WO2003035641A1 - Nouveau derive carbamoyl-pyrrolidone - Google Patents

Nouveau derive carbamoyl-pyrrolidone Download PDF

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Publication number
WO2003035641A1
WO2003035641A1 PCT/JP2002/010877 JP0210877W WO03035641A1 WO 2003035641 A1 WO2003035641 A1 WO 2003035641A1 JP 0210877 W JP0210877 W JP 0210877W WO 03035641 A1 WO03035641 A1 WO 03035641A1
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lower alkyl
receptor
pharmaceutically acceptable
acceptable salt
compound
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PCT/JP2002/010877
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English (en)
Japanese (ja)
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Toshisada Yano
Shunji Shinohara
Chie Takeyama
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Shionogi & Co., Ltd.
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Publication of WO2003035641A1 publication Critical patent/WO2003035641A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—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 chain containing hetero atoms as chain links
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a novel carpamoylpyrrolidone derivative having an antagonistic effect on an NMD A receptor, which is a kind of glutamate receptor of central nervous cells, particularly an NR1 / NR2B complex receptor.
  • Amino acids such as L-glutamic acid and L-aspartic acid are important for neuronal activation as neurotransmitters in the central nervous system.
  • the extracellular accumulation of these excitatory amino acids induces excessive stimulation of nerve cells, causing various neurological diseases such as Parkinson's disease, senile dementia, Huntington's chorea, and epilepsy, and It is thought to cause mental and motor deficits such as those seen during hypoxia, hypoxemia, hypoglycemia, and head or spinal cord injury (McGeer et al., Nature, 263, 517- 519 (1976), Simon et al.
  • glutamic acid is released in large amounts by cerebral ischemia such as cerebral infarction, so antagonists to the glutamic acid receptor are used as a therapeutic drug for acute phase of cerebral infarction and for chronic gods such as Alzheimer's disease. ⁇ It is considered to be useful as a therapeutic agent for degenerative diseases.
  • the glutamate receptors are classified into ion channel type and metabolic type, and the ion channel type is further classified into three types based on selectivity for agonists. These are the N-methyl-D-aspartate (NMDA) receptor, No 3- (3-hydroxy-15-methylisoxazoyl-41-yl) is called propanoic acid (AMP A) receptor and force rice receptor.
  • NMDA N-methyl-D-aspartate
  • AMP A propanoic acid
  • the NMD A receptor is selectively activated by agonists such as glutamate, NMDA, and ibotenic acid. This strong stimulation of the NMD A receptor causes a large amount of calcium ions to enter the nerve cells, which is thought to be one of the causes of neurodegenerative cell death.
  • the gene for the NMD A receptor has been cloned from rat and mouse brain, respectively, and it has been revealed that the NMD A receptor is composed of two subunits, NR1 and NR2 (Katsuwada et al. Nature, 358, 36-41 (1992), Mega et al., Nature, 357, 70-74 (1992)). There are four additional subfamilies (NR2A, 2B, 2C, 2D) in the NR2 subunit (Monyer et al., Science, 256, 1217-1221 (1992), Yamazaki et al., FEBS Lett., 300 , 39-45 (1992)).
  • the role of each of the NR 2 subfamilies is gradually becoming clearer, using the knockout mouse of the NR 2 subfamily.
  • the NR1ZNR2A complex receptor is involved in memory formation and learning acquisition (Sakimura et al., Nature, 373, 151-155 (1995)). It is said to be involved (Di X, Bullock R et al., Stroke, 28, 2244-2251 (1997)).
  • NMD A receptors especially the NR 2 B receptor has also been reported to be associated with analgesic effects, and its antagonists are expected to be analgesics with few side effects (TRENDS in Pharmacological Sciences Vol.22 No.12 December 2001) o
  • NMD A receptor antagonists 1) drugs that competitively bind to agonist, such as glutamate-NMD A, in all subfamilies of NR1ZNR2 complex receptors (hereinafter, referred to as Competitive NMD A antagonists, eg: D-2-amino-5-phosphonovaleric acid) or 2) In the ion channel at the NMD A receptor: Glutamic acid or: NMD A to the PCP (phencyclidine) binding site Drugs that bind non-competitively irrespective of agonist and suppress calcium ion influx into nerve cells (hereinafter referred to as non-competitive NMD A antagonists, eg, MK-801) are known.
  • non-competitive NMD A antagonists eg, MK-801
  • JP-A-113-1155, JP-A-41-21059 and JP-A-61-1968 disclose carpamoylpyrroli useful as an anti-dementia drug, a psychotropic drug and an anti-allergic drug. Don derivatives are described, but no antagonism to the NMDA receptor is described. Disclosure of the invention
  • ⁇ is one NR 1 — (CH 2 ) m— (R 1 is hydrogen or lower alkyl; m is an integer of 2 to 5) or a single bond;
  • Z 1 and Z 2 are each independently hydrogen, lower alkyl, lower alkoxy, lower A substituent selected from the group consisting of alkenyl, halogen, halogenated lower alkyl, halogenated lower alkoxy, hydroxy, carboxy and nitro; n represents an integer of 1-3.
  • Z 1 is hydrogen
  • Z 2 is a substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkenyl, halogen, lower alkyl halide, lower alkoxy halide, hydroxy, carboxy, and nitro
  • the compound according to the above 1, a pharmaceutically acceptable salt thereof, a prodrug thereof or a solvate thereof.
  • Z 1 is hydrogen
  • Z 2 is a substituent selected from the group consisting of methyl, butyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy and hydroxy.
  • a pharmaceutically acceptable salt thereof, a prodrug thereof or a solvate thereof is a pharmaceutically acceptable salt thereof, a prodrug thereof or a solvate thereof.
  • A is —NR 1 — (CH 2 ) m— (where R 1 is hydrogen or lower alkyl; m is 2 or 3); n is 1; Z 1 is hydrogen; Z 2 is lower alkyl, lower alkoxy A compound selected from the group consisting of: lower alkenyl, halogen, lower alkyl halide, lower alkoxylated halogen, hydroxy, carboxy and nitro; the compound according to 1 above, or a pharmaceutically acceptable salt thereof, The prodrugs or their solvates.
  • A is a single bond; n is 1; Z 1 is hydrogen; Z 2 is from the group consisting of lower alkyl, lower alkoxy, lower alkenyl, halogen, halogenated lower alkyl, halogenated lower alkoxy, hydroxy, carboxy and nitro
  • a pharmaceutical composition comprising the compound according to any one of the above 1 to 7, a pharmaceutically acceptable salt thereof, a prodrug thereof or a solvate thereof.
  • composition according to the above 9 which is an antagonist of a complex receptor of NR1 and NR2B, which is a subunit of NMD A receptor.
  • composition according to the above item 8 which is a therapeutic agent for acute phase of cerebral infarction or a therapeutic agent for chronic neurodegenerative disease.
  • Lower alkyl includes straight-chain or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, ⁇ -propyl, i-propyl, n-butyl, i-butyl, tert-butyl, Examples thereof include sec-butyl, n-pentyl, i-pentyl, neo-pentyl, tert-pentyl, n-pentyl, i-pentyl, neo-pentyl, tert-pentyl, n-hexyl and the like. It is preferably an alkyl having 1 to 4 carbon atoms, particularly methyl or ethyl.
  • the lower alkoxy includes the oxy bonded to the lower alkyl, and examples thereof include methoxy, ethoxy, i-propoxy, tert-butoxy, pentyloxy, and hexyloxy. Preferred is methoxy.
  • Lower alkenyl includes straight-chain or branched alkenyl having 2 to 6 carbon atoms, P0210877
  • Examples include vinyl, aryl, i-propenyl, 2-butenyl, 3-pentenyl, 2-hexenyl and the like.
  • it is alkenyl having 2 to 4 carbon atoms.
  • Halogen includes fluorine, chlorine, bromine and iodine. Preferably, it is fluorine or chlorine.
  • Z 1 and Z 2 are the same or different and are selected from the group consisting of chromium, lower alkyl, lower alkoxy, lower alkenyl, halogen, lower alkyl halide, lower alkoxy halide, hydroxy, carboxy and nitro
  • the group is exemplified. These may be present at any substitutable position on the benzene.
  • these substituents include hydrogen, methyl, butyl, methoxy, fluoro, chloro, promo, trifluoromethyl, trifluoromethoxy and hydroxy.
  • a substituent Z 1 is selected from hydrogen
  • Z 2 is lower alkyl, lower alkoxy, lower alkenyl, halogen, halogenated lower alkyl, from the group consisting of halogenated lower alkoxy and human Doroki sheet.
  • Z 1 is hydrogen
  • Z 2 is a substituent selected from the group consisting of methyl, t-butyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy and hydroxy.
  • m is an integer of 2 to 5, preferably 2 or 3.
  • n is an integer of 1 to 3, and is preferably 1. More preferred compound (I) is as follows.
  • A is—NR 1 — (CH 2 ) m— (where R 1 is hydrogen or lower alkyl; m ⁇ is 2 or 3); n is 1; Z 1 is hydrogen; Z 2 is lower alkyl, lower When the substituent is selected from the group consisting of alkoxy, lower alkenyl, halogen, lower alkyl halide, lower alkoxy halide, hydroxy, carboxy and nitro. Particularly preferred is the case where Z 2 is methyl, t-butyl, methoxy, F, C 1, ⁇ 0 CF 3 or the like.
  • Z 2 is methyl, t one-butyl, main butoxy, F, C l, is the case for such -0 C 3.
  • the typical production method of compound (I) is illustrated below.
  • compound (IV) is reacted with compound (V) in the presence of a base, if desired, to give compound (I— 1) get.
  • a base carbonates (K 2 C0 3, Na 2 C0 3 , etc.) or NaOH, 3 tertiary Amin (Example: Et 3 ii) and the like can be used.
  • acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMS 0), tetrahydrofuran (THF) and the like can be used.
  • the reaction temperature is generally about 10 to 200 ° C, preferably room temperature to about 140 ° C, and the reaction time is several hours to several tens hours, preferably about 1 to 20 hours, more preferably about 3 to 1 hour. 5 hours.
  • Compounds (IV) and (V) may be synthesized by well-known reactions or commercially available products may be used.
  • the reaction temperature is generally about 10 to 200 ° C., preferably room temperature to about 14 CTC, and the reaction time is several hours to several tens of hours, preferably about 1 to 20 hours, more preferably about 3 to 20 hours. ⁇ 15 hours.
  • Compounds (IV) and (III) may be synthesized by a well-known reaction, or a commercially available product may be used.
  • an appropriate protection reaction may be performed on the functional group according to a method well known to those skilled in the art, and a deprotection reaction may be performed after the reaction.
  • the pharmaceutically acceptable salt of compound (I) include salts formed with inorganic acids, organic acids, inorganic bases and the like, and inner salts.
  • the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid
  • examples of the organic acid include p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, maleic acid, and oxalic acid.
  • An example is shown.
  • the inorganic base include Na, K and the like.
  • Compound (I) may be a solvate such as aqueous alcohol.
  • a prodrug is a derivative of a compound of the present invention that has a chemically or metabolically degradable group and is a compound that becomes a pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions. Methods for selecting and manufacturing appropriate prodrug derivatives are described in, for example, Design of Prodrugs,
  • a prodrug such as an acyloxy derivative produced by reacting a compound having a hydroxyl group with a suitable acyl halide or a suitable acid anhydride is exemplified.
  • a prodrug such as an acyloxy derivative produced by reacting a compound having a hydroxyl group with a suitable acyl halide or a suitable acid anhydride is exemplified.
  • Compound (I) is useful as a medicament.
  • it since it has an NMD A receptor antagonistic effect, it is effective for various diseases caused by the receptor, such as chronic neurodegeneration.
  • It is useful as a drug for treating diseases (eg, Parkinson's disease, senile dementia, Huntington's chorea), antiepileptic drug or analgesic. It is also effective as a therapeutic agent for acute phase of cerebral infarction because it is effective against neuronal degeneration caused by hypoxia.
  • Compound (I) can be orally or parenterally administered to animals including humans.
  • dosage forms include granules, tablets, capsules, and injections.
  • various additives such as excipients, disintegrants, binders, lubricants, stabilizers, coloring agents, and coating agents can be used, if desired.
  • the dosage varies depending on the age, body weight, condition and administration method of the subject, and is not particularly limited.However, in the case of oral administration per adult per day, it is generally about 20 mg to about 1000 mg, and parenteral administration is usually used. In this case, it is about 2 mg to about 100 mg.
  • compound (I) suppresses neuronal degeneration and chronic neurodegenerative diseases in cerebral infarction.
  • the mechanism of action is as follows: (1) It acts as an antagonist to the NMDA receptor that is excessively generated during neurodegeneration and binds to NMDA glutamate, particularly the NR1 / NR2B complex receptor involved in neuronal degeneration. 2) It is thought that nerve cell degeneration is suppressed by the fact that ion channels in nerve cells do not open and calcium ions do not flow into nerve cells. In addition, since the more preferred compound of the present invention does not bind to the PCP receptor in the ion channel, it is considered that there is no side effect such as mental disorder. (Example)
  • Example 2 The compounds of Examples 2 to 4 were synthesized according to the method of Example 1. The structural formula is shown below. Example 2
  • the complementary DNA (cDNA) of the mouse NMD A receptor subunit was transcribed as type I into the messenger UNA (mRNA), and this mRNA was injected into African Megafrog oocytes. Three days after injection, NMD A was induced using a two-electrode membrane voltage clamp device. The inward current was recorded. The injection amount of mRNA was 12.5 / 12.5 ng corresponding to NR1 / NR2B per oocyte, and co-expression of subunits was performed. The oocytes were placed in a solution (compound concentration: 100 M) containing a test compound (compounds 4, 5, 7, 8), and the NMDA-induced inward current was recorded using a two-electrode voltage clamp device.
  • NMDA currents were evoked by application of NMDA 100 ⁇ , glycine 10M.
  • the recorded NMDA-induced inward current value was substituted into the following equation to calculate the% electrical response.
  • % Electrical response (value of NMDA-evoked inward current in the presence of test compound / value of NMDA-evoked inward current in the absence of test compound) XI 00 Normally, if the test compound exhibits NMDA receptor antagonism However, the inflow of Ca ions into nerve cells is reduced, and the electrical response% is reduced. Table 1 shows the% electrical response of the NR1 / NR2B complex receptor for each compound, and Table 2 shows the% electrical response for each complex receptor of NR1 / NR2AD.
  • MK-801 is said to bind to PCP receptors and cause mental disorders.
  • receptor competition experiments with MK-801 and the compounds of Examples 2 to 4 were performed.
  • the brain was excised after decapitation and the cerebral cortex was fractionated.
  • the cerebral cortex was homogenized with 20 volumes of ice-cold 5 mM Tris ⁇ HC1 buffer (pH 7.8) and centrifuged at 4 ° C and 4000 OXg for 10 minutes.
  • the obtained precipitate was suspended in the same buffer and centrifuged again. This operation was repeated twice, and the obtained precipitate was suspended in a buffer solution and stored at 180 ° C.
  • the mixture was centrifuged at 4 ° C. and 4000 OXg for 10 minutes, and the obtained precipitate was suspended in a buffer. It was further diluted 2.5-fold with a buffer solution and used as a membrane sample in the experiment.
  • the filter paper was immersed in liquid scintillation (Clearsol I, manufactured by Nacalai Tesque, Inc.) in a vial, and the radioactivity was measured with a liquid scintillation counter.
  • the binding inhibition rate was determined by the following equation, and the dose aC 50 ) that inhibited binding by 50 % was calculated.
  • the last 2 for 60 min 25 ° C in the [3 H] MK-801 co the Iotaiotamyu, the nonspecific binding using 10 ⁇ M (+) MK-801.
  • the IC 50 values are shown in the table below. 10877
  • Haloperidol a commercially available NR1 / NI12B complex receptor antagonist, was used as a control.
  • Binding inhibition rate (%) 100-[([2]-[3]) / ([1]-[3]) X 100]
  • HEK293T cells When the NMDA receptor is expressed in HEK293T cells, large amounts of glutamate and aspartate are released from HEK293T cells, which can automatically induce cell degeneration.
  • HEK293T cells were expressed at an NR1 / NR2B complex receptor complementary DNA (cDNA) ratio of 1: 3 (total amount of cDNA; 2 g / well (6-well plate)), and Example 2 for cell degeneration 24 hours later And 3 compounds (compounds 4 and 5) [The cytopathic inhibitory effect at a compound concentration of 2 M or 0.02-200 was examined using LDH activity as an index. As a result, in cells expressing the NR1ZNR2B complex receptor, Compounds 4 and 5 showed a significant cytopathic inhibitory effect at 20 M or more.
  • the preparation method and experimental method of the membrane sample differ depending on each receptor subtype, and are shown below.
  • Binding experiments were performed on a membrane sample of 480 ⁇ 1, 10 ⁇ 1 [1] distilled water (total binding amount, Total), [2] different concentrations of test substance or [3] large amounts of unlabeled ligand (non- Specific binding amount (NS) and 10/1 labeled ligand were further added and incubated for a certain period of time. After the incubation, the conjugate and the free form were separated using Whatman GF / C filter paper, and the filter paper was washed four times with 2.5 ml of ice-cold buffer. Filter paper into liquid vial in vial The sample was immersed in a racion (Clearsol I) and the radioactivity was measured with a liquid scintillation counter. The binding inhibition rate was determined by the following formula, and the dose that inhibited binding by 50% (ICS S ) was calculated.
  • ICS S dose that inhibited binding by 50%
  • Binding inhibition rate «) 100-(([2]-[3]) I ([1]-[3]) X 100)
  • NR1 + NR2B-expressing cells (HEK293T) are buffered with 20 mM HEPES (: N-2-hydroxyhexylpiperazine- ⁇ '-2-ethanesulfonic acid) buffer, ImMEDTA (: ethylenediaminetartaric acid-2-sodium salt) buffer (PH 7.0), centrifuged at 4 ° C, 100, OOOXg for 30 minutes, and used for experiments after resuspension. Incubation was carried out at 4 ° C for 2 hours with a final 5 nM (15 nM cells) [ 3 H] Ifenprodil. For nonspecific binding, 100 IfM Ifenprodil. Tartrate was used, and the filter paper was pretreated with 0.05% polyethyleneimine. The incubation was performed with 3 3M vanoxerine to block the binding of [] ifenprodil to the sigma receptor.
  • HEPES N-2-hydroxyhexylpiperazine- ⁇ '-2-ethanesulfonic
  • Example 2 An appropriate amount of the compound 4, the crystalline cellulose, the magnesium stearate and the like of Example 2 is mixed, and the mixture is compressed to give a tablet.
  • Formulation Example 3 Capsules are obtained by filling the granules of Formulation Example 2 into capsules. Industrial applicability
  • the present compound is useful as a drug for treating acute phase of cerebral infarction or a drug for treating chronic neurodegenerative disease.

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Abstract

L'invention concerne un composé représenté par la formule (I), (dans laquelle A représente NR1-(CH2)m- (R1 représente hydrogène ou alkyle inférieur et m un nombre entier allant de 2 à 5 ou une liaison simple); Z1 et Z2 représentent chacun indépendamment hydrogène ou un substituant choisi dans le groupe comprenant alkyle inférieur, alcoxy inférieur, alcényle inférieur, halogéno, alkyle inférieur halogéné, alcoxy inférieur halogéné, hydroxy, carboxy et nitro, n étant un nombre entier allant de 1 à 3). Il présente un effet antagoniste sur un récepteur NMDA et s'avère utile notamment comme traitement de l'infarctus cérébral au stade aigu, de maladies de dégénérescence nerveuse chronique et comme analgésique.
PCT/JP2002/010877 2001-10-22 2002-10-21 Nouveau derive carbamoyl-pyrrolidone WO2003035641A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005030720A1 (fr) * 2003-09-25 2005-04-07 Shionogi & Co., Ltd. Derive de piperidine presentant une activite antagoniste du recepteur ndma
JP2006526634A (ja) * 2003-06-02 2006-11-24 サマリタン，ファーマスーティカルス，インク． 神経保護作用を有するベンゾアート化合物およびベンズアミド化合物
WO2015105929A1 (fr) * 2014-01-09 2015-07-16 Bristol-Myers Squibb Company (r)-3-((3s,4s)-3-fluoro-4-(4-hydroxyphényl)pipeéridin-1-yl)-1-(4-méthylbenzyl)pyrrolidin-2-one et ses précurseurs pour le traitement de troubles psychiatriques
US9221796B2 (en) 2014-01-09 2015-12-29 Bristol-Myers Squibb Company Selective NR2B antagonists
WO2017066368A1 (fr) 2015-10-14 2017-04-20 Bristol-Myers Squibb Company Antagonistes sélectifs de nr2b
WO2019022179A1 (fr) * 2017-07-28 2019-01-31 武田薬品工業株式会社 Composé hétérocyclique
CN105873915B (zh) * 2014-01-09 2019-07-16 百时美施贵宝公司 用于治疗精神病症的化合物
US11952344B2 (en) 2019-09-25 2024-04-09 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof

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EP0709384A1 (fr) * 1994-10-31 1996-05-01 MERCK PATENT GmbH Dérivés de benzylpiperidine ayant une haute affinité pour les sites de liaison de récepteurs d'aminoacides
WO1997023214A1 (fr) * 1995-12-22 1997-07-03 Warner-Lambert Company Analogues de piperidine a substitution en position 4 et utilisation de ces derniers en tant qu'antagonistes selectivement actifs contre les sous-types du recepteurs de nmda
EP0846683A1 (fr) * 1996-12-03 1998-06-10 F. Hoffmann-La Roche Ag Dérivés de4 la ç-hydroxypipéridine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0709384A1 (fr) * 1994-10-31 1996-05-01 MERCK PATENT GmbH Dérivés de benzylpiperidine ayant une haute affinité pour les sites de liaison de récepteurs d'aminoacides
WO1997023214A1 (fr) * 1995-12-22 1997-07-03 Warner-Lambert Company Analogues de piperidine a substitution en position 4 et utilisation de ces derniers en tant qu'antagonistes selectivement actifs contre les sous-types du recepteurs de nmda
EP0846683A1 (fr) * 1996-12-03 1998-06-10 F. Hoffmann-La Roche Ag Dérivés de4 la ç-hydroxypipéridine

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006526634A (ja) * 2003-06-02 2006-11-24 サマリタン，ファーマスーティカルス，インク． 神経保護作用を有するベンゾアート化合物およびベンズアミド化合物
WO2005030720A1 (fr) * 2003-09-25 2005-04-07 Shionogi & Co., Ltd. Derive de piperidine presentant une activite antagoniste du recepteur ndma
US7786140B2 (en) 2003-09-25 2010-08-31 Shionogi & Co., Ltd. Piperidine derivative having NMDA receptor antagonistic activity
JP2017503804A (ja) * 2014-01-09 2017-02-02 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ 精神障害の治療のための（ｒ）−３−（（３ｓ，４ｓ）−３−フルオロ−４−（４−ヒドロキシフェニル）ピペリジン−１−イル）−１−（４−メチルベンジル）ピロリジン−２−オンおよびそのプロドラッグ
EP3677578A1 (fr) * 2014-01-09 2020-07-08 Bristol-Myers Squibb Company (r)-3-((3s,4s)-3-fluoro-4-(4-hydroxyphényl)pipéridine-1-yl)-1-(4-méthylbenzyle)pyrrolidin-2-one et ses promédicaments pour le traitement de troubles psychiatriques
US9221796B2 (en) 2014-01-09 2015-12-29 Bristol-Myers Squibb Company Selective NR2B antagonists
CN105873915A (zh) * 2014-01-09 2016-08-17 百时美施贵宝公司 用于治疗精神病症的(r)-3-((3s,4s)-3-氟-4-(4-羟基苯基)哌啶-1-基)-1-(4-甲基苄基)吡咯烷-2-酮及其前药
KR20160101194A (ko) * 2014-01-09 2016-08-24 브리스톨-마이어스 스큅 컴퍼니 정신 장애의 치료를 위한 (r)-3-((3s,4s)-3-플루오로-4-(4-히드록시페닐)피페리딘-1-일)-1-(4-메틸벤질)피롤리딘-2-온 및 그의 전구약물
WO2015105929A1 (fr) * 2014-01-09 2015-07-16 Bristol-Myers Squibb Company (r)-3-((3s,4s)-3-fluoro-4-(4-hydroxyphényl)pipeéridin-1-yl)-1-(4-méthylbenzyl)pyrrolidin-2-one et ses précurseurs pour le traitement de troubles psychiatriques
KR102331120B1 (ko) 2014-01-09 2021-11-24 브리스톨-마이어스 스큅 컴퍼니 정신 장애의 치료를 위한 (r)-3-((3s,4s)-3-플루오로-4-(4-히드록시페닐)피페리딘-1-일)-1-(4-메틸벤질)피롤리딘-2-온 및 그의 전구약물
US9187506B2 (en) 2014-01-09 2015-11-17 Bristol-Myers Squibb Company (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one and its prodrugs for the treatment of psychiatric disorders
CN105873915B (zh) * 2014-01-09 2019-07-16 百时美施贵宝公司 用于治疗精神病症的化合物
US10501451B2 (en) 2015-10-14 2019-12-10 Bristol-Myers Squibb Company Selective NR2B antagonists
US10954225B2 (en) 2015-10-14 2021-03-23 Bristol-Myers Squibb Company Selective NR2B antagonists
WO2017066368A1 (fr) 2015-10-14 2017-04-20 Bristol-Myers Squibb Company Antagonistes sélectifs de nr2b
WO2019022179A1 (fr) * 2017-07-28 2019-01-31 武田薬品工業株式会社 Composé hétérocyclique
US11230541B2 (en) 2017-07-28 2022-01-25 Takeda Pharmaceutical Company Limited Heterocyclic compound
US11713311B2 (en) 2017-07-28 2023-08-01 Takeda Pharmaceutical Company Limited Heterocyclic compound
US11952344B2 (en) 2019-09-25 2024-04-09 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof

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