+

WO1994014786A1 - Derives de piperidine utilises en tant qu'antagonistes de canaux a calcium - Google Patents

Derives de piperidine utilises en tant qu'antagonistes de canaux a calcium Download PDF

Info

Publication number
WO1994014786A1
WO1994014786A1 PCT/EP1993/003629 EP9303629W WO9414786A1 WO 1994014786 A1 WO1994014786 A1 WO 1994014786A1 EP 9303629 W EP9303629 W EP 9303629W WO 9414786 A1 WO9414786 A1 WO 9414786A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
tert
hydroxy
piperidine
Prior art date
Application number
PCT/EP1993/003629
Other languages
English (en)
Inventor
Ronald Joseph King
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
Priority claimed from GB929226718A external-priority patent/GB9226718D0/en
Priority claimed from GB939321808A external-priority patent/GB9321808D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to EP94904162A priority Critical patent/EP0675883A1/fr
Priority to JP6514808A priority patent/JPH08504792A/ja
Priority to AU58334/94A priority patent/AU5833494A/en
Priority to KR1019950702552A priority patent/KR950704284A/ko
Publication of WO1994014786A1 publication Critical patent/WO1994014786A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the present invention relates to heterocyclic compounds, processes for preparing them, their use in therapy and pharmaceutical compositions containing them.
  • EP-A- 190685 describes heterocyclic amides which are said to be anti- inflammatory and anti allergy agents.
  • EP-A-476846 describes known phenols and benzamides for use inter alia in preventing ischaemia-induced cell damage.
  • R! represents Cj.galkyl, halogen or phenyl
  • R represents hydrogen, Chalky-, halogen or phenyl;
  • R3 represents hydroxyl or a group convertible thereto in vivo ;
  • R4 represents Cj.galkyl; p is zero, 1 or 2;
  • Alkyl groups present in the compounds of formula (I) may be straight or branched.
  • R* and/or R ⁇ represents C ⁇ . ⁇ alkyl this may be for example a methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, sec-pentyl, 1,1-dimethylpropyl, or n-hexyl group.
  • R and R ⁇ preferably represent branched alkyl groups, most preferably t-butyl.
  • Groups R which are convertible in vivo to hydroxyl include C ⁇ _4alkoxy;
  • n is preferably 5 to 8.
  • m is preferably 4 to 6.
  • p is preferably zero.
  • a salt of a compound (I) should be pharmaceutically acceptable.
  • pharmaceutically acceptable salts include inorganic and organic acid addition salts such as the hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, and tartrate salts, and base salts such as alkali metal e.g. sodium or potassium salts.
  • base salts such as alkali metal e.g. sodium or potassium salts.
  • Other non-pharmaceutically acceptable salts e.g. oxalates, may be used for example in the isolation of the final product and are included within the scope of this invention.
  • the compounds of formula (I) may contain one or more asymmetric centres. Such compounds will exist as optical isomers (enantiomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are included within the scope of the invention. Further, all diastereomeric forms possible (pure enantiomers and mixtures thereof) are within the scope of the invention.
  • Particular compounds according to the invention include : l-f6-oxo-6-(4-hydroxy-3,5-di-tert-butylphenyl)hexyl]piperidine, 1 -f 8-oxo-8-(4-hydroxy-3,5-di-tert-butylphenyl)octyl]piperidine,
  • 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: (a) to prepare a compound (I) wherein X is O or S, reaction of a compound of formula (II):
  • R a and R ⁇ a is hydrogen and the other is selected from hydrogen, halogen, C ⁇ .galkyl or phenyl, and R ⁇ , R4, X. n , m and p are as defined for formula (I)) with a compound serving to introduce R* and/or R ⁇ ; (d) to prepare a compound where X is -CH2-, S or O, reduction of an amide of formula (VII) or (VIII) :
  • the reaction between a compound of formula (II) and a compound of formula (III) can be carried out under standard conditions.
  • I_l is hydroxy
  • 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 e.g. methane-sulphonyloxy or p-toluene sulphonyloxy.
  • reaction may be effected in the absence or presence of solvent such as dimethylformamide or methylethylketone in the presence of a base such as sodium hydride or potassium carbonate and at a temperature in the range 0 to 200°C.
  • solvent such as dimethylformamide or methylethylketone
  • base such as sodium hydride or potassium carbonate
  • the reaction of a compound of formula (IV) with a compound of formula (V) according to process (b) may be effected in conventional manner, for example using excess amine as solvent or alternatively using an organic solvent, such as dichloromethane or dimethyl formamide.
  • the leaving group 1?- may be for example a halide such as bromide or chloride, an acyloxy group such as acetoxy or chloroacetoxy or a sulphonyloxy group such as methanesulphonyloxy or p-toluenesulphonyloxy.
  • the reaction may optionally be carried out in the presence of a base such as sodium hydride or potassium t- butoxide.
  • the groups R ⁇ and R ⁇ may be introduced by standard methods.
  • a halo substituent may be introduced by reaction with the appropriate halogen e.g. Br2 or I2.
  • Reduction of an amide according to process (d) may be effected using a suitable reducing agent such as lithium aluminium hydride and an inert solvent such as diethyl ether or tetrahydrofuran.
  • a suitable reducing agent such as lithium aluminium hydride and an inert solvent such as diethyl ether or tetrahydrofuran.
  • the compounds of formula (II) can be prepared under standard alkylation conditions by reacting compounds of formula (IX) : lA(CH 2 ) n -Ll
  • L* is suitably hydroxy and ⁇ 2 is suitably halo.
  • Hal represents chloro and U- represents bromo.
  • the reaction may be effected using standard conditions, for example in a solvent such as dichloromethane.
  • the Friedel Craft catalyst may be for example aluminium trichloride or stannic chloride.
  • Compounds of formula (V) are commercially available and may be prepared by standard literature methods. Compounds of formula (VI) may be prepared according to one of the general methods (a), (b) or (d) described herein.
  • Compounds of formula (VIII) may be prepared by acylation of a compound of formula (V), for example with an appropriate acid chloride or ester, which may itself be prepared from a compound of formula (IN) by standard methods. Alternatively a compound (VIII) may be prepared by a method analogous to process (a).
  • the compounds of the invention have been found to exhibit high calcium influx blocking activity for example in neurons.
  • the compounds are expected to be of use in therapy in treating conditions and diseases related to an accumulation of calcium in the brain cells of mammals, in particular humans.
  • the compounds are expected to be of use in the treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal.
  • the compounds also have antioxidant properties and are therefore expected to be useful in the treatment of conditions in which free radicals are implicated, for example prevention of ischemic cell damage.
  • the invention also provides a method of treatment of conditions or diseases 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) as hereinbefore defined or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age- related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal, which comprises administering to a subject in need thereof, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention also provides the use of a compound of formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition in which free radicals are implicated and/or in the manufacture of a medicament for the treatment of a condition or disease caused or exacerbated by the accumulation of calcium in the brain cells of a mammal.
  • the compounds of the present invention are usually administered in a standard pharmaceutical composition.
  • the present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • the compounds of the invention may be administered by any convenient method for example by oral, parenteral, buccal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
  • the compounds of formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • Compounds of the invention may also be administered parenterally, by bolus injection or continuous infusion.
  • Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • 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. 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;
  • Peak voltage gated Ca + channel currents of up to 10 nA from dorsal root ganglion neurons were recorded using 10 mM Ba + 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 reaction mixture was heated until an internal temperature of 60°C had been achieved.
  • Lithium aluminium hydride (0.20g) was suspended in anhydrous diethyl ether (70ml) and a solution of l-[8-oxo-8-(4-hydroxy-3,5-di-tert-butyl-phenyl)octyl]piperidine (0.43g) in anhydrous diethyl ether (5ml) was added dropwise. The reaction was left to stir at room temperature for two days. The reaction mixture was treated with brine. The organic phase was dried with anhydrous sodium sulphate and the solvent removed in vacuo. The product was dissolved in anhydrous ether and treated with a slight molar excess of hydrogen chloride in diethyl ether.

Landscapes

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

Abstract

L'invention concerne des composés de formule (I) dans laquelle R1 représente alkyle C¿1-6?, halogène ou phényle; R?2¿ représente hydrogène, alkyle C¿1-6?, halogène ou phényle; R?3¿ représente hydroxyle ou un groupe convertible in vivo en hydroxyle; R4 représente alkyle C¿1-6?; p correspond à zéro, 1 ou 2; X représente -CH2-, -C$(1,3)$O, O ou S; n est un entier de 4 à 10; m est un entier de 3 à 8. Ces composés, ainsi que les sels desdits composés, sont utilisés en tant qu'antagonistes du calcium dans, par exemple, le traitement d'affections relatives à une accumulation de calcium dans les cellules cérébrales.
PCT/EP1993/003629 1992-12-22 1993-12-16 Derives de piperidine utilises en tant qu'antagonistes de canaux a calcium WO1994014786A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP94904162A EP0675883A1 (fr) 1992-12-22 1993-12-16 Derives de piperidine utilises en tant qu'antagonistes de canaux a calcium
JP6514808A JPH08504792A (ja) 1992-12-22 1993-12-16 カルシウムチャンネルアンタゴニストとしてのピペリジン誘導体
AU58334/94A AU5833494A (en) 1992-12-22 1993-12-16 Piperidine derivatives as calcium channel antagonists
KR1019950702552A KR950704284A (ko) 1992-12-22 1993-12-16 칼슘 채널 길항제로서의 피페리딘 유도체(Piperidine Derivatives as Calcium Channel Antagonists)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB929226718A GB9226718D0 (en) 1992-12-22 1992-12-22 Compounds
GB9226718.6 1992-12-22
GB939321808A GB9321808D0 (en) 1993-10-22 1993-10-22 Compounds
GB9321808.9 1993-10-22

Publications (1)

Publication Number Publication Date
WO1994014786A1 true WO1994014786A1 (fr) 1994-07-07

Family

ID=26302202

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1993/003629 WO1994014786A1 (fr) 1992-12-22 1993-12-16 Derives de piperidine utilises en tant qu'antagonistes de canaux a calcium

Country Status (8)

Country Link
EP (1) EP0675883A1 (fr)
JP (1) JPH08504792A (fr)
KR (1) KR950704284A (fr)
CN (1) CN1092415A (fr)
AU (1) AU5833494A (fr)
CA (1) CA2152394A1 (fr)
MX (1) MX9400070A (fr)
WO (1) WO1994014786A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5608095A (en) * 1996-04-30 1997-03-04 Hoechst Marion Roussel, Inc. Alkyl-4-silyl-phenols and esters thereof as antiatherosclerotic agents
US5795876A (en) * 1996-04-30 1998-08-18 Hoechst Marion Rousssel, Inc. Method of inhibiting vascular cell adhesion molecule-1 and treating chronic inflammatory diseases with 2, 6-di-alkyl-4-silyl-phenols
US5962435A (en) * 1993-12-10 1999-10-05 Hoechst Marion Roussel, Inc. Method of lowering serum cholesterol levels with 2,6-di-alkyl-4-silyl-phenols
US6114572A (en) * 1996-11-20 2000-09-05 Hoechst Marion Roussel, Inc. Substituted phenols and thiophenols useful as antioxidant agents
US6121463A (en) * 1997-06-24 2000-09-19 Hoechst Marion Roussel, Inc. Alkyl-4-silylheterocyclic phenols and thiophenols useful as antioxidant agents
US6133467A (en) * 1997-06-25 2000-10-17 Hoechst Marion Roussel, Inc. 2,6-di-t-butyl-4-[(dimethyl-4-methoxyphenylsilyl)-methyl-oxy]phenol and 2,6-di-t-butyl-4-[(dimethyl-2-methoxy-phenylsilyl)methyloxy]phenol
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
WO2001045709A1 (fr) * 1999-12-20 2001-06-28 Neuromed Technologies, Inc. Inhibiteurs calciques a base de piperazine et de piperidine substituees
WO2001045739A1 (fr) * 1999-12-21 2001-06-28 Mitsubishi Pharma Corporation Remedes et/ou medicaments preventifs pour troubles du systeme nerveux
US6943168B2 (en) 1998-06-30 2005-09-13 Neuromed Technologies Inc. Calcium channel inhibitors comprising benzhydril spaced from piperazine
US6949554B2 (en) 1998-06-30 2005-09-27 Neuromed Technologies Inc. Calcium channel blockers comprising two benzhydril moieties
WO2007002884A2 (fr) 2005-06-29 2007-01-04 Merck & Co., Inc. 4-fluoro-piperidines antagonistes du canal calcium de type t
US7186726B2 (en) 1998-06-30 2007-03-06 Neuromed Pharmaceuticals Ltd. Preferentially substituted calcium channel blockers
US11684590B2 (en) 2018-06-27 2023-06-27 Cornell University Substituted alkylphenols as HCN1 antagonists

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3588734B2 (ja) * 1996-07-26 2004-11-17 コニカミノルタホールディングス株式会社 電子写真感光体

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0103252A2 (fr) * 1982-09-11 1984-03-21 BASF Aktiengesellschaft Aryloxyalkylamines, leur procédé de préparation et leur usage pour combattre la végétation indésirable
EP0164706A1 (fr) * 1984-06-12 1985-12-18 BASF Aktiengesellschaft Phénylalkylamines biorégulatrices
WO1988006580A1 (fr) * 1987-02-25 1988-09-07 Schering Aktiengesellschaft Alkylenamine tert. a substitution aryle et aryloxyle, leur procede de production et leur utilisation en pharmacie
WO1993000313A2 (fr) * 1991-06-27 1993-01-07 Virginia Commonwealth University Ligands de recepteurs sigma et leur utilisation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0103252A2 (fr) * 1982-09-11 1984-03-21 BASF Aktiengesellschaft Aryloxyalkylamines, leur procédé de préparation et leur usage pour combattre la végétation indésirable
EP0164706A1 (fr) * 1984-06-12 1985-12-18 BASF Aktiengesellschaft Phénylalkylamines biorégulatrices
WO1988006580A1 (fr) * 1987-02-25 1988-09-07 Schering Aktiengesellschaft Alkylenamine tert. a substitution aryle et aryloxyle, leur procede de production et leur utilisation en pharmacie
WO1993000313A2 (fr) * 1991-06-27 1993-01-07 Virginia Commonwealth University Ligands de recepteurs sigma et leur utilisation

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 111, no. 21, 20 November 1989, Columbus, Ohio, US; abstract no. 194691e, page 766; column R; *
CHEMICAL ABSTRACTS, vol. 112, no. 19, 7 May 1990, Columbus, Ohio, US; abstract no. 178818, page 753; column R; *
KARAULOVA, E. N . ET. AL., KHIM. GETEROSIKL. SOEDIN., no. 11, 1988, RUSSIA *
SAKHAROVA, S.N. ET. AL., IZV. AKAD. NAUK SSSR, SER. KHIM., no. 11, 1989, RUSSIA, pages 2580 - 2585 *

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5962435A (en) * 1993-12-10 1999-10-05 Hoechst Marion Roussel, Inc. Method of lowering serum cholesterol levels with 2,6-di-alkyl-4-silyl-phenols
US5795876A (en) * 1996-04-30 1998-08-18 Hoechst Marion Rousssel, Inc. Method of inhibiting vascular cell adhesion molecule-1 and treating chronic inflammatory diseases with 2, 6-di-alkyl-4-silyl-phenols
US5608095A (en) * 1996-04-30 1997-03-04 Hoechst Marion Roussel, Inc. Alkyl-4-silyl-phenols and esters thereof as antiatherosclerotic agents
US6114572A (en) * 1996-11-20 2000-09-05 Hoechst Marion Roussel, Inc. Substituted phenols and thiophenols useful as antioxidant agents
US6121463A (en) * 1997-06-24 2000-09-19 Hoechst Marion Roussel, Inc. Alkyl-4-silylheterocyclic phenols and thiophenols useful as antioxidant agents
US6133467A (en) * 1997-06-25 2000-10-17 Hoechst Marion Roussel, Inc. 2,6-di-t-butyl-4-[(dimethyl-4-methoxyphenylsilyl)-methyl-oxy]phenol and 2,6-di-t-butyl-4-[(dimethyl-2-methoxy-phenylsilyl)methyloxy]phenol
US6251919B1 (en) 1998-02-27 2001-06-26 Warner-Lambert Heterocyclic substituted aniline 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
US6989448B2 (en) 1998-03-11 2006-01-24 Lain-Yen Hu Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US6617322B2 (en) 1998-06-30 2003-09-09 Neuromed Technologies, Inc. Preferentially substituted calcium channel blockers
US7064128B2 (en) 1998-06-30 2006-06-20 Neuromed Technologies, Inc. Preferentially substituted calcium channel blockers
US7186726B2 (en) 1998-06-30 2007-03-06 Neuromed Pharmaceuticals Ltd. Preferentially substituted calcium channel blockers
US6943168B2 (en) 1998-06-30 2005-09-13 Neuromed Technologies Inc. Calcium channel inhibitors comprising benzhydril spaced from piperazine
US6949554B2 (en) 1998-06-30 2005-09-27 Neuromed Technologies Inc. Calcium channel blockers comprising two benzhydril moieties
US6951862B2 (en) 1998-06-30 2005-10-04 Neuromed Technologies, Inc. Calcium channel blockers comprising two benzhydril moieties
US6387897B1 (en) 1998-06-30 2002-05-14 Neuromed Technologies, Inc. Preferentially substituted calcium channel blockers
WO2001045709A1 (fr) * 1999-12-20 2001-06-28 Neuromed Technologies, Inc. Inhibiteurs calciques a base de piperazine et de piperidine substituees
WO2001045739A1 (fr) * 1999-12-21 2001-06-28 Mitsubishi Pharma Corporation Remedes et/ou medicaments preventifs pour troubles du systeme nerveux
KR100740477B1 (ko) * 1999-12-21 2007-07-19 미쯔비시 웰 파마 가부시키가이샤 신경계 장애의 치료 및/또는 예방약
US7652017B2 (en) 1999-12-21 2010-01-26 Mitsubishi Tanabe Pharma Corporation Remedies and/or preventives for nervous system disorders
WO2007002884A2 (fr) 2005-06-29 2007-01-04 Merck & Co., Inc. 4-fluoro-piperidines antagonistes du canal calcium de type t
EP1901746A2 (fr) * 2005-06-29 2008-03-26 Merck & Co., Inc. 4-fluoro-piperidines antagonistes du canal calcium de type t
EP1901746A4 (fr) * 2005-06-29 2011-11-30 Merck Sharp & Dohme 4-fluoro-piperidines antagonistes du canal calcium de type t
US11684590B2 (en) 2018-06-27 2023-06-27 Cornell University Substituted alkylphenols as HCN1 antagonists

Also Published As

Publication number Publication date
JPH08504792A (ja) 1996-05-21
EP0675883A1 (fr) 1995-10-11
KR950704284A (ko) 1995-11-17
AU5833494A (en) 1994-07-19
CN1092415A (zh) 1994-09-21
CA2152394A1 (fr) 1994-07-07
MX9400070A (es) 1994-07-29

Similar Documents

Publication Publication Date Title
USRE33024E (en) Bronchodilating 8-hydroxy-5-(1R)-1-hydroxy-2-(N-((1R)-2-(p-methoxyphenyl)-1-methylethyl)-amino)ethyl) carbostyril and intermediates thereof
WO1994014786A1 (fr) Derives de piperidine utilises en tant qu'antagonistes de canaux a calcium
AU649468B2 (en) 3-substituted piperidine derivatives
US4879300A (en) Novel piperidine derivatives
JPH075539B2 (ja) 置換スルホンアミドベンズアミド及びその製法
PT1720544E (pt) Novos derivados azabicíclios, o processo para a sua preparação, e os compostos farmacêuticos que os contenham
US5817698A (en) Substituted cycloalkylamine derivatives and their use as calcium channel antagonists
US5082847A (en) Carbostyril compounds connected via an oxyalkyl group with a piperidine ring and having pharmaceutical utility
US5153207A (en) Piperidine derivative, method for preparation thereof, and a pharmaceutical composition comprising the same
US4166120A (en) Analgesic and tranquilizing benzoylpropyl-spiro[dihydrobenzofuran]piperidines and pyrrolidines
JPH0283375A (ja) ２−置換ピペラジニル−２−（１，２−ベンズイソキサゾール−３−イル）酢酸誘導体
US5095022A (en) Piperidine derivatives and pharmaceutical compositions comprising the same
EP0420120B1 (fr) Composé benzylalcool optiquement actif et composition pharmaceutique
WO1994003425A2 (fr) Derives de carbostyrile pour le traitement de l'arythmie cardiaque
US5071858A (en) Antipsychotic benzothiopyranylamines
GB2040933A (en) Cis- and Trans-3-Aryloxy-4- Hydroxypyrrolidines and Derivatives Thereof
WO1995011238A1 (fr) Amines heterocycliques pour le traitement des acces ischemiques
JPH09504014A (ja) カルシウムチャネル拮抗薬としてのアミン誘導体類
WO1995024390A1 (fr) Nouvelles piperidines substituees par phenyl(-alkyl/alkoxy)-1-aminoalkyle et pyrolidines utilisees comme antagonistes des canaux calciques
US4585785A (en) Cis and trans-3-aryloxy-4-hydroxypyrrolidines used as anti-arrhythmics
US4831049A (en) Pyrrolizidine compounds, and their use as antiarrhythmic agents
US4452809A (en) Trans-4-(2-chlorophenoxy)-1-ethyl-3-pyrrolidinol and anti-depressant use thereof
EP0401779A1 (fr) Dérivés de 4,5,5a,6-tétrahydro-3H-isoxazolo(5,4,3-k1)acridines, procédé pour leur utilisation comme médicaments
US4590274A (en) Antihypertensive 1-[bis-(substituted phenyl)methyl]-4[2-(1,2,3,4-tetrahydro-substituted naphthalen-1-ylidene)ethyl]piperazines
AT284828B (de) Verfahren zur Herstellung von neuen N-substituierten 2-Phenyl-2-(2'-hydroxy-1'-naphthyl)-äthylaminen und deren Säureadditionssalzen

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR BY CA CH CZ DE DK ES FI GB HU JP KP KR KZ LK LU LV MG MN MW NL NO NZ PL PT RO RU SD SE SK UA US UZ VN

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 NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1994904162

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 259519

Country of ref document: NZ

ENP Entry into the national phase

Ref document number: 1995 464612

Country of ref document: US

Date of ref document: 19950620

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2152394

Country of ref document: CA

WWP Wipo information: published in national office

Ref document number: 1994904162

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWW Wipo information: withdrawn in national office

Ref document number: 1994904162

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载