WO2001036385A1 - Derives hydroxyethoxybenzamides et medicaments les contenant - Google Patents

Derives hydroxyethoxybenzamides et medicaments les contenant Download PDF

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Publication number
WO2001036385A1
WO2001036385A1 PCT/JP2000/007790 JP0007790W WO0136385A1 WO 2001036385 A1 WO2001036385 A1 WO 2001036385A1 JP 0007790 W JP0007790 W JP 0007790W WO 0136385 A1 WO0136385 A1 WO 0136385A1
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Prior art keywords
amino
group
fluoro
general formula
acid
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PCT/JP2000/007790
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English (en)
Japanese (ja)
Inventor
Kosuke Okazaki
Hiroaki Kobayashi
Masachiyo Hora
Naoyuki Masuda
Makio Kitazawa
Original Assignee
Kissei Pharmaceutical Co., Ltd.
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Application filed by Kissei Pharmaceutical Co., Ltd. filed Critical Kissei Pharmaceutical Co., Ltd.
Priority to AU10571/01A priority Critical patent/AU1057101A/en
Publication of WO2001036385A1 publication Critical patent/WO2001036385A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • 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 hydroxyethoxybenzamide derivative or a pharmacologically acceptable salt thereof, which has both a dopamine D 2 receptor blocking action and a 5-HT 4 receptor stimulating action and is useful as a pharmaceutical. .
  • the present invention provides a compound represented by the general formula
  • R 1 is a halogen atom
  • R 2 is a hydrogen atom or a halogen atom
  • R 3 is a halogen atom
  • R 4 is a lower alkyl group, a lower alkoxy group, an amino group, a halo-lower alkyl group or A hydroxyethoxybenzamide derivative represented by the formula: or a pharmacologically acceptable salt thereof.
  • Gastrointestinal motility dysfunction has been observed in gastro-esophagea 1 refludiseases (GERD), upper abdominal indeterminate complaints (non-ulcerdyspepsia; NUD), stress gastritis, chronic gastritis, gastric ulcer, and other gastrointestinal disorders.
  • the patient presents with symptoms such as delayed gastric emptying, nausea / vomiting, heartburn, nausea, abdominal sensation, upper abdominal pain, and anorexia. Therefore, to alleviate these digestive symptoms, gastrointestinal motility-improving agents such as methoxide-based promid, cisapride, and domperidone, which have a gastrointestinal motility-enhancing action and an antiemetic action, are widely used.
  • Japanese Patent Application Laid-Open No. 50-129573 discloses a general formula
  • R is a lower (Ci-C 6 ) alkoxy or alkenoxy group
  • R 2 is hydrogen, halogen, sulfonamide, amino, lower (Ci-C 6 ) alkylamino or di-lower (C 1 -C 6) alkylamino group, an alkylsulfonyl group, an alkyl sulfonamidyl de group or Ashiruamino group, or different, even the same, is in the 3 or 4 position of the aromatic ring
  • R 3 Is hydrogen, a lower alkyl group or an aryl group
  • Ar is an aryl group, an arylo group or a monocyclic aromatic heterocyclic group
  • X is 0 or 1
  • y is 2 or 3
  • z Is an integer of 1 to 6).
  • JP-A-61-63642 discloses a general formula
  • R 3 is hydrogen, or R 3 is (lower) alkoxy when R 4 and IT are each hydrogen;
  • R 4 is hydrogen, amino or (lower) alkoxy;
  • R 6 is (lower) alkyl, (lower) alkenyl or (lower) alkynyl;
  • IT is
  • n is an integer from 1 to 4;
  • R 7 and R 8 are the same or different and are (lower) alkyl, (lower) alkenyl, (lower) alkynyl,
  • R 1G is hydrogen or (lower) alkoxy;
  • R 17 is hydrogen, halogen, hydroxy, (lower) alkyl or (lower) alkoxy);
  • A is oxygen or 1S ⁇ (O ) n is 1;
  • R 2 is
  • Z is one (CH 2 ) p —, 0, N or one S ⁇ (O);
  • B is o O 9
  • M is 2 or 3; p is 0, 1 or 2; q is a number from 0 to 4; r is 2 or 3; R 9 is hydrogen or (low
  • R iD are the same or different Hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) alkoxy (lower) alkyl, cycloalkyl having 5 to 7 carbon atoms or With the proviso that when R U , R 15 or R 16 is (lower) alkenyl or (lower) alkynyl the unsaturated carbon atom is not added directly to the oxygen or nitrogen atom; R 14 is hydrogen, halogen , (Lower) alkyl, (lower) alkenyl, (lower) alkynyl, cycloalkyl having 5 to 7 carbon atoms, hydroxy, (lower) alkoxy, (lower) alkenyloxy, (lower) alkoxycarbonyl (lower) Alkenyl, hydrazino, acetyl hydrazino, chenyl, phenyl, R 18 and R 19 are the same or different and
  • the compound does not show a dopamine receptor blocking effect, it is a compound having a completely different pharmacological action from the compound of the present invention.
  • various gastrointestinal diseases such as reflux esophagitis, upper abdominal complaints, stress gastritis, chronic gastritis, and gastric ulcer due to westernization of dietary content, excessive stress and the aging society
  • the importance of pharmacotherapy in the prevention or treatment of these gastrointestinal diseases is becoming increasingly important.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems.
  • the benzamide derivative represented by the general formula (I) having a hydroxyethoxy group at the 2-position of benzamide has an excellent dopamine D 2 receptor blocking action.
  • 5-—HT 4 receptor stimulatory activity exhibiting strong gastrointestinal motility and antiemetic effects, and suppressed the occurrence of central nervous system side effects such as extrapyramidal symptoms.
  • the present invention provides a compound represented by the general formula (I) having a hydroxyethoxy group at the 2-position of benzamide has an excellent dopamine D 2 receptor blocking action.
  • 5-—HT 4 receptor stimulatory activity exhibiting strong gastrointestinal motility and antiemetic effects, and suppressed the occurrence of central nervous system side effects such as extrapyramidal symptoms.
  • R 1 is a halogen atom
  • R 2 is a hydrogen atom or a halogen atom
  • R 3 is a halogen atom
  • R 4 is a lower alkyl group, a lower alkoxy group, an amino group, a halo-lower alkyl group or A hydroxyethoxybenzamide derivative represented by the following formula: or a pharmacologically acceptable salt thereof.
  • the present invention also relates to a medicament comprising the hydroxyethoxybenzamide derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof.
  • the lower alkyl group includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a ter-butyl group, a pentyl group, A straight-chain or branched alkyl group having 1 to 6 carbon atoms such as isopentyl group, neopentyl group, t ⁇ rt-pentyl group, hexyl group, etc .; lower alkoxy group means methoxy group, ethoxy group , Propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t ⁇ r ⁇ -butoxy, pentyloxy, isopentyloxy, neopentyloxy, ter-pentyloxy, hexoxy, etc.
  • a halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • a halo-lower alkyl group refers to the lower alkyl group having 1 to 3 halogen atoms.
  • a halo-lower alkoxy group refers to The lower alkoxy group having 1 to 3 halogen atoms.
  • the compound of the present invention represented by the general formula (I) can be produced, for example, according to the following method.
  • P is a leaving group generally used in an anoalkylation reaction such as a halogen atom, a methanesulfonyloxy group, a -tonolenesulfonyloxy group, a trifinoleolomethanesulfonyloxy group, and R 1 , R 2 , R 3 and R 4 have the same meaning as above)
  • the compound represented by the general formula (I) of the present invention comprises a piperidine derivative represented by the general formula (II) and an alkylating agent represented by the general formula (III) in an inert solvent. It can be produced by reacting in the presence or absence of a base.
  • the solvent used for the reaction include N, monomethylhonolemamide, dimethyl sulfoxide, tetrahydrofuran, getyl ether, dioxane and the like.
  • the base used in the reaction for example, N, TV-diisopropylethylamine, triethylamine, pyridine, sodium carbonate, carbonated sodium, sodium hydroxide, hydroxylated sodium, sodium hydrogencarbonate and the like can be mentioned.
  • the reaction temperature is usually from 0 ° C to the boiling point of the solvent. The reaction time varies depending on the raw materials used, the solvent and the reaction temperature. ⁇ 24 hours.
  • the compound represented by the general formula (I) of the present invention is obtained by inactivating the benzoic acid derivative represented by the general formula (IV) and the 4-aminobiperidine derivative represented by the general formula (V). It can be produced by reacting in a solvent in the presence of a condensing agent, in the presence or absence of a base.
  • a condensing agent in the presence or absence of a base.
  • the solvent used in the reaction include N, T-dimethylformamide, tetrahydrofuran, dioxane, and dimethoxetane.
  • Examples of the condensing agent used in the reaction include 1,3-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -1,3-ethylcarbodiimide, 1,1 ′ And benzotriazole-1-yloxytris (dimethylamino) phosphoniumhexafluorophosphate.
  • Examples of the base used in the reaction include N, diisopropylethylamine, triethylamine, pyridine and the like.
  • the reaction temperature is usually from 0 ° C to the boiling point of the solvent.
  • the reaction time varies depending on the starting materials used, the solvent and the reaction temperature, but is usually 1 to 72 hours.
  • the compound represented by the general formula (I) of the present invention includes a reactive functional derivative of a benzoic acid derivative represented by the general formula (VI) and a 4-aminobiperidine derivative represented by the general formula (V).
  • the solvent used in the reaction include N, monodimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane and the like.
  • Examples of the base used in the reaction include N, diisopropylpropylethylamine, triethylamine, pyridine, monomethylmo / rephorin and the like.
  • the reaction temperature is usually from 130 ° C to the boiling point of the solvent.
  • the reaction time varies depending on the starting materials, solvent, reaction temperature, etc., and is usually 1 to 72 hours.
  • the compound represented by the general formula (I) of the present invention comprises a phenol derivative represented by the general formula (VII) and a haloacetic acid ester represented by the general formula (VIII) in an inert solvent.
  • the reaction can be carried out in the presence of a base to obtain a phenoxyacetic acid ester derivative represented by the general formula (IX), and then reduced using a reducing agent such as sodium borohydride.
  • a reducing agent such as sodium borohydride.
  • the solvent used for the reaction include N, 1-dimethylformamide, tetrahydrofuran, dioxane, dimethoxetane, dimethyl sulfoxide and the like.
  • Examples of the base used in the reaction include, for example, N, T-diisopropylethyl Lumamine, triethylamine, pyridine, V-methylmorpholine, sodium methoxide, sodium carbonate, potassium carbonate, sodium hydroxide and the like can be mentioned.
  • the reaction temperature is usually from o ° C to the boiling point of the solvent.
  • the reaction time varies depending on the starting materials used, the solvent used, the reaction temperature, etc., but is usually 1 to 72 hours.
  • the compound used as a starting material in the above production method can be obtained as a commercial product, or can be produced by a method described in a literature or a method similar thereto.
  • the hydroxyethoxybenzamide derivative represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt thereof by a conventional method.
  • salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, methanesulfonic acid, and benzenesulfonic acid.
  • Organic acids such as toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, lingoic acid, carbonic acid, glutamic acid, and aspartic acid And acid addition salts.
  • the compound represented by the general formula U) of the present invention also includes solvates with pharmaceutically acceptable solvents such as hydrates and ethanol.
  • the compound represented by the general formula (I) of the present invention is a compound having both excellent dopamine O 2 receptor blocking action and 5-HT 4 receptor stimulating action, and has a strong gastrointestinal motility-enhancing action. Has a vomiting effect.
  • the above compound has a substantial dopamine D 2 receptor blocking action (Weakly weak) and cisperide with 5-HT 4 receptor stimulatory activity, which is extremely potent in enhancing gastric emptying, and is observed when domperidone and mosapride are used in the same dose. It showed an excellent gastric emptying-enhancing effect equivalent to that of gastric emptying.
  • the compounds of the present invention have a remarkable gastric emptying-enhancing action.
  • the compound represented by the above general formula (I) of the present invention is an excellent compound in which the expression of extrapyramidal symptoms is suppressed. That is, in a measurement test for the induction of force talepsis using mice, for example, 4-amino-15-clo-one-T— [1- (3-phenololero-4-methoxybenzyl) piperidine-1- -)-(2-Hydroxyethoxy) benzamide hydrochloride has a very weak potency of eliciting talepsi as compared to clevopride and is equal to or greater than domperidone, which hardly induces central nervous system effects. Was found to be weak.
  • the compound of the present invention is a compound in which central nervous system action is extremely suppressed, and has side effects such as extrapyramidal symptoms observed in conventional gastrointestinal motility improving agents such as meto-mouth pramido-crepopride. It is extremely excellent as a gastrointestinal motility improver because there is little concern about the nervous system.
  • the compounds of the present invention are particularly suitable for diseases in which the gastrointestinal tract function is reduced or nausea / vomiting is caused, for example, reflux esophagitis, upper abdominal complaints, stress gastritis, chronic gastritis It can be used as a prophylactic or therapeutic agent for various gastrointestinal diseases such as gastric ulcer, constipation during morphine treatment, and various disease states based on drug-induced gastrointestinal dysfunction such as nausea and vomiting.
  • dosage forms are used depending on the usage.
  • dosage forms include powders, granules, fine granules, dry syrups, tablets, capsenoles and injections.
  • These pharmaceutical compositions can be used in the form of excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, etc., depending on the formulation used in the formulation. It can be produced by appropriately mixing, diluting and dissolving with pharmaceutical additives such as wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents, and dispensing according to a conventional method.
  • the dose of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient depends on the age, disease and Depending on the degree of treatment, etc., it is determined as appropriate.
  • synthetic human In general, in the range of 0.1 to 100 Omg per day, for parenteral administration, in the range of approximately 0.01 to 30 Omg per adult per day It can be administered once or several times as appropriate.
  • FIG. 1 is a graph showing the effect of oral administration of various test compounds on gastric emptying.
  • the test compound on the horizontal axis shows the type and dose (mgZkg) of the test compound, and the vertical axis shows the gastric emptying capacity (%).
  • *, ** and *** in the graph indicate that the significant difference from the control is 5% or less, 1% or less, and 0.1% or less, respectively.
  • 4-Amino-5-chloro-2- (2-hydroxymethyl) methyl benzoate 4-Amino-5-chloro-2-methyl-2-methoxycarbonyl methoxybenzoate (78 g) was added to methanol (500 mL) and tetrahydrofuran (500raL). And sodium borohydride (15.09 g) was added thereto under ice-cooling and stirring, followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • N- (1-Benzylpiperidin-1-yl) di-rubberic acid ferf-Butyl 4-amino_1-benzylpiperidine (5.70 g) is dissolved in diisopropyl ether (30 mL), and di-i-tert-butyl dicarbonate (7.85 g) is dissolved. g) was added under stirring at room temperature, and the mixture was stirred for 30 minutes. Hexane (30 mL) was added to the reaction mixture, and the mixture was stirred for 20 minutes under ice-cooling. The precipitate was collected by filtration, and a colorless powder of mono- (1-benzylpiperidine-14-yl) -rubert acid ⁇ ert-butyl (1-butyl) was added. 8.12 g) was obtained.
  • N- (1-benzylpiperidine-1-yl) -capillate er-butyl erbamate (67.5 g) was suspended in ethanol (230 mL), and 2 mol / L hydrochloric acid (116 mL) and 10% palladium carbon (6.7 g) were added. The mixture was stirred at room temperature under a 4.5 atmosphere of hydrogen atmosphere for 15 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. A 2 mol / L aqueous sodium hydroxide solution (116 mL) was added to the residue, and the precipitated crystals were collected by filtration to give a colorless powder, V— (4-piberidinyl). ) T 6 rt Monobutyl rubbamate (42.3 g) was obtained.
  • N- (4-Piperidinyl) potassium erbamate hydrochloride (20.0 g) was suspended in dichloromethane (300 mL), triethylamine (35,3 mL) was added, and trifluoroacetic anhydride (13.1 mL) was added under ice-cooling and stirring. Was added. After stirring for 1 hour under ice-cooling, triethylamine (11.8 mL) was added, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with water, lmol / L hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water.
  • the reaction mixture was concentrated under reduced pressure, a solution of sodium hydrogencarbonate (3.75 g) in water (50 mL) was added to the residue, and the mixture was extracted with a mixed solution of ethyl acetate and toluene.
  • the organic layer was washed successively with a solution of sodium hydrogencarbonate (3.75 g) in water (50 mL) and water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated to a brown oil, 4-amino-15-chloro-T— [1— (3-Fluoro-4-methoxybenzyl) piperidin-4-yl] -12-hydroxybenzamide (8.77 g) was obtained.
  • 4-Amino-TV [1- (4-amino-3,5-dichlorobenzene benzyl) piberidine-1-41] 15-chloro-1-4 (2-hydroxyethoxy) benzamide 4-chloro Using 2-, 6-dichloro-1,4-chloromethylphenylamine in place of methyl-1,2-funoleo-1,4-methoxybenzene, and proceeding in the same manner as in Example 1 (Method 1), using 4-amino-1 TV. — [11- (4-amino-3,5-dichlorobenzene) piperidine-14-yl] -15-chloro-2- (2-hydroxetoki) S) I got benzamide.
  • [3H] spiperone and a test compound were added simultaneously to the homogenate of the striatal crude membrane fraction of Wistar male rats, and incubated at room temperature for 60 minutes. After the incubation, the solution was filtered by suction through a glass fiber filter (GFZB), the radioligand bound to the receptor was collected, and the beta dose was measured using a liquid scintillation counter. 50% inhibitory concentration of test compound (IC 50 value, n
  • Binding inhibition constant IC 5 () value Z (1+ [L] / Kd)
  • [L] indicates the concentration (nM) of the added radioligand
  • Kd indicates the binding dissociation constant (nM) of the radioligand to the homogenate used.
  • the esophageal sphincter was removed from male Wistar rats, the outer layer was peeled off, and a 0.5 g load was applied to a Magnus bath filled with K rebs-Henseleit solution under mucosal muscle plates at 37 ° C under biogas ventilation. I hung up. After standing for a certain period of time, 1 / / carbachol (final concentration) is added in the presence of 3 ⁇ ⁇ ⁇ ⁇ indomethacin (final concentration) and ⁇ ⁇ ⁇ ⁇ ketaserin (final concentration), and contraction by carbachol When the peak reached, the test compound was cumulatively added to relax the specimen. Stimulatory activity was evaluated at the 50% relaxation concentration (ED 50 value) relative to maximal relaxation by serotonin. The results are as shown in Table 2 below.
  • test compound was orally administered 2 hours after the operation.
  • a suspension of a predetermined amount of the test compound in 0.5% methylcellulose aqueous solution (5 mL kg) was administered, and to the non-test compound treated group (normal control, surgical control, control), 0%. Only 5% methylcellulose aqueous solution (5 mL / kg) was administered.
  • a predetermined amount of the test compound is suspended in 0.5% methylcellulose aqueous solution and then administered orally, or a predetermined amount of domperidone or Crepopride was dissolved in a 2% aqueous lactic acid solution, or the compound of the present invention was dissolved in a 0.45% aqueous lactic acid solution containing 5% DMSO, and then administered intravenously.
  • a metal rod horizontally stretched to a height of about 5 cm from the ground, measure the time to keep the posture as it is, score it according to the following procedure, and average Scores were determined.
  • Score 3 60 seconds or more Thereafter, the same measurement was performed over time, and an average score was determined for each dose. Compared your Keru maximum average score to each dose, the score is 1. calculates 5 and a dose of (ED 50 value), was used as an index of forces Tarepushi inducing action. The results are shown in Table 4 below.
  • the hydroxyethoxybenzamide derivative represented by the general formula (I) and a pharmacologically acceptable salt thereof have excellent dopamine D 2 receptor blocking action and 5-HT 4 receptor stimulating action. Strong gastrointestinal motility and antiemetic It is effective in inhibiting the onset of central nervous system side effects such as extrapyramidal symptoms, and is a preventive or therapeutic agent for diseases such as reduced gastrointestinal function, nausea and vomiting caused by the present invention. Can be provided.

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Abstract

L'invention concerne des dérivés hydroxyéthoxybenzamides représentés par la formule générale (I), qui ont un effet d'inhibition du récepteur D2 de la dopamine et un effet de stimulation du récepteur 5-HT4 et sont utilisés comme médicaments destinés à améliorer les fonctions du tube digestif avec l'expression régulée du syndrome extrapyramidal, ou leurs sels acceptables sur le plan pharmaceutique, dans laquelle R1 représente un atome d'halogène; R2 représente un atome d'hydrogène ou d'halogène; R3 représente un atome d'halogène; et R4 représente un groupe alkyle inférieur, alcoxy inférieur, amino, haloalkyle inférieur ou haloalcoxy inférieur. Ces composants se révèlent efficaces dans le traitement de maladies, telles que l'oesophagite par reflux, les maux épigastriques non identifiés, la gastrite et l'ulcère gastrique.
PCT/JP2000/007790 1999-11-17 2000-11-07 Derives hydroxyethoxybenzamides et medicaments les contenant WO2001036385A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU10571/01A AU1057101A (en) 1999-11-17 2000-11-07 Hydroxyethoxybenzamide derivatives and drugs containing the same

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JP32750699 1999-11-17
JP11/327506 1999-11-17

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WO2001036385A1 true WO2001036385A1 (fr) 2001-05-25

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1507462A (en) * 1974-03-21 1978-04-12 Gallardo Antonio Sa N-heterocyclic substituted benzamides methods for their preparation and compositions containing them
GB1575310A (en) * 1976-11-16 1980-09-17 Anphar Sa Piperidine derivatives
GB1593851A (en) * 1976-10-27 1981-07-22 Gallardo Antonio Sa N-(4-piperidyl)-benzamides and pharmaceutical compositions containing them

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1507462A (en) * 1974-03-21 1978-04-12 Gallardo Antonio Sa N-heterocyclic substituted benzamides methods for their preparation and compositions containing them
GB1593851A (en) * 1976-10-27 1981-07-22 Gallardo Antonio Sa N-(4-piperidyl)-benzamides and pharmaceutical compositions containing them
GB1575310A (en) * 1976-11-16 1980-09-17 Anphar Sa Piperidine derivatives

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