WO1997010240A1 - Derives du phenol a activite pharmaceutique - Google Patents

Derives du phenol a activite pharmaceutique Download PDF

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Publication number
WO1997010240A1
WO1997010240A1 PCT/IB1996/000668 IB9600668W WO9710240A1 WO 1997010240 A1 WO1997010240 A1 WO 1997010240A1 IB 9600668 W IB9600668 W IB 9600668W WO 9710240 A1 WO9710240 A1 WO 9710240A1
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Prior art keywords
fluorophenyl
chroman
piperidin
compound
hydroxyl
Prior art date
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PCT/IB1996/000668
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English (en)
Inventor
Bertrand Leo Chenard
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.
Priority to EP96921012A priority Critical patent/EP0859773A1/fr
Priority to JP9502358A priority patent/JPH11509839A/ja
Publication of WO1997010240A1 publication Critical patent/WO1997010240A1/fr
Priority to MXPA/A/1998/002025A priority patent/MXPA98002025A/xx

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention relates to prodrugs for the neuroprotective agent (3R.4S)- 3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-chroman-4,7-diol which is a N-methyl-D- aspartic acid (NMDA) antagonist.
  • the present invention further relates to methods of using, and pharmaceutical compositions containing, the prodrugs described herein.
  • Prodrugs are compounds that have little or no intrinsic biological activity until converted into another, biologically active chemical species in the body of a recipient (e.g. a human).
  • the prodrug Upon delivery to a recipient by any of several routes (such as orally, parenterally, or rectally), the prodrug is transformed into a new compound (parent drug) that possesses desirable bioiogical activity. Conversion of the prodrug into the parent drug can occur in the body at a variety of locations (e.g. gut wall, Iiver, kidney, blood, etc.) and by any of a number of mechanisms (e.g. enzymatic hydrolysis, oxidative metabolism, etc.). Prodrugs can be useful to overcome a variety of limitations of the parent drug.
  • the parent drug may not have an acceptable bioavailability when delivered by an otherwise desirable route of administration.
  • the parent drug may suffer from extensive first pass metabolism that effectively removes the drug from the body at an excessively rapid rate that inhibits effective therapy.
  • the parent drug may have undesirable physical properties, such as poor solubility or stability, or it may have other properties that make formulation of the parent drug difficult or expensive to administer.
  • the prodrug may be easier to synthesize.
  • the prodrugs of the present invention are converted into (3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]- chroman-4,7-diol (parent chromanol) by one or more of the mechanisms described above.
  • the prodrugs of the present invention overcome the limitations of the parent chromanol including one or more of the limitations associated with parent drugs as described above.
  • the prodrugs of the present invention are more stable in solution than the parent chromanol and, as a result, are better suited for intravenous administration.
  • the parent chromanol is an NMDA antagonist and, as such, is useful in the treatment of head trauma, stroke and CNS degenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease and other conditions alleviated by blocking the NMDA receptor.
  • NMDA antagonists are compounds that block the NMDA receptor by interacting with the glutamate binding site or other sites on the receptor molecule.
  • the ability of a particular compound to competitively bind to the NMDA glutamate receptor can be evaluated using a radioligand binding assay. See Murphy et al.. British J. Pharmacol. 95, 932-938 (1988).
  • the antagonists can be distinguished from the agonists using a rat cortical wedge assay. See Harrison and Simmonds, British J. Pharmacol.. 84, 381- 391 (1984).
  • Examples of competitive NMDA antagonists include D-2-amino-5- phosphonopentanoic acid (D-AP5), and D-2-amino-7-phosphonoheptanoic acid, Schoepp et al.. J. Neur. Transm.. 85, 131-143 (1991).
  • Antagonists of neurotransmission at NMDA receptors are useful therapeutic agents for the treatment of neurological disorders.
  • U.S. Pat. No. 4,902,695 is directed to a series of competitive NMDA antagonists useful for the treatment of neurological disorders, including epilepsy, stroke, anxiety, cerebral ischemia, muscular spasms, and neurodegenerative disorders such as Alzheimer's disease and Huntington's disease.
  • U.S. Pat. No. 4,968,878 is directed to a second series of competitive NMDA receptor antagonists useful for the treatment of similar neurological disorders and neurodegenerative disorders.
  • U.S. Pat. No. 5,192,751 provides a method of treating urinary incontinence through use of a competitive NMDA antagonist.
  • NMDA antagonists are also useful therapeutic agents with anticonvulsant, anxiolytic, muscle relaxant, and antipsychotic activity. J. Lehmann, The NMDA Receptor. Drugs of the Future. 14(11), 1059 (1989). NMDA antagonists have also been reported to be effective for treating migraine (Can. J. Neurol. Sci.. 19(4), 487 (1992)); drug addiction (Science. 251 , 85 (1991)); and neuro-psychiatric disorders related to AIDS (PIPS. 11 , 1 , (1990)). Summary of the Invention The invention relates to compounds of the formula
  • R is C,-C ⁇ alkyl, C -C 8 cycloalkyl, R'CfO)-, or R'OCfO)-;
  • R 1 is C C ⁇ alkyl, C 4 -C 8 cycloalkyl, benzyl, C ⁇ -C 10 aryl, or C 3 -C 8 heteroaryl wherein said aryl, heteroaryl and the phenyl moiety of said benzyl are optionally substituted with from one to three substituents selected from the group consisting of hydroxy, chloro, bromo, fluoro, and -NR 2 R 3 , wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, C,-C ⁇ alkyl, (C,-C ⁇ alkyl)C(O)-, (C,-C ⁇ alkyl)OC(O)-, (C ⁇ -C 10 aryl)C(O)-, (benzyl)OC(O)-, and (C ⁇ -C 10 aryl)OC(O)-.
  • alkyl * as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties.
  • cycloalkyl includes saturated monovalent cyclic hydrocarbon radicals including cyclobutyl, cyclopentyl and cycloheptyl.
  • aryl as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, including phenyl and naphthyl.
  • heteroaryl includes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as pyridyl, furyl, pyrryl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl.
  • C 3 -C 9 heteroaryl moieties include thiazolyl (C 3 heteroaryl), furyl (C 4 heteroaryl), and quinolyl (C 9 heteroaryl).
  • treatment includes (i) methods to cure a condition or disease that is actively occurring in a mammal, such as a human, or to relieve the symptoms associated with such condition or disease, (ii) methods to prevent said condition or disease from occurring in a mammal, and (iii) methods to slow the onset of said condition or disease in a mammal.
  • terapéuticaally effective amount means an amount effective to block NMDA sites in a mammal, such as a human, or an amount that is effective in treating or preventing the specific conditions for which the mammal is being treated.
  • Preferred compounds of formula I include those in which R is R 1 C(0)- or R 1 OC(0)-.
  • R is R 1 C(0)- and R 1 is benzyl, C ⁇ -C, 0 aryl, or C 3 -C ⁇ heteroaryl.
  • R is R 1 C(0)- and R 1 is C,-C ⁇ alkyl or C 4 -C 8 cycloalkyl, and more preferably those in which R 1 is C,-C ⁇ alkyl.
  • R is R 1 OC(0)- and R 1 is benzyl, C ⁇ -C, 0 aryl, or C 3 -C 9 heteroaryl.
  • R is R 1 OC(0)- and R 1 is C,-C ⁇ alkyl or C 4 -C 8 cycloalkyl, and more preferably those in which R is C,- C 0 alkyl, and still more preferably those in which R 1 is ethyl.
  • the present invention further relates to a pharmaceutical composition for treating a disease or condition, the treatment of which can be facilitated by blocking NMDA sites in a mammal, such as a human, comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention further relates to a pharmaceutical composition for treating a disease or condition selected from degenerative CNS disorders such as stroke,
  • Alzheimer's disease, Parkinson's disease, and Huntington's disease Alzheimer's disease, Parkinson's disease, and Huntington's disease; epilepsy, anxiety, muscular spasms, multiinfarct dementia, head trauma, traumatic brain injury, pain, AIDS related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcohol addiction, drug and alcohol withdrawal symptoms, psychotic conditions, tinnitus and urinary incontinence in a mammal, such as a human, comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention further relates to a pharmaceutical composition for treating an ischemic event arising from CNS surgery, open heart surgery or any procedure during which the function of the cardiovascular system is compromised in a mammal, such as a human, comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention further relates to a method of treating a disease or condition, the treatment of which can be facilitated by blocking NMDA sites in a mammal, such as a human, comprising administering to said mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • the present invention further relates to a method of treating a disease or condition selected from degenerative CNS disorders such as stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease; epilepsy, anxiety, muscular spasms, muttiinfarct dementia, head trauma, traumatic brain injury, pain, AIDS related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcohol addiction, drug and alcohol withdrawal symptoms, psychotic conditions, tinnitus and urinary incontinence in a mammal, such as a human, comprising administering to said mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • a disease or condition selected from degenerative CNS disorders such as stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease; epilepsy, anxiety, muscular spasms, muttiinfarct dementia, head trauma, traumatic brain injury, pain, AIDS related dementia, hypoglycemia, migraine, amy
  • the present invention further relates to a method of treating an ischemic event arising from CNS surgery, open heart surgery or any procedure during which the function of the cardiovascular system is compromised in a mammal, such as a human, comprising administering to said mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
  • diseases or conditions susceptible to treatment by a compound of formula I, or a pharmaceutically acceptable salt thereof include degenerative CNS disorders such as stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease; epilepsy, anxiety, muscular spasms, murtiinfarct dementia, head trauma, traumatic brain injury, pain, AIDS related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcohol addiction, drug and alcohol withdrawal symptoms, psychotic conditions, tinnitus and urinary incontinence.
  • degenerative CNS disorders such as stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease
  • epilepsy anxiety, muscular spasms, murtiinfarct dementia, head trauma, traumatic brain injury, pain, AIDS related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcohol addiction, drug and alcohol withdrawal symptoms, psychotic conditions, tinnitus and urinary incontinence.
  • Another disease or condition susceptible to treatment by a compound of formula I, or a pharmaceutically acceptable salt thereof is an ischemic event arising from CNS surgery, open heart surgery or any procedure during which the function of the cardiovascular system is compromised.
  • prodrugs of formula I are readily prepared using (3R,4S)-3-[4-(4- fluorophenyl)-4-hydroxy-piperidin-1-yl]-chroman-4,7-diol (the parent chromanol) as a starting material.
  • This chromanol can be prepared as described in U.S. Patent No. 5,356,905 (issued October 18, 1994), U.S. patent application serial no. 08/189,479 (filed January 31 , 1994), and U.S. provisional patent application of M.
  • the parent chromanol can be prepared by fractional crystallization of the L- proline ester of racemic cis-7-benzyloxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]- chroman-4-ol, as described in U.S. patent application serial no. 08/189,479, referred to above. In a preferred method, the resolution method described in U.S.
  • Racemic cis-7-benzyloxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1 - yi]-chroman-4-ol is prepared as described in U.S. patent application serial no. 08/189,479, referred to above.
  • the concentration of aqueous ethanol is not critical and may be varied between 75% and 95% ethanol (ETOH).
  • ETOH 95% ethanol
  • a concentration of 9:1 /ETOH :H 2 0 has been found to be effective and is preferred.
  • a sufficient amount of the aqueous ethanol solvent to dissolve the racemic compound is required. This amount has been found to be about 17ml per gram of racemic compound.
  • (+) isomer can be converted to the parent chromanol by standard procedures. For example, treatment with dilute base can be used to free the piperidinyi base and subsequent hydrogeneration removes the 7-benzyl group to yield the parent chromanol.
  • the parent chromanol is converted to the prodrugs of formula I using simple alkylation and acylation methods well known to those skilled in the art and described in the literature. See, for example, J. March, Advanced Organic Chemistry. 4th edition, J. Wiley and Sons, New York, chapter 10 (pages 293-500) (1992).
  • the parent chromanol is reacted with 1 molar equivalent (preferably a slight excess) of RX where X is an appropriate leaving group, such as halogen, tosylate, triflate, or mesylate.
  • the reaction is performed in a reaction inert solvent, such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetone, methyl ethyl ketone, or tetrahydrofuran (THF) at a temperature from about 0°C up to the reflux temperature of the solvent.
  • a base such as an alkali metal carbonate (e.g. potassium carbonate), trialkylamine (e.g. triethylamine), or sodium hydride.
  • compounds of formula I wherein R is C,-C ⁇ alkyl or C 4 -C 8 cycloalkyl are prepared by reacting the parent chromanol with a C,-C ⁇ alcohol (e.g. ethanol) or a C 4 -C 8 cyclic alcohol (e.g. cyclopentanol) in the presence of triphenylphosphine and a dialkyl azodicarboxylate (e.g. diethyl azodicarboxylate).
  • a C,-C ⁇ alcohol e.g. ethanol
  • C 4 -C 8 cyclic alcohol e.g. cyclopentanol
  • triphenylphosphine and a dialkyl azodicarboxylate e.g. diethyl azodicarboxylate
  • the parent chromanol is reacted with an appropriate acylating agent such as an anhydride (e.g. acetic anhydride) or an acid halide (e.g. benzoyl chloride or ethyl chloroformate) in a reaction inert solvent (e.g. THF or methylene chloride) at a temperature ranging from about 0°C to the reflux temperature of the solvent.
  • an acylating agent such as an anhydride (e.g. acetic anhydride) or an acid halide (e.g. benzoyl chloride or ethyl chloroformate) in a reaction inert solvent (e.g. THF or methylene chloride) at a temperature ranging from about 0°C to the reflux temperature of the solvent.
  • a reaction inert solvent e.g. THF or methylene chloride
  • Another method to prepare compounds of formula I wherein R is R 1 C(0)- is to react the parent chromanol with an acid corresponding to the group to be added (e.g. pivalic acid or phenylacetic acid) employing a reagent, such as dicyclohexylcarbodiamide or carbonyl diimidazole, to activate the acid prior to coupling with the chromanol.
  • a reagent such as dicyclohexylcarbodiamide or carbonyl diimidazole
  • the acylating agent is prepared in sjtu. This process is described in J. March, Advanced Organic Chemistry. 4th Ed., chapter 10, referred to above, and is well known to those skilled in the art.
  • the preferred conditions for the reactions in this method are the same as those described in the preceding paragraph.
  • DMF can be added as a cosolvent to facilitate dissolution of the reagents if necessary.
  • the prodrugs of the present invention are converted in vivo into the parent chromanol, a selective NMDA antagonist. They are therefore useful in the treatment of disorders and conditions, the treatment of which can be facilitated by blocking NMDA sites in a mammal.
  • diseases and conditions include degenerative CNS disorders such as stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease; epilepsy, anxiety, muscular spasms, muttiinfarct dementia, head trauma, traumatic brain injury, pain, AIDS related dementia, hypoglycemia, migraine, amyotrophic lateral sclerosis, drug and alcohol addiction, drug and alcohol withdrawal symptoms, psychotic conditions, tinnitus and urinary incontinence.
  • the prodrugs of the present invention can be administered as pharmaceutically acceptable salts of the compounds of formula I.
  • Such salts include conventional acid addition salts and cation salts.
  • the compounds of formula I contain an amine group which is basic, and so are capable of forming such salts.
  • Said salts include, but are not limited to, those with HCl, HBr, HN0 3 , H 2 S0 4 , H 3 P0 4 , CH 3 S0 3 H, ⁇ -CH 3 C ⁇ H 4 S0 3 H, CH 3 C0 2 H, gluconic acid, tartaric acid, lactic acid, maleic acid and succinic acid.
  • the salts can be prepared by conventional methods, e.g., by combining a compound of formula I with at least one molar equivalent of the acid in a suitable solvent.
  • the prodrugs of formula I convert to the parent chromanol through metabolic processes within the body of a mammal.
  • the parent chromanol has selective neuroprotective antiischemic and excitatory amino acid blocking activity that reflects its valuable utility in the treatment of neurological disorders such as epilepsy and stroke, and degenerative CNS disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease.
  • the dosage is typically from about 0.02 to 20 mg/kg/day (0.001 -1 g/day for a typical human weighing about 50 kg) in single or divided doses, regardless of the route of administration.
  • doses outside this range may be prescribed by the attending physician.
  • compositions comprising at least one of the compounds of the formula I, together with a pharmaceutically acceptable vehicle or diluent.
  • Such compositions are generally formulated in a conventional manner utilizing solid or Iiquid 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; suppositories, including rectal; for parenteral administration (intravenous, subcutaneous, intramuscular), 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.
  • Intravenous administration is the preferred parenteral method of administration.
  • the preparation of solutions for intravenous administration is known to those skilled in the art.
  • the intravenous solution should be osmotically balanced and have a neutral pH.
  • Appropriate solutions include 5% dextrose solution, isotonic saline, and phosphate-buffered saline. In the following Preparation and Examples, unless otherewise indicated, reactions and other procedures were run at ambient temperature (20-25 °C), and all non-aqueous reactions were run under nitrogen for convenience and generally to maximize yields.
  • step B The above product (1.2g) was suspended in 21.4 ml of 90% EtOH:H 2 0, stirred and heated under reflux for 1.5 hours and then cooled to room temperature. The solid product was collected by filtration and washed with two 3 ml portions of 90% ETOH:H 2 0. The yield was 1 Jg of 98.0% optical purity.
  • step B The procedure of step B was repeated with the product of step B yielding
  • Optical purity was determined by HPLC using a 250 x 4.6 mm Chiralpak ® AD column (Chiral Technologies, Exton, PA) with the mobile phase comprising 600 ml hexane, 400 ml isopropanol, 1 ml trifluoroacetic acid and 0.5 ml diethylamine.
  • the flow rate was 0.7 ml/min with an injection volume of 20 jA containing 0J to 0.4 mg sample/ml. Detection was set for 220 nm.
  • the mixture was diluted with ethyl acetate and extracted with 1 N aqueous lithium chloride.
  • the aqueous lithium chloride was back extracted with ethyl acetate (twice) and the combined organic phase was washed ith 1N aqueous lithium chloride and brine.
  • the organic layer was dried over calcium sulfate and concentrated to a white solid.
  • the mixture was diluted with ethyl acetate and extracted with 1 N aqueous lithium chloride.
  • the aqueous lithium chloride was back extracted with ethyl acetate (twice) and the combined organic phase was washed with 1N aqueous lithium chloride and brine.
  • the organic layer was dried over calcium sulfate and concentrated to a white solid.
  • EXAMPLE 8 (3R.4S)-7-Cvclopentyloxy-3-r4-(4-fluorophenyl)-4 hvdroxy-piperidin-1-v ⁇ -chroman-4-ol
  • sodium hydride (60% dispersion in oil, 0.037 g, 0.918 mmol) was washed with hexane to remove the oil.
  • DMF (3 mL) was added and the mixture was chilled to 0°C.
  • the aqueous lithium chloride was back extracted with ethyl acetate (twice) and the combined organic phase was washed with 1 aqueous lithium chloride and brine.
  • the organic layer was dried over calcium sulfate and concentrated to a white solid.
  • the solid was flash chromatographed on silica gel (1 x 43 inches, packed in methylene chloride) with elution proceeding as follows: 3% methanol/methylene chloride (200 mL), 0.220 g of white solid product.

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  • Chemical & Material Sciences (AREA)
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Abstract

Composés de la formule (I) et sels de ces composés acceptables d'un point de vue pharmaceutique, formule dans laquelle R est tel que le définit la description, lesdits composés et sels constituant des promédicaments pour un antagoniste compétitif d'acide N-méthyl D-aspartique (NMDA), qui bloque les sites récepteurs de NMDA et est utile dans le traitement de certains états et certaines maladies réagissant au blocage de sites récepteurs de NMDA, tels que le traumatisme crânien, l'attaque, la démence due à des infarctus multiples, ou d'autres troubles.
PCT/IB1996/000668 1995-09-15 1996-07-11 Derives du phenol a activite pharmaceutique WO1997010240A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP96921012A EP0859773A1 (fr) 1995-09-15 1996-07-11 Derives du phenol a activite pharmaceutique
JP9502358A JPH11509839A (ja) 1995-09-15 1996-07-11 薬剤活性を有するフェノール誘導体
MXPA/A/1998/002025A MXPA98002025A (en) 1995-09-15 1998-03-13 Derivatives of phenol, pharmaceutical compositions that contain them and the use of mis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US385495P 1995-09-15 1995-09-15
US60/003,854 1995-09-15

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WO1997010240A1 true WO1997010240A1 (fr) 1997-03-20

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017093354A1 (fr) 2015-11-30 2017-06-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonistes de nmdar pour le traitement de maladies associées à l'angiogenèse

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995020587A1 (fr) * 1994-01-31 1995-08-03 Pfizer Inc. Composes de chromane neuroprotecteurs

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995020587A1 (fr) * 1994-01-31 1995-08-03 Pfizer Inc. Composes de chromane neuroprotecteurs

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017093354A1 (fr) 2015-11-30 2017-06-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonistes de nmdar pour le traitement de maladies associées à l'angiogenèse

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EP0859773A1 (fr) 1998-08-26
MX9802025A (es) 1998-08-30
JPH11509839A (ja) 1999-08-31

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