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WO1992022527A2 - Derives de pyrrolidine 3-substitues comme antagonistes du calcium - Google Patents

Derives de pyrrolidine 3-substitues comme antagonistes du calcium Download PDF

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Publication number
WO1992022527A2
WO1992022527A2 PCT/GB1992/001088 GB9201088W WO9222527A2 WO 1992022527 A2 WO1992022527 A2 WO 1992022527A2 GB 9201088 W GB9201088 W GB 9201088W WO 9222527 A2 WO9222527 A2 WO 9222527A2
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WO
WIPO (PCT)
Prior art keywords
compound
phenyl
alkyl
compounds
pentylpyrrolidine
Prior art date
Application number
PCT/GB1992/001088
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English (en)
Other versions
WO1992022527A3 (fr
Inventor
Thomas Henry Brown
David Gwynn Cooper
Ronald Joseph King
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Smithkline Beecham Plc
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Filing date
Publication date
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to JP4511090A priority Critical patent/JPH06508353A/ja
Priority to EP92912277A priority patent/EP0589971A1/fr
Publication of WO1992022527A2 publication Critical patent/WO1992022527A2/fr
Publication of WO1992022527A3 publication Critical patent/WO1992022527A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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

  • Y is inter alia a pyrrolidino group which may be substituted on the nitrogen atom by lower alkyl or phenyllower alkyl.
  • EP 338331 describes as intermediates N-protected
  • R 1 is inter alia optionally substituted phenyl or certain bicyclic aryl or heteroaryl groups, m is 2-4, A is inter alia a group where 0 is 4, 5 or 6, n is 1-4
  • R 2 and R 3 are each phenyl or phenylalkyl.
  • US Patent No. 4933346 discloses compounds of formula
  • R 1 S(CH 2 ) m A(CH 2 ) n CH(R 2 ) (R 3 ), wherein R 1 is inter alia
  • the present invention therefore provides, in a first aspect, the use of a compound of structure (I) :
  • R is C 1-8 alkyl, C 1-8 alkyl (phenyl), C 2-8 alkenyl (phenyl)p,
  • p 0 to 2;
  • n 0 to 6;
  • R 1 is hydrogen, C 1-8 alkyl or phenylC 1-4 alkyl
  • n 0 to 3;
  • Ar is aryl or heteroaryl, each of which may be
  • Compounds of formula (I) have been found to exhibit high calcium influx blocking activity.
  • the compounds are expected to be of use in therapy, particularly in treating conditions and diseases related to an accumulation of calcium in the brain cells of mammals, in particular humans.
  • the compounds are expected to be of use in the treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal.
  • the present invention provides a method of treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal, which
  • alkynylphenyl groups are linked to the pyrrolidine nitrogen atom via the alkyl, alkenyl and alkynyl moieties respectively.
  • R is preferably C 1- 8 alkyl, in particular n-pentyl, or C 2-8 alkenyl (phenyl) p where p is 1 eg. cinnamyl.
  • A is preferably oxygen or sulphur; most preferably A is oxygen.
  • n and m depend on the group A.
  • the length of the chain -(CH 2 ) n A(CH 2 ) m is from 2 to 5 atoms.
  • n is preferably 1 or 2 and m is preferably zero.
  • n is suitably 0 to 3 eg. 1 or 2; m is suitably 0 or 1.
  • Ar represents aryl suitable groups include, for example, unsaturated monocyclic and unsaturated or partially saturated bicyclic ring systems of up to 12 carbon atoms 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 1-2 alkylenedioxy group (eg. phenyl substituted by a 3,4- methylenedioxy group) or by 1 to 3 substituents selected from halogen, C 1-4 alkoxy, nitro, SC 1-4 alkyl, NR 2 R 2a (in which R 2 and R 2a independently represent H or C 1-4 alkyl), OCF 3 ,
  • aryl group is a phenyl ring substituted by one or two substituents, in particular, by a single halogen, trifluoromethyl,
  • Suitable optionally substituted ⁇ henylC 1-4 alkyl groups include, for example benzyl or phenethyl. Suitable
  • optionally substituted phenylC 1-4 alkoxy groups include, for example benzyloxy groups.
  • Suitable optionally substituted phenylC 2-4 alkenyl groups include, for example phenethenyl.
  • Suitable substituents for said optionally substituted phenyl, phenoxy, phenylC 1-4 alkyl, phenylC 2-4 alkenyl, and phenylC 1-4 alkoxy groups include for example halogen, C 1- 4 alkyl, C 1-4 alkoxy, nitro and trifluoromethyl groups.
  • suitable groups include, for example, unsaturated or partially saturated bicyclic ring systems of up to 12 carbon atoms 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 3 (where R 3 is hydrogen or C 1-4 alkyl)
  • tricyclic heteroaryl groups include
  • heteroaryl ring can be linked to the remainder of structure (I) via any suitable ring atom.
  • Suitable substituents for said heteroaryl rings include, for example, 1 to 3 substituents selected from halogen,
  • Alkyl groups present in the compounds of structure (I) alone or as part of another group, can be straight or
  • Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as
  • hydrochloride hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically acceptable inorganic or organic acid addition salts.
  • Other non-pharmaceutically acceptable salts may be used, for example, as intermediates and are included within the scope of this invention.
  • the invention also provides novel compounds of structure (IA) :
  • R a is C 5-8 alkyl, C 5-8 alkyl (phenyl), C 2-8 alkenyl (phenyl)p, C 2-8 alkynyl (phenyl)p, C 3-8 cycloalkyl or C 1-8 alkyl-
  • p 0 to 2;
  • n 0 to 6;
  • R 1 is hydrogen, C 1-8 alkyl or phenylCi ⁇ alkyl
  • n 0 to 3;
  • Ar is aryl or heteroaryl, each of which may be
  • R a is preferably C 5-8 alkyl, in particular n-pentyl or C 2-8 alkenyl (phenyl)p where p is 1, eg. cinnamyl.
  • Preferred values for m, n, A and Ar are as set forth hereinbefore for structure (I).
  • Particular compounds of the invention include:
  • the compounds of structure (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
  • geometric isomers and the invention encompasses all such isomers and mixtures thereof.
  • the compounds of the present invention can be prepared by processes analogous to those known in the art.
  • the present invention therefore provides in a further aspect, a process for the preparation of a compound of structure (I) which comprises :
  • R and n are as described for structure (I) and A 1 is O, S or NR 1 , with a compound of structure L(CH 2 ) m Ar in which and Ar are as described for structure (I), and L is a leaving group;
  • n and R are as described for structure (I) and L 1 is a group displaceable by a nucleophile, with a compound of structure HA 1 (CH 2 ) m Ar where m and Ar are as described for structure (I) and A 1 is as described for structure (II); or
  • R 5 is C 1-7 alkyl(phenyl)p, C 2-7 alkenyl (phenyl)p, C 2-7 alkynyl (phenyl) p or C 1-7 alkylC 3-8 cycloalkyl;
  • reaction between a compound of structure (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
  • the reaction is carried out under standard conditions in a solvent, optional 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 dimethyl formamide.
  • the aryl ring in the compound F-Ar is substituted by an activating group such as CF 3 or NO 2 .
  • the reaction between a compound of structure (III) and a compound of structure HA 1 (CH 2 ) m Ar can take place under conditions which depend on the nature of L 1 and A. For example when L 1 is hydroxy, m is O and A 1 is oxygen or
  • the reaction is carried out in the presence of diethyl azodicarboxylate and triphenyl phosphine.
  • diethyl azodicarboxylate diethyl azodicarboxylate
  • triphenyl phosphine triphenyl phosphine.
  • the leaving group L 1 may be for example a halogen atom or a sulphonyloxy group eg.
  • reaction may be effected in the presence or absence of solvent and at a temperature in the range 0 to 200°C,
  • a compound of structure (IV) can be effected by methods known in the art, for example using a reducing agent such as lithium aluminium hydride.
  • a compound of structure (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 structure (V) and a compound of structure X 1 Ar in process (d) can take place under standard conditions known to those skilled in the art for the formation of carbon-carbon bonds.
  • the reaction of a compound of structure (VI) with RL 2 according to process (e) may be effected in conventional manner, for example in an organic solvent, such as dimethylformamide.
  • the leaving group L 2 may be for example a halide such as bromide or chloride, an acyloxy group such as acetoxy or chloroacetoxy or a sulphonyloxy group such as
  • potassium t-butoxide may be employed.
  • Reduction of a compound of structure (VII) according to process (f) may be effected using standard reducing agents such as lithium aluminium hydride.
  • Process (i) may be effected using a Wadsworth-Emmons reagent of the formula Ar (CH 2 ) m+1 P (O) (OAlk) 2 , such as a diethylphosphonate, or a Wittig reagent of the formula
  • tetrahydrofuran optionally containing a crown ether such as 15-crown-5 or 18-crown-6, and in the presence of a strong bas such as sodium hydride, or potassium t-butoxide.
  • Interconversion reactions according to process (j) may be effected by methods well known in the art.
  • conversion of a compound (I) wherein A represents -CH CH- into a compound (I) wherein A represents-CH 2 -CH 2 - or the
  • R is as described for structure (I) according to the method of Y-H Wu (J.Org. Chem. 1961, 26, 1519-24), followed by reduction eg. with lithium aluminium hydride.
  • cyclisation step is conveniently effected in a solvent such as an alcohol e.g. methanol, and at a temperature in the range of +50 to +150°C, advantageously at reflux temperature of the solvent and the reduction may be effected in a solvent such as ether, conveniently at reflux temperature of the solvent .
  • a solvent such as an alcohol e.g. methanol
  • Compounds of structure (II) wherein A 1 is sulphur or NR 1 can be prepared from the hydroxy compounds of
  • compounds of structure (II) can be prepared from the corresponding compounds in which R is hydrogen, by alkylation under standard conditions.
  • compounds of structure (II) in which R is n-pentyl can be prepared from the corresponding precursor in which R is hydrogen by reaction with an n-pentylhalide such as n-pentyl bromide in a suitable solvent, such as a C 1-4 alkanol (e.g.
  • -(CH 2 ) n N(R 1 )C(O) (CH 2 ) m-1 Ar can be prepared by reacting a compound of structure (II) wherein A 1 represents NR 1 with an acylating agent corresponding to the group -(CH 2 ) m Ar, for example an acid chloride ClOC (CH 2 ) m-1 Ar.
  • -(CH 2 ) n-1 C(O)N(R 1 ) (CH 2 ) m Ar may be prepared for example by reaction of a corresponding compound wherein R 4 represents - (CH 2 ) n-1 CO 2 H or an activated derivative thereof such as an acid halide, ester or anhydride, with an amine of formula HN(R 1 ) (CH 2 ) m Ar. It will be appreciated that when the acid itself is employed, reaction with the amine should be effecte in the presence of a coupling agent.
  • the carboxylic acid may itself be prepared for example by oxidation of the
  • Compounds of structure (V) may be prepared in analogous manner to compounds of structure (III); where necessary the chain length may be increased using methods well known in the art.
  • Compounds of structure (VI) may be prepared for example according to any of processes (a) to (d) above, using
  • Suitable protectin groups include aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl and acyl groups such as acetyl,
  • a compound of structure (VII) may be prepared by
  • reaction of a compound of structure (VI) with an appropriate acid derivative for example an acid chloride, or anhydride.
  • R 4 is a group -(CH 2 ) n-1 C(O)N(R 1 ) (CH 2 ) m Ar
  • R 4 represents -(CH 2 ) n-1 CO 2 H or an activated derivative thereof such as an acid halide, ester or anhydride, with an amine of formula HN(R 1 ) (CH 2 ) m Ar in a similar manner as described for the corresponding compound of structure (IV).
  • Compounds of the structure (IX) can be prepared in similar manner to compounds of the structure (I) except that the appropriate starting material has a 5-oxopyrrolidino ring in place of the pyrrolidino ring.
  • a compound of the structure (IX) can be prepared by reaction of a compound of the structure (XII) :
  • n, R and L 1 are as described for structure (III) with a compound of structure HA 1 (CH 2 ) m Ar where m, A 1 and Ar are as described for structure (II).
  • N-methyl-N-methoxycarboxamide which can be reduced to the aldehyde using diisobutylaluminium hydride.
  • Compounds of structure (X) wherein n is 1 may be prepared from the
  • 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.
  • aldehyde may be converted to the
  • the compounds of the present invention are usually administered in a standard
  • compositions comprising a compound of structure (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.
  • compositions for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a
  • 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 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 carrier (s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • suitable pharmaceutical carrier for example aqueous gums, celluloses, silicates or oils
  • 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.
  • 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.
  • liquid and solid compositions may contain other excipients known in the pharmaceutical art, such as
  • 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 each dosage unit for
  • parenteral administration contains preferably from 0.1 to
  • the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg,
  • 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.
  • Methyl 1-pentyl-5-oxopyrrolidine-3-carboxylate (2.13 g) and 3,4-dichlorobenzylamine (1.76 g) were fused together at 150°C under nitrogen for 1 hr.
  • 3-(4-Fluorophenoxymethyl)-pentylpyrrolidine hydrochloride 3-Hydroxymethyl-1-pentylpyrrolidine (0.853g), 4-fluorophenol (0.56g) and triphenylphosphine (1.31g) were stirred together in dry THF (25ml) under nitrogen. The mixture was cooled in an ice-bath and diethylazodicarboxylate (0.79ml) was injected. The mixture was allowed to stand at room temperature overnight, the THF evaporated off and the residue subjected to flash chromatography on silica gel using ethyl acetate as eluent. The resulting oil was dissolved in ether and extracted with 10% hydrochloric acid.
  • the aqueous phase was basified with 2N.NaOH and extracted with ether.
  • the ether was washed with H 2 O, dried and evaporated to give an oil which was free from tri-phenylphosphine oxide.
  • the solvent was evaporated under vacuum and the residue treated with water.
  • the product was obtained by extraction into ether.
  • the ether phase was extracted with hydrochloric acid.
  • the acid solution was basified with a 50% (W/W) solution of sodium hydroxide in water.
  • the resulting oil was extracted into ether.
  • the ether phase on washing (H 2 O) drying (Na 2 SO 4 ) and evaporating yielded an oil (1.763 g).
  • the product was purified as its hydrochloride by column chromatography on silica using dichloromethane/methanol mixtures.
  • the product was reconverted to its free base and then to its oxalate salt using oxalic acid in THF.
  • Lithium aluminium hydride (0.14 g) was suspended in dry tetrahydrofuran (10 ml). 3-[N-(3,4-Dichlorophenyl)methylamino-carboxy]-5-oxo-1-pentylpyrrolidine (0.50 g) dissolved in dry tetrahydrofuran (30 ml) was added at ice temperature over 15 minutes.
  • the reaction mixture was refluxed for 1 hr and left to stand at room temperature for 16 hrs. Water was carefully added to the reaction mixture until the reaction ceased. The mixture was extracted with ether. The ether phase on washing (H 2 O), drying (Na 2 SO 4 ) and evaporating gave an oil.
  • 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.
  • the external solution for recording Ca 2+ channel currents contained in mM: BaCl 2 , 10; TEA-Cl, 130; glucose, 10; HEPES, 10; MgCl 2 , 1; buffered to pH 7.3 with TEA-OH. Barium was used as the charge carrier as this assists in current isolation and calcium dependent inactivation of current is avoided. Compounds were dissolved in DMSO to make a 20 mM stock solution. At the drug concentration used the vehicle (0.1%) had no significant effect on Ca 2+ currents.
  • Peak voltage gated Ca 2+ channel currents of up to 10 nA from dorsal root ganglion neurons were recorded using 10 mM Ba 2+ as charge carrier. Currents were evoked from a holding potential of -80 mV to a test potential of 0 or +10 mV every 15 seconds. This test potential was at the peak of the current voltage relationship and assessing block at this point reduced any errors due to drifting holding potential. Some cells showed slow rundown of current as is commonly seen when recording Ca 2+ currents. The rundown rate was measured in control conditions and extrapolated through the time of drug application to derive a control value to relate the drug affected current to. Block by 20 ⁇ M drug was assessed 3 minutes after drug application.
  • the compounds of Examples 1 to 16 exhibited percentage inhibition of plateau Ca 2+ current in the range 36 to 99%.

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Abstract

Composés de la structure (I): où R représente alkyle C1-8, alkyl(phényle)C1-8, alcényl(phényle)p C2-8, alcynyl(phényle)p C2-8, cycloalkyle C3-8 ou alkyle C1-8 cycloalkyle C3-8; p vaut de 0 à 2; n vaut de 0 à 6; A représente une liaison, -CH=CH-, -C=C-, oxygène, soufre ou NR1; R1 représente hydrogène, alkyle C¿1-8?, ou phényle alkyle C1-4; m vaut de 0 à 3; et Ar représente aryle ou hétéroaryle, dont chacun peut être éventuellement substitué, et sels pharmaceutiquement acceptables de ces composés, lesquels peuvent être utilisés comme antagonistes du calcium. De nouveaux composés de la structure (I), des procédés de préparation et des compositions pharmaceutiques les contenant sont aussi décrits.
PCT/GB1992/001088 1991-06-17 1992-06-17 Derives de pyrrolidine 3-substitues comme antagonistes du calcium WO1992022527A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP4511090A JPH06508353A (ja) 1991-06-17 1992-06-17 化合物
EP92912277A EP0589971A1 (fr) 1991-06-17 1992-06-17 Composes

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GB9113031.0 1991-06-17
GB919113031A GB9113031D0 (en) 1991-06-17 1991-06-17 Compounds

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WO1992022527A2 true WO1992022527A2 (fr) 1992-12-23
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AU (1) AU1975092A (fr)
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Cited By (14)

* 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
WO1994013291A1 (fr) * 1992-12-15 1994-06-23 Smithkline Beecham Plc Utilisation d'amines cycliques a substitution aryloxyalkyle comme antagonistes des canaux a calcium et nouveaux derives de piperidine phenyloxyalkyle
WO1995003302A1 (fr) * 1993-07-20 1995-02-02 Smithkline Beecham Plc Quinolizidines a activite antagoniste des canaux a calcium
WO1995015948A1 (fr) * 1993-12-09 1995-06-15 Institut De Recherche Jouveinal Nouveaux derives de 2-arylalkenyl-azacycloalkanes ligands aux recepteurs sigma, leur procede de preparation et leur application en therapeutique
WO1995024390A1 (fr) * 1994-03-11 1995-09-14 Smithkline Beecham Plc Nouvelles piperidines substituees par phenyl(-alkyl/alkoxy)-1-aminoalkyle et pyrolidines utilisees comme antagonistes des canaux calciques
WO1995033722A1 (fr) * 1994-06-02 1995-12-14 Smithkline Beecham Plc Piperidines, pyrrolidines, morpholines et tiopmorpholines a substitution phenoxyalcoyle en tant qu'antagonistes des canaux calciques
WO1995033723A1 (fr) * 1994-06-02 1995-12-14 Smithkline Beecham Plc Piperidines, pyrrolidines, morpholines et thiomorpholines a substitution phenoxyalcoyle, en tant qu'antagonistes des canaux a calciques
WO1997010210A1 (fr) * 1995-09-12 1997-03-20 Smithkline Beecham Plc Derives de pyrrolidine tricyclique utilises en tant qu'antagonistes des canaux calciques
US5843983A (en) * 1996-02-15 1998-12-01 Sankyo Company, Limited Diphenylethane compounds containing a saturated heterocyclic group, their preparation, and their therapeutic use
US6166015A (en) * 1998-11-20 2000-12-26 Syntex (U.S.A.) Inc. Pyrrolidine derivatives-CCR-3 receptor antagonists
WO2004105750A1 (fr) * 2003-05-30 2004-12-09 Neuromed Technologies, Inc. 3-aminomethyle-pyrrolidines comme inhibiteurs de canaux calciques de type n
US7012085B2 (en) 2000-01-28 2006-03-14 Novartis Ag 1,3 disubstituted pyrrolidines as α-2-adrenoceptor antagonists
WO2008077089A1 (fr) * 2006-12-19 2008-06-26 Smithkline Beecham Corporation Pyrrolidinanilines
US7816395B2 (en) 2006-08-09 2010-10-19 Glaxosmithkline Llc Pyrrolidinone anilines as progesterone receptor modulators

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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
CN1044365C (zh) * 1992-11-30 1999-07-28 三共株式会社 α,ω－二芳基烷烃衍生物,其制备以及它们在治疗和预防循环疾病和精神病中的应用
US5556864A (en) * 1992-11-30 1996-09-17 Sankyo Company, Limited α-ω-diarylalkane compounds serotonin-2 receptor agonists
WO1994013291A1 (fr) * 1992-12-15 1994-06-23 Smithkline Beecham Plc Utilisation d'amines cycliques a substitution aryloxyalkyle comme antagonistes des canaux a calcium et nouveaux derives de piperidine phenyloxyalkyle
WO1995003302A1 (fr) * 1993-07-20 1995-02-02 Smithkline Beecham Plc Quinolizidines a activite antagoniste des canaux a calcium
WO1995015948A1 (fr) * 1993-12-09 1995-06-15 Institut De Recherche Jouveinal Nouveaux derives de 2-arylalkenyl-azacycloalkanes ligands aux recepteurs sigma, leur procede de preparation et leur application en therapeutique
FR2713639A1 (fr) * 1993-12-09 1995-06-16 Irj Nouveaux dérivés de 2-arylalkényl-azacycloalkanes ligands aux récepteurs sigma, leur procédé de préparation et leur application en thérapeutique.
US6013656A (en) * 1993-12-09 2000-01-11 Warner-Lambert Company 2-(arylalkenyl) azacycloalkane derivatives as ligands for sigma receptors
US5849760A (en) * 1993-12-09 1998-12-15 Institut De Recherche Jouveinal 2-(arylalkenyl)azacycloalkane derivatives as ligands for sigma receptors
WO1995024390A1 (fr) * 1994-03-11 1995-09-14 Smithkline Beecham Plc Nouvelles piperidines substituees par phenyl(-alkyl/alkoxy)-1-aminoalkyle et pyrolidines utilisees comme antagonistes des canaux calciques
WO1995033722A1 (fr) * 1994-06-02 1995-12-14 Smithkline Beecham Plc Piperidines, pyrrolidines, morpholines et tiopmorpholines a substitution phenoxyalcoyle en tant qu'antagonistes des canaux calciques
WO1995033723A1 (fr) * 1994-06-02 1995-12-14 Smithkline Beecham Plc Piperidines, pyrrolidines, morpholines et thiomorpholines a substitution phenoxyalcoyle, en tant qu'antagonistes des canaux a calciques
WO1997010210A1 (fr) * 1995-09-12 1997-03-20 Smithkline Beecham Plc Derives de pyrrolidine tricyclique utilises en tant qu'antagonistes des canaux calciques
US5843983A (en) * 1996-02-15 1998-12-01 Sankyo Company, Limited Diphenylethane compounds containing a saturated heterocyclic group, their preparation, and their therapeutic use
US6166015A (en) * 1998-11-20 2000-12-26 Syntex (U.S.A.) Inc. Pyrrolidine derivatives-CCR-3 receptor antagonists
US7012085B2 (en) 2000-01-28 2006-03-14 Novartis Ag 1,3 disubstituted pyrrolidines as α-2-adrenoceptor antagonists
WO2004105750A1 (fr) * 2003-05-30 2004-12-09 Neuromed Technologies, Inc. 3-aminomethyle-pyrrolidines comme inhibiteurs de canaux calciques de type n
JP2006526000A (ja) * 2003-05-30 2006-11-16 ニューロームド テクノロジーズ、インク． Ｎ型カルシウムチャネル遮断薬としての３−アミノメチル−ピロリジン
US7244758B2 (en) 2003-05-30 2007-07-17 Neuromed Pharmaceuticals Ltd. N-type calcium channel blockers
US7816395B2 (en) 2006-08-09 2010-10-19 Glaxosmithkline Llc Pyrrolidinone anilines as progesterone receptor modulators
WO2008077089A1 (fr) * 2006-12-19 2008-06-26 Smithkline Beecham Corporation Pyrrolidinanilines

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AU1975092A (en) 1993-01-12
JPH06508353A (ja) 1994-09-22
EP0589971A1 (fr) 1994-04-06
WO1992022527A3 (fr) 1993-02-18
GB9113031D0 (en) 1991-08-07

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