WO1992002501A1 - Derives de piperidine substitues en position 3 - Google Patents

Derives de piperidine substitues en position 3 Download PDF

Info

Publication number
WO1992002501A1
WO1992002501A1 PCT/GB1991/001339 GB9101339W WO9202501A1 WO 1992002501 A1 WO1992002501 A1 WO 1992002501A1 GB 9101339 W GB9101339 W GB 9101339W WO 9202501 A1 WO9202501 A1 WO 9202501A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pentylpiperidine
phenyl
alkyl
compounds
Prior art date
Application number
PCT/GB1991/001339
Other languages
English (en)
Inventor
Thomas Henry Brown
David Gwynn Cooper
Original Assignee
Smithkline & 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 GB909017225A external-priority patent/GB9017225D0/en
Priority claimed from GB909021852A external-priority patent/GB9021852D0/en
Priority claimed from GB919107780A external-priority patent/GB9107780D0/en
Application filed by Smithkline & French Laboratories Limited filed Critical Smithkline & French Laboratories Limited
Priority to AU83243/91A priority Critical patent/AU649468B2/en
Priority to CA002088490A priority patent/CA2088490A1/fr
Publication of WO1992002501A1 publication Critical patent/WO1992002501A1/fr

Links

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
    • C07D211/18—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
    • 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
    • C07D211/08—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
    • C07D211/26—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 nitrogen atoms

Definitions

  • the present invention relates to 3-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
  • R is C 1-8 alkyl(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 wherein p is 1, such as cinnamyl.
  • n is 0 to 6; preferably n is 0 to 3; most preferably n is 1.
  • m is 0 to 3; preferably m is 0 or 1; most preferably m is 0.
  • 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 1 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,
  • 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
  • Suitable substituents for said optionally substituted phenyl, phenylC 1-4 alkyl and 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 at least one heteroatom, such as pyridyl, thienyl, guinolinyl, tetrahydroquinolinyl 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
  • Particular compounds of the invention include:
  • structure (I) may contain one or more asymmetric centres, in particular at the 3-position of the piperidine ring. Such compounds will exist as optical isomers
  • 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
  • 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 compound 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 dimethylformamide.
  • a strong base such as sodium hydride
  • an inert organic solvent such as dimethylformamide.
  • the aryl group is substituted by an activating group such as CF 3 or NO 2 .
  • a 1 is oxygen or sulphur the reaction is carried out in the presence of diethyl azodicarboxylate and triphenyl phosphine.
  • Such a reaction is known as the Mitsunobu reaction (as described in Synthesis 1981, 1).
  • the leaving group L 1 may be for example a halogen atom or a sulphonyloxy group eg. methanesulphonyloxy or p-toluene sulphonyloxy.
  • the reaction may be effected in the presence or absence of solvent and at temperature in the range 0 to 200oC.
  • 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-toluenesulphonyloxy.
  • 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
  • the corresponding compounds of structure (II) in which R is hydrogen are available commercially, known in the literature or can be prepared by standard techniques; for example by reduction of the corresponding 3-hydroxyalkylpyridine.
  • the compounds of structure (II) in which A 1 is oxygen can be prepared by reduction of a compound of structure (IX): in which R and n are as described for structure (I) and X- is a counter ion.
  • halogen atom, or a mesyloxy or tosyloxy group can be prepared from the corresponding alcohol in conventional manner.
  • 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,
  • benzyloxycarbony1 methoxycarbonyl, ethoxycarbonyl, or benzyloxycarbony1.
  • 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. When compounds of structure (I) are obtained as mixtures of enantiomers, these may be separated by conventional methods such as crystallisation in the presence of a resolving agent, or chromatography, for example using a chiral HPLC column.
  • 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
  • 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
  • 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 suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water
  • suspending agent preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be
  • Such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
  • 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.
  • Compounds of the invention may also be administered parenterally, by bolus injection or continuous
  • Typical parenteral compositions consist of a solution or suspension of the compound or
  • a pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • composition is in unit dose form such as a tablet or capsule.
  • Each 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 examele for a week or more.
  • the pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 10; MgCl 2 , 4; ATP, 2; buffered to pH 7.2 with CsOH.
  • 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 3. 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
  • 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 5 starting from 3-(hydroxymethyl)-1-pentylpiperidine (1.85g), 3-trifluoromethylphenol (1.62g), 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 (0.41g), m.p. 165°C.
  • the title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (2.0g), 4-cyanophenol (1.19g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (0.79g), m.p. 104°C.
  • the title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (2.0g), phenol (0.94g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (1.02g), m.p. 144.5°C.
  • the title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (2.00g), 3,4-dichlorophenol (1.63g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (1.10g), m.p.188-190°C.
  • the title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (2.00g), 4-iso-propylphenol (1.36g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.18g), m.p.172-174°C.
  • the title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (1.5g), 3-iso-propylphenol (1.1g), triphenylphosphine (2.12g) and diethyl azodicarboxylate (1.41g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.8g), m.p.138-140°C.
  • the title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (1.50g), 4-tert-butylphenol (1.22g), triphenylphosphine (2.12g) and diethyl azodicarboxylate (1.41g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.205g), m.p.197-199°C.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés de la structure (I) dans laquelle R représente C1-8 alkyle(phényle)p, C2-8 alcényle(phényle)p, C2-8 alcynyle(phényle)p, C3-8 cycloalkyle ou C1-8 alkyle C3-8 cycloalkyle, p est 0 à 2; n est 0 à 6; A représente une liaison, oxygène, soufre ou NR1; R1 représente hydrogène, C¿1-8? alkyle ou phényle C1-4 alkyle; m est 0 à 3; et Ar est aryle ou hétéroaryle, chacun d'entre eux pouvant être éventuellement substitués, ainsi que leurs sels; procédés de préparation desdits composés (I), compositions pharmaceutiques qui les contiennent et leur utilisation en médecine, particulièrement comme agents de blocage du calcium.
PCT/GB1991/001339 1990-08-06 1991-08-05 Derives de piperidine substitues en position 3 WO1992002501A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU83243/91A AU649468B2 (en) 1990-08-06 1991-08-05 3-substituted piperidine derivatives
CA002088490A CA2088490A1 (fr) 1990-08-06 1991-08-05 Derives de substitution en 3 de la piperidine

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB909017225A GB9017225D0 (en) 1990-08-06 1990-08-06 Compounds
GB9017225.5 1990-08-06
GB909021852A GB9021852D0 (en) 1990-10-08 1990-10-08 Compounds
GB9021852.0 1990-10-08
GB9107780.0 1991-04-12
GB919107780A GB9107780D0 (en) 1991-04-12 1991-04-12 Compounds

Publications (1)

Publication Number Publication Date
WO1992002501A1 true WO1992002501A1 (fr) 1992-02-20

Family

ID=27265217

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1991/001339 WO1992002501A1 (fr) 1990-08-06 1991-08-05 Derives de piperidine substitues en position 3

Country Status (14)

Country Link
EP (1) EP0542844A1 (fr)
JP (1) JPH06500092A (fr)
CN (1) CN1062349A (fr)
AP (1) AP236A (fr)
AU (1) AU649468B2 (fr)
CA (1) CA2088490A1 (fr)
IE (1) IE912760A1 (fr)
IL (1) IL99074A0 (fr)
MA (1) MA22251A1 (fr)
MX (1) MX9100517A (fr)
NZ (1) NZ239267A (fr)
PT (1) PT98575A (fr)
TW (1) TW239860B (fr)
WO (1) WO1992002501A1 (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5290789A (en) * 1992-11-20 1994-03-01 Sterling Wintrop Inc. Penta and tetrasubstituted piperidines and compositions and method of treating psychosis
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
WO1995025091A2 (fr) * 1994-03-16 1995-09-21 Ortho Pharmaceutical Corporation Derives d'acide nipecotique utilises en tant que composes antithrombotiques
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
US5760035A (en) * 1993-09-22 1998-06-02 Knoll Aktiengesellschaft Therapeutic agents
EP0869119A1 (fr) * 1997-04-03 1998-10-07 F. Hoffmann-La Roche Ag Composés de phénoxy pipéridine utilisés en tant qu'agents bloquants de canaux a sodium
US5843983A (en) * 1996-02-15 1998-12-01 Sankyo Company, Limited Diphenylethane compounds containing a saturated heterocyclic group, their preparation, and their therapeutic use
US6110937A (en) * 1997-04-03 2000-08-29 Syntex Usa, Inc. Phenoxymethyl piperidine derivatives for the treatment of neuropathic pain
US6166052A (en) * 1998-03-11 2000-12-26 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
EP1104411A1 (fr) * 1998-08-12 2001-06-06 Smithkline Beecham Corporation Composes calcilytiques
US6251919B1 (en) 1998-02-27 2001-06-26 Warner-Lambert Heterocyclic substituted aniline calcium channel blockers
WO2004002483A1 (fr) * 2002-06-27 2004-01-08 Actelion Pharmaceuticals Ltd 3- et 4- aminomethylpiperidines substituees utilisees comme beta-secretase dans le traitement de la maladie d'alzheimer
US11891369B2 (en) 2016-02-23 2024-02-06 Srx Cardio, Llc Compounds for binding proprotein convertase subtilisin/kexin type 9
US11925637B2 (en) 2015-08-21 2024-03-12 Srx Cardio, Llc Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use
US11944619B2 (en) 2015-08-21 2024-04-02 Srx Cardio, Llc Phenylalanine small organic compounds to directly modulate PCSK9 protein activity
US11945782B2 (en) 2015-08-21 2024-04-02 Srx Cardio, Llc Composition and methods of use of tetrahydroisoquinoline small molecules to bind and modulate PCSK9 protein activity

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2621536A1 (de) * 1975-05-16 1976-11-25 Roussel Uclaf N-substituierte phenyl-piperidinderivate und deren salze, verfahren zu ihrer herstellung und pharmazeutische zusammensetzungen
DE2950135A1 (de) * 1979-12-13 1981-06-19 Merck Patent Gmbh, 6100 Darmstadt Basischer aether, diese enthaltende pharmazeutische zubereitungen und verfahren zu ihrer herstellung
EP0071521A2 (fr) * 1981-07-24 1983-02-09 Roussel-Uclaf Nouveaux dérivés du 2-oxo-pyrid-3-yl ou pipéridin-3-yl indole, leurs sels, procédé de préparation, application à titre de médicaments et compositions les renfermant
EP0149088A1 (fr) * 1983-12-28 1985-07-24 ASTA Pharma Aktiengesellschaft Ethers pyridiques-2 ou thioéthers pyridiques-2 contenant un cycle cycloaliphatique comportant de l'azote et leurs sulfoxides,sulfones et pyridine-N-oxides
EP0184257A1 (fr) * 1984-12-03 1986-06-11 Janssen Pharmaceutica N.V. Dérivés de la benzoxazolamine et de la benzothiazolamine
EP0239309A2 (fr) * 1986-03-27 1987-09-30 Merck Sharp & Dohme Ltd. Oxadiazoles utiles dans le traitement de la démence sénile
EP0259621A2 (fr) * 1986-09-08 1988-03-16 Novo Nordisk A/S Dérivés de pipéridine, leur préparation et leur utilisation
EP0307141A2 (fr) * 1987-09-10 1989-03-15 MERCK SHARP & DOHME LTD. Oxazoles et thiazoles pour le traitement de la démence sénile
DE3834860A1 (de) * 1988-10-13 1990-04-19 Basf Ag Heterocyclisch substituierte alkoxycumarine, verfahren zu ihrer herstellung und diese enthaltende therapeutische mittel

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2636946B1 (fr) * 1988-09-23 1990-11-02 Lipha ((diarylmethoxy)alcoyl)-1 pyrrolidines et piperidines, procedes de preparation et medicaments les contenant

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2621536A1 (de) * 1975-05-16 1976-11-25 Roussel Uclaf N-substituierte phenyl-piperidinderivate und deren salze, verfahren zu ihrer herstellung und pharmazeutische zusammensetzungen
DE2950135A1 (de) * 1979-12-13 1981-06-19 Merck Patent Gmbh, 6100 Darmstadt Basischer aether, diese enthaltende pharmazeutische zubereitungen und verfahren zu ihrer herstellung
EP0071521A2 (fr) * 1981-07-24 1983-02-09 Roussel-Uclaf Nouveaux dérivés du 2-oxo-pyrid-3-yl ou pipéridin-3-yl indole, leurs sels, procédé de préparation, application à titre de médicaments et compositions les renfermant
EP0149088A1 (fr) * 1983-12-28 1985-07-24 ASTA Pharma Aktiengesellschaft Ethers pyridiques-2 ou thioéthers pyridiques-2 contenant un cycle cycloaliphatique comportant de l'azote et leurs sulfoxides,sulfones et pyridine-N-oxides
EP0184257A1 (fr) * 1984-12-03 1986-06-11 Janssen Pharmaceutica N.V. Dérivés de la benzoxazolamine et de la benzothiazolamine
EP0239309A2 (fr) * 1986-03-27 1987-09-30 Merck Sharp & Dohme Ltd. Oxadiazoles utiles dans le traitement de la démence sénile
EP0259621A2 (fr) * 1986-09-08 1988-03-16 Novo Nordisk A/S Dérivés de pipéridine, leur préparation et leur utilisation
EP0307141A2 (fr) * 1987-09-10 1989-03-15 MERCK SHARP & DOHME LTD. Oxazoles et thiazoles pour le traitement de la démence sénile
DE3834860A1 (de) * 1988-10-13 1990-04-19 Basf Ag Heterocyclisch substituierte alkoxycumarine, verfahren zu ihrer herstellung und diese enthaltende therapeutische mittel

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, vol. 106, no. 7, 16 February 1987, (Columbus, Ohio, US) Balsamo A. et al: "3-((2-Ethoxyphenoxy)methyl) piperidine deriva- tives. Synthesis and antidepressant activity", page 622, abstract no. 49983u, & J. Med. Chem. 1987, 30(1), 222-5, see reg.no. 104778-59-8 and 104778-62-3 *
Chemical Abstracts, vol. 56, 1962, (Columbus, Ohio, US), V. Carelli et al: "Substituted N-(pyridylmethyl)anilides with local anesthetic action", columns 5921f-5922e & Farmaco (Pavia) Ed. Sci. 16, 375-86 (1961), see compound IX *
Chemical Abstracts, vol. 89, no. 1, 3 July 1978, (Columbus, Ohio, US), Arya V.P. et al: "Psycho- active agents. Part V. Synthesis and CNS depressant activity of some pyridyl and piperidyl ethers", page 529, abstract 6187a, & Indian J. Chem., Sect. B, 1977, 15B(12), 1125-8, see reg.no. 66496-76-z and 61472-15-9 *

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5290789A (en) * 1992-11-20 1994-03-01 Sterling Wintrop Inc. Penta and tetrasubstituted piperidines and compositions and method of treating psychosis
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
WO1995025091A2 (fr) * 1994-03-16 1995-09-21 Ortho Pharmaceutical Corporation Derives d'acide nipecotique utilises en tant que composes antithrombotiques
WO1995025091A3 (fr) * 1994-03-16 1995-10-12 Ortho Pharma Corp Derives d'acide nipecotique utilises en tant que composes antithrombotiques
CN1083834C (zh) * 1994-03-16 2002-05-01 邻位药品公司 作为抗血栓形成的化合物的3－哌啶甲酸衍生物
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
US5843983A (en) * 1996-02-15 1998-12-01 Sankyo Company, Limited Diphenylethane compounds containing a saturated heterocyclic group, their preparation, and their therapeutic use
EP0869119A1 (fr) * 1997-04-03 1998-10-07 F. Hoffmann-La Roche Ag Composés de phénoxy pipéridine utilisés en tant qu'agents bloquants de canaux a sodium
US6110937A (en) * 1997-04-03 2000-08-29 Syntex Usa, Inc. Phenoxymethyl piperidine derivatives for the treatment of neuropathic pain
US6262078B1 (en) 1997-04-03 2001-07-17 Syntex (U.S.A.) Llc Phenoxymethyl piperidine derivatives for the treatment of neuropathic pain
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
EP1104411A1 (fr) * 1998-08-12 2001-06-06 Smithkline Beecham Corporation Composes calcilytiques
EP1104411A4 (fr) * 1998-08-12 2002-10-24 Smithkline Beecham Corp Composes calcilytiques
WO2004002483A1 (fr) * 2002-06-27 2004-01-08 Actelion Pharmaceuticals Ltd 3- et 4- aminomethylpiperidines substituees utilisees comme beta-secretase dans le traitement de la maladie d'alzheimer
US11925637B2 (en) 2015-08-21 2024-03-12 Srx Cardio, Llc Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use
US11944619B2 (en) 2015-08-21 2024-04-02 Srx Cardio, Llc Phenylalanine small organic compounds to directly modulate PCSK9 protein activity
US11945782B2 (en) 2015-08-21 2024-04-02 Srx Cardio, Llc Composition and methods of use of tetrahydroisoquinoline small molecules to bind and modulate PCSK9 protein activity
US11891369B2 (en) 2016-02-23 2024-02-06 Srx Cardio, Llc Compounds for binding proprotein convertase subtilisin/kexin type 9

Also Published As

Publication number Publication date
IE912760A1 (en) 1992-02-12
MA22251A1 (fr) 1992-04-01
AU8324391A (en) 1992-03-02
EP0542844A1 (fr) 1993-05-26
PT98575A (pt) 1992-06-30
AP9100314A0 (en) 1991-10-31
TW239860B (fr) 1995-02-01
NZ239267A (en) 1994-05-26
JPH06500092A (ja) 1994-01-06
MX9100517A (es) 1992-04-01
CA2088490A1 (fr) 1992-02-07
AU649468B2 (en) 1994-05-26
IL99074A0 (en) 1992-07-15
AP236A (en) 1993-02-24
CN1062349A (zh) 1992-07-01

Similar Documents

Publication Publication Date Title
AP279A (en) 4 substituted piperidine derivatives, processes for their preparation pharmaceutical compositions containing them and their use in therapy.
AP236A (en) "3-substituted piperdine derivatives, pharmaceutical compositions containing them and their use in therapy".
EP0629190A1 (fr) Composes utilises comme antagonistes des canaux calciques
DE69531154T2 (de) Neuroprotektive 3-(piperidinyl-1)-chroman-4,7-diol und 1-(4-hyphoxyphenyl)-2-(piperidinyl-1)-alkanolderivate
EP0674514A1 (fr) Utilisation d'amines cycliques a substitution aryloxyalkyle comme antagonistes des canaux a calcium et nouveaux derives de piperidine phenyloxyalkyle
WO1992022527A2 (fr) Derives de pyrrolidine 3-substitues comme antagonistes du calcium
AU5833494A (en) Piperidine derivatives as calcium channel antagonists
EP1325912A1 (fr) Derives 2,2-diphenylbutanamide et agents pharmaceutiques contenant ces composes
WO1995003302A1 (fr) Quinolizidines a activite antagoniste des canaux a calcium
JPS6337111B2 (fr)
EP0625981A1 (fr) Composes azabicyclo servant d'antagonistes des canaux calciques
WO1995024390A1 (fr) Nouvelles piperidines substituees par phenyl(-alkyl/alkoxy)-1-aminoalkyle et pyrolidines utilisees comme antagonistes des canaux calciques
JPH09504014A (ja) カルシウムチャネル拮抗薬としてのアミン誘導体類
AU3959893A (en) N-aryloxy(thio)alkyl-azacycloalkanes useful as calcium channel antagonists
US5198451A (en) Heterocyclic carboxylic acids
AU703776B2 (en) Derivatives of 4-(cycloalkyl)piperidines and of 4-(cycloalkylalkyl)piperidines, their preparation and their therapeutic application
JP2961995B2 (ja) ピペリジン誘導体およびこれを含有する抗不整脈薬
JP3113447B2 (ja) アミノカルボン酸誘導体、その製造方法および用途
US5608069A (en) 1-substituted, 3-carboxylic acid piperidine derivatives

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BG BR CA CS FI HU JP KP KR LK MC MG MW NO PL RO SD SU US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU NL SE

WWE Wipo information: entry into national phase

Ref document number: 1991914530

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2088490

Country of ref document: CA

WWP Wipo information: published in national office

Ref document number: 1991914530

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1991914530

Country of ref document: EP