WO1993015052A1 - Compounds as calcium channel antagonists - Google Patents

Compounds as calcium channel antagonists Download PDF

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Publication number
WO1993015052A1
WO1993015052A1 PCT/GB1993/000173 GB9300173W WO9315052A1 WO 1993015052 A1 WO1993015052 A1 WO 1993015052A1 GB 9300173 W GB9300173 W GB 9300173W WO 9315052 A1 WO9315052 A1 WO 9315052A1
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Prior art keywords
formula
compound
phenyl
ethyl
compounds
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PCT/GB1993/000173
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French (fr)
Inventor
Thomas Henry Brown
David Gwyn Cooper
Ronald Joseph King
Barry Sidney Orlek
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Smithkline Beecham Plc
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Priority claimed from GB929201745A external-priority patent/GB9201745D0/en
Priority claimed from GB929201744A external-priority patent/GB9201744D0/en
Priority claimed from GB929201746A external-priority patent/GB9201746D0/en
Priority claimed from GB929201752A external-priority patent/GB9201752D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to JP5513047A priority Critical patent/JPH07503461A/en
Priority to EP93902469A priority patent/EP0629190A1/en
Publication of WO1993015052A1 publication Critical patent/WO1993015052A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof

Definitions

  • the present invention relates to nitrogen containing heterocyclic derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
  • EPA 266574 discloses 3-aryloxymethyl-4-phenylpiperidines, which compounds are said to have activity against calcium overload in brain cells and to be useful for the treatment of anoxia, ischemia, migraine and epilepsy.
  • US Patent No. 4,918,073 describes a broad class of diarylaikyl-substituted cyclic amines (such as piperazines and piperidines) where the cyclic amine moiety is further substituted inter alia by a (hetero)atyloxyalkyl group
  • US Patent No. 4,933,346 describes similar compounds having an arythioalkyl substituent. These compounds are said to have calcium antagonistic action.
  • the present invention therefore provides, in a first aspect, a compound of formula (I):
  • W is -CH2-, a bond, O or S;
  • R is C ⁇ _galkyl(phenyl)p, C2-8alkenyl(phenyl)p, C2-8alkynyl(phenyl)p, C3_gcycloalkyl or
  • C ⁇ _galkylC3_gcycloalkyl, or R may also represent hydrogen when k is 2; p is 0 to 2 n is 0 to 6; mis 0 to 6; and
  • R! is hydrogen, C ⁇ _ alkyl or phenylC ⁇ _4alkyl; and
  • Ar is aryl or heteroaryl, each of which may be optionally substitued;
  • Ar is aryl substituted by phenoxy or substituted phenoxy or is a tricyclic heteroaryl group as hereinafter defined;
  • the compound of formula 00 is a monocyclic heterocyclic compound viz a piperidino, pyrrolidino, morpholino or thiomorpholino derivative.
  • the compound (I) is a tropane derivative.
  • alkylcycloalkyl, alkylphenyl, alkenylphenyl and alkynylphenyl R groups are linked to the nitrogen atom via the alkyl, alkenyl and alkynyl moieties respectively.
  • R is C ⁇ _galkyl(phenyl)p in which p is 0 or 1, i.e. C]_galkyl, such as n-pentyl, or phenylC ⁇ _galkyl such as phenylpropyl, or R is C2-galkenyl(phenyl)p wherein p is 1, such as cinnamyl.
  • 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 ⁇ _2alkylenedioxy group (e.g. phenyl substituted by a 3,4-methylenedioxy group) or by 1 to 3 substituents selected from halogen, Cj ⁇ alkoxy, nitro, SC ⁇ alkyl, NRTX. (in which each R group can be H or C ⁇ _4alkyl), OCF3, Cj.galkyl, trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted phenylC ⁇ _4alkyl and optionally substituted phenylCj.4alkoxy.
  • a C ⁇ _2alkylenedioxy group e.g. phenyl substituted by a 3,4-methylenedioxy group
  • substituents selected from halogen, Cj ⁇ alkoxy, nitro, SC ⁇ alkyl, NRTX.
  • each R group can be H or C ⁇ _4alkyl
  • the aryl group is a phenyl ring substituted by one or two substituents, in particular, by a phenyl, phenyl(C ⁇ _4)alkyl, phenoxy or phenylC ⁇ _4alkoxy group; or by two chloro atoms especially in the 3- and 4-positions of the phenyl ring.
  • Suitable optionally substituted phenylC ⁇ _4alkyl groups include, for example benzyl.
  • Suitable optionally substituted ⁇ henylC ⁇ _4alkoxy groups include, for example benzyloxy groups.
  • Suitable substituents for said optionally substituted phenyl, phenoxy, phenylCj ⁇ alkyl and phenylC ⁇ _4alkoxy groups include for example halogen, Cj_4alkyl, C ⁇ _4alkoxy, nitro and trifluoromethyl groups.
  • 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, tetrahydroquinolinyl or benzofuranyl.
  • a tricyclic ring system preferably contains from 11 to 15 ring members, and most preferably has the structure :
  • Y 1 represents Y(CH2>r.
  • 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, C ⁇ _4alko y, phenyl, phenylC ⁇ _4alkyl andphenylC ⁇ _4alkoxy.
  • Alkyl groups present in the compounds of formula 00, alone or as part of another group, can be straight or branched.
  • a C ⁇ _4alkyl group may be for example methyl, ethyl, n- propyl, n-butyl or any branched isomer thereof such as isopropyl or t-butyl.
  • a salt of a compound (I) should be pharmaceutically acceptable.
  • pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, methanesulphonate or similar pharmaceutically acceptable inorganic or organic acid addition salts.
  • Other non- pharmaceutically acceptable salts may be used for example in the isolation of final products and are included within the scope of this invention.
  • R is C ⁇ _galkyl(phenyl)p, C2-galkenyl(phenyl)p, C2-galkynyl(phenyl)p, C3_gcycloalkyl or C ⁇ _galkylC3_gcycloa]kyl;
  • p is 0 to 2;
  • n is 0 to 6;
  • Ar is aryl or heteroaryl, each of which may be optionally substituted; or A is a bond, oxygen, sulphur or NR*; R! is hydrogen, Cj.galkyl or phenylC ⁇ _4alkyl; and
  • Ar is aryl substituted by phenoxy or substituted phenoxy or is a tricyclic heteroaryl group as hereinafter defined;
  • a further group of compounds according to the invention is that of formula (IB):
  • R is C ⁇ _galkyl(phenyl)p, C2-galkenyl(phenyl)p, C2-galkynyl(phenyl)p, C3_gcycloalkyl or
  • R! is hydrogen, Cj.salkyl or phenylC ⁇ alkyl
  • Ar is aryl or heteroaryl, each of which may be optionally substituted
  • a yet further group of compounds according to the invention is that of formula (IC):
  • the group -(CH2) n A(CH2) m Ar is attached at either the 2 or 3 position of the tropane ring;
  • R is hydrogen, C ⁇ _galkyl(phenyl)p, C2-galkenyl(phenyl)p,
  • R! is hydrogen, C ⁇ _8alkyl or phenylC ⁇ _4alkyl;
  • Ar is aryl or heteroaryl, each of which may be optionally substituted
  • W is oxygen or sulphur
  • R is C ⁇ _galkyl(phenyl)p, C2_8alkenyl(phenyl)p, C2-galkynyl(phenyl)p, C3_gcycloalkyl or C ⁇ _galkylC3_gcycloalkyl
  • p is 0 to 2
  • n is 0 to 6
  • m is 0 to 6;
  • R 1 is hydrogen, Cj.galkyl or phenylC ⁇ _4alkyl;
  • Ar is aryl or heteroaryl, each of which may be optionally substituted
  • the chain -(CH2) n A(CH2) m Ar may be attached at either the 2- or 3-position of the ring.
  • Particular compounds of the invention include:
  • 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 formula (I) which comprises:
  • W, k, R and n are as described for formula 00 and A ⁇ is O, S or NRl, with a compound of formula L(CH2) m Ar in which m and Ar are as described for formula 00, and is a leaving group;
  • R, A, Ar m and n are as hereinbefore defined and X " is a counter ion;
  • reaction between a compound of formula (II) and a compound L(CH2) 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 dimethylformamide.
  • the aryl group is substituted by an activating group such as CF3 or NO2.
  • reaction between a compound of formula (HI) and a compound of formula HAl(CH2) m Ar can take place under conditions which depend on the nature of L ⁇ and A.
  • L is hydroxy
  • m is 0
  • A* is oxygen or sulphur
  • the reaction is carried out in the presence of diethyl azodicarboxylate and triphenyl phosphine.
  • the leaving group L 1 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* Ar in process (d) can take place under standard conditions known to those skilled in the art for the formation of carbon-carbon bonds.
  • the reaction of a compound of formula (VT) with RL2 according to process (e) may be effected in conventional manner, for example in an organic solvent, such as dimethyl formamide.
  • the leaving group l 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 is a halide the reaction is preferably carried out in the presence of a weak base such as potassium carbonate, and when ⁇ is sulphonyloxy, a strong base such as sodium hydride or potassium t-butoxide may be employed.
  • Reduction of a compound of formula (VH) according to process (f) may be effected using standard reducing agents such as lithium aluminium hydride.
  • Reduction of a compound of formula (VIE) according to process (g) 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.
  • Process (h) may be effected using a Wadsworth-Emmons reagent of the formula Ar(CH2) m + ⁇ P(O)(OAlk)2, such as a diethylphosphonate, or a Wittig reagent of the formula Ar(CH2) 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 t-butoxide.
  • Interconversion reactions according to process (i) may be effected by methods well known in the art.
  • the compounds of formula (II) wherein W is CH_2 and k is zero can be prepared from the corresponding compounds in which R is hydrogen, by alkylation under standard conditions.
  • compounds of formula (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 ⁇ _4alkanol such as ethanol, in the presence of a base, such as potassium carbonate, or dimethylformamide in the presence of an iodoalkane.
  • a base such as potassium carbonate
  • dimethylformamide in the presence of an iodoalkane.
  • the corresponding compounds of formula (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 2, 3- or 4-hydroxyalkyl-pyridine.
  • the compounds of formula (II) in which W is CH2, k is zero and A* is oxygen can be prepared by reduction of a compound of formula (X):
  • Compounds (X) may be prepared by standard literature methods.
  • Compounds of formula (II) wherein W is CH2, k is 2, A is oxygen, R is methyl and n is 2 may be prepared from tropinone, by reaction with triethylphosphonoacetate, followed by reduction e.g. using catalytic hydrogenation, to give the 3-ethoxycarbonylmethyl- substituted tropane, which is further reduced e.g. using lithium aluminium hydride to the corresponding 3-(2-hydroxyethyl)tropane.
  • the corresponding 2-substituted compounds may be prepared in an analogous manner.
  • the compounds of formula (D) wherein W is oxygen, sulphur or a bond can be prepared from the corresponding compounds in which R is hydrogen, by alkylation under standard conditions, as described above for compounds wherein W is -CH2-.
  • a compound of formula (II) wherein W is sulphur may also be prepared by reduction of an ester of formula (XL) :
  • n is defined as for formula CO
  • Alk is a C ⁇ _6alkyl group (e.g. ethyl) and R > represents a group R or -COR ⁇ as hereinbefore defined.
  • Reduction may be effected using a reducing agent such as lithium aluminium hydride in a solvent such as diethyl ether or tetrahydrofuran.
  • Compounds of formula (XI) may be prepared by N-alkylation or acylation of a corresponding compound wherein R* is hydrogen. Esters of formula CXI) wherein n is 1 and R* is hydrogen are described in EPA 226267.
  • Compounds of formula (II) wherein W and A are both oxygen and n is 1 may be prepared by reduction of the corresponding morpholine carboxylic acid, which itself may be prepared from the corresponding cyanomorpholine for example by acid hydrolysis.
  • the cyano morpholine may be obtained by reaction of a 2-haloacrylonitrile e.g. 2-chloroacrylonitrile, with an appropriately substituted aminoethanol, HO(CH2)2NHR, as described for example in Tett Letts., 1991, 32, 2281.
  • n may be increased by standard homologation methods, for example by sequential conversion of the alcohol to corresponding haloalkyl, cyanoalkyl and ester derivatives, the ester then being reduced to an alcohol, whereby n is increased by 1.
  • -(CH2) n (Rl)C(O)(CH2) m -lAr can be prepared by reacting a compound of formula (II) wherein A ⁇ represents NR* with an acylating agent corresponding to the group -(CH2) m Ar, for example an acid chloride ClOC(CH2) m _iAr.
  • -(CH2) n -lC(O)N(Rl)(CH2) m Ar may be prepared for example by reaction of a corresponding compound wherein R 4 represents -(CH2) n -lCO2H or an activated derivative thereof such as an acid halide, ester or anhydride, with an amine of formula HN(R 1 )(CH2) m Ar. It will be appreciated that when the acid itself is employed, reaction with the amine should be effected in the presence of a coupling agent
  • the carboxylic acid may itself be prepared for example by oxidation of the corresponding alcohol, ie. a compound of formula (II) wherein A* is oxygen.
  • Compounds of formula (V) may be prepared in analogous manner to compounds of formula (HI); where necessary the chain length may be increased using methods well known in the art.
  • Compounds of formula (VI) may be prepared for example according to any of processes (a) to (d) above, using intermediates analogous to formulae (II) to (TV) wherein R is replaced by an N-protecting group, which is subsequently removed by 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, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl or benzyloxycarbonyl.
  • an aralkyl group such as benzyl may be cleaved by hydrogenolysis, and an acyl group such as benzoyl may be cleaved by hydrolysis. It will be appreciated that where the N-protecting group is aralkyl, the compound is of formula (I) and this reaction sequence thus provides a means of converting one compound of formula (I) into a different compound of formula
  • a compound of formula (VH) 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 formula (VIII) may be prepared using the general methods described in processes (a) to (e) above.
  • Compounds of formula (IX) may be prepared by conventional methods, for example the oxidation of a compound of formula (II) wherein A ⁇ 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-methoxycarboxamide which can be reduced to the aldehyde using diisobutylaluminium hydride.
  • Compounds of formula (IX) wherein n is 1 may be prepared from the corresponding compound wherein n is zero by various methods.
  • 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.
  • a strong acid e.g. concentrated sulphuric acid
  • the aldehyde may be converted to the corresponding 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 00 When a compound of formula 00 is obtained as a mixture of enantiomers, these may be separated by conventional methods such as cr stallisation in the presence of a resolving agent, or chromatography, for example using a chiral HPLC column.
  • Compounds of the invention have been found to exhibit high calcium influx blocking activity for example in neurons.
  • 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, 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.
  • 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 invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition or disease caused or exacerbated by the accumulation of calcium in the brain cells of a mammal e.g. a human.
  • 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 or solids, 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 carriers) 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 carriers for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent
  • suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of 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 pharmaceutical carriers), 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 infusion.
  • Typical parenteral 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.
  • the solution can be ly ⁇ philised 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 cyclodextrins.
  • 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 (T) 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 400 mg 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. BIOLOGICAL DATA
  • 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.
  • Cells were bathed in a normal Tyrodes solution before establishment of whole cell recording when the bathing solution was changed to one allowing isolation of Ca 2+ currents.
  • the external solution for recording Ca 2+ channel currents contained in mM: BaCL 2 , 10; TEA-Cl, 130; glucose, 10; HEPES, 10; MgCL 2 , 1; buffered to pH 7.3 with TEA-OH. Barium was used as the charge carrier as this assists in current isolation and calcium dependent inactivation of current is avoided.
  • 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 relationship and assessing block at this point reduced any errors due to drifting holding potential. Some cells showed slow rundown of current as is commonly seen when recording Ca 2+ currents. The rundown rate was measured in control conditions and extrapolated through the time of drug application to derive a control value to relate the drug affected current to. Block by 20 ⁇ M drug was assessed 3 minutes after drug application.
  • a tonicity adjusting agent eg. sodium chloride, dextrose or mannitol may also be added.
  • Potassium carbonate (125g) was added to a stirred solution of ethyl nipecotate (50g, 0.32 mol) in acetone (375 ml). The mixture was treated with 1-bromopentane (57.65g, 0.38 mmol) over 10 min then stirred at room temperature overnight. The mixture was filtered, the solid washed thoroughly with acetone and the combined acetone solutions were concentrated in vacua. The residue was treated with saturated aqueous potassium carbonate (200 ml) then extracted into chloroform (3 x 200 ml).
  • Lithium aluminium hydride (2.55 g) was stirred with anhydrous ether (70 ml) under dry nitrogen at room temperature.
  • Endo-ethyl tropane-3-acetate, (12.86g) dissolved in anhydrous ether (30 ml) was added at such a rate as to maintain a gentle reflux.
  • the reaction mixture was then stirred at room temperature for 16 hrs when water was cautiously added.
  • the inorganics were removed by filtration and washed with diethylether.
  • the combined filtrate and washings were dried (Na2SO4) and evaporated.
  • the residue was distilled (K ⁇ gelrohr) to give the title compound (8.9g), B.P. 135°C at 0.02 mm Hg.
  • the aqueous solution was extracted with diethylether (3 x 200 ml) and the combined organic extracts dried and evaporated to give the crude nitrile as a black oil.
  • the oil was distilled to give the title compound as a colourless oil (34.2g, 55%), b.p. 94-104°C at 0.2 mm Hg.
  • 2-Cyano-4-pentylmorpholine (5.0g) was dissolved in dilute hydrochloric acid (cone. HC1 30 ml/H2 ⁇ 30 ml). The mixture was heated on a steam-bath for four hours and the solvent then evaporated at reduced pressure. The residual material was treated with acetone and the insoluble material collected by filtration to give the title compound (5.5 g) as a white solid which was used in the next stage of the synthesis without further purification.
  • the title compound was prepared in a similar manner to Example 1 and 2 from ( ⁇ ) 1- pentyl-3-piperidylcarboxaldehyde (2g, 10.93 mmol), diethyl (4- biphenylmethyl)phosphonate (3.33g, 10.93 mmol), sodium hydride (328 mg of an 80% dispersion in mineral oil, 10.93 mmol) and 15-crown-5 (60 mg). This afforded the title compound as a white solid (2.22g, 55%) m.p.230-233°C (from methanol-diethyl ether).
  • the title compound was prepared in a similar manner to Example 3 from ( ⁇ ) l-pentyl-3- piperidylcarboxaldehyde (0.5g, 2.73 mmol), diethyl 1-naphthylmethylphosphonate (0.76g, 2.73 mmol), sodium hydride (82 mg of an 80% dispersion in mineral oil, 2.73 mmol) and 15-crown-5 (30 mg). This afforded the title compound as a white solid (0.36g, 37%) m.p. 150-154°C (from methanol-diethyl ether).
  • the title compound was prepared in a similar manner to Example 6 from 2-(2- hydroxyethyl)-l-pentylpiperidine (2.0g, 0.01 mole), 4-fluorophenol (1.12g, 0.01 mole), triphenylphosphine (2.62g, 0.01 mole) and diethyl azodicarboxylate (1.74g, 0.01 mole).
  • Lithium aluminium hydride (350mg, XS) was added to dry THF (20ml). To the stirred mixture at room temperature under nitrogen was added dropwise a solution of 2-[2-(4- benzylphenoxy)ethyl]-l-ethoxycarbonylpiperidine[Preparation 7](0.9g, 3.05mmole) in dry THF (30ml). The mixture was stirred at room temperature for 90 minutes, heated at reflux temperature for one hour and then cooled in an ice-bath during dropwise addition of water to decompose excess lithium aluminium hydride.
  • 2-Hydroxymethyl-4-pentylmorpholine( 1.Og) was dissolved in methylene chloride (50 ml) and to the stirred solution under nitrogen was added p-fluorophenol (0.6g), triphenylphosphine (1.4g) and diethyl azodicarboxylate (0.93g). The mixture was stirred at room temperature overnight and the solvent evaporated. The residual oil was purified by dry flash column chromatography on silica gel (Art 7736) using 0-5% methanol in methylene chloride.
  • the title compound was prepared in a similar manner to Example 16 from 2-hydroxy- methyl-4-pentylmorpholine (2.3 g), 2,4-dichlorophenol (2.0g), triphenylphosphine (3.22g) and diethyl azodicarboxylate (2.14g) in methylene chloride (100 ml). Treating the product as before with oxalic acid gave a white solid which was re-crystallised from methanol/ethyl acetate to give the title compound as white crystals (0.51g), M.P. : 142°C.

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Abstract

Compounds of formula (I) in which W is -CH2-, a bond, O or S; k is 0, or when W represents -CH2- k may also be 2, in which case the dotted lines represent single bonds; R is C1-8alkyl(phenyl)p, C2-8alkenyl(phenyl)p, C2-8alkynyl(phenyl)p, C3-8cycloalkyl or C1-8alkylC3-8cycloalkyl, or R may also represent hydrogen when k is 2; p is 0 to 2; n is 0 to 6; m is 0 to 6; and A is a bond, -CH=CH- or -C=C- oxygen, sulphur or NR1; R1 is hydrogen, C¿1-8?alkyl or phenylC1-4alkyl; and Ar is aryl or heteroaryl, each of which may be optionally substituted; with the provisos that: when W is a bond the side chain is α to the ring nitrogen atom; when W is CH2, k is zero, the side chain is at the 3- or 4-position of the piperidine ring and A is a bond, oxygen, sulphur or NR?1¿ then Ar is aryl substituted by phenoxy or substituted phenoxy or is a tricyclic heteroaryl group as hereinafter defined; and when W is CH¿2? and k is 2 the side chain -(CH2)nA(CH2)mAr is not α to the nitrogen atom, and salts thereof, have activity as calcium channel antagonists. Processes for preparing compounds (I) and compositions containing them are also described.

Description

COMPOUNDS AS CALCIUM CHANNEL ANTAGONISTS
The present invention relates to nitrogen containing heterocyclic derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
EPA 266574 discloses 3-aryloxymethyl-4-phenylpiperidines, which compounds are said to have activity against calcium overload in brain cells and to be useful for the treatment of anoxia, ischemia, migraine and epilepsy. US Patent No. 4,918,073 describes a broad class of diarylaikyl-substituted cyclic amines (such as piperazines and piperidines) where the cyclic amine moiety is further substituted inter alia by a (hetero)atyloxyalkyl group, and US Patent No. 4,933,346 describes similar compounds having an arythioalkyl substituent. These compounds are said to have calcium antagonistic action.
We have now found a group of novel cyclic amine derivatives which exhibit activity as calcium channel antagonists.
The present invention therefore provides, in a first aspect, a compound of formula (I):
Figure imgf000003_0001
Formula (I)
in which
W is -CH2-, a bond, O or S;
k is 0, or when W represents -CH2- k may also be 2, in which case the dotted lines represent single bonds;
R is Cι_galkyl(phenyl)p, C2-8alkenyl(phenyl)p, C2-8alkynyl(phenyl)p, C3_gcycloalkyl or
Cι_galkylC3_gcycloalkyl, or R may also represent hydrogen when k is 2; p is 0 to 2 n is 0 to 6; mis 0 to 6; and
A is a bond, -CH=CH- or -C≡C- oxygen, sulphur or NR*; R! is hydrogen, Cι_ alkyl or phenylCι_4alkyl; and Ar is aryl or heteroaryl, each of which may be optionally substitued;
with the provisos that :
when W is a bond the side chain is α to the ring nitrogen atom;
when W is CH2, k is zero, the side chain is at the 3- or 4-position of the piperidine ring and A is a bond, oxygen, sulphur or NR* then Ar is aryl substituted by phenoxy or substituted phenoxy or is a tricyclic heteroaryl group as hereinafter defined; and
when W is CH2 and k is 2 the side chain - CH2)nA(CH2)mAr is not α to the nitrogen atom,
and salts thereof.
It will be appreciated that when k is zero the compound of formula 00 is a monocyclic heterocyclic compound viz a piperidino, pyrrolidino, morpholino or thiomorpholino derivative. When k is 2 the compound (I) is a tropane derivative.
It will be understood that in the compounds of formula (I) the alkylcycloalkyl, alkylphenyl, alkenylphenyl and alkynylphenyl R groups are linked to the nitrogen atom via the alkyl, alkenyl and alkynyl moieties respectively.
Preferably R is Cι_galkyl(phenyl)p in which p is 0 or 1, i.e. C]_galkyl, such as n-pentyl, or phenylCι_galkyl such as phenylpropyl, or R is C2-galkenyl(phenyl)p wherein p is 1, such as cinnamyl.
The values of m and n should be chosen such that the length of the chain (CH2)nA(CH2)m is at least 2 atoms. In general the length of the chain -(CH2)nA(CH2)m is from 2 to 6 e.g. 2 to 5 atoms. Preferred values for n and m depend on the group A. Thus for example when A is oxygen the sum of n+m is preferably from 1 to 5 for example n may be 1 or 2 and m may be 0. When A is -CH=CH-, m and n may both be zero.
A is preferably oxygen, or -CH=CH-. When Ar represents aryl, 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 Cι_2alkylenedioxy group (e.g. phenyl substituted by a 3,4-methylenedioxy group) or by 1 to 3 substituents selected from halogen, Cj^alkoxy, nitro, SC^alkyl, NRTX. (in which each R group can be H or Cι_4alkyl), OCF3, Cj.galkyl, trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted phenylCι_4alkyl and optionally substituted phenylCj.4alkoxy. Preferably the aryl group is a phenyl ring substituted by one or two substituents, in particular, by a phenyl, phenyl(Cι_4)alkyl, phenoxy or phenylCι_4alkoxy group; or by two chloro atoms especially in the 3- and 4-positions of the phenyl ring.
Suitable optionally substituted phenylCι_4alkyl groups include, for example benzyl. Suitable optionally substituted ρhenylCι_4alkoxy groups include, for example benzyloxy groups.
Suitable substituents for said optionally substituted phenyl, phenoxy, phenylCj^alkyl and phenylCι_4alkoxy groups include for example halogen, Cj_4alkyl, Cι_4alkoxy, nitro and trifluoromethyl groups.
When Ar represents heteroaryl 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, tetrahydroquinolinyl or benzofuranyl. A tricyclic ring system preferably contains from 11 to 15 ring members, and most preferably has the structure :
Figure imgf000005_0001
wherein Y1 represents Y(CH2>r. Y is O, S or NR^ (where R^ is hydrogen or Cι_4alkyl), Z is (CH2)n or -CH=CH-, q is 0, 1 or 2 and r is 0 or 1 or is a corresponding dehydro ring system. Examples of 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, Cι_4alko y, phenyl, phenylCι_4alkyl andphenylCι_4alkoxy.
Alkyl groups present in the compounds of formula 00, alone or as part of another group, can be straight or branched. Thus a Cι_4alkyl group may be for example methyl, ethyl, n- propyl, n-butyl or any branched isomer thereof such as isopropyl or t-butyl.
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, oxalate, methanesulphonate or similar pharmaceutically acceptable inorganic or organic acid addition salts. Other non- pharmaceutically acceptable salts may be used for example in the isolation of final products and are included within the scope of this invention.
A particular group of compounds according to the invention is that of formula (IA) :
Figure imgf000006_0001
Formula (IA)
in which
the group -(CH2)nA(CH2)m Ar is attached at either the 3 or 4 position of the piperidine ring; R is Cι_galkyl(phenyl)p, C2-galkenyl(phenyl)p, C2-galkynyl(phenyl)p, C3_gcycloalkyl or Cι_galkylC3_gcycloa]kyl; p is 0 to 2; n is 0 to 6; m is 0 to 6; and either A is -CH=CH- or -C≡C- and
Ar is aryl or heteroaryl, each of which may be optionally substituted; or A is a bond, oxygen, sulphur or NR*; R! is hydrogen, Cj.galkyl or phenylCι_4alkyl; and
Ar is aryl substituted by phenoxy or substituted phenoxy or is a tricyclic heteroaryl group as hereinafter defined;
and salts thereof.
A further group of compounds according to the invention is that of formula (IB):
Figure imgf000007_0001
Formula (IB)
in which
R is Cι_galkyl(phenyl)p, C2-galkenyl(phenyl)p, C2-galkynyl(phenyl)p, C3_gcycloalkyl or
Cι_galkylC3_8cycloalkyl; p is 0 to 2; n is 0 to 6; m is 0 to 6; A is a bond, -CH=CH-, -C≡C-, oxygen, sulphur or NR* ;
R! is hydrogen, Cj.salkyl or phenylC^alkyl; and
Ar is aryl or heteroaryl, each of which may be optionally substituted;
and salts thereof.
A yet further group of compounds according to the invention is that of formula (IC):
Figure imgf000008_0001
in which
the group -(CH2)nA(CH2)m Ar is attached at either the 2 or 3 position of the tropane ring;
R is hydrogen, Cι_galkyl(phenyl)p, C2-galkenyl(phenyl)p,
C2_8alkynyl(phenyl)p, C3_8cycloalkyl or Cι_galkylC3_8cycloalkyl; p is 0 to 2; n is 0 to 6; m is 0 to 6;
A is a bond, -CH=CH-, -C≡C-, oxygen, sulphur or NR*; R! is hydrogen, Cι_8alkyl or phenylCι_4alkyl; and
Ar is aryl or heteroaryl, each of which may be optionally substituted;
and salts thereof.
Another group of compounds according to the present invention is that of formula (ID) :
Figure imgf000008_0002
I R
Formula (ID)
in which
W is oxygen or sulphur, R is Cι_galkyl(phenyl)p, C2_8alkenyl(phenyl)p, C2-galkynyl(phenyl)p, C3_gcycloalkyl or Cι_galkylC3_gcycloalkyl; p is 0 to 2; n is 0 to 6; m is 0 to 6;
A is a bond, -CH=CH-, -C≡C-, oxygen, sulphur or NR*; R1 is hydrogen, Cj.galkyl or phenylCι_4alkyl; and
Ar is aryl or heteroaryl, each of which may be optionally substituted;
and salts thereof.
In formula (ID) the chain -(CH2)nA(CH2)mAr may be attached at either the 2- or 3-position of the ring.
Particular compounds of the invention include:
(±) E-and Z- 1 -pentyl-3-[2-(4-fluorophenyl)ethenyl]piperidine hydrochloride, (±) E-l-pentyl-3-[2-(4-biphenyl)ethenyl]-piperidine hydrochloride, (±) E-l-pentyl-3-[2-(l-naphthyl)ethenyl]-piperidine hydrochloride, (±) E-l-pentyl-3-[2-(4-chlorophenyl)ethenyl]-piperidine hydrochloride, 2-[2-(3,4-methylenedioxyphenoxy)ethyl]-l-pentylpiperidine oxalate, 2-[2-(4-fluorophenoxy)ethyl]-l-pentylpiperidine oxalate, endo-[2-(3,4-dichlorophenoxy)ethyl]tropane oxalate, endo 3-[2-(3,4-dichlorophenoxy)ethyl]-8-azabicyclo[3.2.1]octane oxalate, endo 3-[2-(3,4-dichlorophenoxy)-ethyl]-8-(n-pentyl)-8-azabicyclo[3^, Ijoctane oxalate, 2-(4-fluorophenoxymethyl)-4-pentylmorpholine oxalate, 2-(3,4-dichlorophenoxymethyl)-4-pentyl morpholine oxalate,
2-[2-(4-benzylphenoxy)ethyl]-l-pentylpiperidine oxalate hemihydrate, 2-[2-(4-benzylphenoxy)ethyl]- 1-methylpiperidine hydrochloride, 2-[2-(2-dibenzofuranyloxy)ethyl]- 1-pentylpiperidine oxalate, 2-[2-(3,4-dichlorophenoxy)ethyl]- 1-pentylpiperidine oxalate, 2-[2-(3,4-dichlorophenoxy)ethyl]- 1-cinnamylpiperidine oxalate hemihydrate, 4-[2-(2-dibenzofuranyloxy)ethyl]-l-pentylpiperidine hydrochloride, 2-(4-benzyloxyphenoxy)methyl]-4-butylthiomorpholine oxalate, 4-[2-(2-dibenzofuranyloxy)ethyl]-l-cinnamylpiperidine oxalate, and endo 3-[2-(3,4-dichlorophenoxy)ethyl]-8-cinnamyl-8-azabicyclo [3.2.1] octane oxalate hydrate.
It will be appreciated that the compounds of formula 00 may contain one or more asymmetric centres. Such compounds will exist as optical isomers (enantiomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are included within the scope of the invention. Further, all diastereomeric forms possible (pure enantiomers and mixtures thereof) are within the scope of the invention. i addition, when A represents -CH=CH- the compounds will exist as geometric isomers, and the invention encompasses all such isomers and mixtures thereof.
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 formula (I) which comprises:
(a) for compounds of formula (I) in which A is O, S or NR*, reaction of a compound of formula QI):
Figure imgf000010_0001
Formula (II)
in which W, k, R and n are as described for formula 00 and A^ is O, S or NRl, with a compound of formula L(CH2)mAr in which m and Ar are as described for formula 00, and is a leaving group;
(b) for compounds of formula (I) in which A is O, S or NR*, reaction of a compound of formula (HI):
Figure imgf000011_0001
Formula (HI)
in which W, k, n and R are as described for formula (I) and * is a group displaceable by a nucleophile, with a compound of formula HAl(CH2)mAr where m and Ar are as described for formula (I) and A 1 is as described for formula (II); or
(c) for compounds of formula (I) in which A is NR*, reduction of a compound of formula (IV) :
Figure imgf000011_0002
Formula (TV)
in which R4 represents the group
-(CH2)nN(Rl)C(O)(CH2 ιAr or -(CH2)n-lC(O)N(Rl)(CH2)mAr,
and k, W, R, n, m and Ar are as described for formula (I);
(d) for compounds of formula (I) in which A is a bond, reaction of a compound of formula (V) :
Figure imgf000012_0001
Formula (V)
(wherein R, W, k, L,l, m and n are as hereinbefore defined).
with a compound of formula X^Ar in which Ar is as described for formula 00, and X* is an alkali metal;
(e) introduction of the group R into a compound of formula (VI) :
Figure imgf000012_0002
Formula (VI)
(wherein W, k, n, m, A and Ar are as defined in formula (I)) by reaction with a compound Rl wherein l is a leaving group;
(f) For compounds where A is O, S, NR! or a bond reduction of a compound of formula (VII) :
Figure imgf000012_0003
Formula (VII) wherein W, k, A, Ar, n and m are as hereinbefore defined and R^ is Cι_7alkyl(phenyl)p, C2-7alkenyl(phenyl)p, C2-7alkynyl(phenyl)p or Cι_7alkylC3_8cycloalkyl;
(g) For compounds where W is CH2, k is zero, and A is O, S, NR* or a bond reduction of a compound of formula (VIII):
Figure imgf000013_0001
Formula (VIII)
wherein R, A, Ar m and n are as hereinbefore defined and X" is a counter ion;
(h) For compounds wherein A is -CH=CH-, reaction of a compound of formula (IX)
Figure imgf000013_0002
Formula (IX)
(wherein W, k, R and n are as hereinbefore defined) with a reagent serving to introduce th group Ar;
(i) Interconversion of one compound of formula (I) to a dif went compound of formula (I), e.g. the reduction of a compound wherein A is -CH=CH- to a compound wherein A is -CH2-CH2-;
and optionally thereafter forming a salt.
In process (a) the reaction between a compound of formula (II) and a compound L(CH2)mAr can take place under conditions which depend on the nature of the group L and the value of m. For example, when 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. When 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 dimethylformamide. Preferably the aryl group is substituted by an activating group such as CF3 or NO2.
The reaction between a compound of formula (HI) and a compound of formula HAl(CH2)mAr (process (b)) can take place under conditions which depend on the nature of L^ and A. For example when L is hydroxy, m is 0 and A* 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). Alternatively the leaving group L 1 may be for example a halogen atom or a sulphonyloxy group eg. methane-sulphonyloxy or p-toluene sulphonyloxy. In this case the reaction may be effected in the presence or absence of solvent and at temperature in the range 0 to 200°C.
The reduction of a compound of formula (IV) according to process (c) can be effected by methods known in the art, for example using a reducing agent such as lithium aluminium hydride. Conveniently 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.
The reaction between a compound of formula (V) and a compound of formula X* Ar in process (d) can take place under standard conditions known to those skilled in the art for the formation of carbon-carbon bonds.
The reaction of a compound of formula (VT) with RL2 according to process (e) may be effected in conventional manner, for example in an organic solvent, such as dimethyl formamide. The leaving group l 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. When l is a halide the reaction is preferably carried out in the presence of a weak base such as potassium carbonate, and when β is sulphonyloxy, a strong base such as sodium hydride or potassium t-butoxide may be employed.
Reduction of a compound of formula (VH) according to process (f) may be effected using standard reducing agents such as lithium aluminium hydride. Reduction of a compound of formula (VIE) according to process (g) 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.
Process (h) may be effected using a Wadsworth-Emmons reagent of the formula Ar(CH2)m+ιP(O)(OAlk)2, such as a diethylphosphonate, or a Wittig reagent of the formula Ar(CH2)m+ιPPh3X (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 t-butoxide.
Interconversion reactions according to process (i) may be effected by methods well known in the art. Thus for example conversion of a compound (I) wherein A represents -CH=CH- into a compound (I) wherein A represents-CH2-CH2- may be effected by catalytic reduction.
The compounds of formula (II) wherein W is CH_2 and k is zero can be prepared from the corresponding compounds in which R is hydrogen, by alkylation under standard conditions. For example, compounds of formula (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 Cι_4alkanol such as ethanol, in the presence of a base, such as potassium carbonate, or dimethylformamide in the presence of an iodoalkane. The corresponding compounds of formula (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 2, 3- or 4-hydroxyalkyl-pyridine.
Alternatively, the compounds of formula (II) in which W is CH2, k is zero and A* is oxygen can be prepared by reduction of a compound of formula (X):
Figure imgf000015_0001
Formula (X) in which R and n are as described for formula (I) and X" is a counter ion.
Compounds (X) may be prepared by standard literature methods.
Compounds of formula (II) wherein W is CH2, k is 2, A is oxygen, R is methyl and n is 2 may be prepared from tropinone, by reaction with triethylphosphonoacetate, followed by reduction e.g. using catalytic hydrogenation, to give the 3-ethoxycarbonylmethyl- substituted tropane, which is further reduced e.g. using lithium aluminium hydride to the corresponding 3-(2-hydroxyethyl)tropane. The corresponding 2-substituted compounds may be prepared in an analogous manner.
The compounds of formula (D) wherein W is oxygen, sulphur or a bond can be prepared from the corresponding compounds in which R is hydrogen, by alkylation under standard conditions, as described above for compounds wherein W is -CH2-.
A compound of formula (II) wherein W is sulphur may also be prepared by reduction of an ester of formula (XL) :
Figure imgf000016_0001
Formula (XI)
wherein n is defined as for formula CO, Alk is a Cι_6alkyl group (e.g. ethyl) and R > represents a group R or -COR^ as hereinbefore defined. Reduction may be effected using a reducing agent such as lithium aluminium hydride in a solvent such as diethyl ether or tetrahydrofuran. Compounds of formula (XI) may be prepared by N-alkylation or acylation of a corresponding compound wherein R* is hydrogen. Esters of formula CXI) wherein n is 1 and R* is hydrogen are described in EPA 226267.
Compounds of formula (II) wherein W and A are both oxygen and n is 1 may be prepared by reduction of the corresponding morpholine carboxylic acid, which itself may be prepared from the corresponding cyanomorpholine for example by acid hydrolysis. The cyano morpholine may be obtained by reaction of a 2-haloacrylonitrile e.g. 2-chloroacrylonitrile, with an appropriately substituted aminoethanol, HO(CH2)2NHR, as described for example in Tett Letts., 1991, 32, 2281. In compounds of formula (II) wherein A* is oxygen, the value of n may be increased by standard homologation methods, for example by sequential conversion of the alcohol to corresponding haloalkyl, cyanoalkyl and ester derivatives, the ester then being reduced to an alcohol, whereby n is increased by 1.
Compounds of formula (II) wherein A* is sulphur or NR* can be prepared from the hydroxy compounds of structure (II), via a corresponding halide, according to methods well known in the art.
Compounds of formula (HI) wherein * is OH can be prepared as described for compounds of formula (II), and compounds of formula (HI) wherein L* is a halogen atom, or a mesyloxy or tosyloxy group can be prepared from the corresponding alcohol in conventional manner.
Compounds of formula (TV) wherein R4 is a group
-(CH2)n (Rl)C(O)(CH2)m-lAr can be prepared by reacting a compound of formula (II) wherein A^ represents NR* with an acylating agent corresponding to the group -(CH2)mAr, for example an acid chloride ClOC(CH2)m_iAr.
Compounds of formula (IV) wherein R4 is a group
-(CH2)n-lC(O)N(Rl)(CH2)mAr may be prepared for example by reaction of a corresponding compound wherein R4 represents -(CH2)n-lCO2H or an activated derivative thereof such as an acid halide, ester or anhydride, with an amine of formula HN(R1)(CH2)m Ar. It will be appreciated that when the acid itself is employed, reaction with the amine should be effected in the presence of a coupling agent The carboxylic acid may itself be prepared for example by oxidation of the corresponding alcohol, ie. a compound of formula (II) wherein A* is oxygen.
Compounds of formula (V) may be prepared in analogous manner to compounds of formula (HI); where necessary the chain length may be increased using methods well known in the art.
Compounds of formula (VI) may be prepared for example according to any of processes (a) to (d) above, using intermediates analogous to formulae (II) to (TV) wherein R is replaced by an N-protecting group, which is subsequently removed by 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, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl or benzyloxycarbonyl. An aralkyl group such as benzyl may be cleaved by hydrogenolysis, and an acyl group such as benzoyl may be cleaved by hydrolysis. It will be appreciated that where the N-protecting group is aralkyl, the compound is of formula (I) and this reaction sequence thus provides a means of converting one compound of formula (I) into a different compound of formula
(0.
A compound of formula (VH) 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 formula (VIII) may be prepared using the general methods described in processes (a) to (e) above.
Compounds of formula (IX) may be prepared by conventional methods, for example the oxidation of a compound of formula (II) wherein A^ 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-methoxycarboxamide which can be reduced to the aldehyde using diisobutylaluminium hydride. Compounds of formula (IX) 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. Alternatively the aldehyde may be converted to the corresponding 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.
When a compound of formula 00 is obtained as a mixture of enantiomers, these may be separated by conventional methods such as cr stallisation in the presence of a resolving agent, or chromatography, for example using a chiral HPLC column.
Compounds of the invention have been found to exhibit high 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. For example, 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.
In a further aspect of the invention there is therefore provided 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 formula (I) or a pharmaceutically acceptable salt thereof . Thus for example, 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 invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition or disease caused or exacerbated by the accumulation of calcium in the brain cells of a mammal e.g. a human.
For use in medicine, 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 or solids, 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 carriers) 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. Examples of 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. For example, 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 carriers), 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 infusion. Typical parenteral 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. Alternatively, the solution can be lyόphilised 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 cyclodextrins.
Preferably the 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 (T) 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. Alternatively the compounds of the invention may be administered by continuous intravenous infusion, preferably at a dose of up to 400 mg per day. Thus 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. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more. BIOLOGICAL DATA
Ca2+ Current Measurement
Cell preparations
Sensory neurons from dorsal root ganglia were dissociated from 1 day old rat pups (Forda et al, Developmental Brain Research, 22 (1985), 55-65). Cells were plated out onto glass coverslips and used within 3 days to permit effective voltage clamp of Ca2+ currents.
Solutions
The pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 10; MgCL2, 4; ATP, 2; buffered to pH 7.2 with CsOH. Cells were bathed in a normal Tyrodes solution before establishment of whole cell recording when the bathing solution was changed to one allowing isolation of Ca2+ currents. The external solution for recording Ca2+ channel currents contained in mM: BaCL2, 10; TEA-Cl, 130; glucose, 10; HEPES, 10; MgCL2, 1; buffered to pH 7.3 with TEA-OH. Barium was used as the charge carrier as this assists in current isolation and calcium dependent inactivation of current is avoided. Compounds were dissolved in DMSO to make a 20 mM stock solution. At the drug concentration used the vehicle (0.1 %) had no significant effect on Ca2+ currents. All experiments were performed at 21 to 24°C. Whole cell currents were recorded using List EPC-7 amplifiers and stored, digitised for later analysis using PC based software similar to that described previously (Benham & Tsien, Journal of Physiology (1988), 404, 767-784);
Ca^+ currents
Peak voltage gated Ca2+ channel currents of up to 10 nA from dorsal root ganglion neurons were recorded using 10 mM Ba2+ 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 relationship and assessing block at this point reduced any errors due to drifting holding potential. Some cells showed slow rundown of current as is commonly seen when recording Ca2+ currents. The rundown rate was measured in control conditions and extrapolated through the time of drug application to derive a control value to relate the drug affected current to. Block by 20 μM drug was assessed 3 minutes after drug application.
Compounds of the invention gave percentage inhibition of plateau Ca2+ current in the range 30 to 100%. PHARMACEUTICAL FORMULATIONS
1. Formulation for intravenous infusion
Compound of formula (I) 0.1 - 60 mg
Sodium hydroxide/hydrochloric acid to pH ca 7 polyethylene glycol 0 - 30 ml propylene glycol 0 - 30 ml alcohol 0 - 10 ml water to 100 ml
2. Formulation for bolus injection
Compound of formula (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 tonicity adjusting agent eg. sodium chloride, dextrose or mannitol may also be added.
3. Tablet for oral administration
Figure imgf000022_0001
The following non-limiting examples illustrate the preparation of compounds of formula CO
Preparation 1
(±)-Ethyl l-pentyl-3-piperidylcarboxylate
Potassium carbonate (125g) was added to a stirred solution of ethyl nipecotate (50g, 0.32 mol) in acetone (375 ml). The mixture was treated with 1-bromopentane (57.65g, 0.38 mmol) over 10 min then stirred at room temperature overnight. The mixture was filtered, the solid washed thoroughly with acetone and the combined acetone solutions were concentrated in vacua. The residue was treated with saturated aqueous potassium carbonate (200 ml) then extracted into chloroform (3 x 200 ml). The combined organic extracts were dried over sodium sulphate then concentrated in vacua to a gum which was chromatographed on silica in a gradient of 1 : 1 diethyl ether/light petroleum. This afforded the title compound as a pale yellow oil (65.42g, 91%).
H Nmr (CDC13) δ : 0.90 (3H, t, J=7Hz), 1.21-1.80 (14H, m), 2.11 (IH, t, J=llHz), 2.29- 2.38 (2H, m), 2.51-2.64 (IH, m), 2.76-2.85 (IH, m), 2.97-3.06 (IH, m), 4.14 (2H, q, J=7Hz).
Preparation 2
(±)-[l-Pentyl-3-piperidyI]-N-methoxy-N-methylcarboxamide
A solution of (±)-ethyl l-pentyl-3-piperidylcarboxylate (20g, 88.1 mmol) in 5N hydrochloric acid (200 ml) was heated at reflux for l h. The mixture was concentrated in vacua then coevaporated with toluene (3 x 30 ml), to remove the last traces of water. The residue was treated with thionyl chloride (150 ml) and heated at reflux for idh. The mixture was concentrated in vacua then coevaporated with toluene (3 x 30 ml), A solution of this residue in absolute chloroform (250 ml) was added over 20 ins to a stirred solution of N,O,-dimethylhydroxylamine hydrochloride (9.45g, 96.9 mmol) and dry pyridine (35.6 ml, 0.44 mol) in absolute chloroform (200 ml), at -20°C, under N2. After warming to room temperature overnight, the solution was treated with saturated aqueous potassium carbonate (200 ml). The aqueous and organic phases were separated and the aqueous phase further extracted into chloroform (2 x 200ml). The combined organic extracts were dried over sodium sulphate and concentrated in vacua. The oil produced was dissolved in diethyl ether, filtered and concentrated in vacua. The residue was distilled to afford the title compound as a yellow oil (13.5g, 64%) b.p. 120°C, 0.5 mmHg.
*H Nmr (CDCI3) δ : 0.89 (3H, t, J=7Hz), 1.21-2.14 (12H, m), 2.29-2.39 (2H, m), 2.88- 3.06 (3H, m), 3.19 (3H, s), 3.71 (3H, s).
Preparation 3
(±)l-Pentyl-3-piperidylcarboxaldehyde
A solution of (±)-[l-pentyl-3-piperidyl]-N-methoxy-N-methylcarboxamide (6g, 24.8 mmol) in dry tetrahydrofuran (100 ml), under N2, at -70°C, was treated with diisobutylaluminium hydride (21.5 ml of a 1.5M solution in hexanes, 32.2 mmol) over 5 mins. The reaction was allowed to warm to room temperature over 2h. It was then cooled to -60°C and poured into vigorously stirred 5N hydrochloric acid (20 ml). The tetrahydrofuran was removed in vacua, then the aqueous solution was carefully basified to pH14 with potassium carbonate and treated with Rochelle salt The solution was extracted into chloroform (3 x 30 ml), the combined organic extracts were dried over sodium sulphate then concentrated in vacua. The residue was dissolved in diethyl ether, filtered, concentrated in vacua and the oil produced was co-evaporated with benzene (3 x 30 ml) to remove any residual water. This afforded the title compound as a clear oil (4.4g, 96%).
Preparation 4
2-(2-Hydroxyethyl)-l-pentylpiperidine
A mixture of 2-(2-hydroxyethyl)piperidine (7.0g, 54mmole), 1-bromopentane (8.18g, 54 mmole), potassium carbonate (7.5g, 54 mmole) and absolute ethanol (400 ml) was heated at reflux temperature with stirring for three days. The solution was filtered and the filtrate evaporated to dryness. The residue was taken up in acetone and insoluble material removed by filtration and the filtrate evaporated to dryness to give a yellow oil (9.0g) which was distilled to give the title compound (5.6g, 52%) as an oil, b.p. = 98°-106°C, 0.2 mmHg. Preparation 5
2-(2-Hydroxyethyl)-l-ethoxycarbonylpiperidine
To a stirred solution of 2-(2-hydroxyethyl)piperidine (27.4g, 0.212 mole) in dry dichloromethane (370 ml) containing triethylamine (29.55 ml, 0.212 mole) at 0°C under nitrogen was added dropwise, ethyl chloroformate (20.27 ml, 0.212 mole) in dry dichloromethane (30 ml). After stirring at room temperature overnight dilute HC1 (200 ml, IN) was added and the organic phase separated off. The aqueous phase was further extracted with dichloromethane (2 x 50 ml), the combined organic extracts dried (K2CO3) and evaporated to give the title compound as an oil which was used without further purification.
Preparation 6
l-t-ButoxycarbonyI-2-(2-hydroxyethyl)piperidine
2-(2-Hydroxyethyl)piperidine (12.22g, 95mmol) was dissolved in dichloromethane (100ml) at room temperature and stirred under nitrogen. A solution of di-t-butyl dicarbonate (20.47g, 94 mmole) in dichloromethane (50ml) was added dropwise over 45 minutes. The resulting yellow solution was stirred at room temperature for a further one hour and the dichloromethane then evaporated off to produce a yellow liquid. This material was further evaporated under high vacuum at 50°C to remove t-butanol. The yellow oil produced (21.6g) was free of t-butanol by N.ΠLΓ. and was used without further purification.
Preparation 7
2-[2-(4-Benzylphenoxy)ethyl]-l-ethoxycarbonyl piperidine
The product of Preparation 5 (4.0g, 20mmole), 4-benzylphenol (3.67g, 20mmole) and triphenylphosphine (5.21g, 20mmole) was dissolved with stirring under nitrogen in dry dichloromethane (100ml). The mixture was cooled in an ice-bath and diethylazodicarboxylate (3.46g, 20mmole) added dropwise in dry dichloromethane (20ml). The clear solution produced was allowed to slowly reach room temperature and stood for three days, when the solution was evaporated. The residue was chromatographed on silica gel using dichloromethane as eluent Monitoring of fractions by tl.c. with combination of appropriate fractions and evaporation gave the title compound as an oil (5.6g). (Mass Spectrum - M+H:368)
*H N.mx (CDCI3) δ: 1.15 (3H, t), 1.30-1.60 (6H, m + H2O), 1.80-1.95 (IH, m) 2.15- 2.30 (IH, m), 2.78-2.95 (IH, t), 3.8-4.1 (7H, m), 4.45-4.60 (IH, m), 6.77 (2H, m), 6.97- 7.30 (7H, m).
Preparation 8
2-[2-(4-Benzylphenoxy)ethyl]piperidine hydrochloride
The product of Preparation 7 (4.6g, 15.6mmole) was dissolved in glacial acetic acid (10ml) and a solution of HBr in glacial acetic acid (10ml, 45% w/v) was added to the stirred solution at room temperature. The mixture was warmed on a steam-bath for three hours, cooled, added to ice-cold water and the mixture basified with 50% sodium hydroxide solution. The mixture was extracted with ether (X2). The combined ethereal solution was extracted with 2N HC1 (X3) and the combined acid extracts basified with 50% sodium hydroxide and extracted with dichloromethane (X3). The combined dichloromethane extracts were washed (H2O, brine) dried (Na2SO4) and evaporated to give an oil (1.84g), Mass Spec M+H:296.
A quantity (0.8g) of this material was dissolved in ethyl acetate and 1M ethereal HC1 added. An oil precipitated and the ether was boiled off. A small quantity of hot methanol was added to produce a clear hot solution from which white crystals separated on cooling. These were collected to give the title compound (0.36g), M_?. = 162-164°C. (C20H25NO.HCI.0.5H2O) Requires: C, 70.5%; H, 8.0%; N, 4.1%
Found: C, 70.5%; H, 7.8%; N, 4.2%
Preparation 9
2-(2-[2-Dibenzofuranyloxy]ethyl)-l-ethoxycarbonyl piperidine
Using the conditions described in Preparation 7, replacing the 4-benzylphenol with 2- hydroxydibenzofuran (3.67g, 20mmole) and using corresponding molar proportions of the other reagents gave the title compound as a brown oil (6.1g). Mass spectrum (M+H=368). !H N.mj. (CDCI3) δ: 1.15 (3H, t), 1.35-1.75 (7H, m), 1.94 (IH, m), 2.30 (IH, m), 2.90 (IH, t), 3.98-4.20 (4H, m), 4.50 (IH, m), 6.95-7.15 (IH, m), 7.25-7.57 (5H, m), 7.81-7.93 (IH, m).
Preparation 10
2-[2-(2-Dibenzofuranyloxy)ethyI]piperidine hydrochloride
The product of Preparation 9 (6.0g, 16.3mmole) was dissolved in glacial acetic acid hydrogen bromide (20ml, 45w/v, xs). 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. Product was eluted in CH2Cl2 2% methanol (methanol contains 10% .88NH4OH) and finally CH2α2/5% methanol. Fractions containing required material were combined and evaporated to dryness to give an oil (2.60g). Some of this material (300mg) was dissolved in ethyl acetate, excess ethereal HC1 (1M) added, the solution concentrated to a low volume and cooled. The title compound separated as white crystals (270mg), M.P. 172-174°C. (Mass Spec M+H=296)
(C19H21NO2HCI 0.2H2O) requires: C, 68.0%, H, 6.7%, N, 4.2%. found: C, 67.9%; H, 6.6%; N, 4.1%
Preparation 11
2-(2-[3,4-Dichlorophenoxy]ethyI)-l-t-butoxycarbonylpiperidine
Using the product of Preparation 6 (4.55g, 20mM), the conditions of Preparation 7 (Mitsunobu reaction) and replacing 4-benzylphenol with 3,4-dichlorophenol (3.24g,
20mM) together with corresponding molar proportions of the other reagents gave the title compound as a colourless oil (6.48g). (Mass Spec. M+H=375)
*H N.m.r. (CDCI3) δ: 1.38 (9H, s), 1.5-1.9 (8H, m), 2.15-2.30 (IH, m), 2.70-2.88 (IH, m), 3.50-4.10 (2H, m), 4.40-4.55 (IH, m), 6.70 (IH, d of d), 6.90-7.01 (IH, m), 7.21-7.31 (IH, m). Preparation 12
2-[2-(3,4-DichIorophenoxy)ethyl]piperidine hydrochloride
The product of Preparation 11 (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 (H2θ> brine), dried (Na2SO4) and evaporated to dryness to leave a colourless oil (3.53g). A portion of this material (0.825g) was dissolved in ethyl acetate and ethereal HC1 (XS, 1M soln) added to the warm solution. On slow cooling the title compound crystallised as white crystals (0.861g), M.P.: 158- 159°C.
(Mass Spec M+H: 274).
(C13H17Cl2NO, HQ) requires: C, 50.3%; H, 5.8%; N, 4.5% found: C, 50.0%; H, 5.7%; N, 4.3%.
Preparation 13
3-Carbethoxymethylenetropane
Following a previously described procedure (Yaoxwe Xwebao 12 (5), 361, (1986) sodium metal (2.47g) was dissolved in ethanol (200 ml). Triethylphosphonoacetate (19.84 ml) was added over 30 minutes followed by a solution of tropinone (12.53g) in ethanol (80 ml). The mixture was allowed to stand at room temperature for 16 hours. The solvent was removed in vacua, the residue partitioned between water and diethylether and the ether phase dried and evaporated to give an oil (14.82g). This was treated with oxalic acid dihydrate (8.97g) in dry tetrahydrofuran to give an oxalate salt (12.05g) which was re- crystallised from methanol/diethylether. Re-basification with aqueous sodium hydroxide, extraction into diethylether, following by drying of the ether phase and evaporation gave the title compound (5.00g) as an oil.
*H Nmr (CDCI3, 250 MHz) δ : 1.3 (t 3H), 1.5 (d, 2H), 1.95 (m, 2H), 2.05, 2.7 (dd, 2H), 2.35 (S, 3H), 2.4, 3.5 (dd, 2H), 3.25 (br.S, 2H), 4.15 (q, 2H), 5.3 (S, IH). Preparation 14
(Endo)-ethyl tropane-3-acetate
3-Carbethoxymethylenetropane (6.43g) was dissolved in ethanol (300 ml). Raney nickel (~0.5g) was added and the mixture hydrogenated for 24 hours at 50 p.s.i. and room temperature. The catalyst was removed by filtration and the solvent removed in vacua. The residue was chromatographed on silica gel to give, following further basification the title compound as an oil (4.15g). MS/EI - Molecular ion = 211.
!H Nmr (CDC13, 400 MHz) δ : 1.25 (t, 3H), 1.3, 1.65 (SM, 4H), 2.05, 2.2 (SM, 4H), 2.3 (s, 3H), 2.45 (m, 3H), 3.1 (br.S, 2H), 4.1 (q, 2H).
Preparation 15
(Endo)-3-(2-hydroxyethyl)tropane
Lithium aluminium hydride (2.55 g) was stirred with anhydrous ether (70 ml) under dry nitrogen at room temperature. Endo-ethyl tropane-3-acetate, (12.86g) dissolved in anhydrous ether (30 ml) was added at such a rate as to maintain a gentle reflux. The reaction mixture was then stirred at room temperature for 16 hrs when water was cautiously added. The inorganics were removed by filtration and washed with diethylether. The combined filtrate and washings were dried (Na2SO4) and evaporated. The residue was distilled (Kϋgelrohr) to give the title compound (8.9g), B.P. 135°C at 0.02 mm Hg.
H Nmr (CDCI3, 250 MHz) δ : 1.1-2.1 (sm, 11H), 2.2 (s, 3H), 3.0 (br.s, 2H), 3.5 (t, 2H), 4.2 (br.s., IH).
Preparation 16
2-Cyano-4-pentylmorphoIine
Following a previously described method (Tet Letts (1991), 22, 2281) a solution of 2-(n- amylamino)ethanol (45.0g) and 2-chloroacrylonitrile (30.0g) in diethylether (750 ml) was allowed to stand at room temperature for 2 days. The ether was evaporated and 1,2- dimethoxyethane (360 ml) added to the residue. The mixture was cooled to 0°C and potassium t-butoxide (41. lg) added portionwise, keeping the temperature below 15°C. The mixture was then stirred at 0°C for two hours, refluxed for one hour, cooled and treated with aqueous sodium bicarbonate solution. The aqueous solution was extracted with diethylether (3 x 200 ml) and the combined organic extracts dried and evaporated to give the crude nitrile as a black oil. The oil was distilled to give the title compound as a colourless oil (34.2g, 55%), b.p. 94-104°C at 0.2 mm Hg.
!Nmr (DMSO-d^) δ : 0.99 (3H, t), 1.39 (4H, m), 1.51 (2H, m), 2.33 (4H, m), 2.7 (IH, d), 2.85 (IH, d), 3.86 (2H, m), 5.5 (IH, t).
Preparation 17
4-Pentyl-2-morpholinecarboxyIic acid hydrochloride
2-Cyano-4-pentylmorpholine (5.0g) was dissolved in dilute hydrochloric acid (cone. HC1 30 ml/H2θ 30 ml). The mixture was heated on a steam-bath for four hours and the solvent then evaporated at reduced pressure. The residual material was treated with acetone and the insoluble material collected by filtration to give the title compound (5.5 g) as a white solid which was used in the next stage of the synthesis without further purification.
iNmr (DMSO δ : 0.88 (3H, t), 1.30 (4H, m), 1.73 (2H, m), 3.3 (4H, m), 3.4 (IH, d), 3.56 (IH, d), 4.1 (2H, m), 4.58 (IH, d).
Preparation 18
2-Hydroxymethyl-4-pentylmorphoIine
Using the method described in Chem. Pharm. Bull. (1968), 1£, 492, a solution of ethyl chlorofσrmate (1.08g, 0.01 mole) in dry tetrahydrofuran (10 ml) was added at -5°C over 30 minutes to a stirred solution of 4-pentyl-2-mσ_φholinecarboxylic acid hydrochloride (2.5g, 0.01 mole) and triethylamine (2.0g, 0.02 mole) in tetrahydrofuran (30 ml). The mixture was stirred for a further 30 minutes at -5°C and the white precipitate filtered off. The filtrate was added during 30 minutes to a solution of sodium borohydride (0.95g, 0.025 mole) in water (10 ml) at 10-15°C. The mixture was then stirred at room temperature for four hours, acidified with dilute HQ and the tetrahydrofuran evaporated. Sodium bicarbonate solution (5%, 50 ml) was added and the mixture extracted with ether (2 x 30 ml). The combined ethereal extracts were washed (Saturated NaCl solution), dried ( gSO4) and evaporated to give the title compound as a pale oil (1. lg). iNmr (CDCI3) δ : 0.88 (3H, t), 1.3 (4H, m), 1.5 (2H, m), 1.98 (2H, m), 2.13 (IH, m), 2.33 (2H, t), 2.74 (2H, t), 3.66 (4H, m), 3.92 (IH, d).
Preparation 19
4-n-ButyI-thiomorpholin-2-methanol
A stirred solution of ethyl thiomorpholin-2-carboxylate (EP 226267) £Δ I P.2139634k (1987) (4.2g) and Et3N (5.5 ml) in CH2C12 (100ml) at 0°C was treated with a solution of n-butyτyl chloride (2.9ml) in CH2C12 (10ml). After stirring at 0°C for lh, the reaction mixture was washed with 2N HCL (2 x 50ml), H2O (2 x 50ml) and dried (K2CO3). The solution was decanted and the solvent removed by rotary evaporation to afford the n- butyramide (4g) which was used without further purification. A solution of the n- butyramide (4g) in dry E^O (50ml) was added dropwise to a stirred suspension of LAH (1.5g) in dry E^O (100ml) at 0°C and the reaction mixture was stirred at room temperature overnight The reaction mixture was cooled to 0°C, carefully treated with H2O (1.5ml), 2.5N NaOH (2.2ml) and H2O (4ml) and stirred at room temperature for lh. The solid was removed by filtration and washed with EtjO (2 x 50ml). The combined filtrates were dried (KjCO3), filtered and the solvent removed by rotary evaporation to give the title compound (2.5g).
Examples 1 and 2
(±) E-and Z-l-Pentyl-3-[2-(4-fluorophenyl)ethenyI]piperidine hydrochloride (El and
E2)
A solution of (±)l-pentyl-3-piperidylcarboxaldehyde (0.5g, 2.73 mmol) in dry tetrahydrofuran (5 ml) was added dropwise to a mixture of potassium t-butoxide (0.34g, 3.0 mmol), p-fluσrobenzyl triphenylphosphonium chloride (1.22g, 3.0 mmol) and 18- crown-6 (15 mg) in dry tetrahydrofuran (10 ml), under nitrogen (R. Baker et al, Synthesis, 1981, 117). After stirring at room temperature for 3 days, the reaction mixture was concentrated in vacua, treated with water (10 ml) then extracted into diethyl ether (3 x 10 ml). The combined organic extracts were dried over sodium sulphate, concentrated in vacua, and chromatographed on silica in a gradient of 0-2% methanol in chloroform. Pooling of the fractions containing the faster running component gave a gum (0. Ig, 13%) which was converted to the hydrochloride salt to afford the Z isomer (E2) as a white solid m.p. 140-141°C (from methanol-diethyl ether). Pooling of the fractions containing the slower running component gave a gum (0.17g, 15%) which was converted to the hydrochloride salt to afford the E isomer (El) as a white solid m.p. 187-189°C (from methanol-diethyl ether).
(E2) Z isomer
*H Nmr (DMSO-d^) δ : 0.97 (3H, t, J=7Hz), 1.25-1.53 (5H, m), 1.69-2.01 (5H, m), 2.73- 3.20 (4H, m), 3.28-3.58 (3H, m), 5.43 (IH, t, J=10Hz), 6.59 (IH, J=10Hz), 7.27 (2H, t, J=9Hz), 7.52 (2H, dd, J=6, 9Hz)
(El) E isomer
IH Nmr (DMSO-d^) δ : 0.97 (3H, t, J=7Hz), 1.27-1.55 (5H,m ), 1.72-2.14 (5H, m), 2.73- 3.15 (5H, m), 3.45-3.61 (2H, m), 6.22 (IH, dd, J=7, 16Hz), 6.59 (IH, d, J=16Hz), 7.25 (2H, t J=9Hz), 7.56 (2H, dd, J=6, 9Hz).
Example 3
(±) E-l-PentyI-3-[2-(4-biphenyl)ethenyl]-piperidine hydrochloride (E3)
The title compound was prepared in a similar manner to Example 1 and 2 from (±) 1- pentyl-3-piperidylcarboxaldehyde (2g, 10.93 mmol), diethyl (4- biphenylmethyl)phosphonate (3.33g, 10.93 mmol), sodium hydride (328 mg of an 80% dispersion in mineral oil, 10.93 mmol) and 15-crown-5 (60 mg). This afforded the title compound as a white solid (2.22g, 55%) m.p.230-233°C (from methanol-diethyl ether).
!H Nmr (DMSO-d^ δ : 0.97 (3H, t, J=7Hz), 1.25-1.58 (5H, m), 1.72-2.14 (5H, m), 2.72- 3.16 (5H, m), 3.45-3.65 (2H, m), 6.31 (IH, dd, J=7, 15Hz), 6.64 (IH, d, J=15Hz), 7.38- 7.87 (9H, m).
Example 4
(±) E-l-Pentyl-3-[2-(l-naphthyl)ethenyl]-piperidine hydrochloride (E4)
The title compound was prepared in a similar manner to Example 3 from (±) l-pentyl-3- piperidylcarboxaldehyde (0.5g, 2.73 mmol), diethyl 1-naphthylmethylphosphonate (0.76g, 2.73 mmol), sodium hydride (82 mg of an 80% dispersion in mineral oil, 2.73 mmol) and 15-crown-5 (30 mg). This afforded the title compound as a white solid (0.36g, 37%) m.p. 150-154°C (from methanol-diethyl ether).
!H Nmr (DMSO-d^ δ : 0.98 (3H, t J=7Hz), 1.26-1.64 (5H, m), 1.78-2.18 (5H, m), 2.80- 3.19 (5H, m), 3.46-3.75 (2H, m), 6.28 (IH, dd, J=7, 16Hz), 7.37 (IH, d, 16Hz), 7.51-7.77 (4H, m), 7.89-8.05 (2H, m), 8.15-8.23 (IH, m).
Example 5
(±) E-l-Pentyl-3-[2-(4-chlorophenyI)ethenyl]-piperidine hydrochloride (E5)
A solution of (±) l-pentyl-3-piperidylcarboxaldehyde (0.5g, 2.73 mmol) and diethyl 4- chlorobenzylphosphonate (0.72g, 2.73 mmol) in dry tetrahydrofuran (5 ml) was added (over 10 min) to an ice cold stirred slurry of sodium hydride (82 mg of an 80% dispersion in mineral oil, 2.73 mmol) and 15-crown-5 (15mg) in dry tetrahydrofuran (10 ml), under N2> The reaction was allowed to warm to room temperature over 214h, then it was quenched by the addition of acetic acid (0.5 ml), and concentrated in vacua. The residue was treated with saturated aqueous potassium carbonate (15 ml) and extracted into chloroform (3 x 15 ml). The combined organic extracts were dried over sodium sulphate, concentrated in vacua and the residue chromatographed on silica in a gradient of 0-2% methanol in chloroform. This afforded a clear oil which was converted to the hydrochloride salt to afford the title compound as a white solid (0.29g, 32%) m.p. 200- 201 °C (from methanol-diethyl ether). *H Nmr (DMSO- δ : 0.97 (3H, t, J=7Hz), 1.27-1.55 (5H, m), 1.72-2.14 (5H, m), 2.72- 3.15 (5H, m), 3.45-3.61 (2H, m), 6.29 (IH, dd, J=7, 16Hz), 6.58 (IH, d, J=16Hz), 7.43- 7.62 (4H, m).
Example 6
2-[2-(3,4-Methylenedioxyphenoxy)ethyI]-l-pentylpiperidine oxalate
A solution of 2-(2-hydroxyethyl)-l-pentylpiperidine (2.0g, 0.01 mole), sesamol (1.39g, 0.01 mole), and triphenylphosphine (2.62g, 0.01 mole) in dry tetrahydrofuran (50 ml) was treated with diethyl azodicarboxylate (1.74g, 0.01 mole). The resulting solution was stirred at room temperature overnight and then evaporated to dryness to give a brown oil. This was purified by dry flash column chromatography on silica gel 7736 with methylene chloride containing 0-2% methanol as eluent and tl.c. monitoring of fractions. An oil (520 mg) was obtained which was taken up into ethyl acetate and oxalic acid (1.1 mol. equiv.) added. The solution was heated on a steam-bath for a few minutes, cooled and the solid filtered off. This solid was re-crystallised from methanol/ethyl acetate to give the title compound (250 mg), MJ».= 108°C.
(C19H29NO3. C2H2O4) requires: C, 61.60; H, 7.63; N, 3.42%.
Found: C, 61.76; H, 7.84; N, 3.40%
Example 7
2-[2-(4-Fluorophenoxy)ethyl]-l-pentylpiperidine oxalate
The title compound was prepared in a similar manner to Example 6 from 2-(2- hydroxyethyl)-l-pentylpiperidine (2.0g, 0.01 mole), 4-fluorophenol (1.12g, 0.01 mole), triphenylphosphine (2.62g, 0.01 mole) and diethyl azodicarboxylate (1.74g, 0.01 mole). Column chromatography as before and treatment with oxalic acid gave a solid which was re-crystallised three times from methanol/ethyl acetate to give the title compound (450 mg), MJ». = 84-85°C.
(Cι8H28FNO.0.95 C2H2O4) requires: C, 62.64; H, 7.89; N, 3.65; F, 4.96%
Found : C, 63.07; H, 7.95; N, 3.70; F, 5.01% Example 8
2-[2-(4-Benzylphenoxy)ethyl]-l-pentylpiperidine oxalate hemihydrate
The product of Preparation 8 as the free base (l.Og, 3.39mM), n-pentyl bromide (0.52g, 3.4mM), and solid potassium carbonate (0.48g, 3.4mM) were heated together in absolute ethanol (50ml) at reflux temperature for 22 hours. The solvent was removed and the residue equilibrated between water and dichloromethane. The organic phase was washed (H2θ/brine), dried (Na2SO4) and evaporated to give an oil (l.Og). This was purified by flash chromatography on a silica gel column, the product eluting in dichloromethane/2% methanol (methanol contains 10% .880 NH4OH). The oily product from the column (0.27g) was dissolved in ethyl acetate and oxalic acid dihydrate (102mg, 1.1 equivs) in warm ethyl acetate added. The mixture was evaporated to dryness, the residue dissolved in the minimum amount of methanol and warm (60°C) water added. The clear solution was allowed to slowly cool and the title compound separated as white crystals (0.175g), M.P.=65-70°C. (Mass Spec. M+H=366)
(C25H35NO, C2H2O4. 0.5H2O) requires: C, 69.8%; H, 8.2%; N, 3.0% found: C, 69.9%; H, 8.0%; N, 3.0%
Example 9
2-[2-(4-Benzylphenoxy)ethyl]-l-methylpiperidine hydrochloride
Lithium aluminium hydride (350mg, XS) was added to dry THF (20ml). To the stirred mixture at room temperature under nitrogen was added dropwise a solution of 2-[2-(4- benzylphenoxy)ethyl]-l-ethoxycarbonylpiperidine[Preparation 7](0.9g, 3.05mmole) in dry THF (30ml). The mixture was stirred at room temperature for 90 minutes, heated at reflux temperature for one hour and then cooled in an ice-bath during dropwise addition of water to decompose excess lithium aluminium hydride. The mixture was extracted (X3) with ether, the combined ethereal extracts washed (water, brine), dried (Na2SO4) and evaporated to give a colourless oil (0.66gm). This was dissolved in ethyl acetate and 1M ethereal HC1 (XS) added. The mixture was evaporated to dryness and the residue twice crystallised from ethyl acetate containing a few drops of methanol to give the title compound as white crystals (345mg), M_P. = 115-117°C. (Mass Spec. M+H=310).
(C21H27NO. HC1) ~ requires: C, 72.9%; H, 8.2%; N, 4.1%. found: C, 72.6%; H, 8.1%; N, 4.1%. Example 10
2-[2-(2-Dibenzofiiranyloxy)ethyl]-l-pentylpiperidine oxalate
Using the conditions described for Example 8 and replacing the product of Preparation 8 with that of Preparation 10 (1.70g free base, 5.76mM) together with the corresponding molar proportions of the other reagents gave the free base of the title compound as a colourless oil (0.67g). This was dissolved in ethyl acetate and oxalic acid dihydrate (0.25g. 1.1 equivalents) in warm ethyl acetate added. The solution was concentrated and stood in the 'fridge overnight to give the title compound as white crystals (0.57g), M J?. = 105-107°C.
(Mass Spec. M+H=366). (C24H31NO2. C2H2O4) requires: C, 68.5%; H, 7.3%; N, 3.1%. found: C, 67.8%; H, 7.1%; N, 3.1%
Example 11
2-[2-(3,4-DichIorophenoxy)ethyI]-l-pentylpiperidine oxalate
The product of Preparation 12 as the free base (l.Og, 3.65mM) was dissolved in dry DMF (20ml) and n-pentyl bromide (0.56g, 3.70mM) and 80% NaH (0.1 lg, 3.70mM) added. The mixture was stirred at 70°C for 18 hours and poured onto water (200ml). The yellow solution was extracted with ether (X3) and the combined ethereal extracts washed with H2O (X3) and brine, dried ( a2SO4) and evaporated to give a pale yellow oil. This material was chromatographed on silica gel using dichloromethane as initial eluant followed by dichloromethane 1% methanol (methanol contains 10% NH4OH). Fractions containing required material were combined and evaporated to give an oil (0.46g). This was dissolved in ethyl acetate and a solution of oxalic acid dihydrate (1.1 equivs) in ethyl acetate added. The solution produced was evaporated to dryness and the residue crystallised, first from methanol/water and finally from ethyl acetate to give the title compound as white crystals (0.1 lg), MJ?.: 70-75°C. (Mass Spec: M+H=344). (CιgH27Cl2NO. C2H2O4) requires: C, 55.3%; H, 6.7%; N, 3.2% found: C, 55.1%; H, 6.5%; N, 3.3%. Example 12
2-[2-(3,4-Dichlorophenoxy)ethyI]-l-cinnamyIpiperidine oxalate hemihydrate
Using the conditions described for Example 11, replacing n-pentyl bromide with cinnamyl bromide (1.14gms, 5.77mM) and using corresponding molar proportions of other reagents gave a yellow oily glass after column chromatography (1.23g). This material as dissolved in ethyl acetate and a solution of oxalic acid dihydrate (0.425g, 1.07 equivs.) in ethyl acetate added. The mixture was concentrated, 1 drop of methanol added to prevent precipitation and the mixture cooled slowly to give white crystals (1.52g). This material was re-crystallised from methanol/ethyl acetate to give the title compound (1.24g), M.P. = 143-145°C. (Mass Spec. MH+=390)
(C22H25CI2NO. C2H2O4. 0.5H2O) requires: C, 58.9%; H, 5.8%; N, 2.9%; Cl, 14.5%.
Found: C, 59.1%; H, 5.8%; N, 2.9%; Cl, 14.8%
Example 13
Endo-[2-(3,4-dichlorophenoxy)ethyI]tropane oxalate
Endo 3-(2-hydroxyethyl)tropane (1.79g), triphenylphosphine (2.90g) and 2,4- dichlorophenol (1.735g) were stirred together in dry tetrahydrofuran (35 ml) under dry nitrogen. Diethylazodicarboxylate (1.75 ml) was added and the mixture allowed to stand at room temperature for 16 hours. The solvent was removed in vacua and the residue partitioned between aqueous sodium hydroxide and diethylether. The ether phase was extracted with aqueous N.HC1. The acid extracts were basified (NaOH) and extracted with diethylether. This ether phase was washed (H2O), dried (Na2SO4) and evaporated to give a yellow solid (2.28g). This solid was dissolved in ethyl acetate and treated with a 10% excess of oxalic acid dihydrate in warm ethyl acetate. On cooling a white solid was produced which was re-crystallised from ethyl acetate to give the title compound (0.64g) as a white crystalline solid, M.P. 130- 131.5°C.
*H Nmr (DMSO, 400 MHz), δ : 1.8 (d, 2H), 1.9-2.5 (sm, 9H), 2.8 (s, 3H), 3.8 (br.s, 2H), 4.15 (t 2H), 7.05 (dd, IH), 7.3 (d, IH), 7.6 (d, IH). Example 14
Endo 3-[2-(3,4-dichlorophenoxy)ethyI]-8-azabicycIo[3.2.1]octane oxalate
Endo 3-[2-(3,4-dichlorophenoxy)ethyl] tropane (4.83g) was dissolved in dichloromethane (55 ml). 2-Chloroethylchloroformate (2.4 ml) was added and the mixture left to stand at room temperature for 72 hours. The solvent was removed in vacua and the residue refluxed in methanol for 1 hour and again evaporated to dryness. The residue was partitioned between aqueous sodium hydroxide and diethylether. The ether phase was washed (H2O) dried (Na2SO4) and evaporated to give a solid (4.73g). This solid was treated with oxalic acid dihydrate (2.33g) in warm ethyl acetate to give, on cooling, a white solid. This was crystallised from ethanol/ethyl acetate to give the title compound as a white crystalline solid (2.20g), M.P. = 154-158°C.
(C15H19Cl2NO. C2H2O4) requires : C, 52.32; H, 5.42; N, 3.59; Cl, 18.17%
Found : C, 52.30; H, 5.37; N, 3.73; Cl, 18.19%
Example 15
Endo 3-[2-(3,4-dichlorophenoxy)-ethyl]-8-(n-pentyI)-8-azabicyclo[3^,l]octane oxalate
3-[2-(3,4-dicMorophenoxy)ethyl]-8-azabicyclo[3,2,l]oxalate, (l.OOg) was stirred with an 80% oil dispersion of sodium hydride (0.32g) in anhydrous dimethylforma ide (30ml) under dry nitrogen. n-Pentylbromide (0.9ml) was added and the stirred mixture heated at 60°C for 48hr. The solvent was removed in vacua and the residue partitioned between water and ether. The ether phase was washed (water), dried (sodium sulphate) and on evaporation gave an oil (0.93g). The product was treated with oxalic acid dihydrate (0.32g) in warm ethyl acetate to give a white solid which was collected and dried (0.900g). This was recrystallised from ethylacetate and acetonitrile to give the title compound (0.626g), M P. = 119-120°C.
(C22H31CI2NOS) Requires : C, 57.39; H.6.79; N, 3.04; Cl, 15.40% Found : C, 57.40; H, 6.77; N. 3.08; Cl, 15.27% Example 16
2-(4-Fluorophenoxymethyl)-4-pentylmorphoIine oxalate
2-Hydroxymethyl-4-pentylmorpholine( 1.Og) was dissolved in methylene chloride (50 ml) and to the stirred solution under nitrogen was added p-fluorophenol (0.6g), triphenylphosphine (1.4g) and diethyl azodicarboxylate (0.93g). The mixture was stirred at room temperature overnight and the solvent evaporated. The residual oil was purified by dry flash column chromatography on silica gel (Art 7736) using 0-5% methanol in methylene chloride. Fractions containing product were combined and evaporated to give an oil (0.6g) which was dissolved in ethyl acetate (40 ml) and 1.1 molar equivalents of oxalic acid added. The mixture was heated on a steam-bath for 5 mins, cooled and the crystalline material collected. This was recrystallised from methanol/ethyl acetate to give the title compound as a white crystalline solid (0.2g), M P. = 108°C.
Mass Spec - M.W = 281
(c16H24FNθ2- C2H2O4. 0.24 H2O) requires : C, 57.52; H, 7.06; N, 3.73%
Found: C, 57.69; H, 7.01; N, 3.75%
Example 17
2-(3,4-DichlorophenoxymethyI)-4-pentyl morpholine oxalate
The title compound was prepared in a similar manner to Example 16 from 2-hydroxy- methyl-4-pentylmorpholine (2.3 g), 2,4-dichlorophenol (2.0g), triphenylphosphine (3.22g) and diethyl azodicarboxylate (2.14g) in methylene chloride (100 ml). Treating the product as before with oxalic acid gave a white solid which was re-crystallised from methanol/ethyl acetate to give the title compound as white crystals (0.51g), M.P. : 142°C.
Mass Spec M.W. 332.
(C16H23CI2NO2. C2H2O4) requires : C, 51.19; H, 5.97; N, 3.22; Cl, 16.79%
Found : C, 51.30; H, 5.98; N, 3.39; Cl, 16.60%. Example 18
4-[2-(2-Dibenzofuranyloxy)ethyI]-l-pentylpiperidine hydrochloride
A solution of 4-(2-hydroxyethyl)-l-pentylpiperidine (Ref WO 92/02502) (0.81g, 0.004 mole), 2-hydroxydibenzofuran (0.75g, 0.004 mole) and triphenylphosphine (1.06g, 0.004 mole) in tetrahydrofuran (30 ml) was treated with diethyl azodicarboxylate (0.7g, 0.004 mole). The resulting solution was stirred at room temperature for 48 hours, the solvent was removed and the residue purified by flash chromatography on silica gel with the product eluting in dichloromethane / 10% methanol/ ammonia (methanol saturated with ammonia gas). The product was dissolved in ethyl acetate and 1M ethereal HC1 was added. The precipitate was collected and recrystallised from acetonitrile to give the title compound as white needles (0.65g), M.P. = 173-4°C.
(C24H31NO2.HCl) requires: C.71.71; H, 8.02; N, 3.48; Cl, 8.82%
Found: C, 71.59; H, 8.03; N, 3.82; Cl, 8.67%
Example 19
2-(4-Benzyloxyphenoxy)methyl]-4-butyIthiomorphoIine oxalate
A solution of 4-n-butyl-thiomorpholin-2-methanol (l.Og, 0.0053 mole), 4- benzyloxyphenol (1.06g, 0.0053 mole) and triphenylphosphine (1.39g, 0.0053 mole) in tetrahydrofuran (30 ml) was treated with diethyl azodicarboxylate (1.92g, 0.0053 mole). The resulting solution was stirred at room temperature for 48 hours, the solvent was removed and the residue was purified by flash chromatography on silica gel the product eluting in dichloromethane / 5% methanol. The product was dissolved in ethyl acetate and oxalic acid was added. The precipitate was collected and recrystallised from acetonitrile to give the title compound as white needles (0.479g), M.P. = 173-4°C.
(C22H29NO2S.C2H2O4) requires: Q62.45; H, 6.76; N, 3.03%
Found: C, 62.07; H, 6.66; N, 3.15% Example 20
4-[2-(2-Dibenzofuranyloxy)ethyI]-l-cinnamylpiperidine oxalate
A solution of 4-(2-hydroxyethyl)-l-cinnamylpiperidine (Ref WO 92/02502) (l.Og, 0.004 mole), 2-hydroxydibenzofuran (0.75g, 0.004 mole) and triphenylphosphine (1.06g, 0.004 mole) in tetrahydrofuran (30 ml) was treated with diethyl azodicarboxylate (0.7g, 0.004 mole). The resulting solution was stirred at room temperature for 48 hours, the solvent was removed and the residue was purified by flash chromatography on silica gel, the product eluting in dichloromethane / 10% methanol/ ammonia (methanol saturated with ammonia gas). The product was dissolved in ethyl acetate and oxalic acid was added. The precipitate was collected and recrystallised from methanol/ethyl acetate to give the title compound as a white solid (0.40g), M.P. = 158°C.
(C28H29NO2.C2H2O4.O.25H2O) requires: C,71.13; H, 6.22; N, 2.76%
Found: C, 71.27; H, 6.29; N, 3.04%
Example 21
Endo 3-[2-(3,4-Dichlorophenoxy)ethyl]-8-cinnamyl-8-azabicyclo [3.2.1] octane oxalate hydrate
Endo 3-[2-(3,4,-Dichlorophenoxy)ethyl]-8-azabicyclo [3.2.1] octane, (example 14) (0.71g) was stirred with an 80% dispersion of sodium hydride (0.18g) in anhydrous dimethylformamide (20ml) under dry nitrogen. Cinnamyl bromide (0.4g) was added and the stirred mixture was heated at 60°C for 16 hr. The solvent was removed and the residue was partitioned between water and ether. The ether layer was separated, washed with water and dried over sodium sulphate. The solvent was removed, the residue was dissolved in ethyl acetate and treated with oxalic acid which gave a precipitate. This was collected and recrystallised from ethanol to give the title compound (0.339g) as a white solid, M.P. = 150-9°C.
(C24H27 CI2NO.C2H2O4.H2O) requires: C,59.54; H, 5.95; N, 2.67%
Found: C, 59.36; H, 5.72; N, 2.99%

Claims

Claims :
A compound of formula (I):
Figure imgf000042_0001
Formula (I)
in which
W is -CH2-, a bond, O or S;
k is 0, or when W represents -CH2- k may also be 2, in which case the dotted lines represent single bonds;
R is C]_galkyl(phenyl)p, C2-galkenyl(phenyl)p, C2_galkynyl(phenyl)p, C3_gcycloalkyl or
Cι_galkylC3_gcycloalkyl, or R may also represent hydrogen when k is 2; p is 0 to 2 n is 0 to 6; m is 0 to 6; and
A is a bond, -CH=CH- or -C≡C- oxygen, sulphur or NRl;
R! is hydrogen, C^.galkyl σrphenylCι_4alkyl; and
Ar is aryl or heteroaryl, each of which may be optionally substitued;
with the provisos that :
when W is a bond the side chain is α to the ring nitrogen atom;
when W is CH2, k is zero, the side chain is at the 3- or 4-position of the piperidine ring and A is a bond, oxygen, sulphur or .1 then Ar is aryl substituted by phenoxy or substituted phenoxy or is a tricyclic heteroaryl group as hereinafter defined; and when W is CH2 and k is 2 the side chain -(CH2)nA(CH2)mAr is not α to the nitrogen atom,
or a salt thereof.
2. A compound according to claim 1 which is a compound of formula (IA):
Figure imgf000043_0001
Formula (IA)
in which
the group -(CH2)nA(CH2)m Ar is attached at either the 3 or 4 position of the piperidine ring;
R is Cι_galkyl(phenyl)p, C2-8alkenyl(phenyl)p,
C2-8alkynyl(phenyl)p, C3_8cycloalkyl or
Cχ_8alkylC3_8cycloalkyl; p is 0 to 2; n is 0 to 6; m is 0 to 6; and either A is -CH=CH- or -C≡C- and
Ar is aryl or heteroaryl, each of which may be optionally substituted; or A is a bond, oxygen, sulphur or NR*; R! is hydrogen, Cχ_8alkyl or phenylCχ_4alkyl; and
Ar is aryl substituted by phenoxy or substitoted phenoxy or is a tricyclic heteroaryl group as hereinafter defined;
or a salt thereof.
3. A compound according to claim 1 which is a compound of formula (IB):
Figure imgf000044_0001
Formula (IB)
in which
R is C]_galkyl(phenyl)p, C2-8alkenyl(phenyl)p,
C2-galkynyl(phenyl)p, C3.gcycloalkyl or
Cι.galkylC3_gcycloalkyl; p is 0 to 2; n is 0 to 6; m is 0 to 6;
A is a bond, -CH=CH-, -C≡C-, oxygen, sulphur or NR*;
R! is hydrogen, Cι_galkyl or phenylCj^alkyl; and Ar is aryl or heteroaryl, each of which may be optionally substituted;
or a salt thereof.
4. A compound according to claim 1 which is a compound of formula (IC):
Figure imgf000044_0002
in which
the group -(CH2)nA(CH2)m Ar is attached at either the 2 or 3 position of the tropane ring; R is hydrogen, Cχ.galkyl(phenyl)p, C2-8alkenyl(phenyl)p, C2-galkynyl(phenyl)p, C3_gcycloalkyl or Cχ_galkylC3_gcycloalkyl; p is 0 to 2; n is 0 to 6; m is 0 to 6;
A is a bond, -CH=CH-, -C≡C-, oxygen, sulphur or NR*; R! is hydrogen, Cj.galkyl or phenylCj^alkyl; and Ar is aryl or heteroaryl, each of which may be optionally substitoted;
or a salt thereof.
5. A compound according to claim 1 which is a compoimd of formula (ID):
Figure imgf000045_0001
Formula (ID)
in which
W is oxygen or sulphur,
R is Cι_galkyl(phenyl)p, C2-galkenyl(phenyl)p,
C2-galkynyl(phenyl)p, C3_gcycloalkyl or Cι_galkylC3_gcycloalkyl; p is 0 to 2; n is 0 to 6; m is 0 to 6;
A is a bond, -CH=CH-, -C≡C-, oxygen, sulphur or NR*; R! is hydrogen, Cj.galkyl or phenylCι_4alkyl; and
Ar is aiyl or heteroaryl, each of which may be optionally substituted;
or a salt thereof.
6. A compound according to any of claims 1 to 5 wherein m is 0 to 3.
7. A compound according to any of claims 1 to 6 wherein R is
Cι_galkyl(phenyl)p in which p is 0 or 1, or R is C2-galkenyl(phenyl)p wherein p is 1.
8. A compound according to any of claims 1 to 7 wherein A is oxygen, or -CH=CH-.
9. A compound according to any of claims 1 to 8 wherein the length of the chain -(CH2)nA(CH2)nι is from 2 to 6 atoms.
10. A compound according to claim 1 sleeted from : (±) E-and Z-l-pentyl-3-[2-(4-fluσrophenyl)ethenyl]piperidine, (±) E-l-pentyl-3-[2-(4-biphenyl)ethenyl]-piperidine, (±) E-l-pentyl-3-[2-(l-naphthyl)ethenyl]-piperidine,
(±) E-l-pentyl-3-[2-(4-chlorophenyl)ethenyl]-piperidine,
2-[2-(3,4-methylenedioxyphenoxy)ethyl]-l-pentylpiperidine,
2-[2-(4-fluorophenoxy)ethyl]-l-pentylpiperidine, endo-[2-(3,4-dichlorophenoxy)ethyl]tropane, endo 3-[2-(3,4-dichlorophenoxy)ethyl]-8-azabicyclo[3.2.1]octane, endo 3-[2-(3,4-dichlorophenoxy)-ethyl]-8-(n-pentyl)-8-azabicyclo[3,2,l]octane,
2-(4-fluσrophenoxymethyl)-4-pentylmorpholine,
2-(3,4-dichlorophenoxymethyl)-4-pentyl morpholine,
2-[2-(4-benzylphenoxy)ethyl]-l-pentylpiperidine, 2-[2-(4-benzylphenoxy)ethyl]- 1-methylpiperidine,
2-[2-(2-dibenzofuranyloxy)ethyl]-l-pentylpiperidine,
2-[2-(3,4-dichlorophenoxy)ethyl]-l-pentylpiperidine,
2-[2-(3,4-dichlorophenoxy)ethyl]-l-cinnamylpipOTdine,
4-[2-(2-dibenzofiιranyloxy)ethyl]-l-pentylpiperidine, 2-(4-benzyloxyphenoxy)methyl]-4-butylthiomorpholine,
4-[2-(2-dibenzofuranyloxy)ethyl]-l-cinnamylpiperidine, and endo 3-[2-(3,4-dichlorophenoxy)ethyl]-8-cinnamyl-8-azabicyclo [3.2.1] octane, or a salt thereof.
11. A process for the preparation of a compound of formula ( ) as defined in any of claims 1 to 10 which comprises: (a) for compounds of formula (I) in which A is O, S or NR*, reaction of a compound of formula (II):
Figure imgf000047_0001
Formula (II)
in which W, k, R and n are as described for formula (I) and A* is O, S or NR*, with a compound of formula L(CH2)mAr in which m and Ar are as described for formula (I), and L is a leaving group;
(b) for compounds of formula (I) in which A is O, S or NR*, reaction of a compound of formula (HI):
Figure imgf000047_0002
Formula (III)
in which W, k, n and R are as described for formula (I) and L is a group displaceable by a nucleophile, with a compound of formula HAl(CH2) Ar where m and Ar are as described for formula (I) and A* is as described for formula (II); or
(c) for compounds of formula (I) in which A is NR * , reduction of a compound of formula (IV) :
Figure imgf000048_0001
Formula (TV)
in which R^ represents the group
-(CH2)nN(Rl)C(O)(CH2)m-lAr or -(CH2)n.ιC(O)N(Rl)(CH2)mAr,
and k, W, R, n, m and Ar are as described for formula ();
(d) for compounds of formula (I) in which A is a bond, reaction of a compound of formula (V) :
Figure imgf000048_0002
Formula (V)
(wherein R, W, k, L^, m and n are as hereinbefore defined).
with a compound of formula X^Ar in which Ar is as described for formula (I), and X* is an alkali metal;
(e) introduction of the group R into a compound of formula (VI)
Figure imgf000049_0001
Formula (VI)
(wherein W, k, n, m, A and Ar are as defined in formula (I)) by reaction with a compound RL2, wherein L2 is a leaving group;
(f) For compounds where A is O, S, NR* or a bond reduction of a compound of formula (VII) :
Figure imgf000049_0002
Formula (VII)
wherein W, k, A, Ar, n and m are as hereinbefore defined and R^ is Cι_7alkyl(phenyl)p, C2-7alkenyl(phenyl)p, C2-7alkynyl(phenyl)p or Cι_7alkylC3_gcycloalkyl;
(g) For compounds where W is CH2, k is zero, and A is O, S, NR or a bond reduction of a compound of formula (VIE):
Figure imgf000049_0003
Formula (VIII)
wherein R, A, Ar m and n are as hereinbefore defined and X" is a counter ion;
(h) For compounds wherein A is -CH=CH-, reaction of a compound of formula (DC)
Figure imgf000050_0001
Formula (IX)
(wherein W, k, R and n are as hCTeinbefore defined) with a reagent serving to introduce the group Ar;
(i) Interconversion of one compound of formula 00 to a different compound of formula (I), e.g. the reduction of a compound wherein A is -CH=CH- to a compound wherein A is -CH2-CH2-;
and optionally thereafter forming a salt
12. A pharmaceutical composition comprising a compound of formula (I) as defined in any of claims 1 to 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient
13. A compound of formula (I) as defined in any of claims 1 to 10 or a pharmaceutically acceptable salt thereof for use in therapy.
14. Use of a compound of formula 00 as defined in any of claims 1 to 10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition related to the accumulation of calcium in the brain cells of a mammal.
15. A method of treatment of a condition or disease related to the accumulation of calcium in the brain cells of a mammal which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in any of claims 1 to 10 or a pharmaceutically acceptable salt thereof.
PCT/GB1993/000173 1992-01-28 1993-01-27 Compounds as calcium channel antagonists WO1993015052A1 (en)

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US7816375B2 (en) 2000-09-11 2010-10-19 Sepracor Inc. Ligands for monoamine receptors and transporters, and methods of use thereof
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US7517892B2 (en) 2000-09-11 2009-04-14 Sepracor Inc. Ligands for monoamine receptors and transporters, and methods of use thereof
US7456192B2 (en) 2001-11-02 2008-11-25 Pierre Fabre Medicament 3β-amino azabicyclooctane heteroaromatic amid derivatives preparation method and therapeutic uses 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
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
US7872017B2 (en) 2006-05-19 2011-01-18 Abbott Laboratories Fused bicycloheterocycle substituted azabicyclic alkane derivatives
US8906908B2 (en) 2010-05-21 2014-12-09 Research Triangle Institute Hydroxybupropion analogues for treating drug dependence
US9527823B2 (en) 2010-05-21 2016-12-27 Research Triangle Institute Hydroxybupropion analogues for treating drug dependence
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