WO1993005772A1 - ACIDES φ-[2-(PHOSPHONOALKYL)PHENYL]-2-AMINO-ALCANOIQUES UTILISES COMME ANTAGONISTES DE RECEPTEURS D'ACIDES AMINES EXCITATEURS - Google Patents

ACIDES φ-[2-(PHOSPHONOALKYL)PHENYL]-2-AMINO-ALCANOIQUES UTILISES COMME ANTAGONISTES DE RECEPTEURS D'ACIDES AMINES EXCITATEURS Download PDF

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Publication number
WO1993005772A1
WO1993005772A1 PCT/US1992/007675 US9207675W WO9305772A1 WO 1993005772 A1 WO1993005772 A1 WO 1993005772A1 US 9207675 W US9207675 W US 9207675W WO 9305772 A1 WO9305772 A1 WO 9305772A1
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Prior art keywords
compound according
phenylalanine
phosphonoethyl
compound
effective amount
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PCT/US1992/007675
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English (en)
Inventor
Waclaw Janusz Rzeszotarski
Suzanne Ray Ellenberger
Maria Elizabeth Guzewska
John William Ferkany
Gregory Scott Hamilton
Raymond Joseph Patch
Edward William Karbon, Jr.
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Nova Pharmaceutical Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3882—Arylalkanephosphonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3834—Aromatic acids (P-C aromatic linkage)

Definitions

  • the present invention pertains to novel non-N- methyl-D-aspartic acid excitatory amino acid (EAA) antagonists and particularly to novel, potent and
  • KA kainic acid
  • AMPA-type [(RS)-alpha-aminomethyl-3-hydroxy-5-methylisoxazole propionic acid] EAA receptors having anxiolytic
  • the invention is directed to: 2-[omega- phosphonoalkyl)phenyl]-2-aminoalkanoic acids and their interaction with KA and AMPA receptors, their
  • EAA Excitatory amino acids
  • AMPA (RS)-alpha- aminomethyl-3-hydroxy-5-methylisoxazole propionic acid]
  • GLU L-glutamate
  • KA pyrrolidine neurotoxin kainic acid
  • NMDA NMDA
  • EAA agonists are potent convulsants in animal models. Additionally, AMPA, KA and the endogenous NMDA agonist, quinolinic acid (QUIN) and the mixed ionotropic/metabotropic agonist ibotenic acid have been used to produce laboratory models of neurodegenerative disorders [K. Biziere, J.T. Slevin, R. Zaczek, J.S.
  • NMDA receptor antagonists may be useful as anxiolytics
  • anticonvulsants include anticonvulsants, antiemetics [European Patent Application No. 432,994], antipsychotics or muscle relaxants, and that these compounds may prevent or reduce neuronal damage in instances of cerebral ischemia, hypoxia, hypoglycemia or trauma [R.P. Simon, J.H. Swan, T.
  • Matoba et al. prepared several amino-phosphonoic acids and notably, 2-amino-5- phosphonopentanoic acid, 2-amino-4-(2-amino-5- phosphonomethyl-phenyl) butyric acid, 2-(2-amino-2- carboxy) ethylphenyl-phosponic acid and N-benzylproline- 4-phosphonic acid.
  • Rzeszotarski et al. disclose potent and selective EAA neurotransmitter receptor antagonists having the general formula:
  • the present invention provides a potent, selective excitatory amino acid kainic acid receptor antagonist compound having the general formula:
  • R 1 is selected from the group consisting of hydrogen and R 2 ;
  • R 2 is selected from the group consisting of hydrogen, halogen, halomethyl, nitro, amino, alkoxy, hydroxyl, hydroxymethyl, C 1 to C 6 lower alkyl, C 7 to C 12 higher alkyl, aryl and aralkyl, wherein if R 2 is hydrogen, R 1 is not hydrogen;
  • R 3 is selected from the group consisting of hydrogen, and C 1 to C 6 lower alkyl; the stereoisomers thereof in their resolved or racemic form, and
  • the invention provides a potent, selective excitatory amino acid kainic acid receptor antagonist compound having the general formula:
  • R 1 is selected from the group consisting of hydrogen, methyl and halogen
  • R 2 is selected from the group consisting of halogen, halomethyl, nitro, amino, alkoxy, hydroxyl, hydroxymethyl, C 1 to C 6 lower alkyl, C 7 to C 12 higher alkyl, aryl and aralkyl
  • R 3 is selected from the group consisting of hydrogen, and C 1 to C 6 lower alkyl; the stereoisomers thereof in their
  • Another aspect of the invention involves use of the pharmaceutical compositions for relieving pain, treatment of convulsions or epilepsy, enhancing cognition, treating psychosis, preventing neurodegeneration, treating
  • a further aspect of the invention involves a method for antagonizing excitatory amino acid kainic acid or AMPA receptors by utilizing a compound having the general formula:
  • R 1 is selected from the group consisting of hydrogen and R 2 ;
  • R 2 is selected from the group consisting of halogen, halomethyl, nitro, amino, alkoxy, hydroxyl, hydroxymethyl, C 1 to C 6 lower alkyl, C 7 to C 12 higher alkyl, aryl and aralkyl;
  • R 3 is selected from the group consisting of hydrogen, and C 1 to C 6 lower alkyl; the stereoisomers thereof in their resolved or racemic form, and
  • Preferred compounds according to the invention include:
  • the structure and formulation of the novel compounds of the invention was the result of an extensive research investigation into the antagonism of excitatory amino acid kainic acid and AMPA neurotransmitter receptors.
  • L-glutamic acid a dicarboxylic amino acid
  • CNS mammalian central nervous system
  • Ion channel-linked or "ionotropic" excitatory amino acid receptor subtypes include those selectively activated by N-methyl-D-aspartic acid (NMDA), ⁇ -amino-3-methyl-4-isoxazole propionic acid (AMPA), and kainic acid (KA).
  • NMDA N-methyl-D-aspartic acid
  • AMPA ⁇ -amino-3-methyl-4-isoxazole propionic acid
  • KA kainic acid
  • L-glutamic acid is believed to have an important physiological role in the functioning of the CNS since a great majority of CNS neurons utilize GLU as their
  • the diversity of receptor subtypes with which GLU interacts contributes to its ability to elicit a variety of synaptic events.
  • Ionotropic GLU receptors mediate fast excitatory
  • Metabotropic GLU receptors are considered to play primarily a neuromodulatory role, although simultaneous activation of ionotropic and metabotropic receptors might be required for the development of neuronal plasticity at certain CNS synapses.
  • GLU has been suggested to have a role in CNS conditions characterized by heightened neuronal activity or sensitivity including epilepsy, ischemia or trauma-induced neuronal damage, and certain neurologic and neurodegenerative disorders. Accordingly,
  • the NMDA receptor is the most well-characterized GLU receptor subtype because of the availability of selective antagonists.
  • AP-5 and D(-)-2-amino-5-phosophoheptanoic acid were among the first NMDA antagonists identified and act competitively by binding to the GLU recognition site.
  • KA- induced seizures have been used as an animal model of temporal lobe epilepsy in humans, suggesting that KA antagonists might be useful in the management of this CNS disorder.
  • a potential therapeutic use for KA or AMPA antagonists in the treatment of neurodegenerative disorders have been demonstrated to possess therapeutic potential as anticonvulsant and cerebroprotective agents.
  • KA and AMPA receptors might also be useful in the treatment of CNS disorders involving glutamatergic neurotransmission.
  • KA- induced seizures have been used as an animal model of temporal lobe epilepsy in humans, suggesting that KA antagonists might be useful in the management of this CNS disorder.
  • a potential therapeutic use for KA or AMPA antagonists in the treatment of neurodegenerative disorders have been demonstrated to possess therapeutic potential as anticonvulsant and cerebroprotective agents.
  • Non-NMDA receptors have also been implicated in neurologic disorders including Lathyrism, an upper motor neuron disease characterized by spastic paraparesis, and Guam's Disease, a form of amyotrophic lateral sclerosis.
  • KA/AMPA receptor antagonists In contrast to NMDA receptors, a limited number of KA/AMPA receptor antagonists have been described, most of which are non-selective and relatively weak, resulting in an inability to fully characterize the functional and physiological properties of these receptors.
  • a series of guinoxalinediones were recently identified as potent non-NMDA antagonists. The therapeutic potential of these compounds is illustrated by their ability to protect against EAA agonist-induced cytotoxicity in cultured cortical neurons and clonic seizures in neonatal rats.
  • novel compounds of this invention relate specifically to excitatory amino acid receptors activated by KA and AMPA for which only a limited number of quinoxalines have been identified as specific antagonists.
  • novel compounds provide potent antagonists having greater affinity for KA and AMPA receptors and lesser or no affinity for other CNS receptors, rendering the compounds very selective. This would therefore permit one to selectively antagonize one excitatory amino acid receptor in the tissues also containing other excitatory amino acid receptors. Fewer side effects can be expected as a result of the greater affinity and selectively of the compounds of the present invention.
  • Preferred compounds of the invention have the formula:
  • R 1 is selected from the group consisting of hydrogen and R 2 ;
  • R 2 is selected from the group consisting of hydrogen, halogen, halomethyl, nitro, amino, alkoxy, hydroxyl, hydroxymethyl, C 1 to C 6 lower alkyl, C 7 to C 12 higher alkyl, aryl and aralkyl, wherein if R 2 is hydrogen, R 1 is not hydrogen;
  • R 3 is selected from the group consisting of hydrogen, and C 1 to C 6 lower alkyl; the stereoisomers thereof in their resolved or racemic form, and
  • a particularly preferred form of the compound has. the formula:
  • R 1 is selected from the group consisting of hydrogen, methyl and halogen
  • R 2 is selected from the group consisting of halogen, halomethyl, nitro, amino, alkoxy, hydroxyl, hydroxymethyl, C 1 to C 6 lower alkyl, C 7 , to C 12 higher alkyl, aryl and aralkyl
  • R 3 is selected from the group consisting of hydrogen, and C 1 to C 6 lower alkyl; the stereoisomers thereof in their resolved or racemic form, and pharmaceutically acceptable salts thereof.
  • Halogen includes bromo, fluoro, chloro and iodo
  • halomethyl includes mono-, di- and tri-halo groups including trifluoromethyl
  • amino compounds include amine (NH 2 ) as well as substituted amino groups comprising alkyls of one through six carbons
  • aryl is an aromatic ring compound such as benzene, phenyl, naphthyl and substituted forms thereof
  • aralkyl is an aryl being attached through an alkyl chain, straight or branch, of from one through six carbons.
  • Particularly preferred specific compounds include:
  • compositions for administration in pharmaceutical preparations may be accomplished in a variety of well known methods known to those skilled in the art of synthetic organic chemistry.
  • Appropriate pharmaceutically acceptable salts within the scope of the invention are those derived from mineral acids such as hydrochloric acid, phosphoric acid, nitric acid and sulfuric acid; and organic acids such as tartaric acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, and the like, giving the
  • suitable organic and inorganic bases include the hydroxides, carbonates, and bicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc, and the like.
  • Salts may also be formed with suitable organic bases.
  • pharmaceutically acceptable base addition salts with compounds of the present invention include organic bases which are non-toxic and strong enough to form such salts. These organic bases form a class whose limits are readily understood by those skilled in the art. Merely for purposes of illustration, the class may be said to include mono-, di-, and trialkylamines, such as
  • methylamine, dimethylamine, and triethylamine methylamine, dimethylamine, and triethylamine; mono-, di- or trihydroxyalkylamines such as mono-, di-, and
  • amino acids such as arginine, and lysine
  • guanidine N-methyl-glucosamine
  • N- methylglucamine N-methylglucamine
  • L-glutamine N-methylpiperazine
  • the compounds of the invention contain an asymmetric carbon atom.
  • the invention includes the individual stereoisomers, and the mixtures thereof.
  • the individual isomers may be prepared or isolated by methods known in the art.
  • the compounds may be formulated in aqueous injection solutions which may contain antioxidants, buffers, bacteriostats, etc.
  • Extemporaneous injection solutions may be prepared from sterile pills, granules or tablets which may contain diluents, dispersing and surface active agents, binders and lubricants.
  • fine powders or granules of the compound may be formulated with diluents and dispersing and surface active agents, and may be prepared in a draft in water or in a syrup, in capsules or cachets in the dry state or in a non-aqueous
  • the compounds may also be administered in tablet form along with optional binders and lubricants, or in a suspension in water or syrup or an oil or in a water/oil emulsion and may include flavoring, preserving,
  • the granules or tablets for oral administration may be coated and other pharmaceutically acceptable agents and
  • formulations may be utilized as known to those skilled in the pharmaceutical art.
  • novel compounds of the invention may be readily prepared by the following synthetic routes:
  • the 7-iodo isochroman was made from 7- bromoisochroman, as described below.
  • the dibromide compound was prepared from 5-nitrohomophthalic acid [W. Borsche, K. Diacont and H. Hanau, Chem. Ber., 67, 675-686 (1934)] according to the following standard series of reactions:
  • the crude acetal was dissolved in 20ml of dry methylene chloride and added via dropping funnel to a stirred, cooled (0°C) solution of titanium tetrachloride (17 mmol) in 85ml of methylene chloride. After stirring at 0°C for 2 hours the reaction was quenched by the successive addition of methanol (5ml) and 1N HCl (100ml). The layers were separated and the organic phase was washed with brine, dried (MgSO 4 ) and freed of solvent.
  • phosphonoethyl phenylalanines was used to prepare the compound of Example X, 5-t-Butyl-2-(2-phosphonoethyl) phenylalanine.
  • the preparation provided 91% yield: mp 216-217°C; 1 H NMR (D 2 O/NaOD) ⁇ 1.12 (s, 9H), 1.32 (m, 2H), 2.80 (m, 3H), 3.34 (t, 1H), 7.16 ppm (m, 3H); IR (KBr)
  • phosphonoethyl phenylalanines was used to prepare the compound of Example XIII, 5-Octyl-2-(2-phosphonoethyl) phenylalanine hydrochloride.
  • the preparation provided a 95% yield: mp 228-230°C; 1 H NMR (D 2 O/NaOD) 5 0.67 (t, 3H), 1.12 (m, 10H), 1.43 (m, 4H), 2.37 (t, 2H), 2.59 (m, 3H), 2.92 (dd, 1H), 3.27 (dd, 1H), 6.90 (d, 2H), 7.06 ppm (d, 1H); IR (KBr) 1720 cm -1 .
  • phosphonoethyl phenylalanines was used to prepare the compound of Example XV, 3-Methyl-2-(2-phosphonoethyl) phenylalanine.
  • the preparation provided a 70% yield: mp 253-255°C (decomp); 1 ⁇ NMR (D 2 O) ⁇ 1.60 (m, 2H), 2.20 (s, 3H), 2.75 (m, 2H), 3.09 (m, 2H), 3.89 (t, 1H), 7.02 ppm (n, 3H); IR (KBr) 1712 cm- 1 .
  • phosphono.ethyl phenylalanines was used to prepare the compound of Example XVI, 3-Phenyl-2-( 2-phosphonoethyl) phenylalanine hydrochloride.
  • the preparation provided a 93% yield: mp 220°C (decomp); 1 H NMR (D 2 O) ⁇ 1.0-1.3 (m, 2H), 2.5-2.7 (m, 2H), 2.8 (m, 2H), 3.3 (t, 1H), 6.8-7.4 ppm (m, 9H); IR (nujol) 1717 cm- 1 .
  • Compound 21 is accomplished by addition of propylene oxide to a solution of Compound 21 (hydrochloride salt) in ethanol.
  • the product 21 thus obtained is washed with ethanol and acetone and dried under vacuum.
  • Oxazoline 23 (10 g; 40.43 mmol) in 200 ml of 3N HCl was refluxed vigorously for 2.5 hours. The reaction mixture was cooled and partitioned between methylene chloride and water. The organic phase was washed several times with brine, dried (MgSO 4 ) and freed of solvent. The crude material was dissolved in anhydrous ether (150 ml) and added in a dropwise fashion to a solution of lithium aluminum hydride (55 mmol) in ether (100 ml). After stirring this mixture for 2.5 hours, water (100 ml) was added slowly and cautiously, followed by 100 ml of 1N HCl.
  • Dibromotriphenylphosphorane (12.66 g; 30 mmol) was added as a methylene chloride solution (100 ml) to a solution of diol 24 (1.80 g; 9.99 mmol) in methylene chloride (50 ml). This mixture was stirred for 3 hours at room temperature and then partitioned between brine and methylene chloride. The layers were separated and the organic phase was dried (MgSO 4 ) and freed of solvent. The crude residue was purified on a silica gel column, eluting with 5% ethyl acetate in hexane, to obtain 1.5 g of Compound 25.
  • 1 H NMR (CDCl 3 ) ⁇ 2.20 (m, 2H); 2.28 (s, 3H); 2.86 (t, 2H); 3.46 (t, 2H); 4.53 (s, 2H); 7.16 (m, 3H).
  • tetrabutylammonium hydrogen sulfate (2.03 g; 5.88 mmol) was stirred in a two phase solvent mixture consisting of methylene chloride (20 ml) and 10% aqueous sodium
  • Oxazoline 30 (1.6 g; 7.05 mmol) in 15 ml of dry THF at -78°C was treated with n-butyllithium (7.76 mmol).
  • Tetraethylmethylenediphosphonate (2.6 g; 8.73 mmol) in THF (7 ml) was added dropwise to a stirred suspension of sodium hydride (288 mg of an 80% suspension; 9.61 mmol) in THF (10 ml). After gas evolution had ceased the mixture was stirred at room temperature for 2 hours and then cooled to -78°C .
  • a solution of lactone 32 (840 mg; 4.16 mmol) in toluene (20 ml) was cooled to -78°C and treated with a solution of
  • tert-butyldimethylsilyl chloride (680 mg; 4.37 mmol) in 8 ml of THF was added. The resulting mixture was allowed to come to room temperature overnight. It was quenched by the successive addition of saturated ammonium chloride (15 ml) and 1N HCl (35 ml). The product was extracted into ethyl acetate and the organic phase was washed with brine, dried (MgSO 4 ) and concentrated. Purification by column chromatography (5% ethanol/ethyl acetate)
  • acetamidomalonate (11 mmol) in methylene chloride (20 ml) was added to a solution of tetrabutylammonium hydrogen sulfate (10 mmol) in 10% aqueous NaOH (25 ml). The two phase mixture was stirred for 4 hours, then the layers were separated. The organic phase was washed with brine, dried (MgSO 4 ) and concentrated in vacuo. Chromatography of the residue on silica gel with ethyl acetate afforded tetraester 36.
  • Oocytes are placed individually in 100 ml of antibiotic- supplemented modified Barthes solution (MBS, containing in mM: NaCl, 88; KCl, 1.0; NaHCO 3 , 2.4; HEPES, 10; MgSO 4 , 0.82; Ca(NO 3 ) 2 , 0.33) in 96-well sterile plates and cultured for 48-120 hours prior to experimentation.
  • MFS antibiotic- supplemented modified Barthes solution
  • Oocytes are inspected every 24 hours at which time the bathing solution is replaced with fresh MBS.
  • oocytes are positioned in a small recording chamber (500 ml) and superfused with antibiotic-free MBS supplemented with CaCl 2 (final concentration - 1.4 mM).
  • MgSO 4 is replaced with NaSO 4 (0.55 mM).
  • Oocytes are impaled with a single glass microelectrode,
  • Antagonists are coperfused with agonists.
  • MBS used in NMDA assays is prepared from
  • NMDA/glycine-induced currents are determined from concentration-response curves.
  • IC 50 values and Hill coefficients are determined by analysis of indirect Hill plots. IC 50 values are converted to K i values for
  • Example I The anticonvulsant properties of Example I, as well as the reference compound CPP, were evaluated using the mouse (male CF-1, 25-30g, Harlan Industries) PTZ seizure model. Test compounds were dissolved in saline or the appropriate vehicle and administered either
  • intracerebroventricularly i.e.v.
  • intraperitoneally i.p.
  • s.c. thirty minutes prior to subcutaneous
  • Example I provided dose-dependent protection against PTZ-induced seizures, and was nearly 2 times more potent than CPP, a competitive NMDA antagonist, when
  • Example I administered i.e.v. Example I was also effective
  • Kainic acid-induced lesion studies were performed using rats (male Sprague-Dawley, 200-250g, Harlan
  • ChAT choline acetyltransferase
  • GAD glutamic acid decarboxylase
  • Table III shows that intrastriatal injection of kainic acid alone produced reductions of 68% and 55% in ChAT and GAD activity, respectively. In contrast, coadministration of kainic acid with Example I resulted in only a 2% reduction in ChAT activity, and a 12% reduction in GAD activity.
  • ED 50 values were determined from dose-response curves using at least 6 concentrations of test agent and groups of 6-10 animals per test dose.
  • Ka-induced lesions were performed as described in the text. The results are expressed as the percentage of enzyme activity in the ipsilateral (injected) striatum relative to enzyme activity in the contralateral (uninjected) striatum. The values represent the mean + standard deviation of 4 (Example I) or 12 (vehicle) determinations.

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Abstract

La présente invention se rapporte à des antagonistes de récepteurs neuromédiateurs d'acides aminés excitateurs, à un procédé de préparation ainsi qu'à des compositions les contenant, répondant à la formule générale (I), dans laquelle n et m valent indépendamment 0, 1, 2 ou 3; R1 est choisi dans le groupe composé d'hydrogène et de R2; R2 est choisi dans le groupe comprenant hydrogène, halogène, halométhyle, nitro, amino, alcoxy, hydroxyle, hydroxyméthyle, alkyle inférieur C1 à C6, alkyle supérieur C7 à C12, aryle et aralkyle, de sorte que, si R2 représente hydrogène, R1 ne représente pas ce dernier; R3 est choisi dans le groupe comprenant hydrogène et alkyle inférieur C1 à C6. On décrit également des stéréoisomères de ces composés dans leur forme résolue ou racémique, ainsi que des sels pharmaceutiquement acceptables.
PCT/US1992/007675 1991-09-26 1992-09-17 ACIDES φ-[2-(PHOSPHONOALKYL)PHENYL]-2-AMINO-ALCANOIQUES UTILISES COMME ANTAGONISTES DE RECEPTEURS D'ACIDES AMINES EXCITATEURS WO1993005772A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995015941A1 (fr) * 1993-12-10 1995-06-15 University Of Bristol Amino-acides substitues par aryle, agents influant sur le snc
US5922697A (en) * 1996-10-02 1999-07-13 Warner-Lambert Company Compounds, compositions and methods for inhibiting the binding of proteins containing an SH2 domain to cognate phosphorylated proteins
WO2011076946A2 (fr) 2009-12-24 2011-06-30 Universidad Del País Vasco Procédés et compositions pour le traitement de la maladie d'alzheimer

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4657899A (en) * 1986-04-09 1987-04-14 Nova Pharmaceutical Corporation Antagonists of specific excitatory amino acid neurotransmitter receptors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4657899A (en) * 1986-04-09 1987-04-14 Nova Pharmaceutical Corporation Antagonists of specific excitatory amino acid neurotransmitter receptors

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995015941A1 (fr) * 1993-12-10 1995-06-15 University Of Bristol Amino-acides substitues par aryle, agents influant sur le snc
US5922697A (en) * 1996-10-02 1999-07-13 Warner-Lambert Company Compounds, compositions and methods for inhibiting the binding of proteins containing an SH2 domain to cognate phosphorylated proteins
WO2011076946A2 (fr) 2009-12-24 2011-06-30 Universidad Del País Vasco Procédés et compositions pour le traitement de la maladie d'alzheimer

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