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WO1992002502A1 - Piperidines a substitution n-hydrocarbyle en position 4, leur preparation et leur utilisation comme agents de blocage du calcium - Google Patents

Piperidines a substitution n-hydrocarbyle en position 4, leur preparation et leur utilisation comme agents de blocage du calcium Download PDF

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Publication number
WO1992002502A1
WO1992002502A1 PCT/GB1991/001340 GB9101340W WO9202502A1 WO 1992002502 A1 WO1992002502 A1 WO 1992002502A1 GB 9101340 W GB9101340 W GB 9101340W WO 9202502 A1 WO9202502 A1 WO 9202502A1
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WO
WIPO (PCT)
Prior art keywords
ethyl
compound
pentylpiperidine
phenyl
title compound
Prior art date
Application number
PCT/GB1991/001340
Other languages
English (en)
Inventor
Thomas Henry Brown
David Gwynn Cooper
Original Assignee
Smith Kline & French Laboratories Limited
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 GB909017224A external-priority patent/GB9017224D0/en
Priority claimed from GB919107757A external-priority patent/GB9107757D0/en
Application filed by Smith Kline & French Laboratories Limited filed Critical Smith Kline & French Laboratories Limited
Priority to KR1019930700352A priority Critical patent/KR930701402A/ko
Priority to CA002088491A priority patent/CA2088491A1/fr
Publication of WO1992002502A1 publication Critical patent/WO1992002502A1/fr

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Classifications

    • 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
    • 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
    • A61P25/08—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
    • A61P25/28—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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4

Definitions

  • the present invention relates to 4-substituted piperidine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
  • the present invention therefore provides, in a first aspect, compounds of structure (I);
  • R is C 1-8 alkyl (phenyl)p, C 2-8 alkenyl (phenyl)p,
  • p is 0 to 2 ;
  • n 0 to 6 ;
  • A is a bond, oxygen, sulphur or NR 1 ;
  • R 1 is hydrogen, C 1-8 alkyl or phenylC 1-4 alkyl
  • n 0 to 3;
  • Ar is aryl or heteroaryl, each of which may be
  • R is C 1-8 alkyl(phenyl)p, C 2-8 alkenyl-(phenyl)p, C 2-8 alkynyl(phenyl)p, C 3-8 cycloalkyl or
  • alkylcycloalkyl, alkylphenyl, alkenylphenyl and alkynylphenyl groups are linked to the piperidine nitrogen atom via the alkyl, alkenyl and alkynyl moieties respectively.
  • R is C 1-8 galkyl(phenyl)p in which p is 0 or 1, i.e. C 1-8 alkyl, such as n-pentyl, or phenylC 1-8 alkyl such as phenylpropyl, or R is C 2-8 alkenyl(phenyl)p where p is 1, such as cinnamyl.
  • n is 0 to 6; preferably n is 0 to 3; most preferably n is 2 or 3.
  • n is 0 to 3; preferably m is 0 or 1;
  • A is a bond, oxygen, sulphur or NR 1 ;
  • A is oxygen or sulphur; most preferably A is oxygen.
  • A is oxygen
  • n is preferably 2 and m is preferably 0.
  • Ar is optionally substituted aryl or heteroaryl; preferably Ar is optionally substituted aryl.
  • Suitable aryl groups include, for example,
  • unsaturated monocyclic and unsaturated or partially saturated bicyclic ring systems of up to 10 carbon atoms, such as, for example, phenyl, naphthyl and
  • Suitable substituted phenyl rings include, for example, phenyl rings substituted by a C 1-2 alkylenedioxy group such as a 3,4-methylenedioxy group or by 1 to 3 substituents selected from halogen, C 1-4 alkoxy,
  • phenyl can be H or C 1-4 alkyl), OCF 3 , C 1-6 alkyl, trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenylC 1-4 alkyl and optionally substituted phenylC 1-4 alkoxy.
  • Suitable optionally substituted phenylC 1-4 alkyl groups include, for example benzyl.
  • Suitable optionally substituted phenylC 1-4 alkoxy groups include, for example
  • phenylC 1-4 alkoxy groups include for example halogen, C 1-4 alkyl, C 1-4 alkoxy, nitro and trifluoromethyl groups.
  • Suitable heteroaryl rings include, for example, unsaturated monocyclic and unsaturated or partially saturated bicyclic ring systems of up to 10 carbon atoms containing lat "least one heteroatom, such as pyridyl, thienyl, quinolinyl, tetrahydroquxnolxnyl and imidazolyl rings.
  • the heteroaryl ring can be linked to the
  • Suitable substituents for said heteroaryl rings include, for example, 1 to 3 substituents selected from halogen, C 1-4 alkyl and C 1-4 alkoxy.
  • Alkyl groups present in the compounds of structure (I), alone or as part of another group, can be straight or branched. It will be appreciated that for use in medicine a salt of a compound (I) should be pharmaceutically
  • salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically acceptable inorganic or organic acid addition salts.
  • Other nonpharmaceutically acceptable salts may be used for example as intermediates and are included within the scope of this invention.
  • Particular compounds of the invention include : 4-[2-(4-trifluoromethylphenoxy)ethyl]-1-pentylpiperidine oxalate,
  • structure (I) may contain one or more asymmetric
  • the compounds of the present invention can be prepared by processes analogous to those known in the art.
  • the present invention therefore provides in a further aspect, a process for the preparation of a compound of structure (I) which comprises:
  • R and n are as described for structure (I) and A 1 is O, S or NR 1 , with a compound of structure
  • n and R are as described for structure (I) and L 1 is a group displaceable by a nucleophile, with a compound of structure HA 1 (CH 2 ) m Ar where m and Ar
  • R 5 is C 1-7 alkyl (phenyl)p, C 2-7 alkenyl(phenyl)p, C 2-7 alkynyl(phenyl)p or C 1-7 alkylC 3-8 cycloalkyl;
  • R, A, Ar m and n are as hereinbefore defined and X ⁇ is a counter ion; and optionally thereafter forming a salt.
  • fluoro-substituted aryl F-Ar is employed in process (a), the reaction is effected in the presence of a strong base such as sodium hydride, and in an inert organic solvent such as dimethyl formamide.
  • a strong base such as sodium hydride
  • an inert organic solvent such as dimethyl formamide.
  • the aryl group is substituted by an activating group such as CF 3 or NO 2 .
  • the reaction between a compound of structure (III) and a compound of structure HA 1 (CH 2 ) m Ar can take
  • the leaving group L 1 may be for example a halogen atom or a sulphonyloxy group eg. methanesulphonyloxy or p-toluenesulphonyloxy.
  • the reaction may be effected in the presence or absence of solvent at a temperature in the range 0 to 200°C
  • the reduction of a compound of structure (IV) can be effected by methods known in the art, for example using a reducing agent such as lithium aluminium hydride.
  • a compound of structure (IV) can be prepared (for example as described below) and reduced in a
  • reaction of a compound of structure (VI) with RL 2 according to process (e) may be effected in
  • the leaving group L 2 may be for example a halide such as bromide or chloride, an acyloxy group such as acetoxy or chloroacetoxy or a sulphonyloxy group such as methanesulphonyloxy or p-toluene sulphonyloxy.
  • L 2 is a halide
  • reaction is preferably carried out in the presence of a weak base such as potassium carbonate, and when L 2 is sulphonyloxy, a strong base such as sodium hydride or potassium t-butoxide may be employed.
  • a weak base such as potassium carbonate
  • a strong base such as sodium hydride or potassium t-butoxide
  • Reduction of a compound of formula (VII) may be effected using standard reducing agents such as lithium aluminium hydride.
  • Reduction of a compound of formula (VIII) may be effected for example by hydrogenation, using a noble metal catalyst such as platinum, palladium or platinum oxide, suitably in a solvent such as an alcohol eg.
  • a noble metal catalyst such as platinum, palladium or platinum oxide
  • the compounds of structure (II) can be prepared from the corresponding compounds in which R is hydrogen, by alkylation under standard conditions.
  • compounds of structure (II) in which R is n-pentyl can be prepared from the corresponding precursor in which R is hydrogen by reaction with an n-pentylhalide such as n-pentyl bromide in a suitable solvent, such as methyl ethyl ketone, or a C 1-4 alkanol such as ethanol, in the presence of a base, such as potassium carbonate, or dimethylformamide in the presence of an iodoalkane.
  • a suitable solvent such as methyl ethyl ketone
  • a C 1-4 alkanol such as ethanol
  • compounds of structure (II) in which A 1 is oxygen can be prepared by reduction of a compound of structure (IX): (IX)
  • halogen atom, or a mesyloxy or tosyloxy group can be prepared from the corresponding alcohol in conventional manner.
  • Compounds of structure (IV) wherein R 4 is a group can be prepared by
  • R 4 represents -(CH 2 ) n-1 CO 2 H or an activated
  • the carboxylic acid may itself be prepared for example by oxidation of the corresponding alcohol, ie. a compound of structure (II) wherein A 1 is oxygen.
  • Compounds of structure (V) may be prepared in analogous manner to compounds of structure (III); where necessary the chain length may be increased using methods well known in the art.
  • Suitable protecting groups include aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl and acyl groups such as acetyl, trifluoroacetyl, benzoyl,
  • benzyloxycarbonyl methoxycarbonyl, ethoxycarbonyl, or benzyloxycarbonyl.
  • An aralkyl group such as benzyl may be cleaved by
  • a compound of formula (VII) may be prepared by reaction of a compound of formula (VI) with an
  • appropriate acid derivative for example an acid chloride, or anhydride.
  • a compound of structure (VIII) may be prepared using the general methods described in processes (a) to (e) above.
  • compounds of structure (VIII) wherein A represents a bond may be prepared from 4-methyl pyridine (picoline) by reaction with a compound of formula L(CH 2 )q Ar wherein L and Ar are as hereinbefore defined and q is (m+n-1), in the presence of a strong base such as sodium amide in liquid ammonia or an alkyl lithium.
  • the resulting substituted pyridine is then reacted with a compound RL 2 , as hereinbefore defined, to give a quaternary pyridinium compound of formula (VIII).
  • Reduction of this compound according to process (g) provides a convenient method of preparing compounds of structure (I) wherein A represents a bond.
  • the compounds of the invention have been found to exhibit high calcium influx blocking activity and as such are expected to be of use in therapy in treating
  • the compounds are expected to be of use in the treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal.
  • a method of treatment of conditions or diseases caused or exacerbated by the accumulation of calcium in the brain cells of mammals which comprises administering to a subject in need thereof an effective amount of a compound of structure (I) or a
  • the present invention also provides a method of treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal, which comprises administering to a subject in need thereof, an effective amount of a compound of structure (I) or a pharmaceutically acceptable salt thereof.
  • the invention also provides the use of a compound of structure (I) or a pharmaceutically
  • the compounds of the present invention are usually administered in a standard
  • compositions comprising a compound of structure (I) or a pharmaceutically acceptable salt thereof and a
  • pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable
  • compositions for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • compositions consist of a solution or suspension of the compound or pharmaceutically acceptabl salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol,
  • the solution can be
  • composition is in unit dose form such as a tablet or capsule.
  • dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral
  • administration contains preferably from 0.1 to 60 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, eg. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 60 mg, eg. 1 to 40 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
  • the compounds of the invention may be administered by continuous intravenous infusion, preferably at a dose of up to 100mg per day.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • the pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 10; MgCl 2 , 4; ATP, 2;
  • Peak voltage gated Ca 2+ channel currents of up to 10 nA from dorsal root ganglion neurons were recorded using 10 mM Ba 2+ as charge carrier. Currents were evoked from a holding potential of -80 mV to a test potential of 0 or +10 mV every 15 seconds. This test potential was at the peak of the current voltage
  • Example 9 did not show any adverse toxicological effects when administered to rats at a dose of 10 mg/kg, i.v. PHARMACEUTICAL FORMULATIONS
  • Compound of structure (I) 0.1 - 60 mg sodium hydroxide or hydrochloric acid to pH ca 7 polyethylene glycol 0 - 2.5 ml alcohol 0 - 2.5 ml water to 5 ml
  • a toxicity adjusting agent eg. sodium chloride, dextrose or mannitol may also be added.
  • the title compound was prepared in a similar manner to example 1 from 4-hydroxy-1-pentylpiperidine (2.0g), sesamol (1.66g), triphenylphosphine (3.15g) and diethyl azodicarboxylate (2.09g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (0.65g), m.p. 164°C.
  • the title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-(3-phenylpropyl)piperidine (2.47g), 4-fluorophenol (1.12g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate (0.65g), m.p. 111-113°C.
  • the title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-heptylpiperidine (2.27g), sesamol (1.38g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate (0.65g), m.p. 129-231°C.
  • Example 42 4- [2- (4-Fluorothiophenoxy) ethyl] -1-pentylpiperidine hydrochloride
  • the title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (2.00g), 4-fluorothiophenol (1.28g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate to give the title compound as white plate crystals (0.33g), m.p.164165°C. Found: C, 62.41; H, 8.47; N, 4.09; Cl, 10.17%
  • triphenylphosphine (1.96g) and diethyl azodicarboxylate
  • the title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (1.5g), 4-isopropylphenol (1.02g), triphenylphosphine (1.96g) and diethyl azodicarboxylate (1.19ml). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (1.21g), m.p.185-187°C.
  • the title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyexhyl)-1-pentylpiperidine (1.5g), 3-isopropylphenol (1.02g), triphenylphosphine (1.96g) and diethyl azodicarboxylate (1.19ml). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.5g), m.p.166-168°C.
  • the title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (1.5g), 3-tert-butylphenol (1.127g), triphenylphosphine (1.96g) and diethyl azodicarboxylate (1.19g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.80g), m.p.171-173°C.
  • the title compound was prepared in a similar manner to example 1 from 4-(2-hydroxyethyl)-1-pentylpiperidine (2.0g), 3,5-dichlorophenol (1.63g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (l.lg), m.p.168-170°C.
  • the title compound was prepared in a similar manner to example 1 from 4- (2-hydroxyethyl) -1-heptylpiperidine (2.27g) , 3, 4 dichlorophenol (1. 63g) , triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.7g), m.p.138-139°C.

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Abstract

Composés de la structure (I) dans laquelle R représente C1-8 alkyle(phényle)p, C2-8 alkényle(phényle)p, C2-8 alcényle(phényle)p, C3-8 cycloalkyle ou C1-8 alkyle C3-8 cycloalkyle; p est compris entre 0 et 2; n est compris entre 0 et 6; A représente une liaison, oxygène, soufre ou NR1; R1 représente hydrogène, C¿1-8? alkyle ou phényle C1-4 alkyle; m est compris entre 0 et 3; et Ar représente aryle ou hétéroaryle, chacun d'entre eux pouvant être éventuelement substitués, ainsi que leurs sels; procédés de préparation desdits composés (I), compositions pharmaceutiques qui les contiennent et leur utilisation thérapeutique, notamment comme agents de blocage du calcium.
PCT/GB1991/001340 1990-08-06 1991-08-05 Piperidines a substitution n-hydrocarbyle en position 4, leur preparation et leur utilisation comme agents de blocage du calcium WO1992002502A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
KR1019930700352A KR930701402A (ko) 1990-08-06 1991-08-05 N- 하이드로 카르빌 -4- 치환된 피페리딘, 이들의 제조 방법 및 이들의 칼슘 차단제로서의 용도
CA002088491A CA2088491A1 (fr) 1990-08-06 1991-08-05 Derives de substitution en 4 de n-hydrocarbylpiperidines; preparation et utilisation comme agents de blocage du calcium

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Application Number Priority Date Filing Date Title
GB909017224A GB9017224D0 (en) 1990-08-06 1990-08-06 Compounds
GB9017224.8 1990-08-06
GB9107757.8 1991-04-12
GB919107757A GB9107757D0 (en) 1991-04-12 1991-04-12 Compounds

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WO1992002502A1 true WO1992002502A1 (fr) 1992-02-20

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EP0490962A1 (fr) * 1989-09-08 1992-06-24 The Du Pont Merck Pharmaceutical Company 1-cycloalkylpiperidines anti-psychotiques
WO1993015052A1 (fr) * 1992-01-28 1993-08-05 Smithkline Beecham Plc Composes utilises comme antagonistes des canaux calciques
EP0600717A1 (fr) 1992-11-30 1994-06-08 Sankyo Company Limited Phénoxyalkylamines, -pyrrolidines et pipéridines pour le traitement et la prevention de maladies de la circulation et de la psychose
WO1994013291A1 (fr) * 1992-12-15 1994-06-23 Smithkline Beecham Plc Utilisation d'amines cycliques a substitution aryloxyalkyle comme antagonistes des canaux a calcium et nouveaux derives de piperidine phenyloxyalkyle
WO1995003302A1 (fr) * 1993-07-20 1995-02-02 Smithkline Beecham Plc Quinolizidines a activite antagoniste des canaux a calcium
WO1995024390A1 (fr) * 1994-03-11 1995-09-14 Smithkline Beecham Plc Nouvelles piperidines substituees par phenyl(-alkyl/alkoxy)-1-aminoalkyle et pyrolidines utilisees comme antagonistes des canaux calciques
WO1995033723A1 (fr) * 1994-06-02 1995-12-14 Smithkline Beecham Plc Piperidines, pyrrolidines, morpholines et thiomorpholines a substitution phenoxyalcoyle, en tant qu'antagonistes des canaux a calciques
WO1995033722A1 (fr) * 1994-06-02 1995-12-14 Smithkline Beecham Plc Piperidines, pyrrolidines, morpholines et tiopmorpholines a substitution phenoxyalcoyle en tant qu'antagonistes des canaux calciques
WO1996019452A1 (fr) * 1994-12-21 1996-06-27 Neurosearch A/S Procede de preparation de 4-ethyl-piperidines substituees et intermediaire pour leur preparation
WO1996020928A1 (fr) * 1995-01-03 1996-07-11 Australian Nuclear Science & Technology Organisation Ligands de recepteurs sigma a base de piperidine
WO1997010212A1 (fr) * 1995-09-15 1997-03-20 Neurosearch A/S Composes de piperidine utilises en tant qu'agents bloquants de canaux a calcium
FR2742051A1 (fr) * 1995-12-06 1997-06-13 Synthelabo Utilisation de composes ayant une affinite pour le site de liaison du (3h)ifenprodil pour la fabrication de medicaments utiles dans la prevention et le traitement des neuropathies
WO1998006396A1 (fr) * 1996-08-12 1998-02-19 Merck & Co., Inc. Inhibiteurs de la thrombine
US5760035A (en) * 1993-09-22 1998-06-02 Knoll Aktiengesellschaft Therapeutic agents
EP0869792A2 (fr) * 1995-12-22 1998-10-14 Warner-Lambert Company Analogues de piperidine a substitution en position 4 et utilisation de ces derniers en tant qu'antagonistes selectivement actifs contre les sous-types du recepteur de nmda
US5843983A (en) * 1996-02-15 1998-12-01 Sankyo Company, Limited Diphenylethane compounds containing a saturated heterocyclic group, their preparation, and their therapeutic use
US6124317A (en) * 1995-12-22 2000-09-26 Warner-Lambert Company 2-substituted piperidine analogs and their use as subtype-selective NMDA receptor antagonists
US6166052A (en) * 1998-03-11 2000-12-26 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US6251919B1 (en) 1998-02-27 2001-06-26 Warner-Lambert Heterocyclic substituted aniline calcium channel blockers
US6448270B1 (en) 1995-12-22 2002-09-10 Warner-Lambert Company 4-substituted piperidine analogs and their use as subtype selective NMDA receptor antagonists
US6534522B2 (en) 1995-12-22 2003-03-18 Warner-Lambert Company Subtype-selective NMDA receptor ligands and the use thereof
WO2004056809A1 (fr) * 2002-12-20 2004-07-08 Astrazeneca Ab Nouveaux derives de piperidine en tant que modulateurs du recepteur ccr5 de la chimiokine
WO2004056773A1 (fr) * 2002-12-20 2004-07-08 Astrazeneca Ab Nouveaux derives de piperidine utilises en tant que modulateurs du recepteur ccr5 des chimiokines
WO2006001752A1 (fr) * 2004-06-24 2006-01-05 Astrazeneca Ab Nouveaux derives de piperidine/8-azabicyclo [3.2.1] octane utilises comme modulateurs des recepteurs ccr5 de la chemokine
FR2872416A1 (fr) * 2004-07-01 2006-01-06 Oreal Utilisation de derives de piperidine pour lutter contre les rides
US6989447B2 (en) 1999-07-23 2006-01-24 Smithkline Beecham P.L.C. Compounds
US7132551B2 (en) 2000-09-11 2006-11-07 Sepracor Inc. Ligands for monoamine receptors and transporters, and methods of use thereof
US7192973B2 (en) 2001-11-15 2007-03-20 Astrazeneca Ab Piperidine derivatives and their use as modulators of chemokine receptor activity (especially CCR5)
US7294636B2 (en) 2003-05-09 2007-11-13 Astrazeneca Ab Chemical compounds
US7294637B2 (en) 2000-09-11 2007-11-13 Sepracor, Inc. Method of treating addiction or dependence using a ligand for a monamine receptor or transporter
WO2008096189A2 (fr) 2005-09-23 2008-08-14 M's Science Corporation Dérivés de pipéridine et de pipérazine
US7615555B2 (en) 2004-04-23 2009-11-10 Astrazeneca Ab Piperidine derivatives as modulators of chemokine receptor CCR5
US7767699B2 (en) 2003-07-03 2010-08-03 Purdue Pharma, L.P. Therapeutic agents useful for treating pain
US8183374B2 (en) 2006-01-27 2012-05-22 M's Science Corporation Piperidine and piperazine derivatives

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JP3294611B2 (ja) * 1991-09-12 2002-06-24 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー ５−ｈｔ４レセプター・アンタゴニスト
US6011035A (en) * 1998-06-30 2000-01-04 Neuromed Technologies Inc. Calcium channel blockers
EP1165508B1 (fr) * 1999-04-07 2004-06-23 The University of Virginia Patent Foundation Bloqueurs du canal calcium anticancereux

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Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0490962A1 (fr) * 1989-09-08 1992-06-24 The Du Pont Merck Pharmaceutical Company 1-cycloalkylpiperidines anti-psychotiques
EP0490962A4 (en) * 1989-09-08 1993-03-03 The Du Pont Merck Pharmaceutical Company Antipsychotic 1-cycloalkylpiperidines
WO1993015052A1 (fr) * 1992-01-28 1993-08-05 Smithkline Beecham Plc Composes utilises comme antagonistes des canaux calciques
EP0600717A1 (fr) 1992-11-30 1994-06-08 Sankyo Company Limited Phénoxyalkylamines, -pyrrolidines et pipéridines pour le traitement et la prevention de maladies de la circulation et de la psychose
WO1994013291A1 (fr) * 1992-12-15 1994-06-23 Smithkline Beecham Plc Utilisation d'amines cycliques a substitution aryloxyalkyle comme antagonistes des canaux a calcium et nouveaux derives de piperidine phenyloxyalkyle
WO1995003302A1 (fr) * 1993-07-20 1995-02-02 Smithkline Beecham Plc Quinolizidines a activite antagoniste des canaux a calcium
US5760035A (en) * 1993-09-22 1998-06-02 Knoll Aktiengesellschaft Therapeutic agents
WO1995024390A1 (fr) * 1994-03-11 1995-09-14 Smithkline Beecham Plc Nouvelles piperidines substituees par phenyl(-alkyl/alkoxy)-1-aminoalkyle et pyrolidines utilisees comme antagonistes des canaux calciques
WO1995033722A1 (fr) * 1994-06-02 1995-12-14 Smithkline Beecham Plc Piperidines, pyrrolidines, morpholines et tiopmorpholines a substitution phenoxyalcoyle en tant qu'antagonistes des canaux calciques
WO1995033723A1 (fr) * 1994-06-02 1995-12-14 Smithkline Beecham Plc Piperidines, pyrrolidines, morpholines et thiomorpholines a substitution phenoxyalcoyle, en tant qu'antagonistes des canaux a calciques
WO1996019452A1 (fr) * 1994-12-21 1996-06-27 Neurosearch A/S Procede de preparation de 4-ethyl-piperidines substituees et intermediaire pour leur preparation
US5892047A (en) * 1994-12-21 1999-04-06 Neurosearch A/S Process for the preparation of substituted 4-ethyl-piperidines and an intermediate for the preparation of same
WO1996020928A1 (fr) * 1995-01-03 1996-07-11 Australian Nuclear Science & Technology Organisation Ligands de recepteurs sigma a base de piperidine
WO1997010212A1 (fr) * 1995-09-15 1997-03-20 Neurosearch A/S Composes de piperidine utilises en tant qu'agents bloquants de canaux a calcium
US5981539A (en) * 1995-09-15 1999-11-09 Neurosearch A/S Piperidine compounds as calcium channel blockers
FR2742051A1 (fr) * 1995-12-06 1997-06-13 Synthelabo Utilisation de composes ayant une affinite pour le site de liaison du (3h)ifenprodil pour la fabrication de medicaments utiles dans la prevention et le traitement des neuropathies
EP0869792A2 (fr) * 1995-12-22 1998-10-14 Warner-Lambert Company Analogues de piperidine a substitution en position 4 et utilisation de ces derniers en tant qu'antagonistes selectivement actifs contre les sous-types du recepteur de nmda
EP0869792A4 (fr) * 1995-12-22 1999-09-22 Warner Lambert Co Analogues de piperidine a substitution en position 4 et utilisation de ces derniers en tant qu'antagonistes selectivement actifs contre les sous-types du recepteur de nmda
US6124317A (en) * 1995-12-22 2000-09-26 Warner-Lambert Company 2-substituted piperidine analogs and their use as subtype-selective NMDA receptor antagonists
US6124323A (en) * 1995-12-22 2000-09-26 Warner-Lambert Company 4-substituted piperidine analogs and their use as subtype selective NMDA receptor antagonists
US6534522B2 (en) 1995-12-22 2003-03-18 Warner-Lambert Company Subtype-selective NMDA receptor ligands and the use thereof
US6448270B1 (en) 1995-12-22 2002-09-10 Warner-Lambert Company 4-substituted piperidine analogs and their use as subtype selective NMDA receptor antagonists
US6534525B1 (en) 1995-12-22 2003-03-18 Warner-Lambert & Company 2-substituted piperidine analogs and their use as subtype-selective NMDA receptor antagonists
US5843983A (en) * 1996-02-15 1998-12-01 Sankyo Company, Limited Diphenylethane compounds containing a saturated heterocyclic group, their preparation, and their therapeutic use
WO1998006396A1 (fr) * 1996-08-12 1998-02-19 Merck & Co., Inc. Inhibiteurs de la thrombine
US6251919B1 (en) 1998-02-27 2001-06-26 Warner-Lambert Heterocyclic substituted aniline calcium channel blockers
US6166052A (en) * 1998-03-11 2000-12-26 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US6469038B1 (en) 1998-03-11 2002-10-22 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US6989448B2 (en) 1998-03-11 2006-01-24 Lain-Yen Hu Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US6989447B2 (en) 1999-07-23 2006-01-24 Smithkline Beecham P.L.C. Compounds
US7517892B2 (en) 2000-09-11 2009-04-14 Sepracor Inc. Ligands for monoamine receptors and transporters, and methods of use thereof
US7816375B2 (en) 2000-09-11 2010-10-19 Sepracor Inc. Ligands for monoamine receptors and transporters, and methods of use thereof
US7294637B2 (en) 2000-09-11 2007-11-13 Sepracor, Inc. Method of treating addiction or dependence using a ligand for a monamine receptor or transporter
US7132551B2 (en) 2000-09-11 2006-11-07 Sepracor Inc. Ligands for monoamine receptors and transporters, and methods of use thereof
US7192973B2 (en) 2001-11-15 2007-03-20 Astrazeneca Ab Piperidine derivatives and their use as modulators of chemokine receptor activity (especially CCR5)
WO2004056773A1 (fr) * 2002-12-20 2004-07-08 Astrazeneca Ab Nouveaux derives de piperidine utilises en tant que modulateurs du recepteur ccr5 des chimiokines
WO2004056809A1 (fr) * 2002-12-20 2004-07-08 Astrazeneca Ab Nouveaux derives de piperidine en tant que modulateurs du recepteur ccr5 de la chimiokine
US7294636B2 (en) 2003-05-09 2007-11-13 Astrazeneca Ab Chemical compounds
US8058292B2 (en) 2003-07-03 2011-11-15 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US7767699B2 (en) 2003-07-03 2010-08-03 Purdue Pharma, L.P. Therapeutic agents useful for treating pain
US7615555B2 (en) 2004-04-23 2009-11-10 Astrazeneca Ab Piperidine derivatives as modulators of chemokine receptor CCR5
WO2006001752A1 (fr) * 2004-06-24 2006-01-05 Astrazeneca Ab Nouveaux derives de piperidine/8-azabicyclo [3.2.1] octane utilises comme modulateurs des recepteurs ccr5 de la chemokine
WO2006003030A1 (fr) * 2004-07-01 2006-01-12 L'oreal Utilisation de derives piperidines en tant qu'agents de dermo-decontraction
US7629359B2 (en) 2004-07-01 2009-12-08 L'oreal Use of piperidine derivatives as dermo-decontracting agents
FR2872416A1 (fr) * 2004-07-01 2006-01-06 Oreal Utilisation de derives de piperidine pour lutter contre les rides
WO2008096189A2 (fr) 2005-09-23 2008-08-14 M's Science Corporation Dérivés de pipéridine et de pipérazine
US8183374B2 (en) 2006-01-27 2012-05-22 M's Science Corporation Piperidine and piperazine derivatives

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CN1061963A (zh) 1992-06-17
TW267164B (fr) 1996-01-01
IE912759A1 (en) 1992-02-12
AP279A (en) 1993-08-01
AU8327191A (en) 1992-03-02
CA2088491A1 (fr) 1992-02-07
AP9100313A0 (en) 1991-10-31
IL99073A0 (en) 1992-07-15
PT98574A (pt) 1992-06-30
MA22250A1 (fr) 1992-04-01
KR930701402A (ko) 1993-06-11
EP0542846A1 (fr) 1993-05-26
JPH06500093A (ja) 1994-01-06
NZ239268A (en) 1994-06-27
MX9100513A (es) 1992-04-01

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