WO1994013291A1 - Utilisation d'amines cycliques a substitution aryloxyalkyle comme antagonistes des canaux a calcium et nouveaux derives de piperidine phenyloxyalkyle - Google Patents

Utilisation d'amines cycliques a substitution aryloxyalkyle comme antagonistes des canaux a calcium et nouveaux derives de piperidine phenyloxyalkyle Download PDF

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Publication number
WO1994013291A1
WO1994013291A1 PCT/EP1993/003473 EP9303473W WO9413291A1 WO 1994013291 A1 WO1994013291 A1 WO 1994013291A1 EP 9303473 W EP9303473 W EP 9303473W WO 9413291 A1 WO9413291 A1 WO 9413291A1
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formula
compound
piperidine
ethyl
group
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PCT/EP1993/003473
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English (en)
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Thomas Henry Brown
David Gywn Cooper
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Smithkline Beecham Plc
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Priority to AU56983/94A priority Critical patent/AU5698394A/en
Priority to EP94902735A priority patent/EP0674514A1/fr
Priority to JP6513782A priority patent/JPH08504419A/ja
Publication of WO1994013291A1 publication Critical patent/WO1994013291A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, substituted by hetero atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to cyclic secondary amine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
  • the present invention therefore provides, in a first aspect, the use of a compound of formula (I):
  • W is -(CH 2 ) 4 , (CH 2 ) 5 , -(CH 2 ) 2 O(CH 2 )2 or -(CH 2 ) 2 S(CH 2 ) 2 n is 0 to 6; is 0 to 3;
  • R 1 is hydrogen, Cj.galkyl or phenylC ⁇ _4alkyl
  • Ar is aryl or heteroaryl, each of which may be optionally substituted; or a pharmaceutically acceptable salt thereof as a therapeutic agent.
  • W preferably represents (CH 2 )4 or (CH 2 )5
  • the group -(CH 2 ) n A(CH 2 ) m Ar may be substituted on any carbon atom in the ring.
  • W is (CH 2 )4 or (CH 2 )5 the substituent is preferably ⁇ to the ring nitrogen atom.
  • n, m and A should be chosen such that the chain (CH 2 ) n A(CH 2 ) m contains at least one atom.
  • the length of the chain -(CH 2 ) n A(CH 2 ) m is from 2 to 6 atoms.
  • Preferred values for n and m depend on the group A.
  • A is oxygen the sum of n+m is from 1 to 5; for example n may be 1 or 2 and m may be zero.
  • A is preferably oxygen or a bond.
  • suitable groups include, for example, unsaturated monocyclic and unsaturated or partially saturated bicyclic and tricyclic ring systems of up to 15 carbon atoms, such as, for example, phenyl, naphthyl, tetrahydronaphthyl, fluorene, fluorenone, dibenzosuberene and dibenzosuberenone. Preferred are optionally substituted phenyl rings.
  • An aryl group may be substituted, for example, by a C ⁇ _ alkylenedioxy group (e.g. phenyl substituted by a 3,4-methylenedioxy group) or by 1 to 3 substituents selected from halogen, C j ⁇ alkoxy, nitro, SC ⁇ _ alkyl, NR 2a R 2b (in which R 2a and R 2b independently represent H or C ⁇ _4alkyl), OCF3, Cj.galkyl, trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted benzoyl, optionally substituted phenylC ⁇ _4alkyl and optionally substituted phenylC 1 _4alkoxy .
  • a C ⁇ _ alkylenedioxy group e.g. phenyl substituted by a 3,4-methylenedioxy group
  • substituents selected from halogen, C j ⁇ alkoxy, nitro, SC ⁇ _ alky
  • Suitable optionally substituted phenylCj_4alkyl groups include, for example benzyl.
  • Suitable optionally substituted phenylC ⁇ _4alkoxy groups include, for example benzyloxy groups.
  • Suitable substituents for said optionally substituted phenyl, phenoxy, benzoyl, phenylC ⁇ _4alkyl and phenylC ⁇ alkoxy groups include for example halogen, Cj ⁇ alkyl, C ⁇ alkoxy, nitro and trifluoromethyl groups.
  • the aryl group is a phenyl ring substituted by one or two substituents, in particular, by a phenyl, phenyl(Cj_4)alkyl, phenoxy, benzoyl or phenylC ⁇ _4alkoxy group; or by two chloro atoms especially in the 3- and 4-positions of the phenyl ring.
  • suitable groups include, for example, unsaturated or partially saturated bicyclic and tricyclic ring systems containing at least one heteroatom.
  • a bicyclic ring system preferably contains 8 to 10 ring members, such as quinolinyl and tetrahydroquinolinyl.
  • a tricyclic ring system preferably contains from 11 to 14 ring members, and most preferably has the structure :
  • Y 1 represents Y(CH 2 ) r
  • Y is O, S or NR ⁇ (where R ⁇ is hydrogen or Cj_4alkyl)
  • q is 0, 1 or 2
  • r is 0 or 1, or is a corresponding dehydro ring system.
  • tricyclic heteroaryl groups include dibenzofuranyl, dibenzothienyl, carbazole, N-methylcarbazole, acridine and dibenzoxepine.
  • the heteroaryl ring can be linked to the remainder of formula (I) via any suitable ring atom.
  • Suitable substituents for said heteroaryl rings include, for example, 1 to 3 substituents selected from halogen, trifluoromethyl, C ⁇ 4alkyl and C ⁇ 4alkoxy.
  • Alkyl groups present in the compounds of formula (I), alone or as part of another group, can be straight or branched.
  • a C ⁇ galkyl group may be for example methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl or any branched isomer thereof such as iso ⁇ propyl, tert-butyl or _yec-pentyl.
  • Particularly preferred compounds of formula (I) for use according to the present invention are those wherein W is (CH 2 )5, the substituent -(CH ) n A(CH 2 ) m Ar is ⁇ to the ring nitrogen atom, A is oxygen, n is 1 or 2, m is zero and Ar is phenyl substituted by one of benzyl, benzoyl, phenoxy or benzyloxy, or by two chloro atoms, or Ar is dibenzofuranyl. It will be appreciated that for use in medicine a salt of a compound (I) should be pharmaceutically acceptable.
  • Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, methanesulphonate or similar pharmaceutically acceptable inorganic or organic acid addition salts.
  • Other non- pharmaceutically acceptable salts, such as oxalates, may be used for example in the isolation of final products and are included within the scope of this invention.
  • Ar represents phenyl substituted by benzoyl
  • a particularly preferred group of compounds wherein Ar represents benzoylphenyl is that in which W is (CH 2 )5, A is oxygen, n is 1 or 2 and m is zero. Most preferably the substituent -(CH 2 ) n A(CH 2 ) m Ar is ⁇ to the ring nitrogen atom.
  • Particular compounds for use according to the invention include: 2-[2-(4-benzyloxyphenoxy)ethyl]piperidine, 2- [2-(4-phenoxyphenoxy)ethyl]piperidine, 2-[2-(2-benzylphenoxy)ethyl]piperidine, 4-f2-(3,4-dichlorophenoxy)ethyl]piperidine, 4-f2-(4-benzyloxyphenoxy)ethyl]piperidine, 4-f2-(4-benzylphenoxy)ethyl]piperidine, 3-(4-benzyloxyphenoxymethyl)piperidine, 3-(4-benzylphenoxymethyl)piperidine, 2-[4-benzylphenoxymethyl]piperidine, 2-[4-benzyloxyphenoxymethyl]piperidine, (S)-2-[4-benzylphenoxymethyl]pyrrolidine, 2-[2-(3-benzoylphenoxy)ethyl]piperidine, 2- [2- (4- benzoylphenoxy)e
  • Other preferred compounds for use according to the present invention include : 2-f2-(2-dibenzofuranyloxy)ethyl]piperidine, 2-[2-(3,4-dichlorophenoxy)ethyl]piperidine, 2-[2-(4-benzylphenoxy)ethyl]piperidine, and salts thereof.
  • a compound of formula (I) may be prepared by a process which comprises:
  • R ⁇ a is hydrogen or an N-protecting group, and W, n, m, and Ar are as described above.
  • the present invention also provides a process for preparing a novel compound of formula (I) e.g a compound of formula (I) wherein W is -(CH 2 )4 and the group -(CH 2 ) n A(CH ) m Ar is ⁇ to the pyrrolidine nitrogen atom, or a compound as specifically named above, which process comprises any of processes (a) to (g) described above,as approporiate, followed where necessary by removal of the N-protecting group R4, and optionally thereafter forming a salt.
  • processes (a) to (g) described above,as approporiate, followed where necessary by removal of the N-protecting group R4, and optionally thereafter forming a salt Those skilled in the an will readily be able to determine which specific processes will be applicable to the preparation of a given compound.
  • reaction between a compound of formula (II) and a compound L(CH 2 ) m Ar can take place under conditions which depend on the nature of the group L and the value of m.
  • L is halogen or a sulphonic acid residue such as a tosylate or mesylate and m is other than zero
  • the reaction is carried out under standard conditions in a solvent, optionally in the presence of a base.
  • a fluoro-substituted aryl compound F-Ar is employed in process (a) (to prepare compounds where m is zero)
  • the reaction is effected in the presence of a strong base such as sodium hydride, and in an inert organic solvent such as DMSO or dimethylformamide.
  • reaction between a compound of formula (IH) and a compound of formula HA (CH 2 ) m Ar can take place under conditions which depend on the nature of L and A.
  • L 1 is hydroxy
  • m is 0
  • a 1 is oxygen or sulphur
  • the reaction is carried out in the presence of diethyl azodicarboxylate and triphenyl phosphine.
  • the leaving group L may be for example a halogen atom or a sulphonyloxy group eg. methane-sulphonyloxy or p-toluene sulphonyloxy.
  • the reaction may be effected in the presence or absence of solvent and at temperature in the range 0 to 200°C.
  • a compound of formula (IV) can be effected by methods known in the art, for example using a reducing agent such as lithium aluminium hydride.
  • a compound of formula (IV) can be prepared (for example as described below) and reduced in a 'one-pot' reaction, without isolation of compound (IV) itself.
  • reaction between a compound of formula (V) and a compound of formula X 1 Ar in process (d) can take place under standard conditions known to those skilled in the an for the formation of carbon-carbon bonds.
  • Reduction of a compound of formula (VI) according to process (e) 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. ethanol.
  • a noble metal catalyst such as platinum, palladium or platinum oxide
  • Process (f) may be effected using a Wadsworth-Emmons reagent of the formula Ar(CH 2 ) m +lP(O)(OAlk) 2 , such as a diethylphosphonate, or a Wittig reagent of the formula Ar(CH 2 ) m+ ⁇ PPh3X" (where X" is an anion) which compounds are available commercially or can be prepared by known methods.
  • the reaction may be carried out in a solvent such as tetrahydrofuran optionally containing a crown ether such as 15-crown-5 or 18-crown-6, and in the presence of a strong base such as sodium hydride, or potassium tert-butoxide.
  • Interconversion reactions according to process (g) may be effected by methods well known in the art.
  • Protecting groups R ⁇ include lower alkyl groups such as methyl; aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl; and acyl groups such as acetyl, trifluoroacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl.
  • a protecting group R ⁇ a is preferably alkyl e.g. methyl or aralkyl e.g. benzyl. Such groups may be removed by methods which are well known in the art.
  • alkyl group such as methyl may be removed by treatment with a haloalkyl haloformate such a 1-chloromethylchloroformate, aralkyl group such as benzyl may be cleaved by hydrogenolysis, and an acyl group such as benzoyl may be cleaved by hydrolysis.
  • a protecting group R ⁇ or R ⁇ a present in any of the above compounds (II) to (VII) as well as compounds (VIII) below should be chosen such that it will not be cleaved by or participate in any of the reactions that the particular compound is intended to undergo, and furthermore such that its removal will not disturb any other groups or moieties present in the molecule. Such factors can be readily ascertained by those skilled in the art, to whom appropriate protecting groups will thus be readily apparent.
  • acyl group may be introduced by reaction with an appropriate acid derivative such as an acid chloride or anhydride, or an activated ester, e.g. an alkyldicarbonate such as di-tert- butyldicarbonate or a haloformate such as ethylchloroformate.
  • an appropriate acid derivative such as an acid chloride or anhydride
  • an activated ester e.g. an alkyldicarbonate such as di-tert- butyldicarbonate or a haloformate such as ethylchloroformate.
  • the compounds of formula (II) in which A 1 is oxygen can be prepared by reduction of a compound of formula (VIII):
  • R ⁇ should be a group such as alkyl, which is not cleaved by reductive conditions.
  • Compounds of formula (HI) wherein L 1 is OH can be prepared as described for compounds of formula (II), and compounds of formula (HI) wherein L 1 is a halogen atom, or a mesyloxy or tosyloxy group can be prepared from the corresponding alcohol in conventional manner.
  • -(CH 2 ) n _ ⁇ C(O)N(R 1 )(CH ) m Ar may be prepared for example by reaction of a corresponding compound wherein R 5 represents -(CH 2 ) n _ ⁇ CO 2 H or an activated derivative thereof such as an acid halide, ester or anhydride, with an amine of formula
  • a compound of formula (VI) may be prepared using the general methods described in processes (a) to (d) above.
  • Compounds of formula (VII) may be prepared by conventional methods, for example the oxidation of a compound of formula (II) wherein A 1 is oxygen, or conversion of the corresponding ester, e.g. by reaction with thionyl chloride and
  • N,O-dimethylhydroxylamine hydrochloride to give the N-methyl-N-methoxy- carboxamide, which can be reduced to the aldehyde using diisobutylaluminium hydride.
  • Compounds of formula (VII) wherein n is 1 may be prepared from the corresponding compound wherein n is zero by various methods. For example the aldehyde wherein n is zero may be treated with (methoxymethyl) triphenylphosphonium chloride and potassium t-butoxide, followed by a strong acid, e.g. concentrated sulphuric acid, resulting in the aldehyde wherein n is 1.
  • aldehyde may be converted to the conesponding cyanomethyl derivative as described in EPA 363085 followed by acid hydrolysis, conversion to the N-methyl-N-methoxycarboxamide and reduction. These procedures may also be used to form higher homologues.
  • a compound of formula (I) When a compound of formula (I) is obtained as a mixture 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.
  • Suitable resolving agents include optically active acids such as R-(-)- or S-(+)-mandelic acid.
  • Compounds of formula (I) have been found to exhibit calcium influx blocking activity for example in neurons. As such the compounds are expected to be of use in therapy in treating conditions and diseases related to an accumulation of calcium in the brain cells of mammals, in particular humans.
  • the compounds are expected to be of use in the treatment of anoxia, ischaemia including for example stroke, migraine, visceral pain, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders; mood disorders and drug addiction withdrawal such as ethanol addiction withdrawal.
  • ischaemia including for example stroke, migraine, visceral pain, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders; mood disorders and drug addiction withdrawal such as ethanol addiction withdrawal.
  • the invention therefore provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment of disorders where a calcium channel antagonist is indicated.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof may be used in the manufacture of a medicament for the treatment of a condition or disease related to (e.g. caused or exacerbated by) the accumulation of calcium in the brain cells of a mammal e.g a human, such as for example, any of the aforementioned conditions.
  • the present invention 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 formula (I) or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention are usually administered in a standard pharmaceutical composition.
  • the present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • the compounds of the invention may be administered by any convenient method for example by oral, parenteral, buccal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
  • the compounds of formula (I) and their 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 prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) 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 pharmaceutical carrier(s), 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 acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • 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.
  • Both liquid and solid compositions may contain other excipients known in the pharmaceutical art, such as a cyclodextrin or a solubilising agent such as Cremophor.
  • composition is in unit dose form such as a tablet, capsule or ampoule.
  • 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 400mg per day.
  • the total daily dosage by oral administration will be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will be in the range 0.1 to 400 mg.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • Ca 2+ current was measured in vitro using cell preparations of sensory neurons from dorsal root ganglia as described in WO92/02501 and WO92/02502.
  • Buffer to pH ca 7 Solvent/complexing agent to 100 ml Buffer : Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.
  • Solvent Typically water but may also include cyclodextrins (1-100 mg) and co-solvents such as propylene glycol, polyethylene glycol and alcohol.
  • Diluent e.g. Microcrystalline cellulose, lactose, starch Binder : e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
  • Disintegrant e.g. Sodium starch glycollate, crospovidone Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate.
  • Suspending agent e.g. Xanthan gum, microcyrstralline cellulose
  • Diluent e.g. sorbitol solution, typically water
  • Preservative e.g. sodium benzoate
  • Buffer e.g. citrate
  • Co-solvent e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin
  • Example la The product of Example la (6.0g, 16.03 mmole) was dissolved in glacial acetic acid/hydrogen bromide (20ml, 45w/v, excess). The solution was stood at room temperature for two hours and heated on a steam-bath for three hours. The material was then cooled, poured onto water and the aqueous phase basified with 50% NaOH. The mixture was extracted with dichloromethane (X2) and the combined organic extracts washed (water, brine), dried (MgSO4) and evaporated to give an oil (4.44g). This material was purified by flash chromatography on silica gel.
  • Example 2a The product of Example 2a (6.0g, 16mM) was dissolved in dichloromethane (80ml) and stirred at room temperature under nitrogen. A solution of trifluoroacetic acid (7.5ml) in dichloromethane (20ml) was added dropwise over 10 minutes and the colourless solution stirred for a further 2 hours. The mixture was evaporated and 2N. NaOH (100ml) added to the oily residue to produce a white, oily solid. This was extracted with dichloromethane (X2) and the combined organic extracts washed (H O, brine), dried (Na 2 SO4) and evaporated to dryness to leave a colourless oil (3.53g).
  • Example 2a Replacing the product of Example 2a with the product of Example 8a (4.5g, 0.011 mole) in the method of Example 2 and using the corresponding molar proportions of the other reagents gave the title compound as the free base.
  • This material was dissolved in ethyl acetate and excess ethereal HCl added. A white solid precipitated which was collected , and recrystallised from ethyl actetate to give the title compound as white needles (2.14g), M.P.
  • Example 12a 2-[4-Benzylphenoxymethyl]piperidine hydrochloride
  • the product of Example 12a 0.5g was converted to free base (equilibration between N. NaOH and CH 2 C1 2 - organic layer dried, washed and evaporated), producing a colourless oil which was dissolved in toluene (10ml).
  • To the stirred solution at room temperature under argon was added dropwise a solution of 1-chloromethyl chloroformate (0.28g, excess) in dry toluene (5ml). The mixture was heated at reflux temperature for 4 hours, concentrated almost to dryness, methanol (20ml) added and die mixture heated again at reflux temperature for 2 hours. The solvent was evaporated off to produce an oil which solidified on standing.
  • Example 3 The product of Example 3 was converted to free base in d e usual way (equilibration between N. NaOH and CH 2 C1 2 ) to produce an oil (1.75g, 5.92mM). This oil was dissolved in ethyl acetate (15ml) and S-(+)-mandelic acid (0.9g, 5.92mM) in etiiyl acetate (15ml) added. On refrigeration crystals separated and were collected (2.31 g). This material was crystallised five times from ethyl acetate/methanol (monitored by chiral HPLC) to give a white solid (0.83g). Conversion to free base in the usual way gave an oil (0.56g).

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Abstract

Utilisation d'un composé de formule (I), ou d'un sel pharmaceutiquement acceptable de ce dernier comme agent thérapeutique. Certains nouveaux composés de formule (I) et des procédés de préparation desdits composés sont également décrits. Dans la formule (I), W représente -(CH2)4, (CH2)5, -(CH2)2O(CH2)2 ou -(CH2)2S(CH2)2; n représente un entier compris entre 0 et 6; m représente un entier compris entre 0 et 3; A représente une liaison, -CH=CH-, -C=C, oxygène, soufre ou NR1; R1 représente hydrogène, C¿1-8? alkyle ou phényle C1-4 alkyle; et Ar représente aryle ou hétéroaryle qui peuvent chacun être facultativement substitués.
PCT/EP1993/003473 1992-12-15 1993-12-07 Utilisation d'amines cycliques a substitution aryloxyalkyle comme antagonistes des canaux a calcium et nouveaux derives de piperidine phenyloxyalkyle WO1994013291A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU56983/94A AU5698394A (en) 1992-12-15 1993-12-07 Use of aryloxyalkyl substituted cyclic amines as calcium channel antagonists and new phenyloxyalkyl piperidin derivatives
EP94902735A EP0674514A1 (fr) 1992-12-15 1993-12-07 Utilisation d'amines cycliques a substitution aryloxyalkyle comme antagonistes des canaux a calcium et nouveaux derives de piperidine phenyloxyalkyle
JP6513782A JPH08504419A (ja) 1992-12-15 1993-12-07 カルシウムチャンネル拮抗薬としてのアリールオキシアルキル置換環状アミンの使用および新規フェニルオキシアルキルピペリジン誘導体

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GB929226111A GB9226111D0 (en) 1992-12-15 1992-12-15 Madicaments
GB9226111.4 1992-12-15

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MX (1) MX9307946A (fr)
WO (1) WO1994013291A1 (fr)
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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995003302A1 (fr) * 1993-07-20 1995-02-02 Smithkline Beecham Plc Quinolizidines a activite antagoniste des canaux a calcium
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
WO1996002494A1 (fr) * 1994-07-14 1996-02-01 Smithkline Beecham Plc Derives de benzocycloalcoylamine utiles comme antagonistes du canal a calcium
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
US6251919B1 (en) 1998-02-27 2001-06-26 Warner-Lambert Heterocyclic substituted aniline calcium channel blockers
WO2001045739A1 (fr) * 1999-12-21 2001-06-28 Mitsubishi Pharma Corporation Remedes et/ou medicaments preventifs pour troubles du systeme nerveux
US6316490B1 (en) 1995-11-17 2001-11-13 Merck & Co., Inc. Substituted aryl compounds useful as modulators of acetylcholine receptors
US7132551B2 (en) 2000-09-11 2006-11-07 Sepracor Inc. Ligands for monoamine receptors and transporters, and methods of use thereof
WO2007040682A1 (fr) 2005-09-21 2007-04-12 Decode Genetics Ehf. Inhibiteurs hétérocycliques de lta4h substitués par biaryle pour le traitement des inflammations
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
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
US7521462B2 (en) 2004-02-27 2009-04-21 Eli Lilly And Company 4-Amino-piperidine derivatives as monoamine uptake inhibitors
US7576102B2 (en) * 2005-12-21 2009-08-18 Decode Genetics Ehf Biaryl substituted nitrogen containing heterocycle inhibitors of LTA4H for treating inflammation
US8044206B2 (en) 2003-03-07 2011-10-25 Astellas Pharma Inc. Nitrogen—containing heterocyclic derivatives having 2,6-disubstituted styryl
WO2016179108A1 (fr) * 2015-05-01 2016-11-10 Georgia State University Research Foundation Dérivés benzhydrol pour la prise en charge d'états associés à des facteurs inductibles par l'hypoxie

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GB1096441A (en) * 1964-01-15 1967-12-29 Bristol Myers Co Ethers of benzyl phenols and a process for the preparation thereof
GB1203149A (en) * 1968-06-10 1970-08-26 Ici Ltd Piperidine derivatives
GB1319252A (en) * 1969-06-05 1973-06-06 Ciba Geigy Ag 1-phenyl-alkanols and process for making same
EP0000693A1 (fr) * 1977-06-27 1979-02-21 Dr. Karl Thomae GmbH Dérivés d'aminophénoxyméthyl-2-morpholine, procédé pour leur préparation et médicaments les contenant
EP0004288A2 (fr) * 1978-03-18 1979-10-03 MERCK PATENT GmbH Phenoxyalcoylamines, compositions pharmaceutiques les contenant et procédé pour leur préparation
EP0012643A2 (fr) * 1978-12-05 1980-06-25 Pharmuka Laboratoires Dérivés de la phényl-1 (pipéridyl-4)-3 propanone-1, procédés pour leur préparation, et médicaments les contenant
EP0266574A2 (fr) * 1986-11-03 1988-05-11 Novo Nordisk A/S Dérivés de la pipéridine, leur préparation et leur utilisation
US4822778A (en) * 1988-01-19 1989-04-18 Gunnar Aberg Membrane stabilizing phenoxy-piperidine compounds and pharmaceutical compositions employing such compounds
EP0339579A2 (fr) * 1988-04-28 1989-11-02 Novo Nordisk A/S Composés de pipéridine et leur préparation et utilisation
EP0449187A2 (fr) * 1990-03-28 1991-10-02 The Du Pont Merck Pharmaceutical Company Dérivés d'éthers de pipéridine et leur application comme agents psychotropiques ou comme agents fongicides de plantes
WO1992002501A1 (fr) * 1990-08-06 1992-02-20 Smithkline & French Laboratories Limited Derives de piperidine substitues en position 3
WO1992002502A1 (fr) * 1990-08-06 1992-02-20 Smith Kline & French Laboratories Limited Piperidines a substitution n-hydrocarbyle en position 4, leur preparation et leur utilisation comme agents de blocage du calcium
WO1992022527A2 (fr) * 1991-06-17 1992-12-23 Smithkline Beecham Plc Derives de pyrrolidine 3-substitues comme antagonistes du calcium
WO1993015052A1 (fr) * 1992-01-28 1993-08-05 Smithkline Beecham Plc Composes utilises comme antagonistes des canaux calciques

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Publication number Priority date Publication date Assignee Title
US3360526A (en) * 1964-01-15 1967-12-26 Bristol Myers Co Heterocyclicamino methylene ethers of benzylphenols
GB1096441A (en) * 1964-01-15 1967-12-29 Bristol Myers Co Ethers of benzyl phenols and a process for the preparation thereof
GB1203149A (en) * 1968-06-10 1970-08-26 Ici Ltd Piperidine derivatives
GB1319252A (en) * 1969-06-05 1973-06-06 Ciba Geigy Ag 1-phenyl-alkanols and process for making same
EP0000693A1 (fr) * 1977-06-27 1979-02-21 Dr. Karl Thomae GmbH Dérivés d'aminophénoxyméthyl-2-morpholine, procédé pour leur préparation et médicaments les contenant
EP0004288A2 (fr) * 1978-03-18 1979-10-03 MERCK PATENT GmbH Phenoxyalcoylamines, compositions pharmaceutiques les contenant et procédé pour leur préparation
EP0012643A2 (fr) * 1978-12-05 1980-06-25 Pharmuka Laboratoires Dérivés de la phényl-1 (pipéridyl-4)-3 propanone-1, procédés pour leur préparation, et médicaments les contenant
EP0266574A2 (fr) * 1986-11-03 1988-05-11 Novo Nordisk A/S Dérivés de la pipéridine, leur préparation et leur utilisation
US4822778A (en) * 1988-01-19 1989-04-18 Gunnar Aberg Membrane stabilizing phenoxy-piperidine compounds and pharmaceutical compositions employing such compounds
EP0339579A2 (fr) * 1988-04-28 1989-11-02 Novo Nordisk A/S Composés de pipéridine et leur préparation et utilisation
EP0449187A2 (fr) * 1990-03-28 1991-10-02 The Du Pont Merck Pharmaceutical Company Dérivés d'éthers de pipéridine et leur application comme agents psychotropiques ou comme agents fongicides de plantes
WO1992002501A1 (fr) * 1990-08-06 1992-02-20 Smithkline & French Laboratories Limited Derives de piperidine substitues en position 3
WO1992002502A1 (fr) * 1990-08-06 1992-02-20 Smith Kline & French Laboratories Limited Piperidines a substitution n-hydrocarbyle en position 4, leur preparation et leur utilisation comme agents de blocage du calcium
WO1992022527A2 (fr) * 1991-06-17 1992-12-23 Smithkline Beecham Plc Derives de pyrrolidine 3-substitues comme antagonistes du calcium
WO1993015052A1 (fr) * 1992-01-28 1993-08-05 Smithkline Beecham Plc Composes utilises comme antagonistes des canaux calciques

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995003302A1 (fr) * 1993-07-20 1995-02-02 Smithkline Beecham Plc Quinolizidines a activite antagoniste des canaux a calcium
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
WO1996002494A1 (fr) * 1994-07-14 1996-02-01 Smithkline Beecham Plc Derives de benzocycloalcoylamine utiles comme antagonistes du canal a calcium
US6316490B1 (en) 1995-11-17 2001-11-13 Merck & Co., Inc. Substituted aryl compounds useful as modulators of acetylcholine receptors
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
AU743476B2 (en) * 1997-04-03 2002-01-24 F. Hoffmann-La Roche Ag Phenoxymethyl piperidine derivatives
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
US6989448B2 (en) 1998-03-11 2006-01-24 Lain-Yen Hu 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
US6166052A (en) * 1998-03-11 2000-12-26 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
KR100740477B1 (ko) * 1999-12-21 2007-07-19 미쯔비시 웰 파마 가부시키가이샤 신경계 장애의 치료 및/또는 예방약
WO2001045739A1 (fr) * 1999-12-21 2001-06-28 Mitsubishi Pharma Corporation Remedes et/ou medicaments preventifs pour troubles du systeme nerveux
US7652017B2 (en) 1999-12-21 2010-01-26 Mitsubishi Tanabe Pharma Corporation Remedies and/or preventives for nervous system disorders
US7816375B2 (en) 2000-09-11 2010-10-19 Sepracor Inc. Ligands for monoamine receptors and transporters, and methods of use thereof
US7132551B2 (en) 2000-09-11 2006-11-07 Sepracor Inc. Ligands for monoamine receptors and transporters, and methods of use thereof
US7517892B2 (en) 2000-09-11 2009-04-14 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
US8044206B2 (en) 2003-03-07 2011-10-25 Astellas Pharma Inc. Nitrogen—containing heterocyclic derivatives having 2,6-disubstituted styryl
US7521462B2 (en) 2004-02-27 2009-04-21 Eli Lilly And Company 4-Amino-piperidine derivatives as monoamine uptake inhibitors
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
WO2007040682A1 (fr) 2005-09-21 2007-04-12 Decode Genetics Ehf. Inhibiteurs hétérocycliques de lta4h substitués par biaryle pour le traitement des inflammations
AU2006297798B2 (en) * 2005-09-21 2013-01-31 Decode Genetics Ehf. Biaryl substituted heterocycle inhibitors of LTA4H for treating inflammation
US8598359B2 (en) 2005-09-21 2013-12-03 Decode Genetics Ehf Biaryl substituted heterocycle inhibitors of LTA4H for treating inflammation
EP1926708B1 (fr) * 2005-09-21 2014-06-18 Decode Genetics EHF Inhibiteurs hétérocycliques de lta4h substitués par biaryle pour le traitement des inflammations
US7576102B2 (en) * 2005-12-21 2009-08-18 Decode Genetics Ehf Biaryl substituted nitrogen containing heterocycle inhibitors of LTA4H for treating inflammation
WO2016179108A1 (fr) * 2015-05-01 2016-11-10 Georgia State University Research Foundation Dérivés benzhydrol pour la prise en charge d'états associés à des facteurs inductibles par l'hypoxie
US10772858B2 (en) 2015-05-01 2020-09-15 Georgia State University Research Foundation, Inc. Benzhydrol derivatives for the management of conditions related to hypoxia inducible factors

Also Published As

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MX9307946A (es) 1994-08-31
GB9226111D0 (en) 1993-02-10
EP0674514A1 (fr) 1995-10-04
ZA939317B (en) 1995-06-13
CN1091636A (zh) 1994-09-07
JPH08504419A (ja) 1996-05-14
AU5698394A (en) 1994-07-04

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