[go: up one dir, main page]

WO1993015073A1 - Composes azabicycliques servant d'antagonistes des canaux calciques - Google Patents

Composes azabicycliques servant d'antagonistes des canaux calciques Download PDF

Info

Publication number
WO1993015073A1
WO1993015073A1 PCT/GB1993/000175 GB9300175W WO9315073A1 WO 1993015073 A1 WO1993015073 A1 WO 1993015073A1 GB 9300175 W GB9300175 W GB 9300175W WO 9315073 A1 WO9315073 A1 WO 9315073A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
azabicyclo
octane
compound
group
Prior art date
Application number
PCT/GB1993/000175
Other languages
English (en)
Inventor
Barry Sidney Orlek
Thomas Henry Brown
David Gwyn Cooper
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to JP5513049A priority Critical patent/JPH07503463A/ja
Priority to EP93902471A priority patent/EP0625979A1/fr
Publication of WO1993015073A1 publication Critical patent/WO1993015073A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to the use of known and novel azabicyclic derivatives in therapy, in particular as calcium channel antagonists, novel compounds pa: .S£ » processes for their preparation, and pharmaceutical compositions containing them.
  • Rj is inter alia hydrogen
  • R-2 is hydrogen or ALK-Z
  • R3 is hydrogen or ALK"-Z
  • ALK is C2-4alkyl
  • ALK" is Cj ⁇ alkyl
  • Z is a mono- or- di-substituted phenyl ring.
  • Ricciardi and Doukas (Heterocycles, Vol 24, No 4, p971, 1986) describe certain styrylquinuclidines, which are said to inhibit cholineacetyl-transferase in vitro.
  • German OLS 41 16582 describes azabicyclic compounds of the formula
  • A, B and C independently represent -CH2- or a single bond; n is zero, 1 or 2; X is oxygen or sulphur and R is inter alia phenylalkyl, diphenylalkyl, heterocyclicalkyl, phenyl, diphenyl or a heterocycle, each of which may be optionally substituted. These compounds are said to be useful as muscaiinic antagonists.
  • EPA 497415 describes 3-(substituted phenoxy and substituted phenylthio)quinuclidines, wherein the phenyl substitutent is selected from inter alia lower alkoxy, lower aralkyloxy, halogen, NO2, CF3, CN and NRjR2, which compounds are said to be muscarinic agonists.
  • certain substituted azabicyclic derivatives including some of the above compounds, exhibit activity as calcium channel antagonists. They are thus of potential use in the treatment of disorders where calcium channel blockade is indicated, in particular disorders related to an accumulation of calcium in the brain cells of mammals.
  • the present invention therefore provides, in a -first aspect, the use of a compound of formula (I):
  • n is 0 to 6, and m is 0 to 6, such that the length of the chain -(CH2) n A(CH2) m is at least two atoms;
  • Ar is aryl or heteroaryl, each of which may be optionally substituted
  • the H atom is shown on the bridgehead carbon atom to make clear that the (CH2) n A(CH2) m Ar chain cannot be attached at this position.
  • the compounds of formula (I) have been found to exhibit high calcium influx blocking activity for example in neurons.
  • the compounds are expected to be of use in therapy, particularly in treating conditions and diseases related to (e.g. caused or exacerbated by) an accumulation of calcium in the brain cells of mammals, in particular humans.
  • the compounds are expected to be of use in the treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AEDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age- related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal.
  • the present invention provides a method of treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age- related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal, which comprises administering to a subject in need thereof, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • p and r are preferably independently 2 or 3; most preferably both are 2.
  • q is preferably 1 or 2.
  • n and m should be chosen such that the length of the chain (CH2) n A(CH2) m is at least 2 atoms. In general the length of the chain -(CH2) n A(CH2) m is from 2 to 6 e.g. 2 to 5 atoms. Preferred values for n and m depend on the group A. Thus for example when A is oxygen the sum of n+m is preferably from 1 to 5, for example n may be 1, 2, 3 or 4 and m may be 0 or 1.
  • n+m When A is a bond the sum of n+m should be at least 2, e.g. n+m may be 2 or 3.
  • a is CH CH one or both of n and m may be zero, e.g. n may be zero or 1 and m may be zero.
  • suitable groups include, for example, unsaturated monocyclic and unsaturated or partially saturated bicyclic or tricyclic ring systems of up to 15 carbon atoms, such as, for example, phenyl, naphthyl, tetrahydronaphthyl, fluorene, fluorenone, dibenzosuberene and dibenzosuberenone. Preferred are optionally substituted phenyl rings.
  • An aryl group may be substituted, for example, by a C ⁇ _2alkylenedioxy group (e.g.
  • Suitable optionally substituted phenylC ⁇ _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, phenylC ⁇ alkyl and phenylC ⁇ _4alkoxy groups include for example halogen, Cj ⁇ alkyl, Cj ⁇ alkoxy, nitro and trifluoromethyl groups.
  • the aryl group is a phenyl ring substituted by one or two substituents, in particular, by a phenyl; phenyl(C ⁇ _4)alkyl, e.g. benzyl or phenethyl; phenoxy; or phenylC ⁇ _4alkoxy group; which groups may themselves be optionally substitued by halo, e.g. chloro.
  • suitable groups include, for example, unsaturated or partially saturated bicyclic and tricyclic ring systems containing at least one heteroatom.
  • a bicyclic ring system preferably contains 8 to 10 ring members, such as quinolinyl, tetrahydroquinolinyl or benzofuranyl.
  • a tricyclic ring system preferably contains from 11 to 15 ring members, and most preferably has the structure :
  • Y 1 represents Y(C ._2) t
  • Y is O, S or NR ⁇ (where R ⁇ is hydrogen or Ci ⁇ alkyl)
  • s is 0, 1 or 2
  • t 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, Cj.4alkyl, C ⁇ _4alkoxy, phenyl, phenylCj ⁇ alkyl and phenylC ⁇ _4alkoxy.
  • Alkyl groups present in the compounds of formula (I), alone or as part of another group, can be straight or branched.
  • a Cj ⁇ alkyl group may be for example methyl, ethyl, n-propyl, n-butyl or any branched isomer thereof such as isopropyl or t-butyl.
  • a salt of a compound (I) should be pharmaceutically acceptable.
  • pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, methanesulphonate or similar pharmaceutically acceptable inorganic or organic acid addition salts.
  • Other non- pharmaceutically acceptable salts may be used for example in the isolation of a final product and are included within the scope of this invention.
  • the invention also provides novel compounds of formula (IA) :
  • n is 0 to 6
  • m is 0 to 6, and either
  • A is -C ⁇ C- or NRl, where R* is hydrogen, C j .galkyl or phenylCj_4alkyl; in which case Ar represents the group Ar as hereinbefore defined;
  • Ar ⁇ represents a group Ar 2 which is phenyl substituted by a C ⁇ _2alkylenedioxy group or by 1 to 3 substituents selected from SC ⁇ _4alkyl, OCF3, Q ⁇ optionally substituted phenoxy, optionally substituted phenylC ⁇ _4alkyl and optionally substituted phenylC ⁇ _4alkoxy; or Ar 2 is
  • Suitable substituents for said optionally substituted phenoxy, phenylC ⁇ alkyl and phenylC ⁇ _4alkoxy groups are as hereinbefore defined.
  • Bicyclic and tricyclic aryl and heteroaryl groups for Ar* and Ar 2 include those defined hereinbefore for the group Ar.
  • p and r are preferably 2 or 3; q is preferably 1 or 2.
  • a bicyclic aryl group is preferably naphthyl.
  • a bicyclic heteroaryl group is preferably benzofuranyl.
  • a tricyclic heteroaryl group is preferably dibenzofuranyl.
  • a particular group of compounds according to the invention is that represented by formula (IB)
  • R ⁇ represents optionally substituted phenoxy, optionally substituted phenylC ⁇ _4alkyl or optionally substituted phenylC ⁇ _4alkoxy, or R ⁇ represents a fused benzene ring; and salts thereof.
  • A represents oxygen
  • R preferably represents benzyl, benzyloxy or phenoxy, or is a fused benzene ring.
  • Particular compounds of the invention include:
  • the compounds of the present invention can be prepared by processes analogous to those known in the art.
  • the present invention therefore provides in a further aspect, a process for the preparation of a compound of formula (I) which comprises:
  • L(CH2)mAr can take place under conditions which depend on the nature of the group L and the value of m.
  • the reaction is carried out under standard conditions in a solvent, optionally in the presence of a base.
  • a fluoro-substituted aryl compound F-Ar is employed in process (a) (to prepare compounds where m is zero)
  • the reaction is effected in the presence of a strong base such as sodium hydride, and in an inert organic solvent such as dimethylformamide.
  • a strong base such as sodium hydride
  • an inert organic solvent such as dimethylformamide.
  • the aryl group is substituted by an activating group such as CF3 or NO2.
  • the azabicyclic nitrogen atom may be protected during the reaction by methods well known in the art, e.g. by prior formation of a quaternary derivative such as an N-benzyl derivative. Protection may also be effected by formation of a borane (BH3) complex.
  • the N- protecting group should be chosen such that it can be removed without affecting other moieties in the molecule.
  • a benzyl protecting group may not be appropriate when the side chain (CH2) n A(CH2) m Ar also contains a benzyl moiety such as a benzyloxy group.
  • N-protection is preferred when the leaving group L represents halogen, e.g. bromine, but when L is a sulphonic acid residue e.g. a tosylate, N- protection may not be necessary.
  • reaction between a compound of formula (El) and a compound of formula HAl(CH2) m Ar can take place under conditions which depend on the nature of i and A.
  • i hydroxy
  • m 0
  • a ⁇ 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 in which case the compound (HI) may preferably be protected, e.g. as an acid salt, such as a hydrochloride salt
  • Reaction may be effected in the presence or absence of solvent, at a temperature in the range 0 to 200°C and may preferably be carried out in the presence of a base.
  • 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 ON) itself.
  • reaction between a compound of formula (N) in process (d) and a compound of formula X ⁇ Ar can take place under standard conditions known to those skilled in the art for the formation of carbon-carbon bonds.
  • Process (e) may be effected using a Wadsworth-Emmons reagent of the formula Ar(CH2) m +iP(O)(OAlk)2, such as a diethylphosphonate, or a Wittig reagent of the formula Ar(CH2) + ⁇ PPh3X (where X is an anion) which compounds are available commercially or can be prepared by known methods.
  • the reaction may be carried out in a solvent such as tetrahydrofuran optionally containing a crown ether such as 15-crown-5, or 18-crown-6, and in the presence of a strong base such as sodium hydride or potassium t-butoxide.
  • Interconversion reactions according to process (f) may be effected by methods well known in the art.
  • Esters wherein n is greater than 1 may be prepared by conversion of an ester wherein n is 1 to the corresponding N-methyl-N-methoxycarboxamide (e.g. by hydrolysis of the ester followed by reaction with thionyl chloride and N, O-dimethylhydroxylamine hydrochloride), which is then reduced to the aldehyde using diisobutylaluminium hydride.
  • the aldehyde is further converted to the cyanomethyl derivative for example as described in EPA 363,085, followed by acid hydrolysis, and esterification to form an ester wherein n is 2.
  • the sequence may be repeated to form higher homologues.
  • Homologation may also be effected by the method described in British Patent No. 1250534, starting with a compound ( ⁇ ) wherein A is O and n is 1 and proceeding via the corresponding halomethyl and cyanomethyl derivatives to an ester of formula (VII) wherein n is 2 which may be reduced to an alcohol (II) wherein n is 2.
  • a further method for the preparation of a compound of formula (II) wherein p, q, r and n each represent 2, A* is oxygen and the group (CH2) n AlH is ⁇ to the ring nitrogen atom involves cyclisation of a 4-piperidyl-but-2-enoic acid ester e.g. a methyl ester.
  • the cyclisation is an intramolecular Michael reaction which may be carried out at elevated temperature in an inert solvent such as refluxing toluene.
  • Methyl 4-piperidyl-but-2-enoate may be obtained from a suitable N-protected precursor such as methyl 4-(4-N-tert- butyloxycarbonylpiperidyl)-but-2-enoate (which may be prepared as described in EP 478363), using e.g. trifluoroacetic acid optionally in a solvent such as dichloromethane.
  • Reduction e.g. with lithium aluminium hydride provides the above mentioned compound of formula (II).
  • triethylphosphonoacetate or triethylphosphonocrotonate followed by catalytic hydrogenation to give an ethoxycarbonylalkyl derivative which is further reduced e.g. using lithium aluminium hydride, to the desired hydroxyalkyl compound.
  • ethoxycarbonylalkyl derivative which is further reduced e.g. using lithium aluminium hydride, to the desired hydroxyalkyl compound.
  • Ketones of formula (VHI) are commercially available or can be prepared by literature methods, generally via a Dieckmann cyclisation, (for example as described in EPA 94742).
  • Compounds of formula (II) wherein A is S or NR ⁇ may be prepared from the corresponding hydroxy compound by standard methods, for example via formation of an alkyl halide followed by reaction with an appropriate amine or thiol.
  • Compounds of formula (HI) wherein L* is OH can be prepared as described for compounds of formula (II), and compounds of formula (III) wherein i is a halogen atom, or a mesyloxy or tosyloxy group can be prepared from the corresponding alcohol in conventional manner.
  • the compounds of formula L(CH2) m Ar and HAl(CH2) m Ar may be prepared by standard methods well known in the art.
  • compounds L(CH2) Ar wherein Ar is a substituted phenyl group and L is halo, e.g. bromo may be prepared by Friedel-Crafts acylation of the corresponding substituted benzene derivative, using an appropriate acid chloride and catalysed by aluminium trichloride, followed by reduction in ⁇ ilji with triethylsilane.
  • the starting materials are available commercially or may be prepared by standard methods, e.g. by reaction of 4-benzyloxybenzaldehyde with triethylphosphonocrotonate in a similar manner to that described for the preparation of compounds (II).
  • -(CH2) n N(R 1 )C(O)(CH2) m -lAr can be prepared by reacting a compound of formula (II) wherein A represents NR* with an acylating agent corresponding to the group - (CH2) m Ar, for example an acid chloride ClOC(CH2) m -iAr.
  • -(CH2) n -lC(O)N(Rl)(CH2) m Ar may be prepared for example by reaction of a corresponding compound wherein R ⁇ represents -(CH2) n _iCO2H or an activated derivative thereof such as an acid halide, ester or anhydride, with an amine of formula HN(Rl)(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 (Q) wherein A* is oxygen.
  • Compounds of formula (V) may be prepared in analogous manner to compounds of formula H); where necessary the chain length may be increased using methods well known in the art.
  • Compounds of formula (VI) may be prepared by conventional methods, for example the oxidation of a compound of formula (II) wherein A ⁇ is oxygen, or conversion of the corresponding ester, e.g. by hydrolysis and subsequent reaction with thionyl chloride and N,O-dimethyl-hydroxylamine, followed by reduction of the resulting N-methyl- N-methoxy-carboxamide, using diisobutylaluminium hydride.
  • Compounds of formula (VI) wherein n is 1 may be prepared from the corresponding compound wherein n is zero by various methods.
  • the aldehyde wherein n is zero may be treated with (methoxymethyl) triphenylphosphonium chloride and potassium t-butoxide, followed by a strong acid, e.g. concentrated sulphuric acid, resulting in the aldehyde wherein n is 1.
  • a strong acid e.g. concentrated sulphuric acid
  • the aldehyde may be converted to the corresponding cyanomethyl derivative as described in EPA 363085 followed by acid hydrolysis, conversion to the N-methyl- N-methoxycarboxamide and reduction. These procedures may also be used to form higher homologues.
  • a compound of formula 0 When a compound of formula 0) 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.
  • 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 novel compound of formula 0) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient
  • the compounds for use according to 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 0) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid 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) 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 ca ⁇ ier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • Compounds for use according to the invention may also be administered parenterally, by bolus injection or continuous infusion.
  • Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be 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 cyclodextrins.
  • composition is in unit dose form such as a tablet, capsule or ampoule.
  • Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 60 mg) of a compound of the formula (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 400 mg per day.
  • the total daily dosage by oral administration will be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will be in the range 0.1 to 400 mg.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • the pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 10; MgCL 2 , 4; ATP, 2; buffered to pH 7.2 with CsOH.
  • Cells were bathed in a normal Tyrodes solution before establishment of whole cell recording when the bathing solution was changed to one allowing isolation of Ca 2+ currents.
  • the external solution for recording Ca 2+ channel currents contained in mM: BaCL 2 , 10; TEA-C1, 130; glucose, 10; HEPES, 10; MgCL 2 , 1; buffered to pH 7.3 with TEA-OH. Barium was used as the charge carrier as this assists in current isolation and calcium dependent inactivation of current is avoided.
  • Peak voltage gated Ca 2+ channel currents of up to 10 nA from dorsal root ganglion neurons were recorded using 10 mM Ba 2+ as charge carrier. Currents were evoked from a holding potential of -80 mV to a test potential of 0 or +10 mV every 15 seconds. This test potential was at the peak of the current voltage relationship and assessing block at this point reduced any errors due to drifting holding potential. Some cells showed slow rundown of current as is commonly seen when recording Ca 2+ currents. The rundown rate was measured in control conditions and extrapolated through the time of drug application to derive a control value to relate the drug affected current to. Block by 20 mM drug was assessed 3 minutes after drug application.
  • a tonicity adjusting agent eg. sodium chloride, dextrose or mannitol may also be added.
  • the title compound was prepared in a similar manner to Preparation 1 from (+) 3- (3- ethoxycarbonylpropyl)-l-azabicyclo[2.2.2]octane (1.94g) and lithium aluminium hydride (1.21g, 32 mmol). This afforded the title compound as an oil (l.Og, 68% based on 3- quinuclidinone) which solidified on standing and was used in the next stage without purification.
  • the mixture was concentrated in vacuo and the residue was treated with 2M orthophosphoric acid (30ml), and washed exhaustively with diethyl ether.
  • the aqueous layer was saturated with potassium carbonate and extracted into chloroform (3x30ml).
  • the combined organic extracts were dried over sodium sulphate and concentrated in vacuo.
  • the crude product was purified by flash chromatography on neutral aluminia using 0-2% methanol in chloroform as eluant.
  • the major faster running component was hydrogenated in ethanol (25 ml) over 5% Pd-C (0.2g) at atmospheric pressure for 4h.
  • the catalyst was removed by filtration through kieselguhr, and the filtrate was concentrated in vacuo.
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ )3- hydroxymethyl-l-azabicyclo[2.2.2]octane (2g, 14.2mmol), 4-(benzyloxy)phenol (8.52g, 42.6mmol), triphenylphosphine (4.84g, 18.4mmol) and diethyl azodicarboxylate (3.21g, 18.4mmol). This afforded the title compound as a white solid (3g) m.p.205-207°C (from methanol-diethyl ether).
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ )3- hydroxymethyl-l-azabicyclo[2.2.2]octane (0.5g, 3.55mmol), , 4-hydroxydiphenylmethane (0.98g, 5.32mmol), triphenylphosphine (1.21g, 4.61mmol) and diethyl azodicarboxylate (0.80g, 4.61mmol). This afforded die title compound as a white solid (0.46g) m.p. 169- 171°C (methanol-diethyl ether).
  • the title compound (E4) was prepared in a similar manner to Example 1 from ( ⁇ )3- hydroxymethyl-l-azabicyclo[2.2.2]octane (0.5g, 3.55mmol), 2-phenylphenol (0.905g, 5.32mmol), triphenylphosphine (1.21g, 4.61mmol) and diethyl azodicarboxylate (0.80g, 4.61mmol). This afforded the title compound as a white solid (0.49g) m.p. 184-187°C (from methanol-diethyl ether).
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ )3- hydroxymethyl-l-azabicyclo[2.2.2]octane (0.5g, 3.55mmol), 4-tert-butylphenol (0.80g, 5.32mmol), triphenylphosphine (1.21g, 4.61mmol) and diethyl azodicarboxylate (0.80g, 4.61mmol). This afforded the title compound (E5) as a white solid (0.35g) m.p. 276- 279°C (from methanol-diethyl ether).
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ )3- hydroxymethyl-l-azabicyclo[2.2.2]octane (0.5g, 3.55mmol), 2-hydroxy-dibenzofuran (0.98g, 5.32mmol), triphenylphosphine (1.21g, 4.61mmol) and dietiiyl azodicarboxylate (0.81g, 4.61mmol).
  • the crude product was purified on neutral alumina in a gradient of 0- 2% methanol in toluene.
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ )3- hydroxymethyl-l-azabicyclo[2.2.2]octane (0.5g, 3.55mmol), 5-hydroxyisoquinoline (0.72g, 5.32mmol), triphenylphosphine (1.21g, 4.61mmol) and dietiiyl azodicarboxylate (0.8g, 4.61mmol). This afforded the title compound as a white solid (0.19g) m.p. 277-280°C (from methanol-diethyl ether).
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ )endo-3- hydroxymethyl-l-azabicyclo[2.2.1]heptane (0.5g, 3.94mmol), 4-hydroxydiphenylmethane (1.09g, 5.91mmol), triphenylphosphine (1.34g, 5.12mmol) and diethyl azodicarboxylate (0.89g, 5.12mmol). This afforded the title compound as a white solid (0.77g) m.p. 153-156°C (from methanol-acetone-diediyl ether).
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ )endo-3- hydroxymethyl-l-azabicyclo[2.2.1]heptane (0.5g, 3.94mmol), 4-benzyloxyphenol (1.18g, 5.91mmol), triphenylphosphine (1.34g, 5.12mmol) and diethyl azodicarboxylate (0.89g, 5.12mmol). This afforded the title compound as a white solid (0.3 lg) m.p. 156-158°C (from methanol-acetone-diethyl ether).
  • the tide compound was prepared in a similar manner to Example 1 from ( ⁇ )exo- and endo-3-hydroxymethyl-l-azabicyclo[2.2.1]heptane (0.5g, 3.94mmol),
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ )exo- and endo-3-hydroxymethyl-l-azabicyclo[2.2.1]heptane (0.5g, 3.94mmol), 4-benzyloxyphenol (1.18g, 5.91mmol), triphenylphosphine (1.34g, 5.12mmol) and dietiiyl azodicarboxylate (0.89g, 5.12mmol).
  • the crude product was chromatographed on silica in a gradient of 5- 20% methanol in chloroform. Pooling of pure fractions containing the major faster running component gave a gum which was converted into the hydrochloride salt to afford the title compound as a white solid (0.29g) m.p. 156-158°C (from methanol-acetone- diediyl ether).
  • the tide compound was prepared in a similar manner to Example 13 from 1- azabicyclo[2.2.2]oct-3-yl-carboxaldehyde (0.78g, 5.61mmol), dietiiyl 4-biphenylmethyl- phosphonate (1.70g, 5.61mmol), sodium hydride (0.17g of an 80% dispersion in mineral oil, 5.61mmol) and 15-crown-5 (60mg). This afforded the title compound as a white solid (1.3g) m.p. 289-290°C (from methanol-diethyl ether).
  • the tide compound was prepared in a similar manner to Example 15 from ( ⁇ )E-3-[2-(4- Biphenyl)ethenyl]-l-azabicyclo[2.2.2]octane hydrochloride (E14) (0.65g, 2mmol) and 10%Pd-C (65mg). This afforded the title compound as a white solid (0.14g) m.p. 236- 238 C (from methanol-acetone-dietiiyl ether).
  • the title compound was prepared in a similar manner to Example 13 from ( ⁇ )3- formylmethyl-l-azabicyclo[2.2.2]octane (0.41g, 2.68mmol), diethyl 1-naphthylmethyl- phosphonate (0.75g, 2.68mmol), sodium hydride (80mg of an 80% dispersion in mineral oil, 2.68mmol) and 15-crown-5 (30mg). This afforded the title compound as a white solid (0.47g) m.p. 174-177°C (from methanol-acetone-diethyl ether).
  • the tide compound was prepared in a similar manner to Example 1 from ( ⁇ )3-(2- hydroxyethyl)-l-azabicyclo[2.2.2]octane (0.5g, 3.23mmol), 2-hydroxydibenzofuran
  • the tide compound was prepared in a similar manner to Example 1 from ( ⁇ )3-(2- hydroxyethyl)-l-azabicyclo[2.2.2]octane (0.5g, 3.23mmol), 4-benzyloxyphenol (lg, 4.84mmol), triphenylphosphine (l.Olg, 4.19mmol) and dietiiyl azodicarboxylate (0.73g, 4.19mmol). This afforded the title compound as a white solid (0.5g) m.p.215-216°C (from methanol-acetone-diethyl ether).
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ )3-(2- hydroxyethyl)-l-azabicyclo[2.2.2]octane (0.5g, 3.23mmol), 4-hydroxydiphenylmethane (0.89g, 4.84mmol), triphenylphosphine (l.Olg, 4.19mmol), and dietiiyl azodicarboxylate (0.73g, 4.19mmol). This afforded the title compound as a white solid (0.69g) m.p 186- 188 C (from methanol-acetone-diethyl ether).
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ )3- hydroxymethyl-l-azabicyclo[2.2.2]octane (0.5g, 3.55mmol), 4-phenoxyphenol (0.99g, 5.32mmol), triphenylphosphine (1.21g, 4.61mmol) and diethyl azodicarboxylate (0.80g, 4.61mmol). This afforded the title compound as a white solid (0.59g) m.p 176-178°C (methanol-acetone-diediyl ether.
  • the title compound was prepared in a similar manner to Example 1 from (+) 3-(2- hydroxyethyl)-l-azabicyclo[2.2.2]octane (0.5g, 3.22mmol), 4-phenoxyphenol (0.90g, 4.84 mmol), triphenylphosphine (l.Og, 4.19 mmol) and diethyl azodicarboxylate 0.66 ml, 4.19 mmol). After stirring at room temperature for 2h, the reaction was concentrated in vacuo. The residue was extracted into diethyl etiier, and treated with ethereal hydrogen chloride.
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ ) 3-(4- hydroxybutyl)-l-azabicyclo[2.2.2]octane (0.5g, 2.73 mmol), 2-hydroxydibenzofuran (0.75g, 4.09 mmol), triphenylphosphine (0.93g, 3.55 mmol) and diethyl azodicarboxylate (0.56 ml, 3.55 mmol). After stirring at room temperature for lh the reaction was concentrated in vacuo. The crude product was converted into the hydrochloride salt, washed with diethyl ether, then partitioned betwen saturated aqueous potassium carbonate (25 ml) and chloroform (25 ml).
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ )3-(3- hydroxypropyl)-l-azabicyclo[2.2.2]octane (0.45g, 2.66 mmol), 4-phenoxyphenol (0.74g, 3.98 mmol), triphenylphosphine (0.91g, 3.47 mmol) and diethyl azodicarboxylate (0.55 ml, 3.47 mmol). After stirring at room temperature for lh the reaction was worked up as described in Example 24.
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ ) 3-(2- hydroxyethyl)-l-azabicyclo[2.2.2]octane (0.5g, 3.23 mmol), trans 4-hydroxystilbene (0.95g, 4.84 mmol), triphenylphosphine (l.lg, 4.19 mmol) and diethyl azodicarboxylate (0.66 ml, 4.19 mmol). After stirring at room temperature for 1.5h the reaction was concentrated in vacuo. The residue was extracted into diethyl ether and treated with ethereal hydrogen chloride to give the hydrochloride salt which was washed with diethyl ether.
  • the title compound was prepared in a similar manner to Example 1 from (+) 3-(2- hydroxyethylH-azabicyclo [2.2.2]octane (0.5g, 3.22 mmol), 4-[2-(4- chl ⁇ rophenyl)ethyl]phenol (1.13g, 4.86 mmol), triphenylphosphine (1.10g, 4.20 mmol) and diethyl azodicarboxylate (0.66 ml, 4.20 mmol). The reaction was worked up as described in Example 24.
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ ) 2-(2- hydroxyethyl)-l-azabicyclo[2.2.2]octane (23mg, 0.15 mmol), 4-hydroxydiphenylmethane (41mg, 0.22 mmol), triphenylphosphine (59 mg, 0.22 mmol) and diethyl azodicarboxylate (39 mg, 0.22 mmol). After stirring at room temperature for 6h the reaction mixture was concentrated in vacuo. The residue was partitioned between water (5 ml) and chloroform (5ml) and the pH of the aqueous phase was adjusted to 12 with potassium carbonate.
  • the tide compound was prepared in a similar manner to Example 30 from ( ⁇ ) 2-(2- hydroxyethyl)-l-azabicyclo[2.2.2]octane (0.5g, 3.22mmol), 4-benzyloxyphenol (0.97g, 4.84mmol), triphenylphosphine (1.27g, 4.84mmol) and diethyl azodicarboxylate (0.76ml, 4.84mmol). This afforded the tide compound as a colourless solid (0.69g) m.p.238- 240°C (from acetone-diethyl ether).
  • the title compound was prepared in a similar manner to Example 1 from ( ⁇ ) 4-(2- hydroxyethyl)-l-azabicyclo[3.3.1]nonane (O.llg, 0.65 mmol), 4-phenoxyphenol (0.18g, 0.98 mmol), triphenylphosphine (0.22g, 0.85 mmol) and diethyl azodicarboxylate (0.13 ml, 0.85 mmol). After stirring at room temperature for 2h the reaction was worked up as described in Example 1 to give the title compound as a colourless solid m.p. 195-197°C (methanol-diethyl ether).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Vascular Medicine (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Composés répondant à la formule (I), dans laquelle p, q et r, indépendamment les uns des autres, représentent un nombre entier compris entre 1 et 4; A représente une liaison, -CH=CH-, (a), oxygène, soufre, ou NR?1, où R1¿ représente hydrogène, alkyle C¿1-8? ou phénylalkyle C1-4; n est compris entre 0 et 6 et m est compris entre 0 et 6, de telle sorte que la longueur de la chaîne -(CH2)nA(CH2)m soit d'au moins deux atomes; et Ar représente aryle ou hétéroaryle dont chacun est éventuellement substitué; et leurs sels pharmaceutiquement acceptables; destinés à la fabrication d'un médicament de traitement des troubles dans lesquels l'emploi d'un antagoniste des canaux calciques est indiqué. On décrit également les nouveaux composés répondant à la formule (I), leurs procédés de préparation et des compositions pharmaceutiques les contenant.
PCT/GB1993/000175 1992-01-28 1993-01-27 Composes azabicycliques servant d'antagonistes des canaux calciques WO1993015073A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5513049A JPH07503463A (ja) 1992-01-28 1993-01-27 カルシウムチャンネル拮抗薬としてのアザビシクロ化合物
EP93902471A EP0625979A1 (fr) 1992-01-28 1993-01-27 Composes azabicycliques servant d'antagonistes des canaux calciques

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929201749A GB9201749D0 (en) 1992-01-28 1992-01-28 Medicaments
GB9201749.0 1992-01-28

Publications (1)

Publication Number Publication Date
WO1993015073A1 true WO1993015073A1 (fr) 1993-08-05

Family

ID=10709348

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/000175 WO1993015073A1 (fr) 1992-01-28 1993-01-27 Composes azabicycliques servant d'antagonistes des canaux calciques

Country Status (7)

Country Link
EP (1) EP0625979A1 (fr)
JP (1) JPH07503463A (fr)
AU (1) AU3364693A (fr)
GB (1) GB9201749D0 (fr)
MX (1) MX9300407A (fr)
WO (1) WO1993015073A1 (fr)
ZA (1) ZA93550B (fr)

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0600717A1 (fr) * 1992-11-30 1994-06-08 Sankyo Company Limited Phénoxyalkylamines, -pyrrolidines et pipéridines pour le traitement et la prevention de maladies de la circulation et de la psychose
WO1994025459A1 (fr) * 1993-04-29 1994-11-10 Zeneca Limited Derives heterocycliques
WO1995003302A1 (fr) * 1993-07-20 1995-02-02 Smithkline Beecham Plc Quinolizidines a activite antagoniste des canaux a calcium
WO1996026938A1 (fr) * 1995-03-02 1996-09-06 Yamanouchi Pharmaceutical Co., Ltd. Nouveaux derives de quinuclidine presentant un noyau hetero tricyclique annele
US5554613A (en) * 1992-06-04 1996-09-10 Zeneca Limited Heterocyclic derivatives
US5612352A (en) * 1992-04-10 1997-03-18 Zeneca Limited Heterocyclic compounds
US5637596A (en) * 1994-05-24 1997-06-10 Pharmacia S.P.A. Azabicycloalkyl derivatives of imidazo[1,5-a]indol-3-one and process for their preparation
US5654315A (en) * 1991-12-23 1997-08-05 Imperial Chemical Industries Plc Quinuclidine compounds useful in treating diseases
US5691349A (en) * 1992-08-06 1997-11-25 Zeneca Limited Quinclidine derivatives as squalene synthase inhibitors
US5714496A (en) * 1992-08-28 1998-02-03 Zeneca Limited Quinuclidine derivatives as squalene synthase inhibitors
US5731323A (en) * 1992-12-21 1998-03-24 Zeneca Limited Quinuclidine derivatives as squalene synthase inhibitors
US5792777A (en) * 1991-10-30 1998-08-11 Zeneca Limited Biphenyl quinuclidines
WO1999015185A1 (fr) * 1997-09-22 1999-04-01 Lisovenko, Vasily Trofimovich Agent permettant de modifier la proliferation, l'activite fonctionnelle et la mort de cellules normales et cancereuses
US6166052A (en) * 1998-03-11 2000-12-26 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US6251919B1 (en) 1998-02-27 2001-06-26 Warner-Lambert Heterocyclic substituted aniline calcium channel blockers
WO2005016923A1 (fr) * 2003-08-13 2005-02-24 Neurosearch A/S Nouveaux derives de quinuclidine et leur utilisation pharmaceutique
WO2005077899A3 (fr) * 2004-02-04 2005-12-01 Abbott Lab Derives tricycliques a substitution amino et leurs procedes d'utilisation
US7094789B2 (en) 2002-07-22 2006-08-22 Asahi Kasei Pharma Corporation 5-substituted isoquinoline derivatives
US7365193B2 (en) 2004-02-04 2008-04-29 Abbott Laboratories Amino-substituted tricyclic derivatives and methods of use
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
US7732477B2 (en) 2001-12-27 2010-06-08 Bayer Schering Pharma Aktiengesellschaft 2-heteroarylcarboxylic acid amides
US7795453B2 (en) 2002-07-29 2010-09-14 Bayer Schering Pharma Aktiengesellschaft Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists
US9108961B2 (en) 2010-05-17 2015-08-18 Forum Pharmaceuticals, Inc. Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride
US9585877B2 (en) 2012-05-08 2017-03-07 Forum Pharmaceuticals, Inc. Methods of maintaining, treating or improving cognitive function
JPWO2015182724A1 (ja) * 2014-05-28 2017-04-20 トーアエイヨー株式会社 置換トロパン誘導体
US9657010B2 (en) 2004-07-14 2017-05-23 Novartis Ag Substituted quinuclidines as alpha 7-nicotinic acetylcholine receptor activity modulators

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1905771A3 (fr) * 2002-08-14 2008-11-26 NeuroSearch A/S Dérivés quinuclidiniques et leur utilisation

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0327155A2 (fr) * 1988-01-30 1989-08-09 Merck Sharp & Dohme Ltd. Pyrazines, pyrimidines et pyridazines utiles dans le traitement de dementia senilis
EP0412797A2 (fr) * 1989-08-08 1991-02-13 MERCK SHARP & DOHME LTD. L'application thérapeutique de benzènes substitués, formulations les contenant et benzènes substitués
EP0416754A2 (fr) * 1989-08-08 1991-03-13 MERCK SHARP & DOHME LTD. Pyrazine substituée,formulations la contenant st son application médicinale
WO1991014686A1 (fr) * 1990-03-21 1991-10-03 Novo Nordisk A/S Composes azacycliques ou azabicyclyques, leur preparation et leur utilisation
EP0470668A1 (fr) * 1990-08-08 1992-02-12 MERCK SHARP & DOHME LTD. Procédé pour préparer des énantiomères de composés à activité de muscarine
EP0473442A1 (fr) * 1990-08-30 1992-03-04 MERCK SHARP & DOHME LTD. Une pyrazine substituée et ses sels, compositions les contenant et leur utilisation médicinale
EP0492904A1 (fr) * 1990-12-21 1992-07-01 MERCK SHARP & DOHME LTD. Dérivés de benzènes substitués utiles dans le traitement de glaucome
EP0492903A1 (fr) * 1990-12-21 1992-07-01 MERCK SHARP & DOHME LTD. Pyrazines, pyrimidines et pyridazines substitués utiles dans le traitement de glaucome
EP0492902A1 (fr) * 1990-12-21 1992-07-01 MERCK SHARP & DOHME LTD. Pyridines substitués utiles dans le traitement de glaucome
EP0497415A1 (fr) * 1991-02-01 1992-08-05 Akzo Nobel N.V. Dérivés de 3-quinuclidine
WO1992015579A1 (fr) * 1991-03-08 1992-09-17 Rhone-Poulenc Rorer International (Holdings) Inc. Composes polyaromatiques et multicycliques a base d'amines tertiaires, ayant une fonction inhibitrice de la squalenesynthetase

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0327155A2 (fr) * 1988-01-30 1989-08-09 Merck Sharp & Dohme Ltd. Pyrazines, pyrimidines et pyridazines utiles dans le traitement de dementia senilis
EP0412797A2 (fr) * 1989-08-08 1991-02-13 MERCK SHARP & DOHME LTD. L'application thérapeutique de benzènes substitués, formulations les contenant et benzènes substitués
EP0416754A2 (fr) * 1989-08-08 1991-03-13 MERCK SHARP & DOHME LTD. Pyrazine substituée,formulations la contenant st son application médicinale
WO1991014686A1 (fr) * 1990-03-21 1991-10-03 Novo Nordisk A/S Composes azacycliques ou azabicyclyques, leur preparation et leur utilisation
EP0470668A1 (fr) * 1990-08-08 1992-02-12 MERCK SHARP & DOHME LTD. Procédé pour préparer des énantiomères de composés à activité de muscarine
EP0473442A1 (fr) * 1990-08-30 1992-03-04 MERCK SHARP & DOHME LTD. Une pyrazine substituée et ses sels, compositions les contenant et leur utilisation médicinale
EP0492904A1 (fr) * 1990-12-21 1992-07-01 MERCK SHARP & DOHME LTD. Dérivés de benzènes substitués utiles dans le traitement de glaucome
EP0492903A1 (fr) * 1990-12-21 1992-07-01 MERCK SHARP & DOHME LTD. Pyrazines, pyrimidines et pyridazines substitués utiles dans le traitement de glaucome
EP0492902A1 (fr) * 1990-12-21 1992-07-01 MERCK SHARP & DOHME LTD. Pyridines substitués utiles dans le traitement de glaucome
EP0497415A1 (fr) * 1991-02-01 1992-08-05 Akzo Nobel N.V. Dérivés de 3-quinuclidine
WO1992015579A1 (fr) * 1991-03-08 1992-09-17 Rhone-Poulenc Rorer International (Holdings) Inc. Composes polyaromatiques et multicycliques a base d'amines tertiaires, ayant une fonction inhibitrice de la squalenesynthetase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 115, 1991, Columbus, Ohio, US; abstract no. 149760y, V.E. DEGTYAR ET AL. 'Common characteristics of calcium-channel and muscarinic-cholinergic receptor inhibitors.' page 18 ; *

Cited By (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5792777A (en) * 1991-10-30 1998-08-11 Zeneca Limited Biphenyl quinuclidines
US5770608A (en) * 1991-12-23 1998-06-23 Imperial Chemical Industries Plc Heterocyclic derivatives
US5654315A (en) * 1991-12-23 1997-08-05 Imperial Chemical Industries Plc Quinuclidine compounds useful in treating diseases
US5612352A (en) * 1992-04-10 1997-03-18 Zeneca Limited Heterocyclic compounds
US5554613A (en) * 1992-06-04 1996-09-10 Zeneca Limited Heterocyclic derivatives
US5691349A (en) * 1992-08-06 1997-11-25 Zeneca Limited Quinclidine derivatives as squalene synthase inhibitors
US5714496A (en) * 1992-08-28 1998-02-03 Zeneca Limited Quinuclidine derivatives as squalene synthase inhibitors
US5556864A (en) * 1992-11-30 1996-09-17 Sankyo Company, Limited α-ω-diarylalkane compounds serotonin-2 receptor agonists
EP0600717A1 (fr) * 1992-11-30 1994-06-08 Sankyo Company Limited Phénoxyalkylamines, -pyrrolidines et pipéridines pour le traitement et la prevention de maladies de la circulation et de la psychose
US5731323A (en) * 1992-12-21 1998-03-24 Zeneca Limited Quinuclidine derivatives as squalene synthase inhibitors
WO1994025459A1 (fr) * 1993-04-29 1994-11-10 Zeneca Limited Derives heterocycliques
US5919793A (en) * 1993-04-29 1999-07-06 Zeneca Limited Heterocyclic derivatives
WO1995003302A1 (fr) * 1993-07-20 1995-02-02 Smithkline Beecham Plc Quinolizidines a activite antagoniste des canaux a calcium
US5637596A (en) * 1994-05-24 1997-06-10 Pharmacia S.P.A. Azabicycloalkyl derivatives of imidazo[1,5-a]indol-3-one and process for their preparation
WO1996026938A1 (fr) * 1995-03-02 1996-09-06 Yamanouchi Pharmaceutical Co., Ltd. Nouveaux derives de quinuclidine presentant un noyau hetero tricyclique annele
US5830902A (en) * 1995-03-02 1998-11-03 Yamanouchi Pharmaceutical Co., Ltd. Quinuclidine derivative having tricyclic hetero condensed ring
WO1999015185A1 (fr) * 1997-09-22 1999-04-01 Lisovenko, Vasily Trofimovich Agent permettant de modifier la proliferation, l'activite fonctionnelle et la mort de cellules normales et cancereuses
US6251919B1 (en) 1998-02-27 2001-06-26 Warner-Lambert Heterocyclic substituted aniline calcium channel blockers
US6989448B2 (en) 1998-03-11 2006-01-24 Lain-Yen Hu Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US6469038B1 (en) 1998-03-11 2002-10-22 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US6166052A (en) * 1998-03-11 2000-12-26 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US8884017B2 (en) 2001-12-27 2014-11-11 Bayer Intellectual Property Gmbh 2-heteroarylcarboxylic acid amides
US8076355B2 (en) 2001-12-27 2011-12-13 Bayer Schering Pharma Aktiengesellschaft 2-heteroarylcarboxylic acid amides
US7732477B2 (en) 2001-12-27 2010-06-08 Bayer Schering Pharma Aktiengesellschaft 2-heteroarylcarboxylic acid amides
US7094789B2 (en) 2002-07-22 2006-08-22 Asahi Kasei Pharma Corporation 5-substituted isoquinoline derivatives
US9714242B2 (en) 2002-07-29 2017-07-25 Bayer Intellectual Property Gmbh Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists
US7795453B2 (en) 2002-07-29 2010-09-14 Bayer Schering Pharma Aktiengesellschaft Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists
US8153799B2 (en) 2002-07-29 2012-04-10 Bayer Schering Pharma Aktiengesellschaft Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists
US8772511B2 (en) 2002-07-29 2014-07-08 Bayer Intellectual Property Gmbh Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists
US10196388B2 (en) 2002-07-29 2019-02-05 Bayer Intellectual Property Gmbh Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists
US7750022B2 (en) 2003-08-13 2010-07-06 Neurosearch A/S Quinuclidine derivatives and their pharmaceutical use
WO2005016923A1 (fr) * 2003-08-13 2005-02-24 Neurosearch A/S Nouveaux derives de quinuclidine et leur utilisation pharmaceutique
US7365193B2 (en) 2004-02-04 2008-04-29 Abbott Laboratories Amino-substituted tricyclic derivatives and methods of use
EP2258682A3 (fr) * 2004-02-04 2011-03-09 Abbott Laboratories Dérivés tricycliques aminosubstitués et méthodes d'utilisation
US7951791B2 (en) 2004-02-04 2011-05-31 Abbott Laboratories Amino-substituted tricyclic derivatives and methods of use
WO2005077899A3 (fr) * 2004-02-04 2005-12-01 Abbott Lab Derives tricycliques a substitution amino et leurs procedes d'utilisation
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
US9657010B2 (en) 2004-07-14 2017-05-23 Novartis Ag Substituted quinuclidines as alpha 7-nicotinic acetylcholine receptor activity modulators
US9550767B2 (en) 2010-05-17 2017-01-24 Forum Pharmaceuticals, Inc. Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate
US9273044B2 (en) 2010-05-17 2016-03-01 Forum Pharmaceuticals, Inc. Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate
US9108961B2 (en) 2010-05-17 2015-08-18 Forum Pharmaceuticals, Inc. Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride
US9585877B2 (en) 2012-05-08 2017-03-07 Forum Pharmaceuticals, Inc. Methods of maintaining, treating or improving cognitive function
JPWO2015182724A1 (ja) * 2014-05-28 2017-04-20 トーアエイヨー株式会社 置換トロパン誘導体
US9856250B2 (en) 2014-05-28 2018-01-02 Toa Eiyo Ltd. Substituted tropane derivatives

Also Published As

Publication number Publication date
JPH07503463A (ja) 1995-04-13
ZA93550B (en) 1994-07-26
EP0625979A1 (fr) 1994-11-30
AU3364693A (en) 1993-09-01
MX9300407A (es) 1994-07-29
GB9201749D0 (en) 1992-03-11

Similar Documents

Publication Publication Date Title
WO1993015073A1 (fr) Composes azabicycliques servant d'antagonistes des canaux calciques
CA2003422C (fr) Quinuclidines, leur utilisation comme medicaments et procede de preparation
US7410964B2 (en) Cyclohexyl sulphones as gamma-secretase inhibitors
KR0185378B1 (ko) 신규 아자비시클릭 화합물, 그의 용도 및 제조방법
JPH0578354A (ja) アザ二環式化合物、これを含有する医薬組成物及び治療のための使用方法
JP2005512974A (ja) キヌクリジン誘導体、その調製方法、及びｍ２及び／又はｍ３ムスカリン受容体阻害剤としてのその使用
US4870081A (en) Aza-bicyclic compounds
EP0629190A1 (fr) Composes utilises comme antagonistes des canaux calciques
US4879300A (en) Novel piperidine derivatives
AU649468B2 (en) 3-substituted piperidine derivatives
PT94259A (pt) Processo para a preparacao de compostos azabiciclicos
US5817698A (en) Substituted cycloalkylamine derivatives and their use as calcium channel antagonists
US5278170A (en) Azabicylo oxime compounds
EP0711271B1 (fr) Aminoindanes et composes apparentes utiles comme antagonistes des canaux a calcium
WO1992022527A2 (fr) Derives de pyrrolidine 3-substitues comme antagonistes du calcium
WO1995003302A1 (fr) Quinolizidines a activite antagoniste des canaux a calcium
WO1993015080A1 (fr) Composes azabicyclo servant d'antagonistes des canaux calciques
NZ232334A (en) Aryl-substituted pyrrolidine derivatives and pharmaceutical compositions
HU187480B (en) Process for producing 1-bracket-4-quinolyl-bracket closed-2-bracket-4-piperidyl-bracket closed-ethanol and 1-bracket-4-quinolyl-bracket closed-3-bracket-4-piperidiyl-bracket closed-propanol and pharmaceutival compositions containing them as active agents
JP3541952B2 (ja) ４−アリールイソインドール鎮痛薬
EP0339834A2 (fr) Composés hétérocycliques, procédé pour leur préparation et compositions pharmaceutiques les contenant
US4507306A (en) cis-4a-Aryl-1,2,3,4,4a,9b-hexahydro-benzofuro[3,2-c]pyridines and their anti-convulsant and analgesic activity
US5434159A (en) 6,11-cyclyl-1,2,3,4,5,6,11,11a-octahydrobenzo[b]quinolines and compositions and method of use thereof
US4544745A (en) Cis-4a-aryl, 1, 2, 3, 4, 4A, 9B-hexahydro-benzofuro-[3,2-C]- pyridines useful as analgesics
JP2719063B2 (ja) 置換３−アミノキヌクリジンｐ物質拮抗剤

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BG BR CA CZ FI HU JP KP KR LK MG MN MW NO NZ PL RO RU SD SK US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 1993902471

Country of ref document: EP

ENP Entry into the national phase

Ref country code: US

Ref document number: 1994 256832

Date of ref document: 19940727

Kind code of ref document: A

Format of ref document f/p: F

WWP Wipo information: published in national office

Ref document number: 1993902471

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: CA

WWW Wipo information: withdrawn in national office

Ref document number: 1993902471

Country of ref document: EP