WO1996025927A1 - Inhibiteur des recepteurs de l'acide glutamique et ameliorant des fonctions cerebrales - Google Patents

Inhibiteur des recepteurs de l'acide glutamique et ameliorant des fonctions cerebrales Download PDF

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Publication number
WO1996025927A1
WO1996025927A1 PCT/JP1996/000399 JP9600399W WO9625927A1 WO 1996025927 A1 WO1996025927 A1 WO 1996025927A1 JP 9600399 W JP9600399 W JP 9600399W WO 9625927 A1 WO9625927 A1 WO 9625927A1
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Prior art keywords
compound
production example
ethyl acetate
oxepin
production
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PCT/JP1996/000399
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English (en)
Japanese (ja)
Inventor
Jiro Takeo
Shinya Yamashita
Keiji Wada
Shuji Jinno
Yasuyo Kogure
Hiroyuki Onuki
Takaaki Okita
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Nippon Suisan Kaisha, Ltd.
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Publication of WO1996025927A1 publication Critical patent/WO1996025927A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/14—[b,f]-condensed

Definitions

  • the present invention relates to various neurological diseases (eg, eclampsia, senile dementia, Huntington's disease, schizophrenia, Parkinson's disease, Alheima type 1 dementia, etc.) or brain.
  • the present invention relates to a glutamate receptor blocker and a cerebral function improving agent useful for preventing and treating neurodegeneration in a pathological condition such as a sequelae caused by neuronal death after ischemia.
  • L-glutamic acid or L-asparaginate a kind of amino acid
  • L-glutamic acid or L-asparaginate a kind of amino acid
  • Numerous studies have shown that such excitatory amino acids can produce synaptic transmission, neurotransmitter regulation, long-term potentiation, learning and memory, synaptic developmental flexibility, and ischemic It has been reported to be involved in a variety of neurological effects, including hypoxia damage and neuronal death, and the etiology of several neurodegenerative diseases.
  • Glutamate receptor blocker can be used in a variety of neurological disorders such as eclampsia, senile dementia, Huntington's chorea, schizophrenia, Parkinson's disease, It has already been proposed that it is useful for the prevention and treatment of neurodegeneration in a pathological condition such as sequelae due to neuronal death after cerebral ischemia (eg, Heimer-type dementia). — 1553680 publication).
  • Glutamate receptors are localized at synapses, and have three types of receptors depending on the affinity of specific ligands and electrophysiological or neurochemical actions. The body is classified.
  • NMDA N-methyl-D-asno, lutet receptor: monovalent or divalent cations such as sodium ion and canoleum ion Transient and ion-related receptors associated with magnesium ion blocked by magnesium ion.
  • AMPA ⁇ -amino-3—hydroxy-5—methinole-4—isoxazolepropionic acid
  • type receptor monovalent force like sodium Receptors involved in ion channels.
  • Caynic acid receptors Receptors with similar ion properties to ⁇ ⁇ ⁇ ⁇ receptors but different levels of conductance or desensitization from ⁇ ⁇ ⁇ ⁇ receptors .
  • ⁇ ⁇ ⁇ ⁇ type receptor and kainate type receptor are sometimes referred to as ⁇ ⁇ ⁇ — ⁇ ⁇ DA type A receptor.
  • drugs that suppress the overactivation of the NMDA-type receptor, which forms a channel that directly penetrates calcium are used in various pathological conditions as described above. It is expected to have an improvement effect.
  • NMDA type receptors are activated during normal excitatory synaptic transmission in the brain. Activation of NMDA type receptors under normal conditions involves long-term synergistic, memory-like phenomena in excitatory synapses. Excessive neurological exacerbations occur in epileptic seizures, and overactivation of NMDA type receptors has been shown to contribute to the pathophysiology of epilepsy.
  • NMDA-type receptors have also been implicated in neuronal cell death that occurs after cerebral ischemia. Following the onset of an ischemic brain attack, such as a stroke or heart attack, there is an over-release of endogenous glutamate, which results in over-activation of NMDA-type receptors. When glutamate interacts with the NMDA-type receptor, it opens up the ion channel, thereby It allows the flow of cations through the membrane, for example, the flow of Ca 2+ and Na + into cells as well as K + from cells.
  • the Lee on-stream generated Ri by the interaction with glutamicum phosphate and NMDA receptors, especially C 3 2 Ryoi on-flow is believe and this plays an important role in neuronal death ing.
  • agents that block response to NMDA-type receptor activation may be associated with the treatment of neurological disorders, such as epilepsy, as well as those resulting from hypoxia or hypoglycemia, or stroke, trauma And has therapeutic use in preventing neuronal death following cerebral ischemia that occurs during a heart attack.
  • neurological disorders such as epilepsy, as well as those resulting from hypoxia or hypoglycemia, or stroke, trauma And has therapeutic use in preventing neuronal death following cerebral ischemia that occurs during a heart attack.
  • Some nervous system disorders involve neurodegeneration, which can be due to over-activation of NMDA type receptors. Therefore, blockers of NMDA-type receptor-mediated responses are promising for the treatment of diseases such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and Dunn's syndrome .
  • An object of the present invention is to provide a compound having a glutamate receptor blocking effect, which is useful for prevention and treatment of various neurological diseases or neurodegeneration such as nerve cell death after cerebral ischemia.
  • the present inventors have focused on tricyclic compounds, synthesized their derivatives by organic synthesis, and searched for the properties of the obtained compounds.
  • the present invention also provides a brain function improving agent comprising the compound represented by the above formula (1) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the “lower alkyl group” means a linear, branched or cyclic group having up to 8 carbon atoms.
  • the “lower alkoxy group” means a formula-0-lower alkyl.
  • the salt of the compound of the present invention means a pharmaceutically acceptable salt, for example, a sodium salt, a potassium salt, a calcium salt, an ammonium salt. , Aluminum salts, hydrochlorides, sulfates, etc.
  • the tricyclic compound represented by the above formula (1) in the present invention is a compound obtained by chemical synthesis, has an inhibitory activity on a glutamate receptor, and has various neurogenic properties.
  • Diseases eg, eclampsia, senile dementia, Huntington's chorea, schizophrenia, Parkinson's disease, Alzheimer's disease, etc.
  • nerve cell death after cerebral ischemia It is useful for the prevention and treatment of neurodegeneration in pathological conditions such as sequelae. It has been confirmed that the tricyclic compound represented by the above formula (1) of the present invention has low toxicity.
  • the compound of the present invention produced according to conventional formulation techniques, for example, powders, granules, tablets, dragees, ampoules, capsules, etc., orally administered, subcutaneous In addition, it can be used as an intramuscular or intravenous agent, a suppository, and the like.
  • usual additives such as bulking agents, binders, disintegrants, pH regulators, solubilizers and the like can be used.
  • the dosage of the compound of the present invention for a treated patient will vary depending on the patient's age, the type and condition of the disease, and the like, but it is usually 1 to 500 mg per day for an adult. Can be divided into several doses o
  • the tricyclic compound represented by the above formula (1) in the present invention and a method for producing the same are exemplified below, but the present invention is not limited to these examples.
  • the results of a test of the compound of the present invention for inhibiting the death of cerebral nerve cells using primary cultured cells showed that the delayed neuronal cells using a gerbil cerebral ischemia model As a result of the death suppression effect test, The effects on glutamate receptor by electrophysiological tests are also shown below.
  • Step 4 2 (2-arylene obtained from the above step 3)
  • Step 5 The 2— (2-ary phenol obtained in the above step 4)
  • Step 6 2-(2-aryloxy) 1,4-diacetoxy 1-6-methoxybenzen obtained in the above step 5-10.6 g of methylene chloride The resulting solution was dissolved in 175 ml of methanol, 175 ml of methanol and 20 ml of acetic acid, and the mixture was stirred at 178 ° C for 20 minutes. Next, the mixture was stirred for 3 hours while bubbling ozone gas, and after confirming that the solution turned blue, 11 ml of dimethyl sulfide was added and the mixture was stirred until the temperature reached room temperature.
  • Step 7 2-(2, 5-diacetoxy 13-methoxyphenoxy) obtained in the above step 6
  • reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Add 120 ml of methanesulfonate thereto stir at room temperature for 7 days, dilute with ethyl acetate, wash with water, then wash with saturated saline, and add magnesium sulfate anhydride. After drying with um, the solvent was distilled off under reduced pressure.
  • Stage 1 2,3—Dimethoxyphenol 5 g, 2′—Promocetonitrile 7 g, potassium carbonate 6.7 g and copper acetate 1.lg
  • 2nd stage 2-(2,3-dimethoxy phenoxy) acetate obtained in the above 1st stage was added to 7.6 g to 2.7 g, monorefo 3.7 ml of phosphorus was added, the mixture was heated with stirring at 150 for 10 minutes, 0.15 g of p-toluenesulfonate was added, and the mixture was heated and stirred at 150 for 8 hours. 300 ml of ethyl acetate and 100 ml of dilute hydrochloric acid were added, and the mixture was partitioned. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Trimethyl xybenzaldehyde (5 g) is suspended in anhydrous methylene chloride (50 ml), and m—curo-peroxybenzoic acid (10 g, purity: 70%) is suspended. ) was added and the mixture was heated and stirred at 50 ° C. for 3 hours. After distilling off the solvent under reduced pressure, the residue was dissolved in 100 mL of ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, washed with water and with a saturated saline solution, and then washed with anhydrous magnesium sulfate. After drying, the solvent was distilled off under reduced pressure.
  • Second stage In the first stage of the manufacturing process of the above-mentioned manufacturing example 8, 3,5—dimethoxy phenol is used instead of 2,3—dimethoxy phenol. 7 and 9 — dimethoxyl 110, 11 — dihydrobenzo [b, f] in the same manner as in the first and second steps of Production Example 8 except that 0.72 g of oxepin—10—one was obtained, and 5 ml of anhydrous methanol was added to the compound, and the mixture was stirred at 0 ° C. under an argon stream. To this was added 0.2 g of sodium hydrogen hydride, and the mixture was stirred at room temperature for 1 hour.
  • the resulting solution was acidified with dilute hydrochloric acid and extracted three times with ethyl acetate.
  • the obtained organic layer was washed with water, further washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Step 2 The residue was placed in a pressure-resistant reaction vessel, 3 g of pyridin hydrochloride was added, and the mixture was stirred at 200 ° C for 1.5 hours, and partitioned by adding ethyl acetate and water. The organic layer was washed with dilute hydrochloric acid, then with water, further washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the starting material which is obtained in the second stage of the above-mentioned production example 17, is 3—Cross mouth 17,8—Dimethoxy 1 10, 11—Di
  • the title compound 1 represented by the following formula (19) was prepared in the same manner as in Production Example 12 except that hydroxybenz [b, f] oxepin 110-one was used. 8 colorless needle crystals were obtained. The melting point of this compound 18 was 11.9-121.9 ° C.
  • the temperature was 226.5-28.5 ° C.
  • the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure H.
  • This compound was used in the same manner as in Production Example 12 except that this compound was used in place of 3,5-dimethoxyphenol in the first step of the production process of Production Example 12, and the following compound was used. Yellow needle crystals of the title compound 42 represented by the formula (43) were obtained. The melting point of this compound 42 was 109.4-11-11.4 ° C.
  • 1,2—Dimethoxybenzen 10 g was dissolved in methylene chloride 50 ml and stirred at 0 ° C. To this, 23.5 ml of chlorosulfonic acid was dropped, and the mixture was stirred at 45 ° C for 1 hour. The reaction solution was added dropwise to 0-methanol (150 ml), concentrated hydrochloric acid (29 ml) and stannous chloride (57 g) were added, and the mixture was stirred at room temperature for one minute. After concentration, 12% hydrochloric acid (125 ml) was added, and the mixture was extracted three times with toluene.
  • the compound was subjected to the reaction of the second and subsequent stages of the production process of Production Example 8 to give pale yellow needle-like crystals of the title compound 49 represented by the following formula (50).
  • the melting point of this compound 49 was 21.7.9-12.19.4.
  • the melting point of this compound 53 was 188.5-189.3 ° C.
  • Equation (55) The melting point of this compound 54 was 119.1-121.1 ° C.
  • This compound was subjected to the same procedures as in the sixth to seventh steps of Production Example 1 to obtain a yellow plate-like crystal of the title compound 57 represented by the following formula (58).
  • the melting point of this compound 57 was 137.1-138.9.
  • Production Example 49 In the manufacturing process of Production Example 49, except that 3,4—difluorophenol was used instead of 3,5-dimethoxyphenol, Production Example 49 In the same manner as in the first and second steps, colorless needle crystals of the title compound 63 represented by the following formula (64) were obtained. The melting point of this compound 63 was 116-117 ° C.
  • Stage 1 2—Black mouth—5—Nitrobenzaldehyde (5.57 g), 3,5—Dimethoxyphenol (4.62 g), Carbonated Lithium (8.29 g), copper powder (0.2 g), copper iodide (1) (0.6 g), N-methyl-2-pyrrolidine (60 mL) ) was added and the mixture was heated and stirred at 120 at 30 minutes. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was diluted with water and extracted with ethyl acetate. The extract was washed successively with water and a saturated saline solution, and dried over anhydrous sodium sulfate.
  • 2nd stage 2-(3, 5-dimethoxyphenoxy)-1-5-nitrobenzene phenol obtained from the above 1st stage (5.64 g) is treated with ethanol. It was dissolved in a mixed solvent of ethanol (70 ml) and THF (70 ml). At C, sodium borohydride (1.40 g) was added. The mixture was stirred at 0 ° C for 30 minutes, and the reaction was stopped by adding a saturated aqueous solution of ammonium chloride. The reaction solution was concentrated under reduced pressure, hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline in this order, and dried over anhydrous sodium sulfate.
  • Step 3 Digest the 2— (3,5—dimethoxyphenoxy) -15—2 trobendinolepromide (3.25 g) obtained in Step 2 above. The residue was dissolved in lorometan (120 ml), and tetraethylammonium cyanide (1.65 g) was added. The mixture was stirred at 40 ° C for 1.5 hours and cooled to room temperature. The reaction mixture was washed successively with water and saturated saline, and dried over anhydrous sodium sulfate.
  • Step 4 The 2— (3,5—dimethoxyphenoxy) 5-2-trobenzircyanide (2.28 g) obtained in the above step 3 is suspended in acetic acid (22 ml). It became cloudy and concentrated hydrochloric acid (20 ml) was added. Heated at 130 ° C for 2 hours and left at room temperature. The precipitated crystals were separated by filtration, washed with water, dried, and added with polyphosphoric acid (65 ml), followed by heating at 130 ° C for 20 minutes. The reaction was poured into water and extracted with ethyl acetate.
  • the melting point of the amorphous solid obtained by recrystallization from hexane monoethyl acetate was 227 to 229 ° C.
  • Wistar pregnancy rat E18 was hemped with ether. After intoxication and laparotomy, the uterus was removed and placed in a large scaffold.
  • the hippocampus was excised from the brain under a stereomicroscope, and placed in an ice-cooled 5 ml HBSS inhaler.
  • Glutamate-induced hippocampal neuronal cell death was induced by a modification of the method of Choi [Choi, DW, J. Neurosci., 7, 369-379 (1987)]. Glutamate treatment was performed by adding HBSS (19.6 mM glueose, 1.8 mM MC a C1) containing 100 // M glutamate to hippocampal neurons on days 8 to 10 of culture. 2 -. 2 H 2 0, 0 8 m MM g C 1 2 -.. 2 H 2 0, 1 3 7 m MN a HC ⁇ 3, 5 m MKC 1, 0 3 m KH 2 P 0 4, 1 3 .
  • MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolivum mouth] is a pale yellow substance that is a mitochondrial substance of living cells. MTT is cleaved by an enzyme involved in the respiratory chain present in the inner membrane of the condria, producing dark blue MTT formazan. It is known that the amount of MTT formazan is significantly correlated with the number of living cells. M T T formazan, Isoprono. When decomposed by knore, color is produced, and the number of living cells can be measured by performing colorimetric quantification under a certain wavelength. Next, the procedure of the MTT method will be described.
  • MK-801 and D-AP5 D-2-amino-5-phosphonovalley, which are the present invention and commercially available typical NMDA-type glutamate receptor blockers G was used as a comparative drug, and its inhibitory effect on glutamate neurotoxicity on hippocampal neurons was evaluated according to the five-point scale shown in Table 1 below. Shown in However, the compound numbers in Table 1 are the same as the compound numbers shown in Production Examples.
  • the tricyclic compound of the present invention showed an action of suppressing neuronal cell death in the cultured hippocampal neuronal cell death induction system.
  • compound 46 has a very strong neuroprotective effect, and can be used for various neurological diseases, for example, neuronal cell death caused by hypoxia or hypoglycemia, or stroke, trauma, It has therapeutic use in the prevention of neuronal cell death after cerebral ischemia caused by myocardial infarction.
  • the effect of the product of the present invention on the glutamate receptor was determined by electrophysiology using an improved method of translating the oocyte of the cell of the frog toad, Masu et al. [Nature 329, 836 (1987)]. Was evaluated.
  • the hippocampus region was extracted from the rat, homogenized in the presence of guanidinium isocyanate, and the total RNA was extracted by ultracentrifugation using cesium chloride.
  • Poly (A) + RNA was purified from the obtained RNA by using oligo d T cell mouth column.
  • Oocytes were transformed with poly (A) + RNA (1 ⁇ g / ⁇ 1) multiplexed using a micromanipulator into oocytes. 5 is injected by O n 1, oocytes medium B arth (8 8 mM n a C l, 1 m MKC 1, 2. 4 m MN a HC 0 3, 0. 3 m MC a ( N_ ⁇ 3 ) 2, 0. 4 1 m MC a C l 2, 0.
  • the compound of the present invention is dissolved in DMSO and added to various concentrations in 100 iMNMDA—10 ⁇ glycine-frog ring solution (control solution).
  • 100 iMNMDA—10 ⁇ glycine-frog ring solution (control solution) The membrane current generated by perfusing the added solution and the membrane current generated by the control solution were measured.
  • Table 2 The results are shown in Table 2 below on a 3-point scale. At this time, D-eight? 5 and 1 ⁇ 1-8 0 1 were used. However, the compound numbers in the table are the same as the compound numbers shown in Production Examples.
  • the product of the present invention suppresses the response mediated by the NMDA type receptor. Also, by adding 100 M kainate and 1 ⁇ MMK-801 to the Frog Ringer's solution, the inward membrane current flowing from the inside of the cell to the outside of the cell was recorded. Was done. This response was inhibited by CNQX (1 ⁇ ), a Non-NMD type I receptor blocker, and was presumed to be via the No ⁇ -NMDA type receptor. It was done. Some of the compounds of the present invention also showed an inhibitory effect on the response mediated by the Non-NMDA type receptor. However, these compounds tended to be more potent at inhibiting NMDA-type receptor-mediated responses than at Non_NMDA-type receptors.
  • the pharmacological action of the product of the present invention is an action of blocking NMDA type receptor and Non-NMDA type receptor. That is, the product of the present invention shows a blocking effect on NMDA type receptor and Non-NMDA type receptor, and it is presumed that this product exhibits the neuroprotective effect shown in Production Example 1 by this effect. Was done.
  • Gerbils Induction of delayed neuronal death by transient cerebral ischemia was described by Kirino et al., CKirino, T. et al., Acta Neuropathol., 62 (3), 201-208 (1984). , Kirino, T. et al., Acta Neuropathol., 62 (3), 209-218 (1984)]. Gerbils were fixed under anesthesia with isoflurane, and the cervical skin was incised about 1 cm along the midline with a razor. Using a pin set, the bilateral common carotid artery was separated and exposed from the surrounding tissue, and a suture was passed.
  • the body temperature of the gerbil was maintained at around 38 ° C on a water bed, and after waking up, the suture was pulled up and the clip was used to occlude the bilateral common carotid artery for 5 minutes. After completion of the occlusion, the clip was removed, blood flow was resumed, and the operation site was closed.
  • the compound of the present invention was dissolved in 10 mM PBS (phosphate-buffered saline) and administered at a concentration of 5 mg ZKG via the jugular vein 10 minutes before bilateral carotid artery occlusion.
  • 10 mM PBS was used as a control group.
  • the brain was removed and fixed with 10% neutral buffered formalin solution.
  • Hippocampal tissue sections were prepared and stained with hematoxylin and eosin according to standard procedures.
  • a photograph of the hippocampal CA1 region was taken under a microscope, and the inhibitory effect on delayed neuronal cell death was evaluated by measuring the number of viable pyramidal cells per mm of the hippocampal CA1 region. The number of animals used in the experiment was 10 in each group.
  • compound 46 is a compound that delays hippocampal CA1 region. It reduced spontaneous neuronal cell death by 90% or more.
  • pentobarbiol was also found to inhibit late neuronal death by 90% or more when administered intraperitoneally at a dose of 40 mg / kg.
  • the compounds of the present invention showed activity comparable to pentobarbital. This indicates that the compounds of the present invention are effective against ischemic diseases in which excitatory amino acids such as glutamate and aspartate are considered to be involved.
  • ischemic diseases it is important for such ischemic diseases to prevent neuronal cell death that occurs after ischemia.
  • the cause of this neuronal cell death is likely to be the influx of calcimuion into cells via glutamate receptors that are excessively activated by ischemia. ing. From the results of this animal experiment, the use of the compound of the present invention makes it possible to protect nerve cells by blocking glutamate receptors when the brain is ischemic This is inferred.
  • various neurological diseases related to the glutamate receptor for example, a preventive or therapeutic drug for epilepsy that is suggested to be related to overactivation of this receptor, or Cardiac arrest-An agent for suppressing neuronal death that occurs after cerebral ischemia caused by cerebral infarction, etc., or an agent for ameliorating these post-symptoms, and an agent for protecting many neurodegenerative diseases. And its application as a therapeutic agent.
  • the compound represented by the formula (1) of the present invention has an inhibitory effect on nerve cell death, and is expected to be applied as a therapeutic drug for various neurological diseases.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés ayant pour effet d'inhiber les récepteurs de l'acide glutamique, utiles à la prévention et au traitement de différentes maladies nerveuses et de la dégénérescence nerveuse, comme par exemple la mort des neurones faisant suite à l'ischémie cérébrale. Cet inhibiteur des récepteurs de l'acide glutamique et améliorant des fonctions cérébrales a pour substance active un composé représenté par la formule générale (1), ou un sel pharmacologiquement acceptable de celui-ci, où X et Y représentent une combinaison arbitraire de groupes choisis de façon indépendante parmi CH2, CHW?1 (où W1¿ représente un halogène, un groupe hydroxy ou alkoxy inférieur) et C=O dans le cas où X et Y sont liés entre eux par une liaison simple, alors qu'X et Y représentent une combinaison arbitraire de groupes choisis de façon indépendante entre CG et COW?2 (où W2¿ représente un alkyle inférieur ou un alkylcarbonyle inférieur) lorsque X et Y sont liés entre eux par une liaison double; Z représente O, S, S=O ou SO¿2?; et R?1 à R8¿ sont choisis individuellement parmi l'hydrogène, OR?9 (où R9¿ représente l'hydrogène, un alkyle inférieur, un alkyle inférieur hydroxylé ou un alkyle inférieur carboxylé), un halogène, un alkyle inférieur, un alkyl cétone inférieur, CF¿3?, les groupes nitro, amine et phényle.
PCT/JP1996/000399 1995-02-22 1996-02-22 Inhibiteur des recepteurs de l'acide glutamique et ameliorant des fonctions cerebrales WO1996025927A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0885610A1 (fr) * 1996-01-19 1998-12-23 Nippon Suisan Kaisha, Ltd. Relaxant des muscles lisses de la trachee
US6602898B1 (en) 1999-06-03 2003-08-05 Nippon Suisan Kaisha, Ltd. Tricyclic fused heterocycle compounds, process for preparing the same and use thereof
WO2008096755A1 (fr) * 2007-02-07 2008-08-14 Nippon Suisan Kaisha, Ltd. Inhibiteur du récepteur vanilloïde (vr1) et son utilisation

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
COLLECT. CZECH. CHEM. COMMUN., Vol. 49, No. 4, (1984), pages 992-1000. *
COLLECT. CZECH. CHEM. COMMUN., Vol. 51, No. 1, (1986), pages 156-166. *
J. MED. CHEM., Vol. 23, No. 5, (1980), pages 494-501. *
NEUROCHEM. INT., Vol. 19, No. 3, (1991), pages 247-253. *
NEUROPSYCOPHARMACOLOGY, Vol. 8, No. 1, (1986), pages 41-44. *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0885610A1 (fr) * 1996-01-19 1998-12-23 Nippon Suisan Kaisha, Ltd. Relaxant des muscles lisses de la trachee
EP0885610A4 (fr) * 1996-01-19 1999-04-21 Nippon Suisan Kaisha Ltd Relaxant des muscles lisses de la trachee
US6495592B1 (en) 1996-01-19 2002-12-17 Nippon Suisan Kaisha, Ltd. Tracheal smooth muscle relaxants
US6602898B1 (en) 1999-06-03 2003-08-05 Nippon Suisan Kaisha, Ltd. Tricyclic fused heterocycle compounds, process for preparing the same and use thereof
US6700013B2 (en) 1999-06-03 2004-03-02 Nippon Suisan Kaisha, Ltd. Tricyclic fused heterocycle compounds, process for preparing the same and use thereof
US7410997B2 (en) 1999-06-03 2008-08-12 Nippon Sulsan Kaisha, Ltd. Tricyclic fused heterocycle compounds, process for preparing the same and use thereof
WO2008096755A1 (fr) * 2007-02-07 2008-08-14 Nippon Suisan Kaisha, Ltd. Inhibiteur du récepteur vanilloïde (vr1) et son utilisation

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