EP0674514A1 - Use of aryloxyalkyl substituted cyclic amines as calcium channel antagonists and new phenyloxyalkyl piperidin derivatives - Google Patents
Use of aryloxyalkyl substituted cyclic amines as calcium channel antagonists and new phenyloxyalkyl piperidin derivativesInfo
- Publication number
- EP0674514A1 EP0674514A1 EP94902735A EP94902735A EP0674514A1 EP 0674514 A1 EP0674514 A1 EP 0674514A1 EP 94902735 A EP94902735 A EP 94902735A EP 94902735 A EP94902735 A EP 94902735A EP 0674514 A1 EP0674514 A1 EP 0674514A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- compound
- piperidine
- ethyl
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to cyclic secondary amine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
- the present invention therefore provides, in a first aspect, the use of a compound of formula (I):
- W is -(CH 2 ) 4 , (CH 2 ) 5 , -(CH 2 ) 2 O(CH 2 )2 or -(CH 2 ) 2 S(CH 2 ) 2 n is 0 to 6; is 0 to 3;
- R 1 is hydrogen, Cj.galkyl or phenylC ⁇ _4alkyl
- Ar is aryl or heteroaryl, each of which may be optionally substituted; or a pharmaceutically acceptable salt thereof as a therapeutic agent.
- W preferably represents (CH 2 )4 or (CH 2 )5
- the group -(CH 2 ) n A(CH 2 ) m Ar may be substituted on any carbon atom in the ring.
- W is (CH 2 )4 or (CH 2 )5 the substituent is preferably ⁇ to the ring nitrogen atom.
- n, m and A should be chosen such that the chain (CH 2 ) n A(CH 2 ) m contains at least one atom.
- the length of the chain -(CH 2 ) n A(CH 2 ) m is from 2 to 6 atoms.
- Preferred values for n and m depend on the group A.
- A is oxygen the sum of n+m is from 1 to 5; for example n may be 1 or 2 and m may be zero.
- A is preferably oxygen or a bond.
- suitable groups include, for example, unsaturated monocyclic and unsaturated or partially saturated bicyclic and tricyclic ring systems of up to 15 carbon atoms, such as, for example, phenyl, naphthyl, tetrahydronaphthyl, fluorene, fluorenone, dibenzosuberene and dibenzosuberenone. Preferred are optionally substituted phenyl rings.
- An aryl group may be substituted, for example, by a C ⁇ _ alkylenedioxy group (e.g. phenyl substituted by a 3,4-methylenedioxy group) or by 1 to 3 substituents selected from halogen, C j ⁇ alkoxy, nitro, SC ⁇ _ alkyl, NR 2a R 2b (in which R 2a and R 2b independently represent H or C ⁇ _4alkyl), OCF3, Cj.galkyl, trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted benzoyl, optionally substituted phenylC ⁇ _4alkyl and optionally substituted phenylC 1 _4alkoxy .
- a C ⁇ _ alkylenedioxy group e.g. phenyl substituted by a 3,4-methylenedioxy group
- substituents selected from halogen, C j ⁇ alkoxy, nitro, SC ⁇ _ alky
- Suitable optionally substituted phenylCj_4alkyl groups include, for example benzyl.
- Suitable optionally substituted phenylC ⁇ _4alkoxy groups include, for example benzyloxy groups.
- Suitable substituents for said optionally substituted phenyl, phenoxy, benzoyl, phenylC ⁇ _4alkyl and phenylC ⁇ alkoxy groups include for example halogen, Cj ⁇ alkyl, C ⁇ alkoxy, nitro and trifluoromethyl groups.
- the aryl group is a phenyl ring substituted by one or two substituents, in particular, by a phenyl, phenyl(Cj_4)alkyl, phenoxy, benzoyl or phenylC ⁇ _4alkoxy group; or by two chloro atoms especially in the 3- and 4-positions of the phenyl ring.
- suitable groups include, for example, unsaturated or partially saturated bicyclic and tricyclic ring systems containing at least one heteroatom.
- a bicyclic ring system preferably contains 8 to 10 ring members, such as quinolinyl and tetrahydroquinolinyl.
- a tricyclic ring system preferably contains from 11 to 14 ring members, and most preferably has the structure :
- Y 1 represents Y(CH 2 ) r
- Y is O, S or NR ⁇ (where R ⁇ is hydrogen or Cj_4alkyl)
- q is 0, 1 or 2
- r is 0 or 1, or is a corresponding dehydro ring system.
- tricyclic heteroaryl groups include dibenzofuranyl, dibenzothienyl, carbazole, N-methylcarbazole, acridine and dibenzoxepine.
- the heteroaryl ring can be linked to the remainder of formula (I) via any suitable ring atom.
- Suitable substituents for said heteroaryl rings include, for example, 1 to 3 substituents selected from halogen, trifluoromethyl, C ⁇ 4alkyl and C ⁇ 4alkoxy.
- Alkyl groups present in the compounds of formula (I), alone or as part of another group, can be straight or branched.
- a C ⁇ galkyl group may be for example methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl or any branched isomer thereof such as iso ⁇ propyl, tert-butyl or _yec-pentyl.
- Particularly preferred compounds of formula (I) for use according to the present invention are those wherein W is (CH 2 )5, the substituent -(CH ) n A(CH 2 ) m Ar is ⁇ to the ring nitrogen atom, A is oxygen, n is 1 or 2, m is zero and Ar is phenyl substituted by one of benzyl, benzoyl, phenoxy or benzyloxy, or by two chloro atoms, or Ar is dibenzofuranyl. It will be appreciated that for use in medicine a salt of a compound (I) should be pharmaceutically acceptable.
- Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, methanesulphonate or similar pharmaceutically acceptable inorganic or organic acid addition salts.
- Other non- pharmaceutically acceptable salts, such as oxalates, may be used for example in the isolation of final products and are included within the scope of this invention.
- Ar represents phenyl substituted by benzoyl
- a particularly preferred group of compounds wherein Ar represents benzoylphenyl is that in which W is (CH 2 )5, A is oxygen, n is 1 or 2 and m is zero. Most preferably the substituent -(CH 2 ) n A(CH 2 ) m Ar is ⁇ to the ring nitrogen atom.
- Particular compounds for use according to the invention include: 2-[2-(4-benzyloxyphenoxy)ethyl]piperidine, 2- [2-(4-phenoxyphenoxy)ethyl]piperidine, 2-[2-(2-benzylphenoxy)ethyl]piperidine, 4-f2-(3,4-dichlorophenoxy)ethyl]piperidine, 4-f2-(4-benzyloxyphenoxy)ethyl]piperidine, 4-f2-(4-benzylphenoxy)ethyl]piperidine, 3-(4-benzyloxyphenoxymethyl)piperidine, 3-(4-benzylphenoxymethyl)piperidine, 2-[4-benzylphenoxymethyl]piperidine, 2-[4-benzyloxyphenoxymethyl]piperidine, (S)-2-[4-benzylphenoxymethyl]pyrrolidine, 2-[2-(3-benzoylphenoxy)ethyl]piperidine, 2- [2- (4- benzoylphenoxy)e
- Other preferred compounds for use according to the present invention include : 2-f2-(2-dibenzofuranyloxy)ethyl]piperidine, 2-[2-(3,4-dichlorophenoxy)ethyl]piperidine, 2-[2-(4-benzylphenoxy)ethyl]piperidine, and salts thereof.
- a compound of formula (I) may be prepared by a process which comprises:
- R ⁇ a is hydrogen or an N-protecting group, and W, n, m, and Ar are as described above.
- the present invention also provides a process for preparing a novel compound of formula (I) e.g a compound of formula (I) wherein W is -(CH 2 )4 and the group -(CH 2 ) n A(CH ) m Ar is ⁇ to the pyrrolidine nitrogen atom, or a compound as specifically named above, which process comprises any of processes (a) to (g) described above,as approporiate, followed where necessary by removal of the N-protecting group R4, and optionally thereafter forming a salt.
- processes (a) to (g) described above,as approporiate, followed where necessary by removal of the N-protecting group R4, and optionally thereafter forming a salt Those skilled in the an will readily be able to determine which specific processes will be applicable to the preparation of a given compound.
- reaction between a compound of formula (II) and a compound L(CH 2 ) m Ar can take place under conditions which depend on the nature of the group L and the value of m.
- L is halogen or a sulphonic acid residue such as a tosylate or mesylate and m is other than zero
- the reaction is carried out under standard conditions in a solvent, optionally in the presence of a base.
- a fluoro-substituted aryl compound F-Ar is employed in process (a) (to prepare compounds where m is zero)
- the reaction is effected in the presence of a strong base such as sodium hydride, and in an inert organic solvent such as DMSO or dimethylformamide.
- reaction between a compound of formula (IH) and a compound of formula HA (CH 2 ) m Ar can take place under conditions which depend on the nature of L and A.
- L 1 is hydroxy
- m is 0
- a 1 is oxygen or sulphur
- the reaction is carried out in the presence of diethyl azodicarboxylate and triphenyl phosphine.
- the leaving group L may be for example a halogen atom or a sulphonyloxy group eg. methane-sulphonyloxy or p-toluene sulphonyloxy.
- the reaction may be effected in the presence or absence of solvent and at temperature in the range 0 to 200°C.
- a compound of formula (IV) can be effected by methods known in the art, for example using a reducing agent such as lithium aluminium hydride.
- a compound of formula (IV) can be prepared (for example as described below) and reduced in a 'one-pot' reaction, without isolation of compound (IV) itself.
- reaction between a compound of formula (V) and a compound of formula X 1 Ar in process (d) can take place under standard conditions known to those skilled in the an for the formation of carbon-carbon bonds.
- Reduction of a compound of formula (VI) according to process (e) may be effected for example by hydrogenation, using a noble metal catalyst such as platinum, palladium or platinum oxide, suitably in a solvent such as an alcohol eg. ethanol.
- a noble metal catalyst such as platinum, palladium or platinum oxide
- Process (f) may be effected using a Wadsworth-Emmons reagent of the formula Ar(CH 2 ) m +lP(O)(OAlk) 2 , such as a diethylphosphonate, or a Wittig reagent of the formula Ar(CH 2 ) m+ ⁇ PPh3X" (where X" is an anion) which compounds are available commercially or can be prepared by known methods.
- the reaction may be carried out in a solvent such as tetrahydrofuran optionally containing a crown ether such as 15-crown-5 or 18-crown-6, and in the presence of a strong base such as sodium hydride, or potassium tert-butoxide.
- Interconversion reactions according to process (g) may be effected by methods well known in the art.
- Protecting groups R ⁇ include lower alkyl groups such as methyl; aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl; and acyl groups such as acetyl, trifluoroacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl.
- a protecting group R ⁇ a is preferably alkyl e.g. methyl or aralkyl e.g. benzyl. Such groups may be removed by methods which are well known in the art.
- alkyl group such as methyl may be removed by treatment with a haloalkyl haloformate such a 1-chloromethylchloroformate, aralkyl group such as benzyl may be cleaved by hydrogenolysis, and an acyl group such as benzoyl may be cleaved by hydrolysis.
- a protecting group R ⁇ or R ⁇ a present in any of the above compounds (II) to (VII) as well as compounds (VIII) below should be chosen such that it will not be cleaved by or participate in any of the reactions that the particular compound is intended to undergo, and furthermore such that its removal will not disturb any other groups or moieties present in the molecule. Such factors can be readily ascertained by those skilled in the art, to whom appropriate protecting groups will thus be readily apparent.
- acyl group may be introduced by reaction with an appropriate acid derivative such as an acid chloride or anhydride, or an activated ester, e.g. an alkyldicarbonate such as di-tert- butyldicarbonate or a haloformate such as ethylchloroformate.
- an appropriate acid derivative such as an acid chloride or anhydride
- an activated ester e.g. an alkyldicarbonate such as di-tert- butyldicarbonate or a haloformate such as ethylchloroformate.
- the compounds of formula (II) in which A 1 is oxygen can be prepared by reduction of a compound of formula (VIII):
- R ⁇ should be a group such as alkyl, which is not cleaved by reductive conditions.
- Compounds of formula (HI) wherein L 1 is OH can be prepared as described for compounds of formula (II), and compounds of formula (HI) wherein L 1 is a halogen atom, or a mesyloxy or tosyloxy group can be prepared from the corresponding alcohol in conventional manner.
- -(CH 2 ) n _ ⁇ C(O)N(R 1 )(CH ) m Ar may be prepared for example by reaction of a corresponding compound wherein R 5 represents -(CH 2 ) n _ ⁇ CO 2 H or an activated derivative thereof such as an acid halide, ester or anhydride, with an amine of formula
- a compound of formula (VI) may be prepared using the general methods described in processes (a) to (d) above.
- Compounds of formula (VII) may be prepared by conventional methods, for example the oxidation of a compound of formula (II) wherein A 1 is oxygen, or conversion of the corresponding ester, e.g. by reaction with thionyl chloride and
- N,O-dimethylhydroxylamine hydrochloride to give the N-methyl-N-methoxy- carboxamide, which can be reduced to the aldehyde using diisobutylaluminium hydride.
- Compounds of formula (VII) wherein n is 1 may be prepared from the corresponding compound wherein n is zero by various methods. For example the aldehyde wherein n is zero may be treated with (methoxymethyl) triphenylphosphonium chloride and potassium t-butoxide, followed by a strong acid, e.g. concentrated sulphuric acid, resulting in the aldehyde wherein n is 1.
- aldehyde may be converted to the conesponding cyanomethyl derivative as described in EPA 363085 followed by acid hydrolysis, conversion to the N-methyl-N-methoxycarboxamide and reduction. These procedures may also be used to form higher homologues.
- a compound of formula (I) When a compound of formula (I) is obtained as a mixture of enantiomers, these may be separated by conventional methods such as crystallisation in the presence of a resolving agent, or chromatography, for example using a chiral HPLC column.
- Suitable resolving agents include optically active acids such as R-(-)- or S-(+)-mandelic acid.
- Compounds of formula (I) have been found to exhibit calcium influx blocking activity for example in neurons. As such the compounds are expected to be of use in therapy in treating conditions and diseases related to an accumulation of calcium in the brain cells of mammals, in particular humans.
- the compounds are expected to be of use in the treatment of anoxia, ischaemia including for example stroke, migraine, visceral pain, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders; mood disorders and drug addiction withdrawal such as ethanol addiction withdrawal.
- ischaemia including for example stroke, migraine, visceral pain, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders; mood disorders and drug addiction withdrawal such as ethanol addiction withdrawal.
- the invention therefore provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment of disorders where a calcium channel antagonist is indicated.
- a compound of formula (I) or a pharmaceutically acceptable salt thereof may be used in the manufacture of a medicament for the treatment of a condition or disease related to (e.g. caused or exacerbated by) the accumulation of calcium in the brain cells of a mammal e.g a human, such as for example, any of the aforementioned conditions.
- the present invention provides a method of treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal, which comprises administering to a subject in need thereof, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- the compounds of the present invention are usually administered in a standard pharmaceutical composition.
- the present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
- the compounds of the invention may be administered by any convenient method for example by oral, parenteral, buccal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
- the compounds of formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
- a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water • with a suspending agent, preservative, flavouring or colouring agent.
- a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water • with a suspending agent, preservative, flavouring or colouring agent.
- a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
- suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
- suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
- a composition in the form of a capsule can be prepared using routine encapsulation procedures.
- pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
- compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
- a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
- the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
- Both liquid and solid compositions may contain other excipients known in the pharmaceutical art, such as a cyclodextrin or a solubilising agent such as Cremophor.
- composition is in unit dose form such as a tablet, capsule or ampoule.
- Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 60 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
- the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, eg. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 60 mg, eg. 1 to 40 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
- the compounds of the invention may be administered by continuous intravenous infusion, preferably at a dose of up to 400mg per day.
- the total daily dosage by oral administration will be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will be in the range 0.1 to 400 mg.
- the compounds will be administered for a period of continuous therapy, for example for a week or more.
- Ca 2+ current was measured in vitro using cell preparations of sensory neurons from dorsal root ganglia as described in WO92/02501 and WO92/02502.
- Buffer to pH ca 7 Solvent/complexing agent to 100 ml Buffer : Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.
- Solvent Typically water but may also include cyclodextrins (1-100 mg) and co-solvents such as propylene glycol, polyethylene glycol and alcohol.
- Diluent e.g. Microcrystalline cellulose, lactose, starch Binder : e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
- Disintegrant e.g. Sodium starch glycollate, crospovidone Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate.
- Suspending agent e.g. Xanthan gum, microcyrstralline cellulose
- Diluent e.g. sorbitol solution, typically water
- Preservative e.g. sodium benzoate
- Buffer e.g. citrate
- Co-solvent e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin
- Example la The product of Example la (6.0g, 16.03 mmole) was dissolved in glacial acetic acid/hydrogen bromide (20ml, 45w/v, excess). The solution was stood at room temperature for two hours and heated on a steam-bath for three hours. The material was then cooled, poured onto water and the aqueous phase basified with 50% NaOH. The mixture was extracted with dichloromethane (X2) and the combined organic extracts washed (water, brine), dried (MgSO4) and evaporated to give an oil (4.44g). This material was purified by flash chromatography on silica gel.
- Example 2a The product of Example 2a (6.0g, 16mM) was dissolved in dichloromethane (80ml) and stirred at room temperature under nitrogen. A solution of trifluoroacetic acid (7.5ml) in dichloromethane (20ml) was added dropwise over 10 minutes and the colourless solution stirred for a further 2 hours. The mixture was evaporated and 2N. NaOH (100ml) added to the oily residue to produce a white, oily solid. This was extracted with dichloromethane (X2) and the combined organic extracts washed (H O, brine), dried (Na 2 SO4) and evaporated to dryness to leave a colourless oil (3.53g).
- Example 2a Replacing the product of Example 2a with the product of Example 8a (4.5g, 0.011 mole) in the method of Example 2 and using the corresponding molar proportions of the other reagents gave the title compound as the free base.
- This material was dissolved in ethyl acetate and excess ethereal HCl added. A white solid precipitated which was collected , and recrystallised from ethyl actetate to give the title compound as white needles (2.14g), M.P.
- Example 12a 2-[4-Benzylphenoxymethyl]piperidine hydrochloride
- the product of Example 12a 0.5g was converted to free base (equilibration between N. NaOH and CH 2 C1 2 - organic layer dried, washed and evaporated), producing a colourless oil which was dissolved in toluene (10ml).
- To the stirred solution at room temperature under argon was added dropwise a solution of 1-chloromethyl chloroformate (0.28g, excess) in dry toluene (5ml). The mixture was heated at reflux temperature for 4 hours, concentrated almost to dryness, methanol (20ml) added and die mixture heated again at reflux temperature for 2 hours. The solvent was evaporated off to produce an oil which solidified on standing.
- Example 3 The product of Example 3 was converted to free base in d e usual way (equilibration between N. NaOH and CH 2 C1 2 ) to produce an oil (1.75g, 5.92mM). This oil was dissolved in ethyl acetate (15ml) and S-(+)-mandelic acid (0.9g, 5.92mM) in etiiyl acetate (15ml) added. On refrigeration crystals separated and were collected (2.31 g). This material was crystallised five times from ethyl acetate/methanol (monitored by chiral HPLC) to give a white solid (0.83g). Conversion to free base in the usual way gave an oil (0.56g).
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Abstract
Use of a compound of formula (I), in which W is -(CH2)4, (CH2)5, -(CH2)2O(CH2)2 or -(CH2)2S(CH2)2, n is 0 to 6; m is 0 to 3; A is a bond, -CH=CH-, -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; or a pharmaceutically acceptable salt thereof as a therapeutic agent. Certain novel compounds of formula (I) and processes for preparing them are also described.
Description
OF ARYLOXYALKYL SUBSTITUTED CYCLIC AMINES AS CALCIUM CHANNEL ANTAGONISTS AND NEW PHENYLOXYALKYL PIPERIDIN DERIVATIVES
The present invention relates to cyclic secondary amine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
International Applications No's WO92/02501, WO92/02502, WO92/22527 and WO93/15052 describe various tertiary nitrogen-containing heterocyclic compounds, which compounds are said to have activity as calcium blocking agents. Corresponding secondary amines are described as potential intermediates. We have now found that certain of these compounds and other secondary cyclic amine derivatives exhibit therapeutic activity in particular as calcium channel antagonists.
The present invention therefore provides, in a first aspect, the use of a compound of formula (I):
Formula (I) in which
W is -(CH2)4, (CH2)5, -(CH2)2O(CH2)2 or -(CH2)2S(CH2)2 n is 0 to 6; is 0 to 3; A is a bond, -CH=CH-, -C≡C-, oxygen, sulphur or NR1;
R1 is hydrogen, Cj.galkyl or phenylCι_4alkyl; and
Ar is aryl or heteroaryl, each of which may be optionally substituted; or a pharmaceutically acceptable salt thereof as a therapeutic agent.
Compounds of formula (I) and their pharmaceutically acceptable salts may for example be used in the treatment of disorders wherein a calcium channel antagonist is indicated.
In the compounds of formula (I) W preferably represents (CH2)4 or (CH2)5 The group -(CH2)nA(CH2)mAr may be substituted on any carbon atom in the ring. When W is (CH2)4 or (CH2)5 the substituent is preferably α to the ring nitrogen atom.
The values of n, m and A should be chosen such that the chain (CH2)nA(CH2)m contains at least one atom. In general, the length of the chain -(CH2)nA(CH2)m is from 2 to 6 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 from 1 to 5; for example n may be 1 or 2 and m may be zero.
A is preferably oxygen or a bond.
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_ alkylenedioxy group (e.g. phenyl substituted by a 3,4-methylenedioxy group) or by 1 to 3 substituents selected from halogen, Cj^alkoxy, nitro, SCι_ alkyl, NR2aR2b (in which R2a and R2b independently represent H or Cι_4alkyl), OCF3, Cj.galkyl, trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted benzoyl, optionally substituted phenylCι_4alkyl and optionally substituted phenylC 1 _4alkoxy .
Suitable optionally substituted phenylCj_4alkyl groups include, for example benzyl. Suitable optionally substituted phenylCι_4alkoxy groups include, for example benzyloxy groups.
Suitable substituents for said optionally substituted phenyl, phenoxy, benzoyl, phenylCι_4alkyl and phenylC^alkoxy groups include for example halogen, Cj^alkyl, C^alkoxy, nitro and trifluoromethyl groups. Preferably the aryl group is a phenyl ring substituted by one or two substituents, in particular, by a phenyl, phenyl(Cj_4)alkyl, phenoxy, benzoyl or phenylCι_4alkoxy group; or by two chloro atoms especially in the 3- and 4-positions of the phenyl ring.
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 and tetrahydroquinolinyl. A tricyclic ring system preferably contains from 11 to 14 ring members, and most preferably has the structure :
wherein Y1 represents Y(CH2)r, Y is O, S or NR^ (where R^ is hydrogen or Cj_4alkyl), Z is (CH2)q 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, Cμ4alkyl and Cμ4alkoxy.
Alkyl groups present in the compounds of formula (I), alone or as part of another group, can be straight or branched. Thus a C^galkyl group may be for example methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl or any branched isomer thereof such as iso¬ propyl, tert-butyl or _yec-pentyl. Particularly preferred compounds of formula (I) for use according to the present invention are those wherein W is (CH2)5, the substituent -(CH )nA(CH2)mAr is α to the ring nitrogen atom, A is oxygen, n is 1 or 2, m is zero and Ar is phenyl substituted by one of benzyl, benzoyl, phenoxy or benzyloxy, or by two chloro atoms, or Ar is dibenzofuranyl. It will be appreciated that for use in medicine a salt of a compound (I) should be pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, methanesulphonate or similar pharmaceutically acceptable inorganic or organic acid addition salts. Other non- pharmaceutically acceptable salts, such as oxalates, may be used for example in the isolation of final products and are included within the scope of this invention.
It will be appreciated that the compounds of formula (I) 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. In addition, when A represents -CH=CH- the compounds will exist as geometric isomers, and the invention encompasses the use of all such isomers and mixtures thereof. Compounds of formula (I) wherein W is -(CH2)4 and the group -(CH2)nA(CH2)mAr is α to the pyrrolidine nitrogen atom are novel compounds and as such form a further aspect of the invention. Preferably A is oxygen, n is 1 or 2 and m is zero. Preferred values of Ar are as defined above.
Compounds of formula (I) wherein Ar represents phenyl substituted by benzoyl are also novel compounds and form a yet further aspect of the invention. A particularly preferred group of compounds wherein Ar represents benzoylphenyl is that in which W is (CH2)5, A is oxygen, n is 1 or 2 and m is zero. Most preferably the substituent -(CH2)nA(CH2)mAr is α to the ring nitrogen atom.
Particular compounds for use according to the invention include: 2-[2-(4-benzyloxyphenoxy)ethyl]piperidine, 2- [2-(4-phenoxyphenoxy)ethyl]piperidine, 2-[2-(2-benzylphenoxy)ethyl]piperidine, 4-f2-(3,4-dichlorophenoxy)ethyl]piperidine, 4-f2-(4-benzyloxyphenoxy)ethyl]piperidine,
4-f2-(4-benzylphenoxy)ethyl]piperidine, 3-(4-benzyloxyphenoxymethyl)piperidine, 3-(4-benzylphenoxymethyl)piperidine, 2-[4-benzylphenoxymethyl]piperidine, 2-[4-benzyloxyphenoxymethyl]piperidine, (S)-2-[4-benzylphenoxymethyl]pyrrolidine, 2-[2-(3-benzoylphenoxy)ethyl]piperidine, 2- [2- (4- benzoylphenoxy)ethyl]piperidine, (+)-2-(2-[4-benzylphenoxy]ethyl)piperidine, (-)-2-(2-[4-benzylphenoxy]ethyl)piperidine, and salts thereof.
The above are also novel compounds and form a yet further aspect of the invention.
Other preferred compounds for use according to the present invention include : 2-f2-(2-dibenzofuranyloxy)ethyl]piperidine, 2-[2-(3,4-dichlorophenoxy)ethyl]piperidine, 2-[2-(4-benzylphenoxy)ethyl]piperidine, and salts thereof.
The compounds for use according to the present invention can be prepared by processes analogous to those known in the art, for example the general methods described in WO92/02501 , WO92/02502, WO92/22527 and WO93/15052. Thus, a compound of formula (I) may be prepared by a process which comprises:
(a) for compounds of formula (I) in which A is O, S or NR1, reaction of a compound of formula (II):
Formula (II) in which W and n are as described for formula (I), A1 is O, S or NR1, and R^ is an N-protecting group 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 NR1, reaction of a compound of formula (III):
Formula (III) in which W, n and R^ are as described above and L1 is a group displaceable by a nucleophile, with a compound of formula HA1(CH2)mAr where m and Ar are as described for formula (I) and A1 is as described for formula (II); or
(c) for compounds of formula (I) in which A is NR 1 , reduction of a compound of formula (IV) :
Formula (IV) in which R^ represents the group
-(CH2)nN(R1)C(O)(CH2)m.1Ar or -(CH2)n.1C(O)N(R1)(CH2)mAr,
R^a is hydrogen or an N-protecting group, and W, n, m, and Ar are as described above.
(d) for compounds of formula (I) in which A is a bond, reaction of a compound of formula (V) :
Formula (V)
(wherein W, R^, L , m and n are as hereinbefore defined); with a compound of formula X1Ar in which Ar is as described for formula (I), and X1 is an alkali metal; (e) For compounds where W is (CH2)5 and A is O, S, NR1 or a bond, reduction of a compound of formula (VI):
Formula (VI)
wherein A, Ar m and n are as hereinbefore defined, R^a is hydrogen or an N-protecting group and X" is a counter ion;
(f) For compounds wherein A is -CH=CH-, reaction of a compound of formula (VII) :
Formula (VII) (wherein W, R^ and n are as hereinbefore defined) with a reagent serving to introduce the group Ar;
(g) Interconversion of one compound of formula (I) 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-, or reduction of a benzoyl substituent on the group Ar to a benzyl group; followed where necessary by removal of the N-protecting group R^, and optionally thereafter forming a salt. In a further aspect the present invention also provides a process for preparing a novel compound of formula (I) e.g a compound of formula (I) wherein W is -(CH2)4 and the group -(CH2)nA(CH )mAr is α to the pyrrolidine nitrogen atom, or a compound as specifically named above, which process comprises any of processes (a) to (g) described above,as approporiate, followed where necessary by removal of the N-protecting group R4, and optionally thereafter forming a salt. Those skilled in the an will readily be able to determine which specific processes will be applicable to the preparation of a given compound.
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 DMSO or dimethylformamide.
The reaction between a compound of formula (IH) and a compound of formula HA (CH2)mAr (process b) can take place under conditions which depend on the nature of L and A. For example when L1 is hydroxy, m is 0 and A1 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 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 1 Ar in process (d) can take place under standard conditions known to those skilled in the an for the formation of carbon-carbon bonds.
Reduction of a compound of formula (VI) according to process (e) may be effected for example by hydrogenation, using a noble metal catalyst such as platinum, palladium or platinum oxide, suitably in a solvent such as an alcohol eg. ethanol.
Process (f) may be effected using a Wadsworth-Emmons reagent of the formula Ar(CH2)m+lP(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 tert-butoxide.
Interconversion reactions according to process (g) 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 and reduction of a benzoyl substituent to benzyl may be carried out using a reducing agent such as sodium borohydride in trifiuoroacetic acid.
Protecting groups R^ include lower alkyl groups such as methyl; aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl; and acyl groups such as acetyl, trifluoroacetyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl. In process (e) a protecting group R^a is preferably alkyl e.g. methyl or aralkyl e.g. benzyl. Such groups may be removed by methods which are well known in the art. An alkyl group such as methyl may be removed by treatment with a haloalkyl haloformate such a 1-chloromethylchloroformate, aralkyl group such as benzyl may be cleaved by hydrogenolysis, and an acyl group such as benzoyl may be cleaved by hydrolysis. It will be appreciated that a protecting group R^ or R^a present in any of the above compounds (II) to (VII) as well as compounds (VIII) below should be chosen such
that it will not be cleaved by or participate in any of the reactions that the particular compound is intended to undergo, and furthermore such that its removal will not disturb any other groups or moieties present in the molecule. Such factors can be readily ascertained by those skilled in the art, to whom appropriate protecting groups will thus be readily apparent.
Compounds of formula (II) can be prepared from the corresponding compounds in which R^ is hydrogen, by methods well known in the art. For example an acyl group may be introduced by reaction with an appropriate acid derivative such as an acid chloride or anhydride, or an activated ester, e.g. an alkyldicarbonate such as di-tert- butyldicarbonate or a haloformate such as ethylchloroformate.
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-hydroxy-alkylpyridine.
Alternatively, the compounds of formula (II) in which A1 is oxygen can be prepared by reduction of a compound of formula (VIII):
Formula (VHI) in which R*+ and n are as hereinbefore described. In this instance R^ should be a group such as alkyl, which is not cleaved by reductive conditions. Compounds of formula (HI) wherein L1 is OH can be prepared as described for compounds of formula (II), and compounds of formula (HI) wherein L1 is a halogen atom, or a mesyloxy or tosyloxy group can be prepared from the corresponding alcohol in conventional manner.
Compounds of formula (IV) wherein R^ is a group -(CH2)nN(R 1 )C(O)(CH2)m_ j Ar can be prepared by reacting a compound of formula (II) wherein A1 represents NR1 with an acylating agent corresponding to the group -
(CH2)mAr, for example an acid chloride ClOC(CH2)m_ιAr. Compounds of formula (IV) wherein R^ is a group
-(CH2)n_ιC(O)N(R1)(CH )mAr may be prepared for example by reaction of a corresponding compound wherein R5 represents -(CH2)n_ιCO2H or an activated derivative thereof such as an acid halide, ester or anhydride, with an amine of formula
HN(R )(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 A1 is oxygen.
Compounds of formula (V) may be prepared in analogous manner to compounds of formula (III); where necessary the chain length may be increased using methods well known in the art.
A compound of formula (VI) may be prepared using the general methods described in processes (a) to (d) above.
Compounds of formula (VII) may be prepared by conventional methods, for example the oxidation of a compound of formula (II) wherein A1 is oxygen, or conversion of the corresponding ester, e.g. by reaction with thionyl chloride and
N,O-dimethylhydroxylamine hydrochloride, to give the N-methyl-N-methoxy- carboxamide, which can be reduced to the aldehyde using diisobutylaluminium hydride. Compounds of formula (VII) wherein n is 1 may be prepared from the corresponding compound wherein n is zero by various methods. For example the aldehyde wherein n is zero may be treated with (methoxymethyl) triphenylphosphonium chloride and potassium t-butoxide, followed by a strong acid, e.g. concentrated sulphuric acid, resulting in the aldehyde wherein n is 1. Alternatively the aldehyde may be converted to the conesponding cyanomethyl derivative as described in EPA 363085 followed by acid hydrolysis, conversion to the N-methyl-N-methoxycarboxamide and reduction. These procedures may also be used to form higher homologues.
When a compound of formula (I) is obtained as a mixture of enantiomers, these may be separated by conventional methods such as crystallisation in the presence of a resolving agent, or chromatography, for example using a chiral HPLC column. Suitable resolving agents include optically active acids such as R-(-)- or S-(+)-mandelic acid. Compounds of formula (I) have been found to exhibit calcium influx blocking activity for example in neurons. As such the compounds are expected to be of use in therapy in treating conditions and diseases related to an accumulation of calcium in the brain cells of mammals, in particular humans. For example, the compounds are expected to be of use in the treatment of anoxia, ischaemia including for example stroke, migraine, visceral pain, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders; mood disorders and drug addiction withdrawal such as ethanol addiction withdrawal.
The invention therefore provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment of disorders where a calcium channel antagonist is indicated. Thus for example a compound of formula (I) or a pharmaceutically acceptable salt thereof may be used in the manufacture of a medicament for the treatment of a condition or disease related to (e.g. caused or exacerbated by) the
accumulation of calcium in the brain cells of a mammal e.g a human, such as for example, any of the aforementioned conditions.
In a further aspect of the invention there is also provided a method of treatment of a condition or disease caused or exacerbated by 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) 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.
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, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water • with a suspending agent, preservative, flavouring or colouring agent.
A 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 carrier(s), 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 lyophilised and then reconstituted with a suitable solvent just prior to administration. Both liquid and solid compositions may contain other excipients known in the pharmaceutical art, such as a cyclodextrin or a solubilising agent such as Cremophor.
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 (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, eg. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 60 mg, eg. 1 to 40 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Alternatively the compounds of the invention may be administered by continuous intravenous infusion, preferably at a dose of up to 400mg 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 was measured in vitro using cell preparations of sensory neurons from dorsal root ganglia as described in WO92/02501 and WO92/02502.
Compounds of Example 1-18 gave percentage inhibition of plateau Ca^+ current in the range 48 to 97% @ 20μM of test compound.
Pharmaceutical Formulations
The following represent typical pharmaceutical formulations according to the present invention, which may be prepared using standard methods.
IV Infusion
Compound of formula (I) 1-40 mg
Buffer to pH ca 7 Solvent/complexing agent to 100 ml
Buffer : Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.
Solvent : Typically water but may also include cyclodextrins (1-100 mg) and co-solvents such as propylene glycol, polyethylene glycol and alcohol.
Tablet Compound 1 - 40 mg
Diluent/Filler * 50 - 250 mg
Binder 5 - 25 mg
Disentegrant * 5 - 50 mg
Lubricant 1 - 5 mg Cyclodextrin 1 - lOO mg
* may also include cyclodextrins
Diluent : e.g. Microcrystalline cellulose, lactose, starch Binder : e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
Disintegrant : e.g. Sodium starch glycollate, crospovidone Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate.
Oral Suspension Compound 1 - 40 mg
Suspending Agent 0.1 - 10 mg
Diluent 20 - 60 mg
Preservative 0.01 - 1.0 mg
Buffer to pH ca 5 - 8 Co-solvent 0 - 40 mg
Flavour 0.01 - 1.0 mg
Colourant 0.001 - 0.1 mg
Suspending agent : e.g. Xanthan gum, microcyrstralline cellulose
Diluent : e.g. sorbitol solution, typically water
Preservative : e.g. sodium benzoate
Buffer : e.g. citrate Co-solvent : e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin
The invention is further illustrated by the following non-limiting examples :
Preparation 1 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 2 l-/ert-ButoxycarbonyI-2-(2-hydroxyethyI)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.m.r. and was used without further purification.
Preparation 3 l-tert-Butoxycarbonyl-4-(2-hydroxyet yl)piperidine
Substituting 4-(2-hydroxyethyl)piperidine (21.7g, 0.176 mole) for 2-(2- hydroxyethyl)piperidine and using the corresponding molar proportions of the other reagents in the method of preparation 2 gave the title compound as a straw coloured viscous oil (36.96g) which was used without further purification.
Preparation 4 l-tert-Butoxycarbonyl-3-hydroxymethylpiperidine
Substituting 3-hydroxymethylpiperidine (19.23g, 0.176 mole) for 2-(2- hydroxyethyl)piperidine and using the corresponding molar proportions of the other reagents in the method of preparation 2 gave the title compound as a straw coloured viscous oil (36.96g) which was used without further purification.
Example 1 a) 2-[2-(2-Dibenzofuranyloxy)ethyI]-l-ethoxycarbonylpiperidine
The product of Preparation 1 (4.0g, 20mM), 2-hydroxydibenzofuran (3.67g, 20mM) and triphenylphosphine (5.2 lg, 20mM) were dissolved with stirring under nitrogen in dry dichloromethane (100ml). The mixture was cooled in an ice-bath and diethylazodicarboxylate (3.46g, 20mM) added dropwise in dichloromethane (20ml). The resulting clear red-brown solution was stood at room temperature for three days and evaporated to dryness to give a sticky brown solid. This material was chromatographed on silica gel using dichloromethane as eluant. Fractions were monitored by t.l.c. and appropriate fractions combined and evaporated to give the title compound as a brown oil (6.1g). Mass Spectrum (M+H = 368)
*H N.m.r. (CDC13) 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 (lH, m).
b) 2-[2-(2-Dibenzofuranyloxy)ethyl]piperidine hydrochloride
The product of Example la (6.0g, 16.03 mmole) was dissolved in glacial acetic acid/hydrogen bromide (20ml, 45w/v, excess). The solution was stood at room temperature for two hours and heated on a steam-bath for three hours. The material was then cooled, poured onto water and the aqueous phase basified with 50% NaOH. The mixture was extracted with dichloromethane (X2) and the combined organic extracts washed (water, brine), dried (MgSO4) and evaporated to give an oil (4.44g). This material was purified by flash chromatography on silica gel. Product was eluted in CH2Cl2/2% methanol (the methanol containing 10% .88NH4OH) and finally CH2Cl2/5% 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) (C19H21NO2HCl 0.2H2O) requires: C, 68.0%, H, 6.7%, N, 4.2%. found: C, 67.9%; H, 6.6%; N, 4.1%
Example 2 a) 2-(2-[3,4-Dichlorophenoxy]ethyl)-l-tert-butoxycarbonyl piperidine
Using the product of Preparation 2 (4.55g, 20mM), the conditions of Example la, and replacing 2-hydroxydibenzofuran 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). lH 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 (lH, m).
b) 2-[2-(3,4-Dichlorophenoxy)ethyl]piperidine hydrochloride
The product of Example 2a (6.0g, 16mM) was dissolved in dichloromethane (80ml) and stirred at room temperature under nitrogen. A solution of trifluoroacetic acid (7.5ml) in dichloromethane (20ml) was added dropwise over 10 minutes and the colourless solution stirred for a further 2 hours. The mixture was evaporated and 2N. NaOH (100ml) added to the oily residue to produce a white, oily solid. This was extracted with dichloromethane (X2) and the combined organic extracts washed (H O, brine), dried (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 excess ethereal HC1 (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). (Ci3H17Cl2NO, HC1) requires: C, 50.3%; H, 5.8%; N, 4.5% found: C, 50.0%; H, 5.7%; N, 4.3%.
Example 3 a) 2-[2-(4-Benzylphenoxy)ethyl]-l-terf-butoxycarbony! piperidine
Replacing the 3,4-dichlorophenol with 4-benzylphenol (3.67 g, 20mM) in the method of Example 2a gave the title compound as an oil (6.82g). (Mass Spec M+H=396).
b) 2-[2-(4-Benzylphenoxy)ethyl]piperidine hydrochloride
Replacing the product of Example 2a with the product of Example 3a (6.7g,17mM) in the method of Example 2 and using corresponding molar proportions of the other reagents gave title compound (free base form) as a colourless oil (3.49g). This material was dissolved in ethyl acetate and excess ethereal HCl (IM) added to the stirred solution. A white solid appeared after about one minute which was collected, washed with ethyl acetate/ether to give the title compound (3.72g), M.P.: 168-170°C. (C20H25NO- HC 0.2H2O) requires: C, 71.6%; H, 7.9%; N, 4.2%; Cl", 10.6%. Found C, 71.5%; H, 7.6%; N, 4.3%; Cl", 10.9%.
Example 4 a) 2-[2-(4-Benzyloxyphenoxy)ethyl]-l-tert-butoxycarbonyI piperidine
Replacing the 3,4-dichlorophenol with 4-benzyloxyphenol (4.0g, 20mM) in the method of Example 2a gave the title compound as an oil (6.97g). N.m.r (CDC13) δ: 1.39 (9H, s), 1.50-1.73 (6H, m), 1.75-1.90 (IH, m), 2.12-2.30 (IH, m), 2.71-2.87 (IH, t), 3.80-4.10 (3H, m), 4.40-4.54 (IH, m), 4.98 (2H, s), 6.75-6.93 (4H, m), 7.28-7.45 (5H, m).
b) 2-[2-(4-Benzyloxyphenoxy)ethyI]piperidine hydrochloride Replacing the product of Example 2a with the product of Example 4a (6.85g, 16.7mM) in the method of Example 2 and using corresponding molar proportions of the other reagents gave the title compound as the free base (4.80g). This material was dissolved in ethyl acetate and excess ethereal HCl added. A white solid precipitated which was collected, washed with cold ethyl acetate and ether and dried (4.05g). This material was crystallised from methanol/ethyl acetate to give the title compound as a white crystalline solid (3.43g), M.P. 215-216°C.
(C20H25NO . HCl) requires: C, 69.0%; H, 7.5%; N, 4.0%; Cl", 10.2%. Found: C, 69.1%; H, 7.5%; N, 4.1%; Cl, 10.0%
Example 5 a) 2-[2-(4-Phenoxyphenoxy)ethyl]-l-/ert-butoxycarbonyl piperidine
Replacing the 3,4-dichlorophenol with 4-phenoxyphenol (1.86g, lOmM) and using corresponding molar proportions of the other reagents in the method of Example 2a gave the title compound as an oil (3.28g).
N.m.r. (CDCI3) δ: 1.38 (9H, s), 1.51-1.70 (6H, m), 1.77-1.91 (IH, m), 2.15-2.31 (IH, m), 2.73-2.88 (IH, t), 3.85-4.10 (3H, m), 4.45-4.57 (IH, m), 6.78-7.05 (6H, m), 7.24-7.34 (3H, m).
b) 2-[2-(4-Phenoxyphenoxy)ethyl]piperidine hydrochloride
Replacing the product of Example 2a with the product of Example 5a (3.2g, 8.06mM) in the method of Example 2 and using corresponding molar proportions of the other reagents gave the title compound as the free base (2.35g, oil). This material was dissovled in ethyl acetate, the solution warmed on a water-bath and ethereal HCl (IM) added in excess. On cooling a copious white solid separated which was collected, washed with ether and dried to give the title compound (1.70g), M.P. = 175°-176°C. (Ci9H23NO2. HCl) requires: C, 68.4%; H, 7.2%; N, 4.2%; Cl", 10.6% Found: C, 68.1%, H, 7.2%; N, 4.2%; Cl", 10.3%
Example 6 a) 2-[2-(2-BenzyIphenoxy)ethyl]-I-/ert-butoxycarbonyl piperidine
Replacing the 4-phenoxyphenol with 2-hydroxydiphenylmethane (1.835g, lOmM) in the method of Example 5a gave the title compound as an oil (2.42g).
N.m.r. (CDCI3) δ: 1.38 (9H, s), 1.50-1.69 (6H, m), 1.75-1.90 (IH, m), 2.10-2.27 (IH, m), 2.72-2.86 (IH, t), [3.95 (s), 3.82-4.08 (m), 5H], 4.38-4.50 (IH, s), 6.75-6.88 (2H, m), 7.00-7.30 (7H, m).
b) 2-[2-(2-Benzylphenoxy)ethyl]piperidine hydrochloride
Replacing the product of Example 2a with the product of Example 6a (2.36g, 6mM) in the method of Example 2 and using corresponding molar proportions of the other reagents gave the free base of the title compound as a colourless oil (1.67g). This was dissolved in ethyl acetate, the solution warmed on a water-bath and ethereal HCl (IM) added in excess.
Slow cooling gave the title compound as a white crystalline solid (1.49g), M.P. =115°-
117°C. (C 0H25NO. HCl) requires: C, 71.6%; H, 7.9%; N, 4.2%; Cl",10.6%.
Found: C, 71.1 %; H, 7.6%; N, 4.2%; Cl' 10.9%
Example 7 a) 4-[2-(3,4-DichIorophenoxy)ethyI]-l-/e/*-butoxycarbonylpiperidine Using the product of preparation 3 (7.40g, 0.032 mole), the conditions of
Example 2a, and the corresponding molar proportions of the other reagents and recrystallising the product from hexane gave the title compound (6.52g) as white needles, m.p. 73-74°C
b) 4-[2-(3,4-Dichlorophenoxy)ethyI]piperidine hydrochloride
Replacing the product of Example 2a with the product of Example7a (3.0g, 0.008 mole) in the method of Example 2 and using the corresponding molar proportions of the other reagents gave the title compound as the free base (2.75g). This material was dissolved in ethyl acetate and excess ethereal HCl added. A white solid precipitated which was collected , and recrystallised from ethyl actetate to give the title compound as white needles (2.17g), M.P. 180-1°C. (Mass Spec M+ = 274)
(C^HπC^NO.HCl 0.2H2O) requires: C, 49.62%, H, 5.89%, N, 4.45%, Cl, 33.80% Found: C, 49.38%, H, 5.55%, N, 4.47%, Cl, 34.05%.
Example 8 a) 4-[2-(4-Benzyloxyphenoxy)ethyl]-l-tert-butoxycarbonylpiperidine
Substituting 4-benzyloxyphenol (4.36g, 0.022 mole) for 3,4-dichlorophenol and using the corresponding molar proportions of the other reagents in the method of Example 7a gave the title compound as a white low melting solid (4.7 lg) which was used without further purification.
b) 4-[2-(4-Benzyloxyphenoxy)ethyl]piperidine hydrochloride
Replacing the product of Example 2a with the product of Example 8a (4.5g, 0.011 mole) in the method of Example 2 and using the corresponding molar proportions of the other reagents gave the title compound as the free base. This material was dissolved in ethyl acetate and excess ethereal HCl added. A white solid precipitated which was collected , and recrystallised from ethyl actetate to give the title compound as white needles (2.14g), M.P. 183-4°C.(Mass Spec M+ = 312) (C20H25NO2.HC1 0.33H2O) requires: C, 67.87%, H, 7.59%, N, 3.95%, Cl, 10.01% Found: C, 67.98%, H, 7.22%, N, 4.03%, Cl, 9.83%.
Example 9 a) 4-[2-(4-Benzylphenoxy)ethyl]-l-tert-butoxycarbonylpiperidine
Substituting 4-benzylphenol (4.05g, 0.022 mole) for 3,4-dichlorophenol and using the corresponding molar proportions of the other reagents in the method of Example 7a gave
the title compound as a colourless oil (5.7 lg) which was used without further purification.
b) 4-[2-(4-Benzylphenoxy)ethyl]piperidine hydrochloride Replacing the product of Example 2a with the product of Example 9a (3.6g, 0.0091 mole) in the method of Example 2 and using the corresponding molar proportions of the other reagents gave the title compound as the free base. This material was dissolved in ethyl acetate and excess ethereal HCl added. A white solid precipitated which was collected , and recrystallised from acetonitrile to give the title compound as white needles (1.49g), M.P. 153-4°C. (Mass Spec M+H = 296)
(C20H25NO.HC1 0.1H2O) requires: C, 71.98%, H, 7.91%, N, 4.19%, Cl, 10.62% Found: C, 71.76%, H, 7.71%, N, 4.26%, Cl, 10.79%.
Example 10 a) 3-(4-BenzyloxyphenoxymethyI)-l-tert-butoxycarbonylpiperidine
Using the product of preparation 4 (lO.Og, 0.046 mole), the conditions of Example 2a, and the corresponding molar proportions of the other reagents gave the title compound
(15.54g).
b) 3-(4-Benzyloxyphenoxymethyl)piperidine hydrochloride
Replacing the product of Example 2a with the product of Example 10a (15.54g, 0.038 mole) in the method of Example 2 and using the corresponding molar proportions of the other reagents gave the title compound as die free base. This material was dissolved in ethyl acetate and excess ethereal HCl added. A white solid precipitated which was collected , and recrystallised from ethanol to give the title compound as white needles (6.30g), M.P. 220-2°C. (Mass Spec M+ = 297)
(C19H23NO2.HCl) requires: C, 68.36%, H, 7.25%, N, 4.20%, Cl, 10.62% Found: C, 67.94%, H, 7.06%, N, 4.07%, Cl, 10.88%.
Example 11 a) 3-(4-Benzylphenoxymethyl)-l-tert-butoxycarbonylpiperidine
Substituting 4-benzylphenol (8.47g, 0.046 mole) for 4-benzyloxyphenol, and using the corresponding molar proportions of the other reagents in the method of Example 10a, gave the title compound (20.5g).
b) 3-(4-Benzylphenoxymethyl)piperidine hydrochloride
Replacing the product of Example 2a with the product of Example 1 la (20.5g) in the method of Example 2 and using the corresponding molar proportions of the other reagents gave the title compound as the free base. This material was dissolved in ethyl acetate and excess ethereal HCl added. A white solid precipitated which was collected , and recrystallised from acetonitrile to give the title compound as white needles (6.96g), M.P. 247-8°C. (Mass Spec M+H = 282)
(Cι9H23NO.HCl) requires: C, 71.80%, H, 7.61%, N, 4.41%. Found: C, 71.85% H, 7.57 N, 4.44%.
Example 12 a) 2-[4-Benzylphenoxymethyl]-N-methylpiperidine oxalate
1 -Methyl-2-piperidinemethanol (2.58g, 20mM), 4-benzylphenol (3.68g, 20mM) and triphenylphosphine (5.2 lg, 20mM) were dissolved with stirring under nitrogen in dry dichloromethane (100ml). The solution was cooled in an ice-bath and diethylazodicarboxylate (3.46g, 20mM) in dry dichloromed ane (20ml) was added dropwise. The mixture was stood at room temperature for 24 hours, concentrated to about half the volume and chromatographed on silica gel using CH2C12 as initial eluent followed by CH2Cl /2% MeOH (MeOH contains 10% NH4OH). Fractions were monitored by t.l.c. and appropriate fractions combined and evaporated to give a white solid. This solid was treated with dietiiyl ether, some insoluble material (PI13P = O) removed and the ether evaporated and the residue re-dissolved in ethyl acetate. A solution of 1 equivalent of oxalic acid dihydrate in etiiyl acetate was added to produce a white precipitate. Methanol was added to the hot mixture to produce a clear solution, from which title product crystallised on standing. (l.Og), M.P. = 107-109°C.
(C 0H25NO, C H2O ) requires C, 68.5%, H, 7.1%, N, 3.6% Found C, 68.2%, H, 6.9%, N, 3.6%
b) 2-[4-Benzylphenoxymethyl]piperidine hydrochloride The product of Example 12a (0.5g) was converted to free base (equilibration between N. NaOH and CH2C12 - organic layer dried, washed and evaporated), producing a colourless oil which was dissolved in toluene (10ml). To the stirred solution at room temperature under argon was added dropwise a solution of 1-chloromethyl chloroformate (0.28g, excess) in dry toluene (5ml). The mixture was heated at reflux temperature for 4 hours, concentrated almost to dryness, methanol (20ml) added and die mixture heated again at reflux temperature for 2 hours. The solvent was evaporated off to produce an oil which
solidified on standing. The material was crystallised from ethyl acetate/methanol to produce the title compound (0.21g) as a white solid, M.P. 95-97°C. (C19H2 NO. HCl) requires C, 71.8%, H, 7.6%, N, 4.4.% Found C, 71.4%, H, 7.4%, N, 4.5%
Example 13 a) 2-[4-Benzyloxyphenoxymethyl]-N-methyIpiperidine hydrochloride
Substituting 4-benzyloxyphenol (4.0g, 20mM) for 4-benzylphenol in the method of Example 12a and using identical reaction conditions gave an oil (4.82g) following the chromatography step. This oil was dissolved in ethyl acetate and excess ethereal HCl added. The mixture was evaporated to dryness and the residue crystallised from ethyl acetate/methanol to give the title compound as a white solid (3.79g), M.P. 83-85°C. (C20H25NO2, HCl, 0.5H2O) requires C, 67.3%, H, 7.6%, N, 3.9% Found C, 67.4%, H, 7.4%, N, 4.2%
b) 2-[4-Benzyloxyphenoxymethyl]piperidine hydrochloride
Substituting the product of Example 13a (2.27 g) for the product of Example 12a in the method of Example 12 and using corresponding molar proportions of d e other reagents gave a white solid (3.5gms) after die methanol treatment. This material was re-crystallised from ethyl acetate/methanol to give the title compound (1.65g) as white crystals (M.P. =178-179°C)
(C19H23NO . HCl) requires C, 68.4%, H, 7.2%, N, 4.2% Found C, 67.8%, H, 7.0%, N, 4.2%
Example 14 a) (S)-2-[4-BenzylphenoxymethyI]-N-methylpyrrolidine oxalate
Substituting (S)-(-)-l-methyl-2-pyτrolidinemethanol (2.3g, 20mM) for l-methyl-2- piperidinemethanol in the method of Example 12a and using identical reaction conditions gave a pale-green oil (2.8g) following the chromatography step. Part of this material (1.47 g) was dissolved in ethyl acetate and to the hot solution was added a solution of oxalic acid dihydrate (0.66g, leq) in methanol. The solution produced was concentrated and refrigerated overnight to give the title compound (1.4g) as a colourless, crystalline solid (M.P. 99-100°C). (C19H23NO. C2H2O4) requires C, 67.9%, H, 6.8% N, 3.8% Found C, 67.8%, H, 6.7%, N, 3.8%
b) (S)-2-[4-Benzylphenoxymethyl]pyrrolidine hydrochloride
Substituting the product of Example 14a (2.0g) for the product of Example 12a in the method of Example 12 and using corresponding molar proportions of the other reagents gave an oil after the methanol treatment stage. This oil was converted to free base (equilibration between N. NaOH and CH2CI2 etc) and the resulting oil chromatographed on silica gel using CH2Cl2/2% MeOH (MeOH contains 10-% NH4OH) as eluting solvent. An initial product eluted (1.6g) and was shown (N.M.R.) to be unreacted starting material. The eluent was changed to CH2θ2/5% MeOH to yield a second product as an oil (0.62g). This material was dissolved in ethyl acetate/methanol, the solution treated with ethereal HCl, concentrated and refrigerated overnight. The title compound crystallised as a buff- coloured solid (0.47g), M.P. 148-150°C. Cι8H2ιNO. HCl) requires C, 71.2%, H, 7.3%, N, 4,6% Found C, 70.8%, H, 7.3%, N, 4.6%
Example 15 a) 2-[2-(4-Benzoylphenoxy)ethyl]-l-tert-butoxycarbonyl piperidine
Substituting 4- hydroxy benzophenone (2.94g, 14.9mM) for 3,4-dichlorophenol in the method of Example 2a and using corresponding molar proportions of the other reagents gave the title compound as a colourless oil (3.03g) following column chromatography in dichloromethane.
1H N.M.R. (CDCI3) δ: 1.38 (9H, s), 1.6-1.8 (6H, m), 1.8-2.0 (IH, m), 2.2-2.4 (IH, m), 2.75-2.9 (IH, m), 3.95-4.15 (3H, m), 4.45-4.6 (IH, m), 6.9 (2H, d), 7.25-7.9 (8H, m).
b) 2-[2-(4-Benzoylphenoxy)ethyl]piperidine hydrochloride Substituting the product of Example 15a (3.0g) for die product of Example 2a in the method of Example 2 and using corresponding molar proportions of the other reagents gave a colourless oil (1.98g) following the basification extraction step. This oil was dissolved in ethyl acetate and d e solution treated witii ethereal/HCl to produce a white precipitate. This was dissolved by adding metiianol, the solution was concentrated and on refrigeration, the title compound separated as white crystals (1.32g), M.P. 208-210°C (c20H23NO2- HCl) requires C, 69.5%, H, 7.0%, N, 4.1% Found C, 69.2%, H, 6.9%, N, 4.1%
Example 16 a) 2-[2-(3-Benzoylphenoxy)ethyl]-l-tert-butoxycarbonyl piperidine
Substituting 3-hydroxybenzophenone (2.0g, lOmM) for 3,4-dichlorophenol in the method of Example 2a and using corresponding molar proportions of the other reagents gave the title compound as a colourless oil (3.43g) following column chromatography in dichloromethane.
1H N.M.R. (CDCI3 δ: 1.37 (9H, s), 1.6-1.8 (6H, m), 1.8-2.0 (IH, m), 2.15-2.35 (IH, m), 2.7-2.9 (IH, m), 3.9-4.1 (3H, m), 4.4-4.6 (IH, m), 7.05-7.15 (IH, m), 7.25-7.65 (6H, m), 7.75-7.85 (2H, d of d)
b) 2-[2-(3-BenzoyIphenoxy)ethyl]piperidine hydrochloride
Substituting the product of Example 16a (1.07 g, 2.23mM) for the product of Example 2a in the method of Example 2 and using corresponding molar proportions of the other reagents gave a colourless oil (0.64g) following the basification step. This oil was dissolved in ethyl acetate and die solution treated with etiiereal HCl to produce on standing a white solid. The material was re-crystallised from acetonitrile to produce the title compound as a white solid (0.3 lg), M.P. 106-108°C (C20H23NO . HCl. 0.25H2O) requires C, 68.5%, H, 7.0%, N, 4.0% Found C, 68.1%, H, 6.8%, N, 4.2%
Example 17
(+)-2-(2-[4-Benzylphenoxy]ethyl)piperidine hydrochloride
The product of Example 3 was converted to free base in d e usual way (equilibration between N. NaOH and CH2C12) to produce an oil (1.75g, 5.92mM). This oil was dissolved in ethyl acetate (15ml) and S-(+)-mandelic acid (0.9g, 5.92mM) in etiiyl acetate (15ml) added. On refrigeration crystals separated and were collected (2.31 g). This material was crystallised five times from ethyl acetate/methanol (monitored by chiral HPLC) to give a white solid (0.83g). Conversion to free base in the usual way gave an oil (0.56g). This was dissolved in ethyl acetate and die solution treated with ethereal HCl. On cooling the title compound separated as white crystals (0.5 lg), M.P. = 170-171°C. Specific Rotation = [α]20 > = + 7.70°. Enantiomeric Purity = 98.6%. (C2oH25NO. HCl, 0.6H2O) requires C, 70.1%, H, 8.0%, N, 4.1%, Cl", 10.4% Found C, 70.1%, H, 7.5%, N, 4.2%, Cl", 10.6%.
Example 18
(-)-2-(2-[4-Benzylphenoxy]ethyl)piperidine hydrochloride
The combined mother liquors from all the crystallisations of the mandelic acid salt in Example 17 were converted to free base in the usual way to give an oil (1.19g). This material was dissolved in metiianol/ethyl acetate heated to boiling and a solution of R-(-)- mandelic acid (0.62g, 1 equiv) in methanol was added. The slightly cloudy solution was filtered, concentrated and slowly cooled to give white crystals (0.9 lg). This material was twice re-crystallised from methanol/ethyl acetate to give a white crystalline solid (0.73g). Conversion to free base in the usual way gave a colourless oil (0.58g). This oil was dissolved in ethyl acetate and die solution treated with ethereal HCl. The mixture was refrigerated until the title compound separated as a white crystalline solid (0.47 g), M.P. = 169-170°C, Specific Rotation = [CC]20D = -7.26°. Enantiomeric Purity = 99.7% (C20H25NO. HCl. 0.4 H2O) requires C, 70.8%, H, 8.0%, N, 4.1%, Cl', 10.5% Found C, 70.8%, H, 7.6%, N, 4.2%, Cl", 10.5%
Claims
1. Use of a compound of formula (I):
Formula (I) in which
W is -(CH2)4, (CH2)5, -(CH2)2O(CH2)2 or -(CH2)2S(CH2)2 n is 0 to 6; m is 0 to 3; A is a bond, -CH=CH-, -G≡C-, oxygen, sulphur or NR1; R1 is hydrogen, Cj.galkyl or henylC^alkyl; and Ar is aryl or heteroaryl, each of which may be optionally substituted;
or a pharmaceutically acceptable salt thereof as a therapeutic agent.
2. Use of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of disorders where a calcium channel antagonist is indicated.
3. Use according to claim 2 wherein the disorder is a condition or disease related to an accumulation of calcium in die brain cells of mammals.
4. Use according to any of claims 1 to 3 of a compound of foπnula (I) wherein W represents (CH2)4, or (CH )5.
5. Use according to any of claims 1 to 4 of a compound of formula (I) wherein the group -(CH2)nA(CH2)mAr is α to the ring nitrogen atom.
6. Use according to any of claims 1 to 5 of a compound of formula (I) wherein the length of the chain -(CH2)nA(CH2)m is from 2 to 6 atoms.
7. Use according to any of claims 1 to 6 of a compound of formula (I) wherein A is oxygen or a bond.
8. Use according to any of claims 1 to 7 of a compound of formula (I) wherein Ar represents a phenyl ring substituted by one or two substituents selected from phenyl, phenyl(Cι_4)alkyl, phenoxy, benzoyl or phenylCi^alkoxy group; or by two chloro atoms.
9. Use according to any of claims 1 to 7 of a compound of formula (I) wherein Ar represents a tricyclic ring system of the structure :
wherein Y1 represents Y(CH2)r, Y is O, S or NR^ (where R^ is hydrogen or Cι_4alkyl), Z is (CH2)q or -CH=CH-, q is 0, 1 or 2 and r is 0 or 1, or is a corresponding dehydro ring system.
10. Use according to any of claims 1 to 3 of a compound of formula (I) wherein W is (CH2)5, the substituent -(CH2)nA(CH )mAr is α to the ring nitrogen atom, A is oxygen, n is 1 or 2, m is zero and Ar is phenyl substituted by one of benzyl, benzoyl, phenoxy or benzyloxy, or by two chloro atoms, or Ar is dibenzofuranyl.
11. A method of treatment of a condition or disease caused or exacerbated by the accumulation of calcium in die brain cells of a mammal which comprises administering to a subject in need tiiereof an effective amount of a compound of formula (I) as defined in any of claims 1 to 10 or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
13. A compound of formula (I) wherein W is -(CH2)4 and die group -(CH2)nA(CH2)mAr is α to the pyrrolidine nitrogen atom, or a salt tiiereof.
14. A compound of formula (I) wherein Ar is a phenyl group substituted by benzoyl, or a salt thereof.
15. A compound according to claim 14 wherein W is (CH2)5, A is oxygen, n is 1 or 2 and m is zero, or a salt thereof.
16. A compound of formula (I) selected from :
2- [2-(4-benzyloxyphenoxy)ethyl]piperidine ,
2-[2-(4-phenoxyphenoxy)ethyl]piperidine, 2-[2-(2-benzylphenoxy)ethyl]piperidine,
4-[2-(3,4-dichlorophenoxy)edιyl]piperidine,
4-[2-(4-benzyloxyphenoxy)ethyl]piperidine,
4-[2-(4-benzylphenoxy)ethyl]piperidine,
3-(4-benzyloxyphenoxymethyl)piperidine, 3-(4-benzylphenoxymethyl)piperidine,
2-[4-benzylphenoxymethyl]piperidine,
2-[4-benzyloxyphenoxymethyl]piperidine,
(S)-2-[4-benzylphenoxymethyl]pyrrolidine,
2-[2-(3-benzoylphenoxy)ethyl]piperidine, 2-[2-(4-benzoylphenoxy)ethyl]piperidine,
(+)-2-(2-[4-benzylphenoxy]ethyl)piperidine,
(-)-2-(2-[4-benzylphenoxy]ethyl)piperidine, or a salt thereof.
17. A process for the preparation of a novel compound of formula (I) which comprises:
(a) for compounds of formula (I) in which A is O, S or NR1, reaction of a compound of formula (II):
Formula (II) in which W and n are as described for formula (I), A1 is O, S or NR1, and R^ is an N-protecting group 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 NR1, reaction of a compound of formula (HI):
Formula (III) in which W, n and R^ are as described above and L is a group displaceable by a nucleophile, with a compound of formula HA^CH^ujAr where m and Ar are as described for formula (I) and A1 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) :
Formula (IV) in which R^ represents the group
-(CH2)nN(R1)C(O)(CH2)m.1Ar or -(CH2)n.1C(O)N(R1)(CH2)mAr,
R4a is hydrogen or an N-protecting group, and W, n, m, and Ar are as described above. (d) for compounds of formula (I) in which A is a bond, reaction of a compound of formula (V) :
Formula (V)
(wherein W, R^, L1, m and n are as hereinbefore defined);
with a compound of formula X1Ar in which Ar is as described for formula (I), and X1 is an alkali metal;
(e) For compounds where W is (CH2)5 and A is O, S, NR1 or a bond, reduction of a compound of formula (VI): Formula (VI) wherein A, Ar m and n are as hereinbefore defined, R^a is hydrogen or an N-protecting group and X" is a counter ion;
(f) For compounds wherein A is -CH=CH-, reaction of a compound of formula (VII) :
I 4
R Formula (VII)
(wherein W, R^ and n are as hereinbefore defined) widi a reagent serving to introduce the group Ar;
(g) Interconversion of one compound of formula (I) 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- or reduction of a benzoyl substituent in die group Ar to a benzyl group; followed where necessary by removal of the N-protecting group R^, and optionally thereafter forming a salt.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB929226111A GB9226111D0 (en) | 1992-12-15 | 1992-12-15 | Madicaments |
GB9226111 | 1992-12-15 | ||
PCT/EP1993/003473 WO1994013291A1 (en) | 1992-12-15 | 1993-12-07 | Use of aryloxyalkyl substituted cyclic amines as calcium channel antagonists and new phenyloxyalkyl piperidin derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0674514A1 true EP0674514A1 (en) | 1995-10-04 |
Family
ID=10726633
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP94902735A Withdrawn EP0674514A1 (en) | 1992-12-15 | 1993-12-07 | Use of aryloxyalkyl substituted cyclic amines as calcium channel antagonists and new phenyloxyalkyl piperidin derivatives |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0674514A1 (en) |
JP (1) | JPH08504419A (en) |
CN (1) | CN1091636A (en) |
AU (1) | AU5698394A (en) |
GB (1) | GB9226111D0 (en) |
MX (1) | MX9307946A (en) |
WO (1) | WO1994013291A1 (en) |
ZA (1) | ZA939317B (en) |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
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GB9314973D0 (en) * | 1993-07-20 | 1993-09-01 | Smithkline Beecham Plc | Medicaments |
GB9411045D0 (en) * | 1994-06-02 | 1994-07-20 | Smithkline Beecham Plc | Compounds and use |
GB9411052D0 (en) * | 1994-06-02 | 1994-07-20 | Smithkline Beecham Plc | Medicaments |
WO1996002494A1 (en) * | 1994-07-14 | 1996-02-01 | Smithkline Beecham Plc | Benzocycloalkylamine derivatives as calcium channel antagonists |
US5794887A (en) | 1995-11-17 | 1998-08-18 | Komerath; Narayanan M. | Stagnation point vortex controller |
US5843983A (en) * | 1996-02-15 | 1998-12-01 | Sankyo Company, Limited | Diphenylethane compounds containing a saturated heterocyclic group, their preparation, and their therapeutic use |
CA2232147A1 (en) * | 1997-04-03 | 1998-10-03 | F. Hoffmann-La Roche Ag | Phenoxymethyl piperidine derivatives |
US6110937A (en) * | 1997-04-03 | 2000-08-29 | Syntex Usa, Inc. | Phenoxymethyl piperidine derivatives for the treatment of neuropathic pain |
AU1600599A (en) | 1998-02-27 | 1999-09-15 | Warner-Lambert Company | Heterocyclic substituted aniline calcium channel blockers |
US6166052A (en) | 1998-03-11 | 2000-12-26 | Warner-Lambert Company | Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers |
ATE284711T1 (en) * | 1999-12-21 | 2005-01-15 | Mitsubishi Pharma Corp | MEDICINAL AND/OR PROPHYLACTIC AGENTS FOR THE TREATMENT OF NERVOUS SYSTEM DISORDERS |
CA2422055A1 (en) | 2000-09-11 | 2002-03-21 | Sepracor, Inc. | Ligands for monoamine receptors and transporters, and methods of use thereof (neurotransmission) |
US7294637B2 (en) | 2000-09-11 | 2007-11-13 | Sepracor, Inc. | Method of treating addiction or dependence using a ligand for a monamine receptor or transporter |
ZA200507486B (en) | 2003-03-07 | 2007-03-28 | Astellas Pharma Inc | Nitrogenous heterocyclic derivative having 2,6-disubstituted styryl |
EP1735302B1 (en) | 2004-02-27 | 2010-06-16 | Eli Lilly And Company | 4-amino-piperidine derivatives as monoamine uptake inhibitors |
US7417040B2 (en) | 2004-03-01 | 2008-08-26 | Bristol-Myers Squibb Company | Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3 |
US20070078263A1 (en) * | 2005-09-21 | 2007-04-05 | Decode Chemistry, Inc. | Biaryl substituted heterocycle inhibitors of lta4h for treating inflammation |
CA2634701C (en) * | 2005-12-21 | 2014-07-29 | Decode Genetics Ehf | Biaryl substituted nitrogen containing heterocycle inhibitors of lta4h for treating inflammation |
CN107846898B (en) | 2015-05-01 | 2023-07-14 | 佐治亚州立大学研究基金会 | Diphenyl methanol derivatives for management of hypoxia inducible factor related disorders |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3381013A (en) * | 1964-01-15 | 1968-04-30 | Bristol Myers Co | Heterocyclicamino ethers of benzylphenols |
GB1096441A (en) * | 1964-01-15 | 1967-12-29 | Bristol Myers Co | Ethers of benzyl phenols and a process for the preparation thereof |
GB1203149A (en) * | 1968-06-10 | 1970-08-26 | Ici Ltd | Piperidine derivatives |
GB1319252A (en) * | 1969-06-05 | 1973-06-06 | Ciba Geigy Ag | 1-phenyl-alkanols and process for making same |
DE2728898A1 (en) * | 1977-06-27 | 1979-01-18 | Thomae Gmbh Dr K | NEW MORPHOLINE DERIVATIVES |
DE2811952A1 (en) * | 1978-03-18 | 1979-10-31 | Merck Patent Gmbh | PHENOXYALKYLAMINE AND METHOD FOR THE PRODUCTION THEREOF |
FR2443246A1 (en) * | 1978-12-05 | 1980-07-04 | Pharmindustrie | NOVEL PHENYL-1 (PIPERIDYL-4) -3 PROPANONE-1 DERIVATIVES |
DK231088D0 (en) * | 1988-04-28 | 1988-04-28 | Ferrosan As | PIPERIDE CONNECTIONS, THEIR PREPARATION AND USE |
IE66332B1 (en) * | 1986-11-03 | 1995-12-27 | Novo Nordisk As | Piperidine compounds and their preparation and use |
US4822778A (en) * | 1988-01-19 | 1989-04-18 | Gunnar Aberg | Membrane stabilizing phenoxy-piperidine compounds and pharmaceutical compositions employing such compounds |
US5169855A (en) * | 1990-03-28 | 1992-12-08 | Du Pont Merck Pharmaceutical Company | Piperidine ether derivatives as psychotropic drugs or plant fungicides |
MX9100517A (en) * | 1990-08-06 | 1992-04-01 | Smith Kline French Lab | COMPOUNDS |
IE912759A1 (en) * | 1990-08-06 | 1992-02-12 | Smith Kline French Lab | Compounds |
GB9113031D0 (en) * | 1991-06-17 | 1991-08-07 | Smithkline Beecham Plc | Compounds |
WO1993015052A1 (en) * | 1992-01-28 | 1993-08-05 | Smithkline Beecham Plc | Compounds as calcium channel antagonists |
-
1992
- 1992-12-15 GB GB929226111A patent/GB9226111D0/en active Pending
-
1993
- 1993-12-07 EP EP94902735A patent/EP0674514A1/en not_active Withdrawn
- 1993-12-07 AU AU56983/94A patent/AU5698394A/en not_active Abandoned
- 1993-12-07 WO PCT/EP1993/003473 patent/WO1994013291A1/en not_active Application Discontinuation
- 1993-12-07 JP JP6513782A patent/JPH08504419A/en active Pending
- 1993-12-13 ZA ZA939317A patent/ZA939317B/en unknown
- 1993-12-14 CN CN93112828A patent/CN1091636A/en active Pending
- 1993-12-14 MX MX9307946A patent/MX9307946A/en unknown
Non-Patent Citations (1)
Title |
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See references of WO9413291A1 * |
Also Published As
Publication number | Publication date |
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AU5698394A (en) | 1994-07-04 |
MX9307946A (en) | 1994-08-31 |
JPH08504419A (en) | 1996-05-14 |
ZA939317B (en) | 1995-06-13 |
GB9226111D0 (en) | 1993-02-10 |
WO1994013291A1 (en) | 1994-06-23 |
CN1091636A (en) | 1994-09-07 |
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