WO2001064641A1 - Derives d'hydroxyethoxybenzamide et medicaments les contenant - Google Patents

Derives d'hydroxyethoxybenzamide et medicaments les contenant Download PDF

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Publication number
WO2001064641A1
WO2001064641A1 PCT/JP2001/001445 JP0101445W WO0164641A1 WO 2001064641 A1 WO2001064641 A1 WO 2001064641A1 JP 0101445 W JP0101445 W JP 0101445W WO 0164641 A1 WO0164641 A1 WO 0164641A1
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Prior art keywords
amino
chloro
group
acid
hydroxyethoxy
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PCT/JP2001/001445
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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.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Kissei Pharmaceutical Co., Ltd. filed Critical Kissei Pharmaceutical Co., Ltd.
Priority to AU2001234187A priority Critical patent/AU2001234187A1/en
Publication of WO2001064641A1 publication Critical patent/WO2001064641A1/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 a dopamine D 2 receptor blocking action and a 5-HT 4 receptor stimulating action, and is useful as a pharmaceutical. It is.
  • the present invention provides a compound represented by the general formula
  • R 1 is a halogen atom
  • R 2 is a lower alkyl group, a lower alkoxy group, a halo-lower alkyl group, a halo-lower alkoxy group or a halogen atom
  • ring A is a benzene ring or a cyclohexane ring.
  • N is 0, 1 or 2 or a pharmacologically acceptable salt thereof.
  • Gastrointestinal motility dysfunction has been observed in gastrointestinal disorders such as gastro-esophagea 1 refluxdiseases (GERD), non-ulcerdyspepsia (NUD), stress gastritis, chronic gastritis, and gastric ulcer.
  • GFD gastro-esophagea 1 refluxdiseases
  • NUD non-ulcerdyspepsia
  • stress gastritis chronic gastritis
  • gastric ulcer gastric ulcer.
  • the patient presents with symptoms such as delayed gastric emptying, nausea-vomiting, heartburn, nausea, abdominal distension, upper abdominal pain and anorexia. Therefore, to alleviate these digestive symptoms, gastrointestinal motility-improving agents having a gastrointestinal motility-enhancing action and an antiemetic action, such as methoctamide pramid, cisapride and domperidone, are widely used.
  • metoclopramide has a side effect of extrapyramidal symptoms caused by dopamine D 2 receptor blockade (Current Therapeutic Research, Vol. 38, No. 5, p. 790-797 (1 985) etc.).
  • R is a lower (Ci -C 6) alkoxy group or an alkenoxy group
  • Ri and R 2 is hydrogen, halogen, sulfonamido group, an amino group, a lower (Ci ⁇ C 6) ⁇ alkylamino or di-lower ( Ci Cg) an alkylamino group, an alkylsulfonyl group, an alkylsulfonamide group or an acylamino group, which may be the same or different, is located at position 3 or 4 of the aromatic ring
  • R 3 is hydrogen
  • 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 1 to Which is an integer of 6).
  • JP-A-61-63642 discloses a general formula
  • n is an integer from 1 to 4;
  • R ′ and R 8 are the same or different and are (lower) alkyl, (lower) alkenyl, (lower) alkynyl, 17
  • R 1Q is hydrogen or (lower) alkoxy; is hydrogen, halogen, hydroxy, (lower) alkyl or (lower) alkoxy); A is oxygen or 1S ⁇ (O) p One; R 2 is
  • Z is one (CH 2 ).
  • One, ⁇ , N or one S ⁇ (O) p —; B is
  • R 15 and R 16 are the same or different Hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkyl, (lower) alkoxy (lower) alkyl, cycloalkyl having 5 to 7 carbon atoms or Although where R U, 15 or scale 16 months (lower) Aruke - le or (lower) alkyl - unsaturated carbon atoms in the case of the Le is not directly attached to an oxygen atom or a 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, acetinolehi drazino, cheninore, fuenolle, R 18 and
  • ⁇ 1 are the same or different and are hydrogen or (lower) alkyl; and R 20 and R 21 are each hydrogen or are together and> C (CH 3 ) Or 2 or 1 CH 2 —C (CH 3 ) 2 _; or R 12 and R 13 together with the carbon atom attached thereto form a saturated ring having 5 to 7 carbon atoms, wherein the ring is oxygen, At least one of all SANYO having heteroatoms arbitrarily selected from the group consisting of oxygen, sulfur and nitrogen; saturated ring having or R 12 and 5-7 atoms together with the carbon atoms to adhere to them with R 14 or not Form a saturated ring, wherein said ring optionally has at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R 14 and R 15 are carbon atoms attached thereto and To form an oxygen-containing saturated 3- to 7-membered ring together with an oxygen atom.
  • 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.
  • patients suffering from various digestive diseases such as reflux esophagitis, upper abdominal complaints, stress gastritis, chronic gastritis, gastric ulcer, etc. due to westernization of dietary content, excessive stress and aging society
  • digestive diseases such as reflux esophagitis, upper abdominal complaints, stress gastritis, chronic gastritis, gastric ulcer, etc. due to westernization of dietary content, excessive stress and aging society
  • the progress of pharmacotherapy in the prevention or treatment of these gastrointestinal diseases is becoming increasingly important.
  • a benzamide derivative represented by the aforementioned general formula (I) having a hydroxyethoxy group at the 2-position of benzamide is an excellent dopamine D 2 receptor. It has both a blocking effect and a 5 HT 4 receptor stimulating effect, has a strong gastrointestinal motility-increasing effect and an antiemetic effect, and suppresses the occurrence of central nervous system side effects such as extrapyramidal symptoms.
  • the present invention provides a compound represented by the general formula
  • R 1 is a halogen atom
  • R 2 is a lower alkyl group, a lower alkoxy group, a halo-lower alkyl group, a halo-lower alkoxy group or a halogen atom
  • ring A is a benzene ring or a cyclohexane ring.
  • N is 0, 1 or 2), 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 means a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butylinole group, a pentinole group
  • 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, and a halo-lower alkoxy group. 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.
  • Method 1
  • P is a leaving group generally used in alkylation reactions such as a halogen atom, a methanesulfonyloxy group, a --toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and RR 2 and n Has 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.
  • a base examples include N, monomethylformamide, dimethyl sulfoxide, tetrahydrofuran, getyl ether, dioxane and the like.
  • Examples of the base used in the reaction include N, N-diisopropylethylamine, triethylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, 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 raw materials used, the solvent and the reaction temperature. ⁇ 24 hours.
  • the compound represented by the general formula (I) of the present invention comprises a benzoic acid derivative represented by the general formula (IV) and the general formula (IV)
  • the compound can be produced by reacting the 4-aminobiperidine derivative represented by V) in an inert solvent in the presence of a condensing agent, in the presence or absence of a base.
  • the solvent used in the reaction include N, 1-dimethylformamide, tetrahydrofuran, dioxane, dimethoxetane and the like.
  • Examples of the condensing agent used in the reaction include 1,3-dicyclohexylcarboimide, 1- (3-dimethylaminopropyl) -1-ethylcarbodiimide, 1,1, Monocarbonyldiimidazole, benzotriazole-11-yloxytris (dimethylamino) phosphoniumhexafluorophosphate and the like.
  • Examples of the base used in the reaction include N, TV-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 for the reaction include N, -dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane and the like.
  • Examples of the base used in the reaction include iV, diisopropylethylamine, triethylamine, pyridine, and -methylmorpholine.
  • the reaction temperature is usually from 130 ° 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 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.
  • reaction temperature is usually from o ° C to the boiling point of the solvent.
  • reaction time varies depending on the starting materials used, the solvent used, the reaction temperature and the like, 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.
  • P-Toluenesulfonic acid propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, and aspartic acid And acid addition salts.
  • the compound represented by the general formula (I) of the present invention also includes a solvate with a pharmaceutically acceptable solvent such as hydrate and ethanol.
  • the compound represented by the general formula (I) of the present invention is a compound having both an excellent dopamine D 2 receptor blocking action and a 5-HT 4 receptor stimulating action, and has a strong gastrointestinal motility-enhancing action and a potent inhibitory action. Has a vomiting effect.
  • the compound of the present invention has an excellent gastric emptying-enhancing activity.
  • 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 test for evoking a force talepsy effect using a mouse, for example, 4-amino-15-clo-I-T- [1- (3-fluoro-1-4-methoxybenzyl) piperidine-14- 2- (2-Hydroxyethoxy) benzamide hydrochloride has a very weak catalepsy-inducing effect as compared to clevopride and is at least equal to domperidone, which hardly causes central nervous system effects. It was confirmed that it was weak.
  • the compound of the present invention is a compound in which the action of the central nervous system is extremely suppressed, and there is a concern about side effects such as extrapyramidal symptoms observed in conventional gastrointestinal motility improving agents such as metoclopramide ⁇ crepopride. It is extremely excellent as a gastrointestinal motility improver because of its low content.
  • the compounds of the present invention are particularly suitable for diseases in which the gastrointestinal tract function is reduced or nausea / vomiting occurs.
  • diseases in which the gastrointestinal tract function is reduced or nausea / vomiting occurs For example, reflux esophagitis, upper abdominal complaints, stress gastritis, chronic gastritis, It can be used as a prophylactic or therapeutic agent for various gastrointestinal disorders such as gastric ulcer, constipation during morphine treatment, various pathologies based on drug-induced gastrointestinal dysfunction such as nausea and vomiting.
  • Such dosage forms include, for example, powders, granules, fine granules, dry syrups, tablets, capsules or 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, but in the case of oral administration Synthetic human In the range of approximately 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 divided into 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 indicates the type and dose (mg / kg) of the test compound, and the vertical axis indicates the gastric emptying ability (%).
  • * And *** in the graph indicate that the significant difference is 5% or less and 0.1% or less, respectively, with respect to the control.
  • FIG. 2 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 and 1% or less, respectively.
  • FIG. 3 is a graph showing the effect of oral administration of various test compounds on gastric emptying.
  • the test compound on the horizontal axis indicates the type and dose (mg / kg), and the vertical axis indicates gastric emptying (%).
  • the * in the graph indicates that the significant difference from the control is 5% or less.
  • Methyl 4-amino-5-chloro-2-methoxycarbonylmethoxybenzoate (78 g) was suspended in methanol (500 mL) and tetrahydrofuran (500 raL), and sodium borohydride (15.09 g) was added under ice-cooling and stirring. And stirred 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-benzylpiperidine-4-yl) carbamic acid erer-butynole (67.5 g) is suspended in ethanol (230 mL), and 2 mol / L hydrochloric acid (116 mL) and 10% palladium carbon (6.7 g) are added. The mixture was stirred at room temperature under a hydrogen atmosphere of 4.5 atm 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 raL) was added to the residue, and the precipitated crystals were collected by filtration to obtain a colorless powder (4-piberidinyl). There was obtained t-butyl monobutyl rubinate (42.3 g). ⁇ -NMR (CDC 1 3) ⁇ p pm:
  • 3,4-Difluorobenzaldehyde (2.84 g) was dissolved in ethanol (60 mL) under ice-cooling, and sodium borohydride (2.27 g) was added to the solution, followed by stirring at room temperature for 2 hours.
  • Ether and 2 mol / L hydrochloric acid were added to the reaction mixture under ice-cooling and stirring, and the mixture was stirred at room temperature for 30 minutes.
  • the organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a colorless oily substance, 3,4-difluorophenolmethanol (2.56 g).
  • N- (4-Piperidinyl) potassium erbamate hydrochloride (20.Og) is suspended in dichloromethane (300mL), triethylamine (35.3mL) is added, and trifluoroacetic anhydride (13.ImL) is added under ice-cooling and stirring. 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.
  • N- (4-Piperidinyl) capilluvamic acid ⁇ ert Monobutyl hydrochloride (70.0 g) is suspended in TV, TV-dimethylformamide (700raL), and triethylamine (103mL), 4-fluorobenzyl chloride (44.9g) is suspended. g) were sequentially added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (500 mL) and a 2 mol / L aqueous sodium hydroxide solution (150 mL), and extracted with a mixed solvent of ethyl acetate-toluene. The organic layer was washed with water and dried under reduced pressure. After washing with water, a pale red powder of TV- [1- (4-fluorobenzyl) piperidine-14-yl] -potassium rubumate (76.4 g) was obtained.
  • N- (4-Piperidinyl) potassium ert-butyl (200 mg) and triethylamine (279 / zL) were dissolved in TV, 1-dimethylformamide (10 mL), and the mixture was stirred at room temperature with 4-methoxybenzyl chloride. (157 mg) was added and the mixture was stirred for 20 hours.
  • the reaction mixture was diluted with water, added with a lmol / L aqueous sodium hydroxide solution, and extracted with a mixed solvent of ethyl acetate-toluene.
  • N- [1- (4-Methoxybenzyl) piperidine-4-yl] tert-butyl carbamic acid (3.48 g) is dissolved in 2-propanol (50 mL), and concentrated hydrochloric acid (30 mL) is stirred at room temperature. It was added below and stirred for 2 hours. A 5 mol / L aqueous sodium hydroxide solution (72 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate.
  • the reaction mixture was diluted with water and an aqueous solution of lmol / L sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from water-saturated ethyl acetate diisopropyl ether to give 4-amino-5-chloro-1- [1- (4-fluorobenzyl) piperidin-4-yl] -12- (2-hydr) (Roxyethoxy) benzamido hydrate (917 mg) was obtained.
  • [3H] spiperone and a test compound were simultaneously added 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 suction filtered through a glass fiber filter (GF / B), the radioligand bound to the receptor was collected, and the beta dose was measured using a liquid scintillation counter.
  • the 50% inhibitory concentration (IC5 () value, nM) of the test compound was 100% for the binding amount of only the solvent (5 mM hydrochloric acid) and 3 ⁇ of (Sat)
  • the binding amount at the time of adding the pyrid (final concentration) was set to 0%, and the value was determined using GraphPad Prism.
  • the binding inhibition constant (K i value) of the test compound was calculated based on the following Chung and P rusoff equation. The results are as shown in Table 1 below.
  • Binding inhibition constant IC 5 () value Z (1+ (L) no Kd)
  • [L] indicates the concentration (nM) of the added radioactive 14 ligand
  • Kd indicates the binding dissociation constant (nM) of the radioactive ligand to the homogenate used.
  • the esophageal sphincter was removed from male Wistar rats, the outer layer was peeled off, and the mucosa was used as a mucosal muscle plate at 37 ° C, and a 0.5 g load was applied to a Magnus bath filled with Krebs-Hense 1 eit solution under biogas ventilation. And suspended. After standing for a certain period of time, 1% carbachol (final concentration) was added in the presence of 3 ⁇ 3 indomethacin (final concentration) and 1 // ⁇ ⁇ ⁇ ketaserin (final concentration), and the contraction by carbachol peaked. At this time, the specimen was relaxed by cumulative addition of the test ligature. 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 Suspend a predetermined amount of the test compound in a 0.5% aqueous solution of methylcellulose and orally administer it using dd Y male mice (3 cases each) weighing about 40 g, or administer a predetermined amount of domperidone or Clevoprid 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 intravenously administered.
  • the two forelimbs of the mouse are hung on a metal rod horizontally stretched to a height of about 5 cm from the ground, the time to keep the posture as it is is measured, scored according to the following procedure, and averaged Scores were determined.
  • 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. It exerts a potent gastrointestinal motility-increasing effect and antiemetic effect, and suppresses the occurrence of central nervous system side effects such as extrapyramidal symptoms. Or a prophylactic or therapeutic agent for diseases causing nausea and vomiting.

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Abstract

La présente invention concerne des dérivés d'hydroxyéthoxybenzamide représentés par la formule générale (I), ou des sels de deux-ci acceptables sur le plan pharmaceutique, qui présentent à la fois une activité de blocage du récepteur de la dopamine D2 et une activité de stimulation du récepteur de 5-HT4, en plus de leur utilité comme agents améliorant la fonction gastro-intestinale supprimés lors de développement de symptômes extrapyramidaux. Dans cette formule, R1 représente halogéno; R2 représente alkyle inférieur, alcoxy inférieur, haloalkyle inférieur, haloalcoxy inférieur, ou halogéno; le noyau A est un noyau benzène ou un noyau cyclohexane; et n est égal à 0, 1, ou 2. Ces dérivés et leurs sels sont efficaces contre le reflux oesophagien, l'affection épigastrique non identifiée, la gastrite, l'ulcère gastrique et d'autres maladies.
PCT/JP2001/001445 2000-03-02 2001-02-27 Derives d'hydroxyethoxybenzamide et medicaments les contenant WO2001064641A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2207673A (en) * 1987-08-03 1989-02-08 Fordonal Sa 2, 4, 5-tri-substituted benzamide derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2207673A (en) * 1987-08-03 1989-02-08 Fordonal Sa 2, 4, 5-tri-substituted benzamide derivatives

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