Classifications

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  • 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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• 1993
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