WO1997010210A1 - Derives de pyrrolidine tricyclique utilises en tant qu'antagonistes des canaux calciques - Google Patents

Derives de pyrrolidine tricyclique utilises en tant qu'antagonistes des canaux calciques Download PDF

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Publication number
WO1997010210A1
WO1997010210A1 PCT/EP1996/003990 EP9603990W WO9710210A1 WO 1997010210 A1 WO1997010210 A1 WO 1997010210A1 EP 9603990 W EP9603990 W EP 9603990W WO 9710210 A1 WO9710210 A1 WO 9710210A1
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optionally substituted
formula
compound
hydrogen
group
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PCT/EP1996/003990
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English (en)
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John David Harling
Barry Sidney Orlek
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Smithkline Beecham Plc
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Priority to JP51165897A priority Critical patent/JP2001527510A/ja
Priority to EP96931071A priority patent/EP0859760A1/fr
Publication of WO1997010210A1 publication Critical patent/WO1997010210A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/70—[b]- or [c]-condensed containing carbocyclic rings other than six-membered
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

Definitions

  • the present invention relates to tricyclic heterocyclic derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, in particular as calcium channel antagonists, e.g. for the treatment of ischaemia, in particular ischaemic stroke.
  • Stroke is reportedly the third most common cause of death in the developed world.
  • Current therapies for ischaemic stroke are limited and have a number of disadvantages, such as the risk of exacerbating haemorrhage. There is therefore a need for new and improved treatments for ischaemic stroke.
  • X a represents O, S, NH
  • X D represents O, S, NH or a bond
  • pb and qb independently represent 0-4 such that the sum of pb+qb is at least 1
  • pc and qc independently represent 0-4
  • X c represents O, S, NH or, provided that the sum of pc and qc is at least 1, a bond
  • Ar a and Ar D each represents phenyl optionally substituted by inter alia Ph(CH2) r Y(CH2) s - where Ph is optionally substituted phenyl, Y is oxygen or a bond and r and s each independently represent 0-4 provided that the sum of r+s is not greater than 4
  • Ar° represents phenyl substituted by -Y-CR ⁇ R ⁇ -Ph, where Y is oxygen or a bond, R ⁇ and R ⁇ are independently, H, methyl or ethyl, provided that R ⁇ and R ⁇ are not both H,
  • A represents (CH2)n in which one -CH2- moiety may be optionally replaced by O, -C(CH 3 ) 2 or -OC(CH 3 ) 2 ; n is 1,2 or 3;
  • Rl represents hydrogen, Cj.galkyl, C3_gcycloalkyl, C3_6cycloalkylC ⁇ 4alkyl, benzyl or 4-methoxybenzyl;
  • R 2 represents a substituent selected from one or more of a hydrogen or halogen atom (e.g. fluorine, chlorine or bromine), or a hydroxy, C ⁇ _4_lkyl, Cj ⁇ alkoxy, amino, ono-or di-Cj.4 alkylamino, trifluoromethyl, trifluoromethoxy, cyano, nitro, formyl, C ⁇ _4_lkanoyl, or C1.4 alkoxycarbonyl group or a group R ⁇ R ⁇ NCO- wherein and R ⁇ each independently represent a hydrogen atom or a Ci _4alkyl group or R ⁇ R ⁇ N forms a 5-7 membered heterocyclic ring; m represents 1, 2, 3, or 4;
  • a hydrogen or halogen atom e.g. fluorine, chlorine or bromine
  • Ar represents phenyl optionally substituted by 1 to 3 substituents selected from one or more of : halo, C ⁇ _4alkyl, C ⁇ .4alkoxy, C ⁇ _2 a lkylenedioxy, trifluoromethyl, trifluoromethoxy, CN, NO2, amino, mono- or di- alkylamino, optionally substituted benzoyl or a group Ph(Alk ⁇ ) r Y(Alk ) s - wherein Ph is optionally substituted phenyl, Y is oxygen or a bond, Alk* and Alk 2 each independently represent C ⁇ _4 alkyl which may be straight or branched and r and s are independently zero or 1 , provided that the length of the chain (Alkl) r Y(Alk ) s does not exceed 5 atoms; or
  • Ar represents an optionally substituted unsaturated monocyclic heteroaryl ring system containing 5 or 6 ring members, or an optionally substituted, unsaturated or partially saturated bicyclic aryl or heteroaryl ring system containing 8-10 ring members; and salts thereof.
  • R ⁇ is preferably hydrogen or methyl.
  • R 2 is suitably hydrogen.
  • the group A is preferably (CH2) n .
  • n is 1.
  • Ar represents phenyl substituted by a group Ph(Alkl) r Y(Alk 2 ) s - the groups Alk ⁇ and Alk 2 preferably each independently represent -(CH2K -C(H)(CH3>- or -C(CH3) _-•
  • Y oxygen
  • s preferably represents zero and r represents zero or 1.
  • Y is a bond
  • the sum of r and s is preferably 1 or 2.
  • Alk* represents -C(CH3>2 and r is 1, s is preferably zero.
  • Alk* and Alk 2 each represent -(CH2)-, such that the group Ph(Alk 1 ) r Y(Alk 2 ) s - can be represented as Ph(CH2) v Y(CH2) w - wherein v and w each represent 0-4 such that the sum of v+w is not greater than 4 and preferably not greater than 1.
  • Alk* represents -CRSR -, where R ⁇ is hydrogen, methyl or ethyl and R > is methyl or ethyl; r represents 1 and s represents zero. At least one, preferably both, of R ⁇ and R ⁇ represent methyl.
  • Particularly preferred substituents of the formula Ph(Alk ⁇ ) r Y(Alk 2 ) s - include optionally substituted benzyloxy, benzyl, phenoxy, benzoyl or Ph(CH3)2C-.
  • Suitable substituents for the group Ph include halogen, C ⁇ _4alkoxy; C1.4a_.yl; trifluoromethyl; and trifluoromethoxy.
  • Ar represents a bicyclic aryl suitable groups include naphthyl.
  • Ar unsaturated monocyclic heteroaryl
  • suitable groups include optionally substituted pyridyl, thienyl and furyl.
  • suitable groups include benzofuranyl e.g. 5-benzo[b]furanyl.
  • Suitable substituents for bicyclic aryl and monocyclic and bicyclic heteroaryl groups include halogen; Cj ⁇ alkyl; C ⁇ _4alkoxy; trifluoromethyl; trifluoromethoxy; phenyl; phenylCj ⁇ alkyl; and phenyl Cj ⁇ alkoxy.
  • Ar preferably represents phenyl, most preferably substituted by halogen, e.g. 3,4-dichloro.
  • Ci .galkyl groups present in the compounds of formula (I), alone or as part of another group, can be straight or branched.
  • a Ci .galkyl group may be for example methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl or any branched isomer thereof such as isopropyl or t-butyl.
  • Preferred meanings of C3_6cycloalkyl are cyclopropyl and cyclohexyl
  • preferred meanings of C3.6cycloa_.ylC1 _4_lkyl are cyclopropylmethyl and cyclohexylmethyl.
  • 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, methanesulphonate or similar pharmaceutically acceptable inorganic or organic acid addition salts.
  • Other non- pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of final products and are included within the scope of this invention.
  • solvates and hydrates of formula (I) are also included within the scope of this invention. It will be appreciated that the compounds of formula (I) contain three or more asymmetric centres.
  • Such compounds will exist as optical isomers (enantiomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are included within the scope of the invention. Further, all diastereomeric forms possible (pure enantiomers and mixtures thereof) are within the scope of the invention. For example, it will be appreciated that when A is (CH2) n and n is 1, ie compounds having the structure:
  • the substituents at the 3/3a and 3a/8a positions may lie on the same side with respect to the plane of the ring (ris-configuration) or on opposite sides (trans-configuration). All forms and mixtures thereof are included within the scope of this invention.
  • n is 1
  • the hydrogen atoms at the 3a/8a positions are in the cis-configuration
  • the 3/3a hydrogen atoms may be in either the cis- or trans -configuration.
  • Particular compounds of the formula (I) include : (3RS, 3aRS, 8aSR)-l-methyl-3-(3,4-dichlorophenyl)-l,2,3,3a,8,8a-hexahydro-l- azacyclopenta[a]indene;
  • 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 compounds of formula (I) which comprises : reaction of a compound of formula (II):
  • R ⁇ is as defined for formula (I)); followed, where necessary or desired by one or more of the following steps: i) conversion of a compound (I) wherein R is benzyl or 4-methoxybenzyl to a compound wherein R * is hydrogen; ii) conversion of a benzoyl substitutent in the group Ar to benzyl or to a group -C(CH 3 ) 2 Ph; iii) separation of diastereoisomers; iv) salt formation.
  • Reaction of a compound (II) with a compound (HI) may be carried out in an inert solvent such as toluene, under reflux conditions.
  • a compound of formula (II) may be employed as a mixtue of geometric (E and Z) isomers or altematively the isomers may be separated prior to reaction with a compound of formula (III).
  • a single E or Z isomer of formula (II) will cyclise with a compound (III) in a stereospecific manner to give a single diastereoisomer of formula (I)
  • An aldehyde of formula (II) may be prepared by oxidation of the corresponding alcohol, with for example sulphur rrioxide-pyridine complex in a solvent such as dimethylsulphoxide.
  • A is (CH2) n "d n is 1
  • the alcohol may be prepared by reaction of an optionally substituted isochroman-1-ol of formula (IV):
  • die alkylene chain may be lengthened by methods well known in the art.
  • a mixture of E and Z isomers of formula (II) may be separated by standard methods, e.g. by HPLC.
  • Compounds of formula (III) are commercially available or may be prepared by methods well known in the art.
  • Compounds of formula (IV) and (V) may also be prepared by standard procedures.
  • Conversion of a compound of formula(I) wherein Rl is 4- methoxybenzyl, into a compound (I) wherein R is hydrogen may be effected by treatment with a haloformate such as 1-chloroethylchloroformate.
  • Reduction of a benzoyl substitutent to benzyl may be effected using e.g. sodium borohydride in trifluoracetic acid.
  • -C(CH3)2Ph can be effected by reaction with (CH3)2TiC-2, for example in dichloromethane at -40°C (as generally described by Reetz et al. J.Org.Chem.48254 (1983)) and analogues can be prepared by variations of this method.
  • a mixture of enantiomers of a compound of formula (I) 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.
  • An ischaemic event such as stroke results in disruption of the blood supply to the brain, depriving it of essential oxygen and glucose.
  • a cascade of biochemical reactions ensues, a consequence of which is to permit the influx of calcium ions into the brain cells (neurons) via so-called Voltage Operated Calcium Channels (VOCCs) causing cell death. It is believed that agents which inhibit such calcium influx will minimise cell death and hence increase the potential for recovery.
  • VOCCs Voltage Operated Calcium Channels
  • Compounds of formula (I) have been found to exhibit high calcium influx blocking activity, for example in neurons.
  • the compounds may thus be referred to as neuronal calcium antagonists.
  • the compounds are expected to be of use in therapy in treating conditions and diseases related to an accumulation of calcium in the brain cells of mammals, in particular humans.
  • the compounds are expected to be of use in the treatment of ischaemia, including for example stroke; anoxia, due to causes including cardiac arrest, and cardiac surgery; and traumatic head injury. They may also be of use in the treatment of migraine; pain; epilepsy; AIDS-related dementia; neuro ⁇ degenerative diseases, such as Alzheimer's disease and age-related memory disorders; mood disorders; and drug addiction withdrawal such as ethanol addiction withdrawal.
  • a method of treatment of conditions or diseases related to (e.g. caused or exacerbated by) the accumulation of calcium in the brain cells of mammals which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treatment of ischaemia including for example stroke, anoxia or traumatic head injury which comprises administering to a subject in need thereof, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof..
  • the invention also provides a method of treatment of migraine, pain, epilepsy, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease, and age-related memory disorders, mood disorders and drug addiction withdrawal such as ethanol addiction withdrawal, which comprises administering to a subject in need thereof, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition or disease related to the accumulation of calcium in the brain cells of a mammal.
  • compositions comprising a novel compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • the compounds of formula (I) may be administered by any convenient method for example by oral, parenteral, buccal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
  • the compounds of formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) 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;
  • 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(s) for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • Compounds of the invention may also be administered parenterally, by bolus injection or continuous infusion.
  • Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Altematively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • 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.
  • the composition is in unit dose form such as a tablet, capsule or ampoule.
  • Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 60 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, e.g. 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, e.g.
  • 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.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in combination or concurrently with one or more other therapeutic agents, for example a thrombolytic agent such as anistreplase, streptokinase or a tissue plasminogen activator; an excitatory amino acid antagonist such as an NMDA antagonists; a free radical inhibitor; or a calpain inhibitor.
  • a thrombolytic agent such as anistreplase, streptokinase or a tissue plasminogen activator
  • an excitatory amino acid antagonist such as an NMDA antagonists
  • a free radical inhibitor such as an NMDA antagonists
  • Superior cervical ganglion neurons were isolated and cultured following a method modified from Marrion et al, Neurosci. Lett., 77, 55-60 (1987). Cells were plated onto laminin coated plastic tissue culture dishes and incubated at 37°C until just prior to recording. Electrophysiological recordings were performed from 2 to 9 days after dissociation.
  • the pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 10; MgCl2, 4; ATP, 2; buffered to pH 7.2 with CsOH.
  • Cells were bathed in a normal Tyrodes solution before establishment of whole cell recording when the bathing solution was changed to one allowing isolation of Ca 2+ currents.
  • the extemal solution for recording Ca 2+ channel currents contained in mM: BaCl2, 10; TEA-C1, 130; glucose, 10; HEPES, 10; MgCl2, 1; buffered to pH 7.3 with TEA-OH. Barium was used as the charge carrier as this assists in current isolation and calcium dependent inactivation of current is avoided.
  • Buffer Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.
  • Solvent Typically water but may also include cyclodextrins, e.g. hydroxypropyl- ⁇ - cyclodextrin (1-100 mg) and co-solvents such as propylene glycol, polyethylene glycol and alcohol.
  • cyclodextrins e.g. hydroxypropyl- ⁇ - cyclodextrin (1-100 mg) and co-solvents such as propylene glycol, polyethylene glycol and alcohol.
  • Diluent e.g. Microcrystalline cellulose, lactose, starch Binder : e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
  • Disintegrant e.g. Sodium starch glycollate, crospovidone Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate.
  • Suspending agent e.g. Xanthan gum, microcrystalline cellulose
  • Diluent e.g. sorbitol solution, typically water
  • Preservative e.g. sodium benzoate
  • Buffer e.g. citrate
  • Co-solvent e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin

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Abstract

Composés de la formule (I) et leurs sels, formule dans laquelle A représente (CH2)n dans lequel une fraction -CH2- peut être éventuellement remplacée par O, -C(CH3)2 ou -OC(CH3)2, et n vaut 1, 2 ou 3; R1 représente hydrogène, alkyle C¿1-6?, cycloalkyle C3-6, cycloalkyle C3-6alkyle C1-4, benzyle ou 4-méthoxybenzyle; R?2¿ représente un substituant choisi dans le groupe constitué par un ou plusieurs atomes d'hydrogène ou d'halogène, ou un ou plusieurs hydroxy, alkyle C¿1-4?, alcoxy C1-4, amino, mono- ou di-alkylamino C1-4, trifluorométhyle, trifluorométhoxy, cyano, nitro, formyle, alcanoyle C1-4, ou un ou plusieurs groupes alcoxycarbonyle C1-4, ou R?3R4¿NCO- dans lequel R3 et R4 représentent chacun indépendamment un atome d'hydrogène ou un groupe alkyle C¿1-4? ou bien R?3R4¿N forme un noyau hétérocyclique possédant 5 à 7 chaînons; m vaut 1, 2, 3, ou 4; Ar représente phényle éventuellement substitué par 1 à 3 substituants choisis dans le groupe constitué par un ou plusieurs halo, alkyle C¿1-4?, alcoxy C1-4, alkylènedioxy C1-2, trifluorométhyle, trifluorométhoxy, CN, NO2, amino, mono- ou di-alkylamino, benzoyle éventuellement substitué, ou un ou plusieurs groupes Ph(Alk?1)¿rY(Alk2)s- où Ph est phényle éventuellement substitué, Y représente oxygène ou une liaison, Alk?1 et Alk2¿ représentent chacun indépendamment alkyle C¿1-4? qui peut être droit ou ramifié, et r et s valent indépendamment zéro ou 1, à condition que la longueur de la chaîne (Alk?1)¿rY(Alk2)s ne dépasse pas 5 atomes; ou bien Ar représente un système de noyau hétéroaryle monocyclique insaturé, éventuellement substitué, pentagonal ou hexagonal, ou bien un système de noyau hétéroaryle ou aryle bicyclique, insaturé ou partiellement saturé, éventuellement substitué, octogonal ou décagonal. Ces composés constituent des antagonistes des canaux calciques neuronaux, utiles dans le traitement d'états ischémiques, par exemple l'ictus.
PCT/EP1996/003990 1995-09-12 1996-09-09 Derives de pyrrolidine tricyclique utilises en tant qu'antagonistes des canaux calciques WO1997010210A1 (fr)

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Application Number Priority Date Filing Date Title
JP51165897A JP2001527510A (ja) 1995-09-12 1996-09-09 カルシウムチャンネル拮抗物質としての三環式ピロリジン誘導体
EP96931071A EP0859760A1 (fr) 1995-09-12 1996-09-09 Derives de pyrrolidine tricyclique utilises en tant qu'antagonistes des canaux calciques

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GBGB9518572.4A GB9518572D0 (en) 1995-09-12 1995-09-12 Compounds
GB9518572.4 1995-09-12

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000021550A2 (fr) * 1998-10-13 2000-04-20 President And Fellows Of Harvard College Methodes et compositions de traitement des maladies neurodegeneratives
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
US6579892B1 (en) 1999-01-12 2003-06-17 Abbott Laboratories Triazole compounds with dopamine-D3-receptor affinity
US6956052B2 (en) 2001-09-19 2005-10-18 Pharmacia Corporation Substituted pyrazolyl compounds for the treatment of inflammation
US7855227B2 (en) 2005-12-22 2010-12-21 Newron Pharmaceuticals S.P.A. 2-phenylethylamino derivatives as calcium and/or sodium channel modulators
WO2013000651A1 (fr) 2011-06-27 2013-01-03 Newron Pharmaceuticals S.P.A. Dérivés d'arylalkylaminocarboxamides fluorés
US8519000B2 (en) 2007-06-15 2013-08-27 Newron Pharmaceuticals S.P.A. Substituted 2-[2-(phenyl) ethylamino] alkaneamide derivatives and their use as sodium and/or calcium channel modulators

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992022527A2 (fr) * 1991-06-17 1992-12-23 Smithkline Beecham Plc Derives de pyrrolidine 3-substitues comme antagonistes du calcium
WO1995004027A1 (fr) * 1993-07-28 1995-02-09 Smithkline Beecham Plc Aminoindanes et composes apparentes utiles comme antagonistes des canaux a calcium
WO1995004028A1 (fr) * 1993-07-28 1995-02-09 Smithkline Beecham Plc Derives d'indane et de tetrahydronaphtalene a titre d'antagonistes des canaux a calcium
EP0657426A2 (fr) * 1993-10-22 1995-06-14 F. Hoffmann-La Roche Ag Dérivés tricycliques de pyrrole
WO1996021641A1 (fr) * 1995-01-13 1996-07-18 Smithkline Beecham Plc Enantiomeres de 1-(3,4-dichlorobenzyl)-2-methylaminoindane

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992022527A2 (fr) * 1991-06-17 1992-12-23 Smithkline Beecham Plc Derives de pyrrolidine 3-substitues comme antagonistes du calcium
WO1995004027A1 (fr) * 1993-07-28 1995-02-09 Smithkline Beecham Plc Aminoindanes et composes apparentes utiles comme antagonistes des canaux a calcium
WO1995004028A1 (fr) * 1993-07-28 1995-02-09 Smithkline Beecham Plc Derives d'indane et de tetrahydronaphtalene a titre d'antagonistes des canaux a calcium
EP0657426A2 (fr) * 1993-10-22 1995-06-14 F. Hoffmann-La Roche Ag Dérivés tricycliques de pyrrole
WO1996021641A1 (fr) * 1995-01-13 1996-07-18 Smithkline Beecham Plc Enantiomeres de 1-(3,4-dichlorobenzyl)-2-methylaminoindane

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6251919B1 (en) 1998-02-27 2001-06-26 Warner-Lambert Heterocyclic substituted aniline calcium channel blockers
US6166052A (en) * 1998-03-11 2000-12-26 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US6469038B1 (en) 1998-03-11 2002-10-22 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US6989448B2 (en) 1998-03-11 2006-01-24 Lain-Yen Hu Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
WO2000021550A2 (fr) * 1998-10-13 2000-04-20 President And Fellows Of Harvard College Methodes et compositions de traitement des maladies neurodegeneratives
WO2000021550A3 (fr) * 1998-10-13 2000-07-27 Harvard College Methodes et compositions de traitement des maladies neurodegeneratives
US6579892B1 (en) 1999-01-12 2003-06-17 Abbott Laboratories Triazole compounds with dopamine-D3-receptor affinity
US6583166B1 (en) 1999-01-12 2003-06-24 Abbott Laboratories Triazole compounds with dopamine-D3-receptor affinity
US6602867B1 (en) 1999-01-12 2003-08-05 Abbott Laboratories Triazole compounds with dopamine-D3-receptor affinity
US6956052B2 (en) 2001-09-19 2005-10-18 Pharmacia Corporation Substituted pyrazolyl compounds for the treatment of inflammation
US7855227B2 (en) 2005-12-22 2010-12-21 Newron Pharmaceuticals S.P.A. 2-phenylethylamino derivatives as calcium and/or sodium channel modulators
US8129427B2 (en) 2005-12-22 2012-03-06 Newron Pharmaceuticals S.P.A. 2-phenylethylamino derivatives as calcium and/or sodium channel modulators
US8470877B2 (en) 2005-12-22 2013-06-25 Newron Pharmaceuticals S.P.A. 2-phenylethylamino derivatives as calcium and/or sodium channel modulators
US8519000B2 (en) 2007-06-15 2013-08-27 Newron Pharmaceuticals S.P.A. Substituted 2-[2-(phenyl) ethylamino] alkaneamide derivatives and their use as sodium and/or calcium channel modulators
US9051240B2 (en) 2007-06-15 2015-06-09 Newron Pharmaceuticals S.P.A. Substituted 2-[2-(phenyl) ethylamino] alkaneamide derivatives and their use as sodium and/or calcium channel modulators
US9248116B2 (en) 2007-06-15 2016-02-02 Newron Pharmaceuticals S.P.A. Substituted 2-[2-(phenyl) ethylamino] alkaneamide derivatives and their use as sodium and/or calcium channel modulators
US9474738B2 (en) 2007-06-15 2016-10-25 Newron Pharmaceuticals S.P.A. Substituted 2-[2-(phenyl) ethylamino] alkaneamide derivatives and their use as sodium and/or calcium channel modulators
US9474739B2 (en) 2007-06-15 2016-10-25 Newron Pharmaceuticals S.P.A. Substituted 2-[2-(phenyl) ethylamino] alkaneamide derivatives and their use as sodium and/or calcium channel modulators
US9474737B2 (en) 2007-06-15 2016-10-25 Newron Pharmaceuticals S.P.A. Substituted 2-[2-(phenyl) ethylamino] alkaneamide derivatives and their use as sodium and/or calcium channel modulators
US9585869B2 (en) 2007-06-15 2017-03-07 Newron Pharmaceuticals, S.P.A. Substituted 2-[2-(phenyl) ethylamino] alkaneamide derivatives and their use as sodium and/or calcium channel modulators
US9603832B2 (en) 2007-06-15 2017-03-28 Newron Pharmaceuticals S.P.A. Substituted 2-[2-(phenyl) ethylamino]alkaneamide derivatives and their use as sodium and/or calcium channel modulators
WO2013000651A1 (fr) 2011-06-27 2013-01-03 Newron Pharmaceuticals S.P.A. Dérivés d'arylalkylaminocarboxamides fluorés

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