WO2002018367A1 - Derives de tetrahydrobenzindole pouvant se fixer sur le recepteur 5-ht7 et metaboliquement stables - Google Patents

Derives de tetrahydrobenzindole pouvant se fixer sur le recepteur 5-ht7 et metaboliquement stables Download PDF

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Publication number
WO2002018367A1
WO2002018367A1 PCT/JP2001/007573 JP0107573W WO0218367A1 WO 2002018367 A1 WO2002018367 A1 WO 2002018367A1 JP 0107573 W JP0107573 W JP 0107573W WO 0218367 A1 WO0218367 A1 WO 0218367A1
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Prior art keywords
atom
compound
tetrahydrobenz
indole
salt
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PCT/JP2001/007573
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English (en)
Japanese (ja)
Inventor
Chika Kikuchi
Masao Koyama
Kazuyuki Fuji
Masayo Okuno
Toyokazu Hiranuma
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Meiji Seika Kaisha, Ltd.
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Priority to AU2001282595A priority Critical patent/AU2001282595A1/en
Publication of WO2002018367A1 publication Critical patent/WO2002018367A1/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
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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

Definitions

  • the present invention relates to a tetrahydropentzuindole derivative having a selective binding ability to a serotonin receptor in a living body and having high metabolic stability, and a pharmaceutical composition comprising the same.
  • 5-HT7 receptor is thought to play an important role in controlling circadian rhythms in humans, suggesting its involvement in sleep disorders and biological rhythm disorders [TW Lovenberg et al. Neuron, 11, 449-458, 1993]. Moreover, control over the 5-HT 7 receptor density in rat suprachiasmatic nuclei was reduced by given continuous projection of several depression drugs, 5-HT 7 receptor is expressed Ya circadian rhythms of antidepressant action Has been suggested to be involved [UL Mullins et al., Neurosychopharmacology, 21, 352-367, 1999]. .
  • the present inventors have already found the quality ones having strong ability to bind to 5-HT 7 receptor in vivo. That invention related to the present inventors (W098 / 00400, EP97928490, WO 99/33804, EP1057814, WO 99 Z54303, EP 1081136) According to the novel binding strongly against the 5-HT 7 receptors in vivo
  • the present invention provides a novel tetrahydrobenzindole derivative and a pharmaceutical composition comprising the compound.
  • the present inventors have now found that the introduction of a halogen atom or a hydroxyl group into the aromatic ring portion of the tetrahydrobenzindole derivative significantly enhances metabolic stability, and has completed the present invention.
  • an object of the present invention is to provide a tetrahydrobenzindole derivative having a selective binding ability to a serotonin receptor in a living body and having high metabolic stability, and a medicament comprising the compound. I do.
  • the compound according to the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof It is.
  • R 1 represents a hydrogen atom or a Hagengen atom
  • R 2 represents a hydroxyl group or a halogen atom
  • R 3 represents a hydrogen atom or a halogen atom
  • the compounds according to the invention bind to human 'serotonin 5- H ⁇ receptor subtypes expressed in clonal cell lines [3 H] - 5 CT strongly and selectively inhibit, also evident from the below test examples Thus, it is remarkably stable against metabolism as compared with known compounds.
  • the compounds according to the invention may be used for diseases caused by abnormal central and peripheral serotonin control functions, such as mental disorders (manic depression, anxiety, schizophrenia, epilepsy, sleep disorders, biological rhythm disorders, migraines, etc.), circulation, It is useful for the prevention or treatment of systemic diseases (such as hypertension) and gastrointestinal dysfunction.
  • the pharmaceutical composition according to the invention comprises the compound according to the invention or a pharmacologically acceptable salt thereof, and optionally a pharmaceutical additive.
  • the present invention also provides the use of a compound according to the present invention for the manufacture of a medicament for use in the prevention or treatment of mental illness.
  • the present invention further provides a method for preventing or treating a psychiatric disorder, comprising the step of administering a therapeutically effective amount of a compound according to the present invention to a mammal, including a human.
  • a method for preventing or treating a psychiatric disorder comprising the step of administering a therapeutically effective amount of a compound according to the present invention to a mammal, including a human.
  • Halogen atom means each atom of fluorine, chlorine, bromine and iodine
  • base used as a catalyst means sodium hydroxide, potassium carbonate, triethylamine and the like.
  • R 1 is preferably a hydrogen atom, a fluorine atom, a chlorine atom, or a bromine atom, and more preferably a fluorine atom, a chlorine atom, or a bromine atom.
  • R 2 is preferably a hydroxyl group, a fluorine atom, a chlorine atom or a bromine atom, more preferably a fluorine atom, a chlorine atom or a bromine atom, and particularly preferably a chlorine atom.
  • R 3 is preferably a hydrogen atom, a fluorine atom, a chlorine atom, or a bromine atom, and more preferably a hydrogen atom.
  • Preferred compounds of the formula (I) include those in which R 1 and R 2 may be the same or different and are a fluorine atom, a chlorine atom or a bromine atom.
  • R 1 is a fluorine, chlorine or bromine atom and R 2 is a hydroxyl group.
  • a more preferred compound group includes compounds in which R 1 is a fluorine atom, a chlorine atom, or a bromine atom, and R 2 is a chlorine atom.
  • R 1 is a fluorine atom, a chlorine atom or a bromine atom
  • R 2 is a chlorine atom
  • R 3 is a hydrogen atom.
  • the compound represented by the formula (I) has an asymmetric carbon at one place, and optical isomers based on the asymmetric carbon exist.
  • optical isomers in pure form, any mixtures of optical isomers, racemates, etc. are all included in the scope of the present invention, and any of those substances may be used as an active ingredient of the medicament of the present invention. Good.
  • the compounds according to the invention are characterized in that they have an affinity for the serotonin 5-HT7 receptor. Therefore, the compound according to the present invention is useful for preventing or treating mental disorders such as manic depression, anxiety, schizophrenia, epilepsy, sleep disorders, biological rhythm disorders, or migraine involving the serotonin 5-HT? Receptor. Useful for
  • the compounds of the formula (I) according to the invention can be prepared starting from compounds of the formula (II).
  • halogenation examples include disulfide in the presence and absence of a suitable catalyst.
  • the reaction is carried out in a solvent such as carbon, carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, and acetic acid at 0 ° C to heating under reflux.
  • a solvent such as carbon, carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, and acetic acid at 0 ° C to heating under reflux.
  • non-fluorinated compounds such as 1-fluoropyridinium triflate, 1-fluoro 2,6-dichloropyridinium tetrafluoroborate, etc.
  • N-fluoro-N-alkylsulfonamides such as substituted or substituted N-fluoropyridinium salts, N-fluoro-N-propyl-p-toluenesulfonamide, N-fluorobenzenesulfone N-fluorosulfonimides such as imide, sodium hypochlorite N-promosuccinimide, sulfuryl chloride, etc. are used.
  • the introduction of hydroxyl groups is carried out by converting the acyl group introduced by the Friedel-Crafts reaction, which is an aromatic nucleophilic substitution reaction, by a chemical reaction.
  • the Friedel-Crafts reaction is carried out in the presence of a catalyst in a solvent such as carbon disulfide, chloroform, dichloromethane, 1,2-dichloroethane, or nitrobenzene at 0 ° C to heating under reflux.
  • acylating agent include acyl halides such as acetyl chloride and propyl chloride, as well as acid anhydrides such as acetic anhydride and carboxylic acids such as acetic acid and propionic acid.
  • Preferred catalysts include Lewis acids such as aluminum chloride, iron chloride, boron trifluoride, tin chloride and zinc chloride, as well as protonic acids such as hydrogen fluoride, sulfuric acid and polyphosphoric acid.
  • the acyl group introduced by the Friedel-Crafts reaction is reacted with a peroxide such as m-chloroperbenzoic acid or pertrifluoroacetic acid, and if necessary, in the presence of an acid catalyst such as trifluoroacetic acid.
  • a peroxide such as m-chloroperbenzoic acid or pertrifluoroacetic acid
  • an acid catalyst such as trifluoroacetic acid.
  • An oxygen atom is inserted between the ring and the carbonyl group to convert to an acyloxy group, and further, to a hydroxyl group by hydrolysis.
  • the compound of formula (II) can be produced by the method described in WO98 / 4000.
  • This reaction is carried out in the absence of a solvent or after being diluted with an inert solvent, and proceeds in the range of room temperature to heating in the presence or absence of an acid absorbent.
  • inert solvent include dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, and the like.
  • acid absorbent include salts of alkali metals, carbonates (eg, sodium carbonate, potassium carbonate, etc.), and bicarbonate. Salts (sodium bicarbonate, potassium bicarbonate, etc.), trialkylamines, pyridine bases, etc. are used, and secondary amine itself used as a raw material can be used in excess to serve as an acid absorbent. .
  • the compound of the formula (IV) can be produced by using a commercially available product or by dehydrating a corresponding commercially available piperidinol compound with an acid.
  • Representative compounds of the present invention are specifically and specifically described in the working examples of the present specification. Therefore, based on the above-mentioned general production method and the description of the examples described below, the starting compounds, the reaction reagents, the reaction conditions, and the like are appropriately selected and disclosed in the examples as necessary. By making appropriate modifications or alterations to the method, those skilled in the art can produce any of the compounds encompassed by the above general formula (I).
  • the compounds according to the present invention are amines and exist as bases. Therefore, it forms salts with many inorganic and organic acids, and this property is used in the production of pure substances and in the form of delivery as pharmaceuticals.
  • Possible salt forms include acid addition salts with inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid and sulfuric acid, or aliphatic monocarboxylic acids, dicarboxylic acids, hydroxyalconic acids, hydroxyalkanediacids, There are salts derived from non-toxic organic acids such as amino acids and also aromatic acids, aliphatic and aromatic sulfonic acids.
  • Such acid salts include hydrochloride, hydrobromide, nitrate, sulfate, bisulfate, phosphorus Monohydrogen acid, dihydrogen phosphate, acetate, propionate, tartrate, oxalate, malonate, succinate, fumarate, maleate, mandelate, benzoate, benzoate Examples include butyrate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, lactate, malate, and glycolate.
  • the above-mentioned acid addition salts are preferable as pharmacologically acceptable medicaments. That is, it is advantageous in the formulation from the viewpoint of the dissolution rate in water, and is also advantageous from the viewpoint of dispersibility and absorption when administered to the human body.
  • the medicament provided by the present invention is characterized by comprising at least one compound represented by the formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the medicament according to the present invention can be administered to humans and non-human animals by any of oral and parenteral (for example, intravenous, intramuscular, subcutaneous, rectal, transdermal) administration routes. .
  • the above-mentioned substance which is an active ingredient may be administered as it is, but generally, a pharmaceutical composition is prepared and administered using one or more pharmaceutical additives. It is preferable that the dosage form is appropriate for the administration route.
  • oral preparations include tablets, capsules, powders, granules, syrups, and the like.
  • Parenteral preparations include injections such as intravenous injections and intramuscular injections, rectal preparations, and oily seats. And aqueous suppositories.
  • excipients include, for example, lactose, pudose, corn starch, sorbitol, crystalline cellulose, and disintegrants, for example, starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, dextrin, etc.
  • the above injection can be produced by adding a buffer, a pH adjuster, a stabilizer and the like as necessary.
  • the content of the compound according to the present invention in the pharmaceutical composition varies depending on its dosage form, Usually, it is 0.1 to 50% by weight, preferably about 0.1 to 20% by weight in the whole composition.
  • the dose is appropriately determined depending on the individual case in consideration of the patient's age, weight, sex, difference in disease, degree of symptoms, and the like. Usually, the dose is 0.1 to 0.1 mg / day; The preferred dose is 0.1 to 30 mg, which is administered once or several times a day.
  • the organic layer was washed with saturated saline, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • the obtained substance was separated and purified by silica gel column chromatography to obtain 1.5 g of the above-mentioned target substance ( 4.4 t ol, yield 87%).
  • the obtained prepolymer was dissolved in methanol and hydrochloric acid was added dropwise, and then the solvent was distilled off under reduced pressure to obtain a hydrochloride.
  • Example 7 2a- (4- (4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridin-1-yl) butyl) -6,8-dichloro-2a, 3, 4, 5-tetrahydrobenz [cd] indole-2 (1H) on
  • the obtained prepolymer was dissolved in methanol and hydrochloric acid was added dropwise, and then the solvent was distilled off under reduced pressure to obtain a hydrochloride.
  • Example 8 2a- (4- (4-phenyl-1,2,3,6-tetrahydropyridine-; 1-yl) butyl) -6,8-dichloro-2a, 3,4,5-tetrahydro Penz [cd] Indole -2 (1H) on
  • the obtained monolith was dissolved in methanol, hydrochloric acid was added dropwise, and the solvent was distilled off under reduced pressure to obtain a hydrochloride.
  • Example 9 2a- (4-bromobutyl) -6-fluoro-2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one and 2a- (4-bromobutyl) -6,8 -Difluoro-2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H) one
  • Example 10 2a- (4- (4-phenyl-1,2,3,6-tetrahydropyridine-tolyl) butyl) -6-fluoro mouth-2a, 3,4,5-tetrahydrobenz [ cd] Indole-2 (1H) _ ON 2a- (4-bromobutyl)-6-chloro- 2a, 3,4,5-tetrahydrobenz [cd] indole-2 (1H)
  • 2a- (4-bromobutyl) -6-fluoro- 2a 3,4,5-tetrahydrobenz [cd] indole-2 (1H)
  • 4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride Synthesized in the same manner as in Example 2 except that phenyl-1,2,3,6-tetrahydropyridine hydrochloride was used (yield: 60%).
  • the obtained monolith was dissolved in methanol, hydrochloric acid was added dropwise, and the solvent was distilled off under reduced pressure to obtain a hydrochloride.
  • Example 11 1 2a- (4- (4-phenyl-1,2,3,6-tetrahydropyridine-; [-yl) butyl) -6,8-difluoro mouth-2a, 3,4,5- Tetrahydrobenz [cd] indonyl -2 (1H) on
  • Example 13 3 2a- (4- (4- (4-fluorophenyl-1,2,3,6-tetrahydropyridin-1-yl) butyl) -6-hydroxy-2a, 3,4, 5-tetrahydrobenz [cd, indole-2 (1H) on
  • Test results showing the usefulness of typical examples of the compounds of the present invention are shown below.
  • Test Example 1 Binding affinity tests with 5-HT 7 receptor
  • Cultured cells expressing human seotonin 5-HT, receptor subtype are harvested in Atsushi buffer (50 mM Tris-HCl pH7.4 containing lOmM MgCL, and 0.5 mM EDTA), and homogenized with a Pouniyu type homogenizer. After homogenization, the membrane fraction was centrifuged at 39,000 g for 20 minutes at 4 ° C. The obtained pellet was resuspended by adding 1 ml of Atsushi buffer per cell for one culture dish having a diameter of 10 cm and re-homogenized.
  • Atsushi buffer 50 mM Tris-HCl pH7.4 containing lOmM MgCL, and 0.5 mM EDTA
  • the binding experiments were performed with a final concentration of 1 ⁇ [ ⁇ ] -5CT (carboxamide tryptamine) and a test substance of 1 to: ⁇ (in the examples, compounds represented by the general formula (I) of the present invention).
  • a final suspension volume of 300/1 was added by adding 100 ⁇ 1 of the fraction suspension, and the mixture was incubated at 37 ° C for 30 minutes. The incubation was stopped by rapid filtration over a GF / B filter and washed with 6 ml of cold 50 iM Tris-HCl (pH 7.4). Radioactivity was measured in the liquid scintillation count. Non-specific binding was determined with 10 zM metergoline, and specific binding was calculated from the difference. ICse was determined from the inhibition curve of each compound, and the binding inhibition constant Ki was calculated from this.
  • the rat cerebral cortex was homogenized in 10 volumes of 0.32M sucrose solution, and the supernatant obtained by centrifugation at 900 ⁇ g for 10 minutes was further centrifuged at 500 ⁇ g for 20 minutes.
  • the obtained precipitate was resuspended in 50 mM Tris-HCl (pH 7.4) buffer and centrifuged at 39,900 xg for 20 minutes, and the obtained precipitate was used as a P2 fraction.
  • the P2 fraction was incubated for 15 minutes at 37 ° C. in 50 mM Tris-HCl (pH 7.4) buffer containing InM [ ⁇ ]conceserin and a compound according to the present invention. After the reaction, the Whatman GF / B Glass Fill Filtered in the evening. The radioactivity of the fill was measured at the liquid scintillation county. Non-specific binding was determined using 10 zM kerosene, and specific binding was calculated from the difference. IC 5 »was determined from the inhibition curve of each compound, and the binding inhibition constant Ki was calculated from this. And Ki for 5-HT 2, the Ki and the ratio of 5-HT 7 obtained from Test Example 1 are shown in Table 1. As can be seen from Table 1, the compound of the present invention was found to bind strongly and selectively to the 5-11 receptor.
  • Example 4 1 1.6> 1 0 0 0> 8 6
  • Compound A, Compound B and Compound C in the table are the following compounds described in WO 98/400, EP 979 280 490, and Compound A is a tetrahydropenzindole derivative.
  • Compound A is a tetrahydropenzindole derivative.
  • Compound A 2a- (4- (4-phenyl-1,2,3,6-tetrahydropyridine-1-yl) butyl) -2a, 3,4,5-tetrahydrobenz [cd] indole-2 ( 1H)-ON
  • the reaction solution was subjected to centrifugation to perform protein reduction, and the amount of the test substance remaining in the obtained supernatant was measured by high performance liquid chromatography.
  • the reaction solution to which the test substance was added was measured to obtain the initial amount of the test substance.
  • the initial rate (maximum rate) of the metabolic reaction was calculated as the metabolic rate.

Abstract

L'invention concerne des composés représentés par la formule générale suivante (I), dans laquelle R1 représente un hydrogène ou un halogéno ; R2 représente un hydroxy ou un halogéno ; et R3 représente un hydrogène ou un halogéno, à condition que R1 et R3 ne soient pas tous deux des hydrogènes ; ainsi que des sels pharmaceutiquement acceptables de ces composés. Ces composés sont utiles pour prévenir ou traiter des pathologies induites par des troubles de la régulation centrale et périphérique de la sérotonine, telles que les maladies mentales (la maladie affective bipolaire, l'anxiété, la schizophrénie, l'épilepsie, les troubles du sommeil, les troubles du rythme biologique, la migraine, etc.), les maladies du système circulatoire (hypertension, etc.) et les troubles de la fonction digestive, par exemple.
PCT/JP2001/007573 2000-08-31 2001-08-31 Derives de tetrahydrobenzindole pouvant se fixer sur le recepteur 5-ht7 et metaboliquement stables WO2002018367A1 (fr)

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JP2000262597A JP2004231514A (ja) 2000-08-31 2000-08-31 ５−ｈｔ７受容体結合能を有し、かつ代謝的に安定なテトラヒドロベンズインドール誘導体
JP2000-262597 2000-08-31

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092339A1 (fr) * 2004-03-25 2005-10-06 Solvay Pharmaceuticals B.V. Derives de 1-[2h-1-benzopyran-2-one-8-yl]-piperazine utilises dans le traitement des troubles du mouvement
WO2005108388A1 (fr) * 2004-05-11 2005-11-17 Egis Gyógyszergyár Nyrt. Derives pyridine d'alkyl oxindoles utiles en tant qu'agents actifs se liant au recepteur 5-ht7
US7776860B2 (en) 2004-03-25 2010-08-17 Solvay Pharmaceuticals B.V. Process for the preparation of 3-amino-8-(1-piperazinyl)-2H-1-benzopyran-2-one and salts and solvates thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998000400A1 (fr) * 1996-06-28 1998-01-08 Meiji Seika Kaisha, Ltd. Composes de tetrahydrobenzindole
WO1999054303A1 (fr) * 1998-04-22 1999-10-28 Meiji Seika Kaisha, Ltd. Derives tetrahydrobenzindoles actifs au plan optique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998000400A1 (fr) * 1996-06-28 1998-01-08 Meiji Seika Kaisha, Ltd. Composes de tetrahydrobenzindole
WO1999054303A1 (fr) * 1998-04-22 1999-10-28 Meiji Seika Kaisha, Ltd. Derives tetrahydrobenzindoles actifs au plan optique

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092339A1 (fr) * 2004-03-25 2005-10-06 Solvay Pharmaceuticals B.V. Derives de 1-[2h-1-benzopyran-2-one-8-yl]-piperazine utilises dans le traitement des troubles du mouvement
JP2007530508A (ja) * 2004-03-25 2007-11-01 ソルベイ・フアーマシユーチカルズ・ベー・ブイ 運動障害の処置のための１−［２ｈ−１−ベンゾピラン−２−オン−８−イル］−ピペラジン誘導体
US7776860B2 (en) 2004-03-25 2010-08-17 Solvay Pharmaceuticals B.V. Process for the preparation of 3-amino-8-(1-piperazinyl)-2H-1-benzopyran-2-one and salts and solvates thereof
US8173660B2 (en) 2004-03-25 2012-05-08 Solvay Pharmaceuticals B.V. Process for the preparation of 3-amino-8-(1-piperazinyl)-2H-1-benzopyran-2-one and salts and solvates thereof
WO2005108388A1 (fr) * 2004-05-11 2005-11-17 Egis Gyógyszergyár Nyrt. Derives pyridine d'alkyl oxindoles utiles en tant qu'agents actifs se liant au recepteur 5-ht7
JP2007537225A (ja) * 2004-05-11 2007-12-20 エギシュ ヂョヂセルヂャール エンニュ・エル・テー ５−ｈｔ７活性剤としてのアルキルオキシインドールのピリジン誘導体
EA010154B1 (ru) * 2004-05-11 2008-06-30 Эгиш Дьёдьсердьяр Нирт. Пиридиновые производные алкилоксиндолов в качестве агентов, активных в отношении рецептора 5-нт7

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AU2001282595A1 (en) 2002-03-13

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