMS ether in tetrahydrofuran (30ml) over 45 mins at - 78°C.
  • the reaction mixture was maintained under argon at -78°C for lh.
  • N,O- dimethylhydroxy pivaloyl amide (2.43g, 0.0167 mole) was added dropwise with stirring at -78°C.
  • the resulting mixture was allowed to stir at -78°C for 2.5h, quenched with NH 4 C1 solution and allowed to warm to room temperature.
  • Example 1(b) The compound of Example 1(b) (150mg; 0.30 mmol) and 40% aqueous formaldehyde (0.12ml; 1.5 mmol) in acetonitrile (3ml) was stirred at 0°C and sodium cyanoborohydride (38mg; 1 mmol) added.
  • Chromatography on Kieselgel 60 in 10% methanol-ethyl acetate gave the title compound as an off white solid (44mg; 35%).
  • the title compound was prepared from the N-boc amine (a) using a method similar to that of Examples 1(b) and 5(b).
  • WO 92/22293 discloses compounds having anti-convulsant activity, including inter alia the compound tr ⁇ /w-(+)-6-acetyl-4S-(4-fluorobenzoylamino)- 3,4-dihydro-2,2-dimethyl-2H-l-benzopyran-3R-ol (hereinafter referred to as Compound A). It has been found that the compounds of WO 92/22293 bind to a novel receptor obtainable from rat forebrain tissue, as described in WO 96/18650 (SmithKline Beecham). The affinity of test compounds to the novel receptor site is assessed as follows.
  • Whole forebrain tissue is obtained from rats.
  • the tissue is first homogenised in buffer (usually 50mM Tris/HCl, pH 7.4).
  • the homogenised tissue is washed by centrifugation and resuspension in the same buffer, then stored at -70°C until used.
  • the affinity of the binding of test compounds to the novel site can be estimated by incubating together [3H]-Compound A and tissue in the presence of a range of concentrations of the compound to be tested.
  • the decrease in the level of specific [3H]- Compound A binding as a result of competition by increasing concentrations of the compound under test is plotted graphically, and non-linear regression analysis of the resultant curve is used to provide an estimate of compound affinity in terms of pKi value.
  • the maximal electroshock seizure (MEST) threshold test in rodents is particularly sensitive for detecting potential anticonvulsant properties! .
  • anticonvulsant agents elevate the threshold to electrically-induced seizures whilst proconvulsants lower the seizure threshold.
  • mice (naive male, Charles River, U.K. CD-I strain, 25 - 30g) are randomly assigned to groups of 10 - 20 and dosed orally or intraperitoneally at a dose volume of 10 ml/kg with various doses of compound (0.3 - 300 mg/kg) or vehicle. Mice are then subjected at 30 or 60 min post dose to a single electroshock (0.1 sec, 50Hz, sine wave form) administered via corneal electrodes. The mean current and standard error required to induce a tonic seizure in 50%) (CC50) of the mice in a particular treatment group is determined by the 'up and down' method of Dixon and Mood (1948)2. Statistical comparisons between vehicle- and drug-treated groups are made using the method of Litchfield and Wilcoxon (1949)3.
  • the CC50 In control animals the CC50 is usually 14 - 18 mA. Hence the first animal in the control group is subjected to a current of 16 mA. If a tonic seizure does not ensue, the current is increased for a subsequent mouse. If a tonic convulsion does occur, then the current is decreased, and so on until all the animals in the group have been tested.
  • the percentage increase or decrease in CC50 for each group compared to the control is calculated.
  • Drugs are suspended in 1% methyl cellulose.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux composés correspondant à la formule (I) ou leurs sels pharmaceutiquement acceptables dans laquelle le cercle éclaté est un aryle monocyclique ou bicyclique ou un noyau hétéroaryle; n et p sont indépendamment des nombres entiers entre 1 et 4, (n+p) étant compris entre 2 et 5; R est hydrogène ou jusqu'à trois substitutifs sélectionnés parmi halogène, NO2, CN, N3, CF3O-, CH3S-, CF3CO-, trifluorométhyldiazirinyle, C1-6alkyle, C1-6alcényle, C1-6alkynyle, C1-6perfluoroalkyle, C1-6cycloalkyle, C3-6cycloalkyle-C1-4alkyle, C1-6alkylO-, C1-6alkylCO, C3-6cycloalkylO, C3-6cycloalkylCO, C3-6cycloalkyl-C1-4alkylO-, C3-6cycloalkyl-C1-4alkylCO-, phényle, phénoxy, benzyloxy, benzoyle, phényl-C1-4alkyle, C1-6alkylS-, C1-6alkylSO2-, (C1-4alkyl)2NSO2-, (C1-4alkyl)2NHSO2-, (C1-4alkyl)2NCO-, (C1-4alkyl)NHCO, CONH2, CF3SO2, C1-6alcényle, C1-6alkynyle ou C1-6hydroxyalkyle, ou -NRaRb dans lequel Ra est hydrogène ou C¿1-4?alkyle, et R?b¿ est hydrogène, C¿1-4?alkyle, formyle, -CO2C1-4alkyle ou -COC1-4alkyle; ou les deux groupes R forment ensemble un noyau carbocyclique, saturé ou insaturé et non substitué ou substitué par -OH ou par =O; et R?4¿ est hydrogène ou C¿1-6?alkyle; ou R?5¿ est hydrogène ou C¿1-6?alkyle. Les substances de l'invention servant au traitement et à la prophylaxie de certains troubles du SNC.
PCT/GB1999/001135 1998-04-14 1999-04-14 Nouveaux composes Ceased WO1999052857A1 (fr)

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GB9807903.1 1998-04-14
GBGB9807903.1A GB9807903D0 (en) 1998-04-14 1998-04-14 Novel compounds

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WO1999052857A1 true WO1999052857A1 (fr) 1999-10-21

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PCT/GB1999/001135 Ceased WO1999052857A1 (fr) 1998-04-14 1999-04-14 Nouveaux composes

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WO (1) WO1999052857A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
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US7115750B1 (en) 1999-09-20 2006-10-03 Takeda Pharmaceutical Company Limited Melanin concentrating hormone antagonist
WO2007120827A3 (fr) * 2006-04-14 2007-12-13 Novartis Ag Utilisation de biarylcarboxamides dans le traitement de troubles associés à la voie hedgehog
KR101023635B1 (ko) 2006-03-06 2011-03-22 니뽄 다바코 산교 가부시키가이샤 4-옥소퀴놀린 화합물 제조 방법
US8232401B2 (en) 2002-11-20 2012-07-31 Japan Tobacco Inc. 4-oxoquinoline compound and use thereof as HIV integrase inhibitor
US8420821B2 (en) 2006-03-06 2013-04-16 Japan Tobacco Inc. Process for production of 4-oxoquinoline compound
JP2017523194A (ja) * 2014-07-30 2017-08-17 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Ｔａａｒ調節因子としての６−アミノ−５，６，７，８−テトラヒドロナフタレン−２−イル又は３−アミノクロマン−７−イル誘導体

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US3022308A (en) * 1957-12-03 1962-02-20 Irwin Neisler And Co Decahydrobenzopyridine quaternaries
US3674791A (en) * 1968-03-26 1972-07-04 Marion Laboratories Inc Benzamido 2 lower alkyl decahydroisoquinolines

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US3022308A (en) * 1957-12-03 1962-02-20 Irwin Neisler And Co Decahydrobenzopyridine quaternaries
US3674791A (en) * 1968-03-26 1972-07-04 Marion Laboratories Inc Benzamido 2 lower alkyl decahydroisoquinolines

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7115750B1 (en) 1999-09-20 2006-10-03 Takeda Pharmaceutical Company Limited Melanin concentrating hormone antagonist
US8232401B2 (en) 2002-11-20 2012-07-31 Japan Tobacco Inc. 4-oxoquinoline compound and use thereof as HIV integrase inhibitor
KR101023635B1 (ko) 2006-03-06 2011-03-22 니뽄 다바코 산교 가부시키가이샤 4-옥소퀴놀린 화합물 제조 방법
US8383819B2 (en) 2006-03-06 2013-02-26 Japan Tobacco Inc. Method for producing 4-oxoquinoline compound
US8420821B2 (en) 2006-03-06 2013-04-16 Japan Tobacco Inc. Process for production of 4-oxoquinoline compound
WO2007120827A3 (fr) * 2006-04-14 2007-12-13 Novartis Ag Utilisation de biarylcarboxamides dans le traitement de troubles associés à la voie hedgehog
JP2017523194A (ja) * 2014-07-30 2017-08-17 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Ｔａａｒ調節因子としての６−アミノ−５，６，７，８−テトラヒドロナフタレン−２−イル又は３−アミノクロマン−７−イル誘導体

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