EP0594729A1 - 2-(4-hydroxypiperidino)-1-alkanol derivatives as antiischemic agents - Google Patents

2-(4-hydroxypiperidino)-1-alkanol derivatives as antiischemic agents

Info

Publication number
EP0594729A1
EP0594729A1 EP92915510A EP92915510A EP0594729A1 EP 0594729 A1 EP0594729 A1 EP 0594729A1 EP 92915510 A EP92915510 A EP 92915510A EP 92915510 A EP92915510 A EP 92915510A EP 0594729 A1 EP0594729 A1 EP 0594729A1
Authority
EP
European Patent Office
Prior art keywords
carbons
group
alkyl
hydrogen
hydroxy
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP92915510A
Other languages
German (de)
French (fr)
Inventor
Willard Mckowan Welch, Jr.
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Inc
Original Assignee
Pfizer Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Inc filed Critical Pfizer Inc
Publication of EP0594729A1 publication Critical patent/EP0594729A1/en
Ceased legal-status Critical Current

Links

Classifications

    • 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%) .

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

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.Series of 2- (4-hydroxypiperidino) -1-alkanol (I) derivatives used as medicaments in the treatment of traumatic lesions of the brain and spinal cord as well as degenerative neuronal conditions such as senile dementia, in mammals and in particular in humans.

Description

* 2-(4-HYDROXYPIPERIDINO)-l-ALKANOL
DERIVATIVES AS ANTIISCHE IC AGENTS BACKGROUND OF THE INVENTION 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
which is marketed as a hypotensive agent, a utility shared by a number of close analogs. Carron et al. , U.S. Patent 3,509,164; Carron et al. , Drug Res., v. 21, pp. 1992-1999 (1971) . More recently, ifenprodil has been shown to possess antiischemic and excitatory amino acid receptor blocking activity. Gotti et al . , J. Pharm. Exp. Therap. , v. 247, pp. 1211-21 (1988); Carter et ai. , loc. cit. , pp. 1222-32 (1988) . See also French Patent 2546166 and EPO publication EP-A1-351282, published January 17, 1990. A goal, substantially met by the present invention, has been to find compounds possessing neuroprotective activity in good measure, while at the same time having lowered or no significant hypotensive effect.
Certain l-phenyl-3-(4-aryl-4-acyloxy-piperidino)-1- propanols have also been reported to be useful as analgesics, U.S. Patent 3,294,804; l-[4-(amino-and hydroxy-alkyl)phenyl]-2-(4-hydroxy-4-tolylpiperazino)-1- alkanols and alkanones have been reported to possess analgesic, antihypertensive, psycho- tropic or antiinflammatory activity, Japanese Kokai 53-02,474 (CA 89:43498y; Derwent Abs. 14858A) and 53-59,675 (CA 89:146938w; Derwent Abs. 48671A) ; and 2-piperidino-l- alkanol derivatives have been reported to be active as antiischemics, EP 398,578-A and Der 90-350,327/47.
SUMMARY OF THE INVENTION The present invention is directed to compounds of the formula
CD
wherein Rlf R2 and R3 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 R2 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, chloro, bromo, fluoro, trifluoromethyl, nitro, amino and alkoxy 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, NHCOR4, NHCOOR5 and NHS02R6,* wherein R4 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 R5 and R„ are each selected from the group consisting of 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; or M and Q when taken together form a divalent radical Z, wherein Z is selected from the group consisting of
H
wherein R7 and Rg are each selected from the group consisting of hydrogen and methyl; and the pharmaceutically acceptable acid addition salts of these compounds.
The expression "pharmaceutically acceptable acid addition salts" is 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,
wherein Z is . Ri and R2 are hydrogen and R3 is methyl
and the compounds possess lr*. 2s* or erythro relative stereochemistry at the 1- and 2-positions of the propanol chain, i.e.,
OH
A second preferred group of compounds of this invention are those in which M and Q form a radical Z, wherein Z
is I , R, and R2 are hydrogen and R3 is methyl and
H
the compounds possess Is*. 2s* or threo relative stereochemistry at the 1- and 2- positions of the propanol chain, i.e. , OH
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
(IV)
wherein
R2 and R3 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; 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 1 to 4 carbons, NHCOR4, NHCOOR5 and NHSO^; wherein R» is 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, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, alkyl having 1 to 4 carbons and alkoxy having 1 to 4 carbons; and wherein R5 and Rή are each selected from the group consisting of 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; or M and Q when taken together form a divalent radical Z, wherein Z is selected from the group consisting of
H
and wherein R7 and R8 are each selected from the group consisting of hydrogen and methyl.
Depending on the precise values of R, R2 and R3, 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.
DETAILED DESCRIPTION OF THE INVENTION
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 -NH2 substituent groups in protected form, i.e., as -0A,, or -NHA2 groups in the compounds of formula (IV) . At and A2 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.,
(III)
(IV)
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. If desired, the reaction is catalyzed by the addition of up to one molar equivalent or more of 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. As used in the preceding paragraph, and elsewhere herein, the expression "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. If desired, those ketone intermediates (IV) having OH or NH2 groups in protected form (OAt or NHA2) , can be deprotected at this stage by conventional methods.
For example when A, is triisopropylsilyl or tert- butyldimethylsilyl, 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. When Ax is benzyl or A2 is benzyloxycarbony1, 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. Generally, 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) . As used in the preceding paragraph, and elsewhere herein, the term "threo" or lr*, 2s_* refers to the relative stereochemistry at the 1- and 2- positions of the propano1 chain, i.e.,
OH
and the term "erythro" or lr*, 2s* refers to the relative stereochemistry at the 1- and 2-positions of the propanol chain, i.e.,
OH
To obtain the desired erythro compounds of formula (I) 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. To obtain the desired threo compounds of formula (I) 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) .
Any protecting groups which are still in place after ketone reduction are then removed according to standard methods described above.
The starting materials and reagents required for the synthesis of the compounds of the present invention are readily available, either commercially, according to literature methods, or by methods exemplified in Preparations below.
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.
Part I: Cell Isolation:
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. Next, 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. When all of the dissection is completed, 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 μl of a 10 mg/ml stock sterile solution) . The tube is incubated for 1 hour at 37 degrees Centigrade. After trypsin incubation the tissue is washed with 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) . The plates are fed on day 3 with fresh medium. Then on day 6 cytosine arabinoside at 10 μm is added to the cultures with fresh medium. Then two days later the cytosine arabinoside is removed and replaced with Maintenance medium, which is complete medium minus the Fetal Calf Serum. The plates are then fed twice a week. Three weeks from the time of dissection the plates are used in the glutamate toxicity experiments, in order to insure proper development of the neurons in culture.
Part 2: Glutamate Treatment and Post-Glutamate Drug Addition:
After three weeks in culture, the medium is removed from the cells and the cells are washed three times in chloride free controlled salt solution (CSS-Cl) . CSS-C1 contains 69 mM Na2S04, 2.67 mM K2S04, 0.33 mM NaHP04, 0.44 mM KH2P04, 1 mM NaHC03, 1 mM MgS04, 10 mM HEPES (N-2- hydroxyethylpiperazine-N1-2-ethanesulfonic acid), 22.2 mM glucose, and 71 mM sucrose at pH 7.4. After washing, 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 μl 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 μl of medium from each plate is removed and transferred to a clean plate to be assayed for the amount of LDH released. Then 100 μl per well of MTT solution is added. This MTT solution is prepared by adding 10 μl of MTT stock (5 mg/ml in PBS, phosphate buffered saline) for every 100 μl serum free medium. Plates are incubated at 37 degrees for 4 to 6 hours. Then 100 μl 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.
The medium which is removed is then assayed for LDH. Equal volumes of the samples removed are added to LDH reaction mixture. In this case appropriate wells are pooled to make 500 μl samples. For each sample, reaction mixture is prepared by mixing 480 μl of 0.1 M sodium phosphate buffer, pH 7.5, 10 μl of sodium pyruvate (66 mM) and 10 μl NADH reduced (each vial of NADH containing 5 g is reconstituted in 440 μl 0.1 N NaOH and 10 μl 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. In the systemic treatment of such diseases in a human subject with a neuroprotective amount of compounds of the formula (I) , 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. Of course, depending upon the exact compound and the exact nature of the individual illness, 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.
The compounds of the present invention are generally administered in the form of pharmaceutical 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.
The present invention is illustrated by the following examples, but is not limited to the details thereof.
All non-aqueous reactions were run under dry, oxygen free nitrogen for convenience and generally to maximize yields. All solvents/diluents were dried according to standard published procedures or purchased in a predried form. All reactions were stirred either magnetically or mechanically. NMR spectra are recorded at 300 MHz and are reported in ppm downfield from trimethylsilane. The NMR solvent was CDC13 unless otherwise specified. IR spectra are reported in micrometers, generally specifying only strong signals. Example 1 (±)-3,4-Dihydro-6-(l-hydroxy-2-(1-(4-hydroxy-4-phenoxy- methyl.piperidinyl)ethyl) uinoline-2-.1H. -one
A mixture of 300 mg (1.23 mmol) of 4-hydroxy-4-(phenoxy- methyl)piperidine hydrochloride, 409 mg (1.84 mmol) of 6- (2-chloroacetyl)-3,4-dihydroquinolin-2(lH)-one and 0.514 mL (0.373 g, 3.7 mmol) of triethylamine in 25 mL of acetonitrile was heated at 60°C overnight. The solvent was then removed in vacuo and the residues partitioned between water and ethyl acetate and the organic layer was washed again with water and with brine. The ethyl acetate layer was dried with brine and magnesium sulfate and the solvent was evaporated to give 3,4-dihydro-6- (l-oxo-2-(1-(4-hydroxy-4-phenoxymethyl)piperidinyl)ethyl) quinoline-2-(lH)-one as a brown solid which was used in the subsequent reduction step without further purification.
The above ketone was dissolved in 25 mL of absolute ethanol and 500 mg (13.1 mmol) of NaBH4 was added portion- wise over 20 min. The reaction mixture was stirred at room temperature for 4 hrs. and then the solvent was removed and the residues were partitioned between water and ethyl acetate. After drying, the ethyl acetate was removed in vacuo and the residue was chromatographed on silica gel to give the product, 73 mg (15%) , m.p. 186- 188°C. NMR (CD3OD) S 1.70-2.10 (4H, m) , 2.52-3.07 (10H, m) , 3.33 (2H, S) , 3.83 (2H, s) , 6.82-7.38 (8H, m) .
Example 2 (±)-5-(l-Hydroxy-2-(1-(4-hydroxy-4-phenoxymethyl)- piperidinyl)ethyl)benzimidazolin-2-one
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. Anal. Calcd. for C^H^N^-H : C, 62.81; H, 6.77; N, 10.46. Found: C, 62.98; H, 6.54; N, 10.32.
Example 3 (±)-5-(l-Hydroxy-2-(1-(4-hydroxy-4-phenoxymethy1)- piperidinyl)ethyl)-2-oxindole
Following the procedure of Example 1, the present title compound was obtained from 4-hydroxy-4-
(phenoxymethy1)piperidine hydrochloride (1.23 mmol), 5-(2- chloroacetyl)oxindole (1.84 mmol) and triethylamine (3.7 mmol) in 25 ml of acetonitrile. The resulting ketone was stirred with sodium borohydride (13.1 mmol) in absolute ethanol to yield the desired compound after chromatography on silica gel. Yield 40%, m.p. 171-174°C.
Example 4 (±)-Erythro-5-(l-hydroxy-2-(1-(4-hydroxy-4-phenoxymethy1) piperidinyl)propyl)benzimidazolin-2-one
A solution of 933 mg (2.36 mmol) of (±)-l-(5-(2- hydroxybenzimidazolyl) )-2-(1-( -hydroxy-4-phenoxymethy1) piperidinyl)propan-1-one in 10 mL of glacial acetic acid and 50 mL of absolute ethanol was treated portionwise with 944 mg (17.48 mmol) of potassium borohydride between 15- 20°C and the resulting solution was stirred overnight at room temperature. The reaction mixture was then evaporated to dryness and the residues taken up in minimal water. The pH of this solution was adjusted to 7-8 with solid NaHC03, precipitating a solid. This material was insoluble in chloroform and relatively insoluble in ethyl acetate. The whole was again evaporated to dryness and the residues, which had crystallized, were taken up in ethanol and filtered to remove salts. The ethanol was evaporated and the residue taken up in isopropanol and treated with HC1 gas in ether to precipitate a non- crystalline salt which was separated by filtration and dried in a stream of dry nitrogen. This material was dissolved in hot ethyl acetate with methanol and clarified with decolorizing charcoal and then the methanol was boiled off. Cooling gave a colorless crystalline product, 410 mg (40%), m.p. 254-255°C. IR (KBr) 5.90 μm; NMR (CD30D) δ 1.22 (3H, d, J=7) , 1.95-2.09 (2H, m) , 2.15-2.30 (2H, m) , 3.42-3.76 (4H, m) , 3.91 (2H, s) , 5.47 (1H, s) , 6.92-7.35 (8H, m) .
Example 5 (±)-Threo-5-(l-hydroxy-2-(1-(4-hydroxy-4-phenoxymethy1)- piperidinyl)propyl)benzimidazolin-2-one:
A total of 700 mg (18.4 mmol) of sodium borohydride was added portionwise to a suspension of 325 mg (0.82 mmol) of (±)-l-(5-(2-hydroxybenzimidazolyl)-2-(l-(4- hydroxy-4-phenoxymethy1)piperidinyl)propan-1-one in 20 mL of absolute ethanol and the reaction mixture was stirred overnight at room temp. The solvent was then evaporated and the residual foam was taken up between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate extracts were dried and evaporated and the residual foam was chromatographed on silica gel using 1:1 ethanol/ethyl acetate to give the product as a white solid, m.p.>250°C. NMR (Acetone-d6) δ 0.79 (3H, d, J=7), 1.71-1.88 (2H, m) , 11.90-2.08 (2H, m) , 2.48-2.88 (4H, m) , 3.01 (1H, t, J=7) , 3.88 (2H, s) , 4.26 (1H, d, J=7) , 6.86-7.32 (8H, m) ; Anal. Calcd for C^H^N^.l.S H20:C, 62.24; H, 7.12; N, 9.89. Found: C, 61.72; H, 6.73; N, 9.03.
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 KBH4 at 15- 20°C and was then allowed to warm to room temperature for 30 min. The reaction mixture was evaporated to dryness and the residue was taken up in ice and cold water and this was basified with solid NaHC03. The solid which precipitated was separated by filtration, washed with water and air dried to give 3.66 g of crystalline free base, m.p. 192-196°C. The filtrate was extracted with ethyl acetate and the combined extracts were dried with brine and with MgS04 and evaporated to give an additional 786 mg of product (total yield 62%) . A 510 mg sample of this material was dissolved in ethyl acetate and treated with a solution of HCl gas in ether to give 475 mg of the crystalline hydrochloride salt, m.p. 214-216°C (dec) . IR (KBr) μm; NMR (CD30D) δ 1.15 (3H, d, J=7) , 1.86-2.04 (2H, m) , 3.52-3.66 (2H, m) , 3.69-3.80 (1H, m) , 3.86 (2H, S) , 5.34 (1H, s) , 6.81-6.96 (4H, m) , 7.17-7.28 (4H, m) . Example 7
(±)-Threo-3,4-dihydro-6-(l-hydroxy-2-(1-(4-hydroxy-4- phenoxymethyl)piperidinyl) ropyl)quinolin-2 (1H)one:
A total of 1.50 g (39.5 mmol) of NaBH4 was added portionwise to a suspension of 700 mg (1.71 mmol) of (±)- 1-(5-(2-hydroxybenzimidazolyl) )-2-(1-(4-hydroxy-4- phenoxymethyl)piperidinyl)propan-1-one in 20 mL of absolute ethanol and the reaction mixture was stirred overnight at room temperature. The solvent was then evaporated and the residual foam was taken up between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The combined extracts were dried and evaporated and the residual foam was chromatographed on silica gel using 1:1 ethanol/ethyl acetate to give the product as a white solid, m.p. 192- 196°C. A small amount of the erythro compound was formed in this reduction and could be separated from the column. NMR (CD3OD) δ 0.82 (3H, d, J=7) , 1.72-2.06 (4H, m) , 2.50- 2.82 (6H, m) , 2.88-3.02 (2H, t, J=7) , 3.02 (IH, t, J=7) , 3.84 (2H, s) , 4.28 (IH, d, J=7) , 6.80-7.34 (8 H, m) ; Anal. Calcd for H20:C, 65.88; H, 7.60; N, 6.40. Found: C, 65.74; H, 7.09; N, 6.31.
Example 8
(±)-Erythro-5-(l-hydroxy-2-(1-(4-hydroxy-4-phenoxymethy1) piperidinyl)propyl)oxindole A mixture of 0.5 g (2.05 mmol) of 4-hydroxy-4- phenoxy ethyl)piperidine hydrochloride, 0.5 g (2.25 mmol) of 5-(2-chloropropionyl)oxindole and 1 ml (0.725 g, 7.18 mmol) triethylamine in 20 mL of acetonitrile was refluxed for 24 h. The solvent was then removed in vacuo and the residues were partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water and brine and was dried over MgS04 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 NaBH4 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 MgS04 and then evaporated to dryness. The residues were chromatographed on silica gel using ethyl acetate and gradually increasing concentrations of ethanol to give the threo product in pure fractions, 121 mg (24%), m.p. 204-207°C. NMR (DMS0-d6) .5* 0.70 (3H, d,
J=7), 1.58-1.92 (4H, m) , 2.40-2.65 (4H, m) , 2.86 (IH, m) , 3.32-3.40 (2H, m) , 3.79 (2H, s) , 4.20 (IH, d, J=7) , 6.70- 7.35 (8H, m) , 10.34 (IH, s) . Example 9 (±)-1-(6-(1,2,3,4-Tetrahydro-2-oxoquinolinyl) )-2-(1-(4- hvdroxy-4-phenoxymethyl)piperidinyl)propan-1-one
A suspension of 8.30 g (34.06 mmol) of 4-hydroxy-4- phenoxymethylpiperidine hydrochloride and 8.09 g (34.06 mmol) of 6-(2-chloro-l-propionyl)-l,2,3,4-tetrahydroquin- olin-2(lH)-one in 100 mL of acetonitrile was treated with 16.61 mL (12.04 g, 0.12 mol) of triethylamine and the mixture was heated at reflux for 3 h and then stirred overnight at room temperature.
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. NMR (CD30D) δ 1.28 (3H, d, J=7) , 1.60-1.92 (4H, m) , 2.52-2.84 (6H, m) , 3.00 (2H, t, J=7) , 3.75 (2H, s) , 4.22 (IH, q, J=7), 6.82-7.00 (4H, m) , 7.16 (2H, m) , 7.82-7.98 (2H, m) ; Anal. Calcd for C24H28N204:C, 70.56; H, 6.91; N, 6.86. Found: C, 70.16; H, 6.78; N, 6.76.
Example 10 (±)-l-(5-(2-Hydroxybenzimidazolyl) )-2-(l-(4-hydroxy-4- ^
A suspension of 2.43 g (10.0 mmol) of 4-hydroxy-4- phenoxymethylpiperidine hydrochloride and 2.25 g (10.0 mmol) of 5-(2-chloro-l-propionyl)-2-hydroxybenzimidazole in 40 mL of acetonitrile was treated with 4.88 mL (3.53 g, 35.0 mmol) of triethylamine and the reaction mixture was heated at reflux for 90 min and then let sit over a weekend at room temperature.
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. The filtrate was adjusted to pH=7.0 and extracted with ethyl acetate several times to give, after drying with brine solution and MgS04, a colorless solid which was recrystallized from hot ethyl acetate/methanol to give an additional 560 mg of product (total yield, 43%), m.p. 230-235°C (dec). NMR (CD^D/DMSO-d δ 1.29 (2H, d, J=7) , 1.60-1.92 (4H, m) , 2.54-2.84 (4H, m) , 3.77 (2H, s) , 4.26 (IH, q, J=7) , 6.86- 7.10 (6H, m) , 7.75-7.92 (2H, m) .
Example 11 (±)-1-(5-(Oxindolyl))-2-(1-(4-hydroxy-4-phenoxymethy1) piperidinyl)propan-1-one
Following the procedure of preparation 10, the present title compound was obtained from 4-hydroxy-4- phenoxymethylpiperidine hydrochloride (10.0 mmol), 5-(2- chloropropionyl)oxindole (10 mmol) and triethylamine (35 mmol) in 50 ml of acetonitrile. The title compound was isolated by crystallization from hot ethyl acetate/ methanol to give an amorphous foam. Yield 66.4%.
NMR (CDC13) δ 1.28 (3H, d, J=7) , 1.58-1.78 (4H, m) , 2.40- 2.84 (4H, m) , 3.54 (2H, s) , 3.76 (2H, s) , 4.09 (IH, q, J=7) , 6.78-6.96 (3H, m) , 7.14-7.26 (2H, m) , 7.84-8.05 (3H, m) , 9.52 (IH, broad s) , 9.64 (IH, broad s) . Preparation 1 3,4 Dihydroquinolin-2-(IH)-one A slurry of 50.0 g (0.259 mol) of o-nitrocinnamic acid in 500 mL of ethanol was treated with 5 teaspoons of Raney Ni and hydrogenated on a Parr shaker overnight at an initial pressure of 50 psi. In the morning, the pressure was increased again to 50 psi and the reaction was continued for an additional 5 h. The reaction mixture was filtered to remove the catalyst and then washed through a bed of silica gel with a mixture of ethyl acetate and ethanol to remove traces of nickel salts. Evaporation of the filtrate gave the desired product in 57% yield. NMR (DMSO-d6) δ 2.45 (2H, t, J=7) , 2.87 (2H, t, J=7) , 6.87 (2H, d of d, J=7, 7), 7.12 (2H, d of d, J=7, 10), 10.08 (IH, S) . m.p. 165-166°C.
Preparation 2 6-(2-Chloropropionyl)-3,4-dihydroquinolin-2-.IH)-one
A suspension of 72.5 g (0.544 mol) of A1C13 in 800 mL of CS2 was stirred under dry N2 while 14.1 mL (20.0 g, 0.177 mol) of 2-chloropropionyl chloride was added followed by 20.0 g (0.136 mol) of 3,4-dihydroquinolin- 2(lH)-one. The reaction mixture was refluxed for 4 h at which time a separation of phases was noted. The reaction was quenched by pouring onto ice with vigorous stirring. The pale yellow precipitate which formed was separated by filtration, washed with water and dried overnight over P205 to give 27.7 g (91%) of the desired product, m.p. 236.5- 238°C.
Preparation 3 5-f2-Chloropropionyl)-2-hvdroxybenzimidazole Following the procedure of Preparation 2, the present title compound was obtained from 2-hydroxybenzi- midazole (0.136 mol), aluminum chloride (0.544 mol) and 2- chloropropionyl chloride (0.177 mol) in 800 ml CS2. The title compound was isolated by filtration. Yield 92%, m.p. 245° dec. Anal. Calcd for Ci0H9ClN2O2: C, 53.47; H, 4.04; N, 12.47. Found C, 54.41; H, 4.07; N, 13.25.
Preparation 4
5-.2-Chloropropionyl)oxindole Following the procedure of Preparation 2, the present title compound was obtained from oxindole (0.136 mol), aluminum chloride (0.544 mol) and 2-chloropropionyl chloride (0.177 mol) in 800 ml CS2. The title compound was isolated by filtration. Yield 91%, m.p. 157-158°C.
Preparation 5 6-(2-Chloroacetyl)-3.4-dihydroquinolin-2(IH)-one Following the procedure of Preparation 2, the present title compound was obtained from 3,4-dihydroquinolin-2- (lH)-one (0.136 mol), aluminum chloride (0.544 mol) and 2- chloroacetyl chloride (0.177 mol) in 800 ml CS2. The title compound was isolated by filtration. Yield 50%, m.p. 215- 216°C.
Preparation 6 5-f2-Chloroacetyl)-2-hvdroxybenzimidazole Following the procedure of Preparation 2, the present title compound was obtained from 2-hydroxybenzimidazole (0.136 mol), aluminum chloride (0.544 mol) and 2- chloroacetyl chloride (0.177 mol) in 800 ml CS2. The title compound was isolated by filtration. Quantitative yield, m.p. 273-275°C (dec) .
Preparation 7 5- (2-Chloroacetyl)-oxindole Following the procedure of Preparation 2, the present title compound was obtained from oxindole (0.136 mol), aluminum chloride (0.544 mol) and 2-chloroacetyl chloride (0.177 mol) in 800 ml CS2. The title compound was isolated by filtration. Yield 90%, m.p. 236.5-239°C.
Preparation 8 4-Hvdroxy-4-phenoxymethylpiperidine hydrochloride Oil free sodium hydride (2.16 g, 0.09 M) was added to dry dimethyl sulfoxide (250 mL) under nitrogen gas and the mixture was heated to 60-65°C until a uniform black solution was formed, about 1 h. Then 19.83 g (0.09 M) of trimethylsulfoxonium iodide was added (slight exotherm) and the mixture was stirred until a brown solution occurred, about 30 min. Then a solution of 13.40 g (67.3mM) of N-t-butyloxycarbonyl-4-piperidone in 50 mL of dimethyl sulfoxide was stirred at room temperature for 1 h. The 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).
Further extraction of the aqueous layers with 3X 50 mL of hexane gave a further 650 mg of product for a total yield of 82.5%. m.p. 57.5-59.5°C; IR(KBr) 5.90 μm; NMR δ 1.32-1.48 (2H, m) , 1.42 (9H, s) , 1.74-1.80 (2H, m) , 2.65 (2H, s) , 3.31-3.43 (2H, m) , 3.61-3.72 (2H, m) ; Anal. Calcd for CnHjgNOa: C, 61.94; H, 8.98; N, 6.57. Found: C, 62.05; H, 9.09; N, 6.58.
A solution of 10.37 g (0.11 M) of phenol in 100 mL of dry dimethyl sulfoxide treated portionwise with 1.99 g (82.8 mmol) of oil-free sodium hydride keeping the temperature between 20-25°C with a cold water bath. The reaction mixture was then stirred at room temperature for 45 min to give a grey suspension. The 11.75 g (55.2 mmol) of 6-t-butyloxycarbonyl-l-oxa-6-azaspiro[2.5]octane dissolved in 65 mL of dimethyl sulfoxide was added dropwise after which the reaction mixture was heated to 55-60°C for 7 h and was then stirred at room temperature overnight.
The 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%) .
IR (Film) 5.91, 2.95 μM; NMR (CDC13) δ 1.46 (9H, s) ; 1.53-1.80 (4H, m) , 3.13-3.30 (2H, m) , 3.80 (2H, s) , 3.80- 3.98 (2H, m) , 6.84-6.99 (2H, m) , 7.22-7.44 (3H, m) ; Anal. Calcd for C^H^NO^ C, 66.42; H, 8.20; N, 4.56. Found: C, 65.72; H, 8.21; N, 4.77.
A solution of 17.0 g (0.055 M) of N-t- Butyloxycarbonyl-4-hydroxy-4-phenoxymethylpiperidine in 150 mL of methanol was saturated with HCl gas. After the mixture had cooled, it was again treated with HCl gas and this procedure was again repeated. After crystals had formed, the reaction mixture was treated with 500 mL of anhydrous ether and let stir at room temperature overnight.
The product was filtered and washed with dry ether and dried under a stream of dry N2 to give 10.85 g (80.6%) of crystalline material, m.p. 202-204°C. IR (KBr) 3.06, 3.14, 3.44, 3.57, 3.56, 6.33, 8.06 μm; NMR (D20) δ 2.00 (4 H, broad S) , 3.34 (4H, broad S) , 4.00 (2H, S) , 6.98-7.09 (3H, m) , 7.30-7.43 (2H, m) . Anal. Calcd for C,2H17N02.HCl: C, 59.13; H, 7.44; N, 5.75. Found: C, 58.98; H, 7.11; N, 5.65.

Claims

CLAIMS I claim: 1. A compound of the formula:
CD
and the pharmaceutically-acceptable salts thereof; wherein R,, R2 and R3 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 1 to 4 carbons; or R, and R2 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, chloro, bromo, fluoro, trifluoromethyl, nitro, amino and alkoxy 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 1 to
4 carbons, NHCOR^ NHCOOR5 and NHSO^; wherein R, 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 R5 and Rg are each selected from the group consisting of 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; or M and Q when taken together form a divalent radical z, wherein Z is selected from the group consisting of
H H
H
and
wherein R7 and Rg are each selected from the group consisting of hydrogen and methyl.
2. A compound according to claim 1, wherein R2 is hydrogen; R3 is hydrogen or methyl; and M and Q form the radical Z, wherein Z is selected from the group consisting of
3. A compound according to claim 2, wherein n is 1 and m is 0.
4. A compound according to claim 3, wherein Rj is hydrogen.
5. A compound according to claim 4, wherein R3 is hydrogen.
6. A compound according to claim 5, wherein X and Y are each hydrogen.
7. A compound according to claim 4 of the formula
8. A compound according to claim 7, wherein X and Y are each hydrogen.
9. A compound according to claim 4 of the formula -32-
10. A compound according to claim 9, wherein X and Y are each hydrogen.
11. A compound according to claim 6, wherein Z is
12. A compound according to claim 6, wherein Z is
H N-
0 H
13. A compound according to claim 6, wherein Z is
14. The compound according to claim 8, wherein Z is
15. The compound according to claim 8, wherein Z is
H N-
0 H
16. The compound according to claim 8, wherein Z is
17. The compound according to claim 10, wherein Z is
18. A pharmaceutical composition comprising a neuro¬ protective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
19. A method of treating traumatic injury to the brain and spinal cord, stroke or a CNS degenerative disease in a human subject which comprises administering to said human subject a neuroprotective amount of a compound of claim 1.
20. A compound of the formula:
(IV)
wherein
R2 and R3 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 1 to 4 carbons; i 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, chloro, bromo, fluoro, trifluoro¬ methyl, nitro, amino and alkoxy 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 l 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 1 to 4 carbons, NHCOR,, NHCOOR5 and NHSO^; wherein R» 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 R5 and Rg are each selected from the group consisting of 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; or M and Q when taken together form a divalent radical Z, wherein Z is selected from the group consisting of
H
and wherein R7 and R8 are each selected from the group consisting of hydrogen and methyl.
21. A process for a compound of the formula:
(I)
and the pharmaceutically-acceptable salts thereof; wherein Rx, R2 and R3 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 1 to 4 carbons; or R, and R2 when taken together form a ethylene, 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, chloro, bromo, fluoro, trifluoromethyl, nitro, amino and alkoxy 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 1 to 4 carbons, NHCOR,, HCOORj and wherein 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 R5 and Rg are each selected from the group consisting of 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; or M and Q when taken together form a divalent radical Z, wherein Z is selected from the group consisting of
H
wherein R7 and Rg are each selected from the group consisting of hydrogen and methyl.
EP92915510A 1991-07-17 1992-06-19 2-(4-hydroxypiperidino)-1-alkanol derivatives as antiischemic agents Ceased EP0594729A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US73157791A 1991-07-17 1991-07-17
US731577 1991-07-17
PCT/US1992/004973 WO1993002052A1 (en) 1991-07-17 1992-06-19 2-(4-hydroxypiperidino)-1-alkanol derivatives as antiischemic agents

Publications (1)

Publication Number Publication Date
EP0594729A1 true EP0594729A1 (en) 1994-05-04

Family

ID=24940103

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92915510A Ceased EP0594729A1 (en) 1991-07-17 1992-06-19 2-(4-hydroxypiperidino)-1-alkanol derivatives as antiischemic agents

Country Status (22)

Country Link
EP (1) EP0594729A1 (en)
JP (1) JP2571904B2 (en)
KR (1) KR0165003B1 (en)
CN (1) CN1043759C (en)
AU (1) AU655840B2 (en)
BR (1) BR9206272A (en)
CA (1) CA2113568A1 (en)
CZ (1) CZ284133B6 (en)
EG (1) EG20048A (en)
FI (2) FI940192A0 (en)
HU (1) HUT70528A (en)
IE (1) IE922311A1 (en)
IL (1) IL102473A (en)
MX (1) MX9204190A (en)
NO (1) NO180445C (en)
NZ (1) NZ243580A (en)
PL (1) PL169884B1 (en)
PT (1) PT100689B (en)
RU (1) RU2065859C1 (en)
TW (1) TW201732B (en)
WO (1) WO1993002052A1 (en)
ZA (1) ZA925306B (en)

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5436255A (en) * 1992-07-23 1995-07-25 Pfizer Inc. Method of treating diseases susceptable to treatment by blocking NMDA-receptors
CZ280669B6 (en) * 1992-10-30 1996-03-13 Pfizer Inc. Derivatives of 3,4-dihydro-2(1h)-quinolone and pharmaceutical composition based thereon
US5498610A (en) * 1992-11-06 1996-03-12 Pfizer Inc. Neuroprotective indolone and related derivatives
ZA9610741B (en) 1995-12-22 1997-06-24 Warner Lambert Co 4-Substituted piperidine analogs and their use as subtype selective nmda receptor antagonists
ZA9610738B (en) 1995-12-22 1997-06-24 Warner Lambert Co Subtype selective nmda receptor ligands and the use thereof
ZA9610736B (en) 1995-12-22 1997-06-27 Warner Lambert Co 2-Substituted piperidine analogs and their use as subtypeselective nmda receptor antagonists
ZA9610745B (en) * 1995-12-22 1997-06-24 Warner Lambert Co 4-Subsituted piperidine analogs and their use as subtype selective nmda receptor antagonists
CA2369695A1 (en) * 1999-04-09 2000-10-19 Manabu Itoh Agent for treating neuropathic pain
WO2001030330A2 (en) 1999-10-29 2001-05-03 Merck Sharp & Dohme Limited Method to treat pain utilizing benzimidazole nmda/nr2b antagonists
US6291499B1 (en) 1999-10-29 2001-09-18 Merck & Co., Inc. 2-cyclohexyl 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
US6489477B1 (en) 1999-10-29 2002-12-03 Merck & Co., Inc. 2-aza-bicyclo[2.2.2]octane NMDA/NR2B antigonists
US6476041B1 (en) 1999-10-29 2002-11-05 Merck & Co., Inc. 1,4 substituted piperidinyl NMDA/NR2B antagonists
US6316474B1 (en) 1999-10-29 2001-11-13 Merck & Co., Inc. 2-benzyl and 2-heteroaryl benzimidazole NMDA/NR2B antagonists
US6495561B2 (en) 1999-10-29 2002-12-17 Merck & Co., Inc. 2-cyclohexyl imidazopyridine NMDA/NR2B antagonists
US7217716B2 (en) 2001-02-23 2007-05-15 Merck & Co., Inc. N-substituted nonaryl-heterocyclic NMDA/NR2B antagonists
WO2002080928A1 (en) 2001-04-03 2002-10-17 Merck & Co., Inc. N-substituted nonaryl-heterocyclo amidyl nmda/nr2b antagonists
CA2507509A1 (en) 2002-11-25 2004-06-10 Mochida Pharmaceutical Co., Ltd. Therapeutic agent for respiratory disease containing 4-hydroxypiperidine derivative as active ingredient
JP2007508288A (en) * 2003-10-08 2007-04-05 ファイザー株式会社 Condensed lactam compounds
TWI409289B (en) 2010-09-02 2013-09-21 Taiwan Union Technology Corp Stable solution of the polymer prepared from n,o-heterocycles and its preparinging method and use

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PH17194A (en) * 1980-03-06 1984-06-19 Otsuka Pharma Co Ltd Novel carbostyril derivatives,and pharmaceutical composition containing the same
FR2546166B1 (en) * 1983-05-19 1985-10-25 Synthelabo ENANTIOMERS OF ERYTHRO (BENZYL-4 PIPERIDINO) -2 (HYDROXY-4 OR BENZYLOXY-4 PHENYL) -1 PROPANOL, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
FR2640266B2 (en) * 1988-07-12 1992-07-10 Synthelabo INDOLONES-2, QUINOLEINONES-2, BENZO (B) AZEPINONES-2 AND BENZIMIDAZOLONES-2 DERIVATIVES OF (HYDROXY-1 PIPERIDINYL-2 ALKYL), THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
EP0398578B1 (en) * 1989-05-17 1997-03-12 Pfizer Inc. 2-piperidino-1-alkanol derivatives as antiischemic agents
DK0554247T3 (en) * 1990-05-10 2000-08-07 Pfizer Neuroprotective indolone and related derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9302052A1 *

Also Published As

Publication number Publication date
IL102473A0 (en) 1993-01-14
NZ243580A (en) 1994-10-26
JPH06504293A (en) 1994-05-19
BR9206272A (en) 1995-04-11
ZA925306B (en) 1994-01-17
NO180445C (en) 1997-04-23
KR0165003B1 (en) 1999-01-15
MX9204190A (en) 1993-01-01
CZ284133B6 (en) 1998-08-12
PT100689B (en) 1999-06-30
PL169884B1 (en) 1996-09-30
HUT70528A (en) 1995-10-30
NO940144D0 (en) 1994-01-14
NO180445B (en) 1997-01-13
AU2322592A (en) 1993-02-23
HU9400136D0 (en) 1994-05-30
FI981956A (en) 1998-09-11
IE922311A1 (en) 1993-01-27
FI981956A0 (en) 1998-09-11
JP2571904B2 (en) 1997-01-16
FI940192A (en) 1994-01-14
NO940144L (en) 1994-01-14
FI940192A0 (en) 1994-01-14
WO1993002052A1 (en) 1993-02-04
CN1043759C (en) 1999-06-23
EG20048A (en) 1997-03-27
PT100689A (en) 1993-10-29
IL102473A (en) 1997-07-13
TW201732B (en) 1993-03-11
CZ400892A3 (en) 1994-03-16
AU655840B2 (en) 1995-01-12
RU2065859C1 (en) 1996-08-27
CA2113568A1 (en) 1993-02-04
CN1068566A (en) 1993-02-03

Similar Documents

Publication Publication Date Title
AU655840B2 (en) 2-(4-hydroxypiperidino)-1-alkanol derivatives as antiischemic agents
KR970005927B1 (en) Pyridine and dyridine n-oxide derivatives of diaryl methyl piperidines or piperazines, and compositions and process for preparation thereof
EP1499589B1 (en) Derivatives of n-phenyl(piperidin-2-yl)methyl benzamide, the preparation method thereof and application of same in therapeutics
KR910001042B1 (en) 4-aminoalkyl-2(3h)-indolones and their preparations
JPH08508974A (en) Anilide derivative
EP0319429B1 (en) 9-Acylamino-tetrahydroacridine derivatives and memory enhancing agent containing said derivative as active ingredient
JPH10510536A (en) 2-Substituted 1,2,5-thiadiazolidine-3-one 1,1-dioxides and compositions thereof
US20230056365A1 (en) PROCESS FOR MAKING CRYSTALLINE 2-(3-(4-(7H-PYRROLO[2,3-d]PYRIMIDIN-4-YL)-1H-PYRAZOL-1-YL)-1-(CYCLOPROPYLSULFONYL)AZETIDIN-3-YL)ACETONITRILE
Chapleo et al. Heteroaromatic analogs of the. alpha. 2-adrenoreceptor partial agonist clonidine
JPS6320226B2 (en)
CA2077098A1 (en) Benzopyran derivatives
JP5894164B2 (en) Chromene derivatives
EP0007399B1 (en) Indolylalkyl amines, pharmaceutical preparations containing them and process for their manufacture
EP1790646A1 (en) Isoquinoline und benzo[h]isoquinoline derivatives, their preparation and their therapeutical application as antagonists of histamine H3 receptor .
EP1776339B1 (en) 3-(((4-phenyl)-piperazin-1-yl)-alkyl)-3-alkyl-1,3-dihydro-2h-indol-2-one derivatives and related compounds for the treatment of central nervous system disorders
US6255322B1 (en) 2-(4-hydroxypiperidino)-1-alkanol derivatives as antiischemic agents
CA1266270A (en) Imidazolidinedione derivatives
JPH0375542B2 (en)
EP0079675A1 (en) Oxazolidinedione derivatives
KR100255619B1 (en) Novel piperidine derivatives and preparation method thereof
JP2956788B2 (en) Spiroisoindoline compound, method for producing the same, medicament for treating neurosis containing the same, and intermediate for producing the same
JPH07133274A (en) Pyprole derivative
EP0639568A1 (en) Piperidine compounds, their preparation and use in the treatment of neurodegenerative disorders
JP2000026297A (en) Treatment of glaucauma and ischemic retinopathy
KR20030036834A (en) 5-phenylbenzylamine compounds, process for their production and intermediates for their synthesis

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19940110

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

17Q First examination report despatched

Effective date: 19940729

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 20000813