WO1993002052A1 - Derives 2-(4-hydroxypiperidino)-1-alcanol utilises comme agents anti-ischemiques - Google Patents

Derives 2-(4-hydroxypiperidino)-1-alcanol utilises comme agents anti-ischemiques Download PDF

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Publication number
WO1993002052A1
WO1993002052A1 PCT/US1992/004973 US9204973W WO9302052A1 WO 1993002052 A1 WO1993002052 A1 WO 1993002052A1 US 9204973 W US9204973 W US 9204973W WO 9302052 A1 WO9302052 A1 WO 9302052A1
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carbons
group
alkyl
hydrogen
hydroxy
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PCT/US1992/004973
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English (en)
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Willard Mckowan Welch, Jr.
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Pfizer Inc.
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Priority to CS924008A priority Critical patent/CZ284133B6/cs
Priority to US08/178,269 priority patent/US6255322B1/en
Priority to PL92302290A priority patent/PL169884B1/pl
Priority to AU23225/92A priority patent/AU655840B2/en
Priority to EP92915510A priority patent/EP0594729A1/fr
Priority to BR9206272A priority patent/BR9206272A/pt
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to RU9294012366A priority patent/RU2065859C1/ru
Publication of WO1993002052A1 publication Critical patent/WO1993002052A1/fr
Priority to NO940144A priority patent/NO180445C/no
Priority to FI940192A priority patent/FI940192A/fi
Priority to KR1019940700124A priority patent/KR0165003B1/ko
Priority to FI981956A priority patent/FI981956A0/fi

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic 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
    • 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

Definitions

  • the present invention is directed to neuroprotective (antiischemic excitatory amino acid receptor blocking) 2- (4-hydroxypiperidino)-l-alkanol derivatives defined by formula (I) below; pharmaceutically acceptable salts thereof; a method of using these compounds in the treat ⁇ ment of stroke, traumatic injury to the brain and spinal cord, and neuronal degenerative diseases including (but not limited to) senile dementias such as Alzheimer's disease, Huntington's disease and Parkinson's disease in mammals, especially humans; and to certain intermediates therefor.
  • Ifenprodil (A) is a racemic, so-called dl-ervthro compound having the relative stereochemical formula
  • R lf R 2 and R 3 are each selected from the group consisting of hydrogen, alkyl having 1 to 6 carbons, phenyl and substituted phenyl, wherein the substituent on said substituted phenyl is selected from the group consisting of hydroxy, alkyl having l to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, amino, nitro and alkoxy having 1 to 4 carbons; or R, and R 2 when taken together form a methylene, ethylene, propylene or butylene group; m is 0 to 2; n is 1 or 2; X and Y are each selected from the group consisting of hydrogen, chloro, bromo, fluoro, trifluoromethyl, alkoxy having 1 to 4 carbons, alkyl having 1 to 4 carbons, hydroxy, amino, nitro and substituted phenoxy, wherein the substituent on said substituted phenoxy is selected from the group consisting of hydrogen, hydroxy, alkyl having 1 to 4 carbons,
  • M and Q are each selected from the group consisting of hydrogen, hydroxy, amino, chloro, bromo, fluoro, trifluoromethyl, nitro, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons, N,N-dialkylamino having 1 to 4 carbons in each of said alkyls, N-alkylamino having l to 4 carbons, NHCOR 4 , NHCOOR 5 and NHS0 2 R 6 ,* wherein R 4 is selected from the group consisting of hydrogen, alkyl having 1 to 6 carbons, phenyl and substituted phenyl, wherein the substituent on said substituted phenyl is selected from the group consisting of hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, alkyl having 1 to 4 carbons and alkoxy having 1 to 4 carbons; and wherein R 5 and R violence are each selected from the group consisting of alkyl having 1 to 6 carbons, phenyl and substituted
  • R 7 and R g are each selected from the group consisting of hydrogen and methyl; and the pharmaceutically acceptable acid addition salts of these compounds.
  • salts are intended to include but is not limited to such salts as the hydrochloride, hydrobromide, hydro- iodide, nitrate, hydrogen sulf te, dihydrogen phosphate, mesylate, maleate, and succinate.
  • Such salts are conventionally prepared by reacting the free base form of the compound (I) with an appropriate acid, usually one molar equivalent, and in a solvent. Those salts which do not precipitate directly are generally isolated by evaporation of the solvent and/or addition of a non- solvent followed by filtration.
  • a preferred group of compounds of the present invention are those in which M and Q form a radical Z,
  • Ri and R 2 are hydrogen and R 3 is methyl
  • a second preferred group of compounds of this invention are those in which M and Q form a radical Z, wherein Z
  • the present invention is also directed to pharma ⁇ ceutical compositions containing a compound of the invention of formula I, and to methods of treating a mammal, particularly human subject, suffering from a central nervous disorder, which comprises administering to said mammal a neuroprotective effective amount of a compound of the formula (I) .
  • Said compositions and methods are particularly valuable in the treatment of traumatic injury to the brain and spinal cord, stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease and related disorders of the central nervous system.
  • the present invention is further directed to intermediate compounds of the formula
  • R 2 and R 3 are each selected from the group consisting of hydrogen, alkyl having 1 to 6 carbons, phenyl and substituted phenyl, wherein the substituent on said substituted phenyl is selected from the group consisting of hydroxy, alkyl having 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, amino, nitro and alkoxy having l to 4 carbons; m is 0 to 2; n is 1 or 2; X and Y are each selected from the group consisting of hydrogen, chloro, bromo, fluoro, trifluoromethyl, alkoxy having 1 to 4 carbons, alkyl having 1 to 4 carbons, hydroxy, amino, nitro and substituted phenoxy, wherein the substituent on said substituted phenoxy is selected from the group consisting of hydrogen, hydroxy, alkyl having l to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, nitro, amino and alkoxy having 1 to 4 carbons
  • R 7 and R 8 are each selected from the group consisting of hydrogen and methyl.
  • the compounds of formula (I) can have one or two asymmetric centers, and can therefore exist in various isomeric forms. All such isomers are within the scope of this invention.
  • the individual isomers can be separated by classical methods well-known to those skilled in the art.
  • the compounds of the present invention having the formula (I) defined above, are readily and generally prepared by reaction of chloro compound (II) with piper- idine (III) , followed by reduction of the resulting ketone (IV) to an alcohol as detailed below.
  • the precursor ketones are generally initially prepared with -OH and -NH 2 substituent groups in protected form, i.e., as -0A,, or -NHA 2 groups in the compounds of formula (IV) .
  • a t and A 2 are defined below.
  • Such protected ketones are generally formed by reacting an appropriately substituted 2-halo-l-alkanone (II) with an appropriately substituted piperidino derivative (III), e.g.,
  • Reaction of compound (II) with compound (III) is carried out under conditions typical of nucleophilic displacements in general. Where the two reactants are about equivalent in availability, close to substantially molar equivalents may be used; although when one is more readily available, it is usually preferred to use that one in excess, in order to force this bimolecular reaction to completion in a shorter period of time.
  • the reaction is generally carried out in the presence of at least 1 molar equivalent of a base, the piperidine derivative itself, if it is readily available, but more usually a tertiary amine which is at least comparable in base strength to the nucleophilic piperidine; and in a reaction inert solvent such as ethanol.
  • reaction is catalyzed by the addition of up to one molar equivalent or more of an iodide salt (e.g., Nal, KI) .
  • an iodide salt e.g., Nal, KI
  • Temperature is not critical, but will generally be somewhat elevated in order to force the reaction to completion within a shorter time period, but not so high as to lead to undue decomposition. A temperature in the range of 50-120°C is generally satisfactory. Conveniently, the temperature is the reflux temperature of the reaction mixture.
  • reaction inert solvent refers to any solvent which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
  • those ketone intermediates (IV) having OH or NH 2 groups in protected form OA t or NHA 2 ) , can be deprotected at this stage by conventional methods.
  • the protecting group is conveniently removed by reaction with tetrabutylammonium fluoride (generally, substantially 2 molar equivalents) in a reaction inert solvent such as tetrahydrof ran.
  • a reaction inert solvent such as tetrahydrof ran.
  • the protecting group will generally be removed by conventional hydrogenolysis over a noble metal catalyst in a reaction inert solvent, e.g., using 10% Pd/C as catalyst, preferable at low pressures (e.g., 1-10 atmospheres) and temperatures (e.g., 20-75°C) and generally in a reaction inert solvent such as methanol.
  • the ketone intermediates (IV) are conveniently converted to corresponding alcohols by one of two conventional reduction methods, to selectively produce either the threo compounds or the erythro compounds of formula (I) .
  • threo or lr*, 2s_* refers to the relative stereochemistry at the 1- and 2- positions of the propano1 chain, i.e.,
  • erythro or lr*, 2s* refers to the relative stereochemistry at the 1- and 2-positions of the propanol chain, i.e.,
  • the corresponding ketone intermediates (IV) are conveniently reduced with potassium borohydride, usually in excess (e.g. greater than 5 mole equivalents) , in the presence of glacial acetic acid in a protic solvent such as ethanol, generally at a temperature range of 15-25°C.
  • the corresponding ketone intermediates (IV) are conveniently reduced with sodium borohydride, usually in excess (e.g. greater than 5 mole equivalents) , in a protic solvent such as ethanol, generally at a temperature range of 15-25°C.
  • the resulting reaction mixture is chromatographed on a silica gel column to obtain the said threo compounds of formula (I) .
  • the present compounds of the formula (I) possess selective neuroprotective activity, based upon their antiischemic activity and ability to block excitatory amino acid receptors, while at the same time having lowered or no significant hypotensive activity.
  • the antiischemic activity of the present compounds is determined according to one or more of the methods which have been detailed previously by Gotti et al. and Carter et al. cited above, or by similar methods.
  • the ability of the compounds of the present invention to block excitatory amino acid receptors is demonstrated by the drugs ability to rescue fetal rat neurons in culture which have been exposed to the excitotoxic amino acid glutamate. The following is a typical procedure.
  • Embryos at 17 days gestation are removed from rats and placed into Tyrode's solution.
  • the brains are then removed and placed into fresh Tyrode's solution.
  • Using fine iris knives the hindbrain and thalamus are removed.
  • the forebrain is then separated into two hemispheres.
  • the meninges are removed gently.
  • the hippocampus appears as a darkened folded area on the inner side of the cortex edge.
  • the hippocampus is carefully cut away from the rest of the tissue and placed in a separate corner of the dish.
  • the hippocampal tissue reserved in the corner is minced into 1 mm pieces. These pieces are removed, using a Pasteur pipette and placed into a sterile tube.
  • the Tyrode's solution is aspirated off gently and Calcium-Magnesium Free Tyrode's solution is added.
  • the tissue is washed 3 times with Calcium-Magnesium Free Tyrode's solution. This final wash is incubated 15 minutes at 37 degrees Centigrade.
  • the buffer is again removed and replaced with 1 ml fresh Calcium-Magnesium Free Tyrode's solution.
  • Trypsin is now added at 0.1% (100 ⁇ l of a 10 mg/ml stock sterile solution) .
  • the tube is incubated for 1 hour at 37 degrees Centigrade.
  • serum containing medium in order to stop the action of the trypsin.
  • the tissue is resuspended in 1 ml of fresh medium and triturated with a fine bore Pasteur pipette.
  • Cells are then counted using a hemocytometer. Cells are then seeded onto a 96-well Falcon Primeria tissue culture plates at 75000 cells per well in complete medium.
  • Complete medium is composed of Minimal Essential Medium (MEM) with Earle's salts, 10% Fetal Calf Serum (Hyclone) , 10% Equine Serum, L-glutamine (2mM) , Penicillin- Streptomycin (100U per ml) and Glucose (to make the final concentration 21 mM a lOOx stock containing 27.8 g per 100 ml is prepared) .
  • MEM Minimal Essential Medium
  • Fetal Calf Serum Hyclone
  • 10% Equine Serum L-glutamine (2mM)
  • Penicillin- Streptomycin 100U per ml
  • Glucose to make the final concentration 21 mM a lOOx stock containing 27.8 g per 100 ml is prepared
  • CSS-C1 contains 69 mM Na 2 S0 4 , 2.67 mM K 2 S0 4 , 0.33 mM NaHP0 4 , 0.44 mM KH 2 P0 4 , 1 mM NaHC0 3 , 1 mM MgS0 4 , 10 mM HEPES (N-2- hydroxyethylpiperazine-N 1 -2-ethanesulfonic acid), 22.2 mM glucose, and 71 mM sucrose at pH 7.4.
  • glutamate is added at 1 to 3 mM in CSS-Cl buffer with appropriate control wells containing buffer without glutamate.
  • the plates are incubated at 37 degrees celsius for 15 to 20 minutes. Following glutamate incubation, the plates are washed with serum free medium twice.
  • the test drugs are prepared at the appropriate concentrations in serum free medium and added to the corresponding wells of the microtiter plate (100 ⁇ l per well) .
  • Negative control wells receive serum free medium with no drug.
  • Several glutamate treated wells are also given serum free medium with no drug to serve as positive controls.
  • the plate is incubated overnight at 37 degrees celsius and the following day viability is assessed using the LDH (lactate dehydrogenase) and MTT (methyl thiotetrazolinium) assays.
  • Part 3 Assessment of Cell Viability: The 100 ⁇ l of medium from each plate is removed and transferred to a clean plate to be assayed for the amount of LDH released. Then 100 ⁇ l per well of MTT solution is added. This MTT solution is prepared by adding 10 ⁇ l of MTT stock (5 mg/ml in PBS, phosphate buffered saline) for every 100 ⁇ l serum free medium. Plates are incubated at 37 degrees for 4 to 6 hours. Then 100 ⁇ l of acid-alcohol solution (0.08 N HC1 in isopropanol) is added to each well and the wells were mixed vigorously in order to dissolve the purple crystals. Control wells should contain medium with MTT and acid-alcohol, but no cells. The plates are then read on a microplate reader, using a dual wavelength setting test filter at 570 nm and reference filter at 630 nm. The plates must be read within 1 hour.
  • reaction mixture is prepared by mixing 480 ⁇ l of 0.1 M sodium phosphate buffer, pH 7.5, 10 ⁇ l of sodium pyruvate (66 mM) and 10 ⁇ l NADH reduced (each vial of NADH containing 5 g is reconstituted in 440 ⁇ l 0.1 N NaOH and 10 ⁇ l of this is used per sample) .
  • the sample is quickly added to the reaction mixture in cuvettes and the disappearance of absorbance at 340 nm is measured on a Beck an DU-8 spectrophoto eter.
  • Undesired hypotensive activity is also determined by known methods, for example, according to the methods of Carron et al, also cited above.
  • Such selective neuroprotective antiischemic and excitatory amino acid blocking activities make the compounds of the present invention useful in the treatment of traumatic injury to the brain and spinal cord, degenerative CNS (central nervous system) disorders such as stroke, Alzheimer's disease, Parkinson's disease and Huntington's disease, without significant potential for concurrent undue drop in blood pressure.
  • the dosage is typically from about 0.02 to 10 mg/kg/ day (1-500 mg/day in a typical human weighing 50 kg) in single or divided doses, regardless of the route of administration.
  • doses outside this range may be prescribed by the attending physician.
  • the oral route of administration is generally preferred. However, if the patient is unable to swallow, or oral absorption is otherwise impaired, the preferred route of administration will be parenteral (i.m., i.v.) or topical.
  • compositions comprising at least one of the compounds of the formula (I) , together with a pharmaceutically acceptable vehicle or diluent in a ratio of 1:20 to 20:1 respectively.
  • Such compositions are generally formulated in a conventional manner utilizing solid or liquid vehicles or diluents as appropriate to the mode of desired administration: for oral administration, in the form of tablets, hard or soft gelatin capsules, suspensions, granules, powders and the like; for parenteral administration, in the form of injectable solutions or suspensions, and the like, and for topical administration, in the form of solutions, lotions, ointments, salves and the like.
  • Example l Following the procedure of Example l, the present title compound was obtained from 4-hydroxy-4-(phenoxy- methyl)piperidine hydrochloride (1.23 mmol), 5-(2- chloroacetyl)-2-hydroxybenzimidazole (1.84 mmol) and tri- ethylamine (3.7 mmol) in 25 ml of acetonitrile.
  • the resulting ketone was stirred with sodium borohydride (13.1 m ol) in absolute ethanol to yield the desired compound after chromatography on silica gel. Yield 35%, .p. 232- 235°C.
  • Example 6 ( ⁇ )-Erythro-3,4-dihydro-6-(l-hydroxy-2-(1-(4-hydroxy-4- henoxymethyl)piperidinyl) ropyl)quinolin-2 (1H)one: A solution of 7.13 g (17.5 mmol) of ( ⁇ )-l-(6-(l,2,3,4- tetrahydro-2-oxoquinolinyl) )-2-(1-(4-hydroxy-4- phenoxymethyl)piperidinyl)propan-1-one in 135 mL of absolute ethanol and 70 mL of glacial acetic acid was treated portionwise with 6.22 g (115 mmol) of KBH 4 at 15- 20°C and was then allowed to warm to room temperature for 30 min.
  • the ethyl acetate layer was washed with water and brine and was dried over MgS0 4 and concentrated to yield the ketone as a tan foam which was used for the following reaction without further purification, 537 mg (66%) .
  • a solution of 500 mg (1.26 mmol) of the ketone in 20 mL of ethanol was treated portionwise with 1.0 g (26.3 mmol) of NaBH 4 and the resulting mixture was stirred at room temperature for 24 h. The solvent was removed in vacuo and the residues were partitioned between ethyl acetate and water. The ethyl acetate layer was washed and dried with brine and MgS0 4 and then evaporated to dryness.
  • the reaction mixture was poured into water and extracted 3 times with ethyl acetate and the combined extracts were dried with brine solution and magnesium sulfate and evaporated to give a foam.
  • This foam was dissolved in hot methanol and ethyl acetate and cooled to give a tan solid which was found to be starting chloroketone and discarded.
  • the filtrates were evaporated and dissolved in ethyl acetate and ether was added to facilitate crystallization.
  • the product was filtered and washed with ether to give 8.84 g (63.6%) of the product as a cream-colored solid, m.p. 137-139°C.
  • the analytical sample was crystallized from hot ethyl acetate.
  • the reaction mixture was then poured into a mixture of water and ethyl acetate and the resulting suspended solid was separated by filtration and found to be pure product, 1.15 g after drying.
  • reaction mixture was then poured into 1 L of cold water and the whole was extracted 4X with 100 mL portions of hexane.
  • the combined hexane extracts was back-washed with 50 mL of water and with brine solution and was dried with magnesium sulfate, filtered and evaporated to give 11.75 g of white crystalline product, 6-t-butyloxycar- bonyl-l-oxa-6-azaspiro[2.5]octane, (78% yield).
  • reaction mixture was then poured into 1 L of cold water and extracted 4X with ether.
  • the combined ether extracts was backwashed with 10% NaOH and with brine and was dried with magnesium sulfate evaporated to give the desired product, N-t-butyloxycarbony1-4-hydroxy- 4-phenoxymethylpiperidine, as an oil weighing 17.01 g (100%) .

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Abstract

Série de dérivés 2-(4-hydroxypipéridino)-1-alcanol (I) employés comme médicaments dans le traitement des lésions traumatiques du cerveau et de la moelle épinière ainsi que des affections neuronales dégénératives telles que la démence sénile, chez les mammiféres et notamment chez l'homme.
PCT/US1992/004973 1991-07-17 1992-06-19 Derives 2-(4-hydroxypiperidino)-1-alcanol utilises comme agents anti-ischemiques WO1993002052A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
US08/178,269 US6255322B1 (en) 1992-06-19 1992-06-19 2-(4-hydroxypiperidino)-1-alkanol derivatives as antiischemic agents
PL92302290A PL169884B1 (pl) 1991-07-17 1992-06-19 Sposób wytwarzania nowych pochodnych 2-(4-hydroksypiperydyno)-1-alkanolowych PL PL PL
AU23225/92A AU655840B2 (en) 1991-07-17 1992-06-19 2-(4-hydroxypiperidino)-1-alkanol derivatives as antiischemic agents
EP92915510A EP0594729A1 (fr) 1991-07-17 1992-06-19 Derives 2-(4-hydroxypiperidino)-1-alcanol utilises comme agents anti-ischemiques
BR9206272A BR9206272A (pt) 1991-07-17 1992-06-19 Derivados de 2-(4-hidroxipiperidino)-1-alcanol, como agentes anti-isquêmicos.
CS924008A CZ284133B6 (cs) 1991-07-17 1992-06-19 2-/4-Hydroxypiperidino/-1-alkanolové deriváty jako antiischemická činidla. způsob jejich přípravy a použití.
RU9294012366A RU2065859C1 (ru) 1991-07-17 1992-06-19 Производные 2-(4-гидроксипиперидино)-1-алканола и производные 2-(4-гидроксипиперидино)-1-алканона
NO940144A NO180445C (no) 1991-07-17 1994-01-14 2-(4-hydroksypiperidino)-1-alkanol-derivater som anti-iskemiske midler
FI940192A FI940192A (fi) 1991-07-17 1994-01-14 2-(4-hydroksipiperidino)-1-alkonolijohdannaisia verettömyyden vastaisina aineina
KR1019940700124A KR0165003B1 (en) 1991-07-17 1994-01-15 2-(4-hydroxypiperidino)-1-alkanol derivatives as antiischem ic agents
FI981956A FI981956A0 (fi) 1991-07-17 1998-09-11 2-(4-hydroksipiperidino)-1-alkanolijohdannaisia verettömyyden vastaisia aineina

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US73157791A 1991-07-17 1991-07-17
US731,577 1991-07-17

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WO1993002052A1 true WO1993002052A1 (fr) 1993-02-04

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EP (1) EP0594729A1 (fr)
JP (1) JP2571904B2 (fr)
KR (1) KR0165003B1 (fr)
CN (1) CN1043759C (fr)
AU (1) AU655840B2 (fr)
BR (1) BR9206272A (fr)
CA (1) CA2113568A1 (fr)
CZ (1) CZ284133B6 (fr)
EG (1) EG20048A (fr)
FI (2) FI940192A (fr)
HU (1) HUT70528A (fr)
IE (1) IE922311A1 (fr)
IL (1) IL102473A (fr)
MX (1) MX9204190A (fr)
NO (1) NO180445C (fr)
NZ (1) NZ243580A (fr)
PL (1) PL169884B1 (fr)
PT (1) PT100689B (fr)
RU (1) RU2065859C1 (fr)
TW (1) TW201732B (fr)
WO (1) WO1993002052A1 (fr)
ZA (1) ZA925306B (fr)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994010166A1 (fr) * 1992-10-30 1994-05-11 Pfizer Inc. Composes neuroprotecteurs de 3,4-dihydro-2(1h)-quinolone
US5436255A (en) * 1992-07-23 1995-07-25 Pfizer Inc. Method of treating diseases susceptable to treatment by blocking NMDA-receptors
US5498610A (en) * 1992-11-06 1996-03-12 Pfizer Inc. Neuroprotective indolone and related derivatives
US6124317A (en) * 1995-12-22 2000-09-26 Warner-Lambert Company 2-substituted piperidine analogs and their use as subtype-selective NMDA receptor antagonists
US6124323A (en) * 1995-12-22 2000-09-26 Warner-Lambert Company 4-substituted piperidine analogs and their use as subtype selective NMDA receptor antagonists
US6291499B1 (en) 1999-10-29 2001-09-18 Merck & Co., Inc. 2-cyclohexyl benzimidazole NMDA/NR2B antagonists
US6316474B1 (en) 1999-10-29 2001-11-13 Merck & Co., Inc. 2-benzyl and 2-heteroaryl benzimidazole NMDA/NR2B antagonists
EP1182193A1 (fr) * 1999-04-09 2002-02-27 Mochida Pharmaceutical Co., Ltd. Remedes pour douleurs neurogenes
US6362196B1 (en) 1999-10-29 2002-03-26 Merck & Co., Inc. Method to treat pain utilizing benzimidazole NMDA/NR2B antagonists
US6369076B1 (en) 1999-10-29 2002-04-09 Merck & Co. Inc. 5-benzyl-octahydroindole and 6-benzyl-decahydroquinoline NMDA/NR2B antagonists
US6380205B1 (en) 1999-10-29 2002-04-30 Merck & Co., Inc. 2-cyclohexyl quinazoline NMDA/NR2B antagonists
US6432976B1 (en) 1999-10-29 2002-08-13 Merck & Co., Inc. 8-aza-bicyclo[3.2.1]octane NMDA/NR2B antagonists
US6448270B1 (en) 1995-12-22 2002-09-10 Warner-Lambert Company 4-substituted piperidine analogs and their use as subtype selective NMDA receptor antagonists
US6476041B1 (en) 1999-10-29 2002-11-05 Merck & Co., Inc. 1,4 substituted piperidinyl NMDA/NR2B antagonists
US6489477B1 (en) 1999-10-29 2002-12-03 Merck & Co., Inc. 2-aza-bicyclo[2.2.2]octane NMDA/NR2B antigonists
US6495561B2 (en) 1999-10-29 2002-12-17 Merck & Co., Inc. 2-cyclohexyl imidazopyridine NMDA/NR2B antagonists
US6534522B2 (en) 1995-12-22 2003-03-18 Warner-Lambert Company Subtype-selective NMDA receptor ligands and the use thereof
WO2005035523A1 (fr) * 2003-10-08 2005-04-21 Pfizer Japan Inc. Composes de lactame condense
US7053089B2 (en) 2001-02-23 2006-05-30 Merck & Co., Inc. N-substituted nonaryl-heterocyclic NMDA/NR2B antagonists
US7259157B2 (en) 2001-04-03 2007-08-21 Merck & Co., Inc. N-substituted nonaryl-heterocyclo amidyl NMDA/NR2B Antagonists
US7494987B2 (en) 2002-11-25 2009-02-24 Mochida Pharmaceutical Co., Ltd. Agent for treating respiratory diseases containing 4-hydroxypiperidine derivative as active ingredient

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TWI409289B (zh) 2010-09-02 2013-09-21 Taiwan Union Technology Corp 由氮氧雜環化合物所製得之聚合物之穩態溶液及其製法與用途

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FR2546166A1 (fr) * 1983-05-19 1984-11-23 Synthelabo Enantiomeres du erythro (benzyl-4 piperidino)-2 (hydroxy-4 ou benzyloxy-4 phenyl)-1 propanol, leur preparation et leur application en therapeutique
EP0351282A1 (fr) * 1988-07-12 1990-01-17 Synthelabo Dérivés de (hydroxy-1 pipéridinyl-2 alkyl)indolones-2, quinoléinones-2, benzo[b]azépinones-2, benzimidazolones-2 et quinazolinones-2, leur préparation et leur application en thérapeutique
EP0398578A2 (fr) * 1989-05-17 1990-11-22 Pfizer Inc. 2-Pipéridino-1-alkanol dérivés comme agents anti-ischémiques
WO1991017156A1 (fr) * 1990-05-10 1991-11-14 Pfizer Inc Indolone neuroprotecteur et derives apparentes

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US5436255A (en) * 1992-07-23 1995-07-25 Pfizer Inc. Method of treating diseases susceptable to treatment by blocking NMDA-receptors
US5852040A (en) * 1992-10-30 1998-12-22 Pfizer Inc. Neuroprotective 3,4-dihydro-2(1H)-quinolone compounds
WO1994010166A1 (fr) * 1992-10-30 1994-05-11 Pfizer Inc. Composes neuroprotecteurs de 3,4-dihydro-2(1h)-quinolone
US5498610A (en) * 1992-11-06 1996-03-12 Pfizer Inc. Neuroprotective indolone and related derivatives
US6448270B1 (en) 1995-12-22 2002-09-10 Warner-Lambert Company 4-substituted piperidine analogs and their use as subtype selective NMDA receptor antagonists
US6124317A (en) * 1995-12-22 2000-09-26 Warner-Lambert Company 2-substituted piperidine analogs and their use as subtype-selective NMDA receptor antagonists
US6124323A (en) * 1995-12-22 2000-09-26 Warner-Lambert Company 4-substituted piperidine analogs and their use as subtype selective NMDA receptor antagonists
US6534525B1 (en) 1995-12-22 2003-03-18 Warner-Lambert & Company 2-substituted piperidine analogs and their use as subtype-selective NMDA receptor antagonists
US6534522B2 (en) 1995-12-22 2003-03-18 Warner-Lambert Company Subtype-selective NMDA receptor ligands and the use thereof
EP1182193A1 (fr) * 1999-04-09 2002-02-27 Mochida Pharmaceutical Co., Ltd. Remedes pour douleurs neurogenes
EP1182193A4 (fr) * 1999-04-09 2002-09-11 Mochida Pharm Co Ltd Remedes pour douleurs neurogenes
US6291499B1 (en) 1999-10-29 2001-09-18 Merck & Co., Inc. 2-cyclohexyl benzimidazole NMDA/NR2B antagonists
US6432976B1 (en) 1999-10-29 2002-08-13 Merck & Co., Inc. 8-aza-bicyclo[3.2.1]octane NMDA/NR2B antagonists
US6380205B1 (en) 1999-10-29 2002-04-30 Merck & Co., Inc. 2-cyclohexyl quinazoline NMDA/NR2B antagonists
US6369076B1 (en) 1999-10-29 2002-04-09 Merck & Co. Inc. 5-benzyl-octahydroindole and 6-benzyl-decahydroquinoline NMDA/NR2B antagonists
US6476041B1 (en) 1999-10-29 2002-11-05 Merck & Co., Inc. 1,4 substituted piperidinyl NMDA/NR2B antagonists
US6489477B1 (en) 1999-10-29 2002-12-03 Merck & Co., Inc. 2-aza-bicyclo[2.2.2]octane NMDA/NR2B antigonists
US6495561B2 (en) 1999-10-29 2002-12-17 Merck & Co., Inc. 2-cyclohexyl imidazopyridine NMDA/NR2B antagonists
US6362196B1 (en) 1999-10-29 2002-03-26 Merck & Co., Inc. Method to treat pain utilizing benzimidazole NMDA/NR2B antagonists
US6316474B1 (en) 1999-10-29 2001-11-13 Merck & Co., Inc. 2-benzyl and 2-heteroaryl benzimidazole NMDA/NR2B antagonists
US7053089B2 (en) 2001-02-23 2006-05-30 Merck & Co., Inc. N-substituted nonaryl-heterocyclic NMDA/NR2B antagonists
US7259157B2 (en) 2001-04-03 2007-08-21 Merck & Co., Inc. N-substituted nonaryl-heterocyclo amidyl NMDA/NR2B Antagonists
US7494987B2 (en) 2002-11-25 2009-02-24 Mochida Pharmaceutical Co., Ltd. Agent for treating respiratory diseases containing 4-hydroxypiperidine derivative as active ingredient
WO2005035523A1 (fr) * 2003-10-08 2005-04-21 Pfizer Japan Inc. Composes de lactame condense

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PL169884B1 (pl) 1996-09-30
RU2065859C1 (ru) 1996-08-27
MX9204190A (es) 1993-01-01
FI981956A (fi) 1998-09-11
FI940192A0 (fi) 1994-01-14
IL102473A0 (en) 1993-01-14
NO180445B (no) 1997-01-13
NZ243580A (en) 1994-10-26
HU9400136D0 (en) 1994-05-30
IL102473A (en) 1997-07-13
TW201732B (fr) 1993-03-11
AU2322592A (en) 1993-02-23
AU655840B2 (en) 1995-01-12
IE922311A1 (en) 1993-01-27
ZA925306B (en) 1994-01-17
PT100689A (pt) 1993-10-29
CN1068566A (zh) 1993-02-03
JPH06504293A (ja) 1994-05-19
EP0594729A1 (fr) 1994-05-04
FI981956A0 (fi) 1998-09-11
NO940144L (no) 1994-01-14
CA2113568A1 (fr) 1993-02-04
FI940192A (fi) 1994-01-14
HUT70528A (en) 1995-10-30
CN1043759C (zh) 1999-06-23
PT100689B (pt) 1999-06-30
JP2571904B2 (ja) 1997-01-16
NO940144D0 (no) 1994-01-14
KR0165003B1 (en) 1999-01-15
EG20048A (en) 1997-03-27
CZ400892A3 (en) 1994-03-16
NO180445C (no) 1997-04-23
CZ284133B6 (cs) 1998-08-12

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