WO2010024586A2 - Nouveau composé dérivé de benzamide et son procédé de fabrication - Google Patents

Nouveau composé dérivé de benzamide et son procédé de fabrication Download PDF

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WO2010024586A2
WO2010024586A2 PCT/KR2009/004754 KR2009004754W WO2010024586A2 WO 2010024586 A2 WO2010024586 A2 WO 2010024586A2 KR 2009004754 W KR2009004754 W KR 2009004754W WO 2010024586 A2 WO2010024586 A2 WO 2010024586A2
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formula
compound
amino
cis
chloro
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WO2010024586A3 (fr
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유무희
이재걸
임원빈
최성학
박정상
최선호
손태경
성현정
손주희
조강훈
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동아제약주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel benzamide derivative compound, a preparation method thereof and a pharmaceutical composition using the same as an active ingredient.
  • 5-HT 4 receptor agonists can be used for various diseases, including reflux esophagitis, gastrointestinal disorders, gastrointestinal disorders, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, indigestion, esophagitis, gastritis It has been shown to be useful in the treatment of degree disease, motion sickness, central nervous system disease, Alzheimer's disease, cognitive impairment, vomiting, migraine, neurological disease, pain, cardiovascular disorders, heart failure, deep vein, diabetes and apnea syndrome (Tips, 1992, 13, 141; Ford APDW et al., Med. Res. Rev., 1993, 13. 633; Gullikson GW et al., Drug Dev.
  • IBS irritable bowel syndrome
  • Cisapride a representative 5-HT 4 receptor agonist
  • Cisapride is one of the benzamide derivatives, the origin of which is metocloprid
  • US Pat. Nos. 4,962,115, 5,057,525 and 5,137,896 are N- (3-hydroxy including cisapride 4-piperidinyl) benzamide is disclosed. These compounds are known to stimulate gastrointestinal motility.
  • Benzamide derivatives have several excellent pharmacological actions.
  • the superior pharmacological action of benzamide derivatives is due to their effect on the nervous system regulated by the neurotransmitter serotonin.
  • the role of serotonin, the pharmacological action of benzamide derivatives has been extensively studied in various diseases for many years.
  • research has been focused on the production and storage of serotonin, as well as on the location of serotonin receptors in humans to determine the correlation between various disease states or diseases.
  • Benzamide derivatives increase gastrointestinal smooth muscle activity from the esophagus to the adjacent small intestine, accelerating esophagus and small intestinal movement, emptying the stomach and increasing esophageal sphincter tension (Decktor et al., Eur. J. Pharmacol. 147: 313-316, 1988).
  • Benzamide derivatives are not cholinergic receptor agonists, but the aforementioned smooth muscle effect can be blocked by muscarinic receptor blockers such as atropine or neurotransmitter inhibitors such as tetrodotoxin that block sodium channels.
  • the small intestine has been reported to show similar blocking activity on the contractile effects of serotonin.
  • benzamide derivatives on smooth muscle is the 5-HT 4 receptor located on interneurons in the myenteric plexus of the gut wall. It has been reported to act as an agonist on serotonin receptors and to show excellent activating effects on smooth muscle. Activation of these receptors subsequently enhances the release of acetylcholine from parasympathetic nerve terminals located around smooth muscle fibres. This is the combination of acetylcholine and its receptor on the smooth muscle membrane that actually causes muscle contraction.
  • Cisaprid cures reflux esophagitis (GERD) by inhibiting gastrointestinal contents from reflux into the esophagus.
  • GFD reflux esophagitis
  • One of the most important factors in the pathogenesis of reflux esophagitis is the lowering of the pressure barrier due to loss of function of the subesophageal sphincter. Malfunction of the lower esophageal sphincter is caused by low basal pressure, sphincter relaxation, and a non-compensated increase in gastric internal pressure.
  • Other pathogenesis factors include delayed emptying of the stomach, insufficient emptying of the esophagus due to impaired peristalsis, and corrosiveness of reflux substances that damage the esophageal mucosa.
  • Cisaprid is expected to increase esophageal sphincter pressure and improve esophageal passage.
  • Cisapride may be usefully used to treat indigestion, gastrointestinal discomfort, postoperative ileus, and pseudo ileus because of its activity as a prokinetic substance.
  • Indigestion is a symptom mainly of gastrointestinal dysfunction, which is also a disease characterized by impaired digestive or digestive function that can result from complications from other diseases such as appendicitis, gallbladder disorders or malnutrition.
  • Gastric disability refers to gastrointestinal paralysis due to gastric dyskinesia or complications of diseases such as diabetes mellitus, progressive systemic sclerosis, anorexia nervosa or dystonia.
  • Constipation is a disease characterized by infrequent or difficult excretion due to diseases caused by intestinal muscle tension or lack of stiffness.
  • Postoperative intestinal obstruction is an intestinal obstruction caused by the destruction of muscle tension following surgery.
  • False ileus is a symptom characterized by constipation, abdominal pain and vomiting, but there is no evidence of physical obstruction.
  • cisapride When cisapride was administered to humans, serious side effects were found, including CNS disorders, elevated blood pressure, interaction with other drugs, diarrhea and abdominal cramps. In addition, intravenous administration of cisapride resulted in additional adverse events that were not present in oral administration (Stacher et al. 1987 Digestive Diseases and Sciences 31 (11): 1223-1230). The causes of these side effects are known to be metabolites from the oxidative dealkylation or aromatic hydrolysis of compounds occurring in the P450 detoxification system. Cisapride is also susceptible to numerous undesirable drugs or drug interactions, which are also metabolic consequences of the cytochrome P450 system.
  • the stability of 5-HT 4 receptor agonists with prokinetic motility in the gastrointestinal tract is influenced by adverse effects of the drug due to cardiac effects (extending QT interval, cardiac arrest, ventricular arrhythmias) and liver cytochrome P450 metabolism. It has been limited. Gastrointestinal prokinetic drugs that do not have this disorder would be invaluable for diseases such as reflux esophagitis and gastric emptying disorders.
  • Several derivatives of cisaprid are described by US Pat. No. 6,552,046 and World Patent 01/093849, but many are required for compounds.
  • the present invention provides a compound of formula (I)
  • R 1 is hydrogen or C 1-6 alkyl
  • R 2 is hydrogen or C 1-6 alkyl
  • R 3 , R 4 and R 5 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, amino, hydroxy, cyano, nitro or halogen;
  • X is -O- or a direct bond and R 6 is C 1-10 alkyl
  • R 7 is C 1-10 alkyl
  • X is as defined in (a), n is 0 or 1, R 8 is cycloC 3-8 alkyl, heterocycloC 3-8 alkyl, C 3-8 aryl, arylC 1- 4 alkyl or hetero C 3-12 aryl, wherein the heteroatom is an atom selected from one or more of S, N, O,
  • Y is hydrogen or hydroxy
  • R is heterocyclo C 3-6 alkyl comprising at least one N (nitrogen atom), wherein the heteroatom is an atom selected from one or more of S, N, O .
  • the present invention also provides pharmaceutically acceptable salts of the compounds of formula (I). That is, salts of compounds of formula (I) are acid addition salts formed by pharmaceutically acceptable free acids.
  • Inorganic and organic acids may be used as the free acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. may be used as the inorganic acid, and citric acid, acetic acid, lactic acid, maleic acid, umarin acid, gluconic acid, methanesulfonic acid may be used as the organic acid.
  • Glyconic acid, succinic acid, 4-toluenesulfonic acid, trifluoroacetic acid, galluxuronic acid, embonic acid, glutamic acid, aspartic acid, or the like can be used.
  • the present invention also provides isomers (optical isomers) and hydrates of the compounds of formula (I).
  • Alkyl means a branched or unbranched monovalent saturated hydrocarbon radical having only 1 to 20 carbon atoms, but having only carbon and hydrogen atoms.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, 2,2-dimethylpropyl, butyl, isobutyl, secondary-butyl, tert-butyl, 3-methylbutyl, pentyl, 3-methylpentyl, 4- Methylpentyl, n-hexyl, 2-ethylhexyl, octyl, dodecyl, and the like.
  • Alkoxy means a radical -0-alkyl.
  • alkoxy radicals include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary-butoxy, tert-butoxy, pentoxy, hexoxy.
  • Cycloalkyl is a monovalent saturated consisting of one or more rings which may be optionally substituted with hydroxy, cyano, alkyl, alkoxy, halogen, nitro, alkoxycarbonyl, amino, dialkylamino, aminocarbonyl, carbonylamino It means a carbocyclic radical.
  • cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, and the like.
  • Heterocycloalkyl is one or more independently N, optionally substituted by hydroxy, cyano, alkyl, alkoxy, halogen, nitro, alkoxycarbonyl, amino, dialkylamino, aminocarbonyl, carbonylamino A monovalent saturated carbocyclic radical containing one or more O and S elements and consisting of one or more rings.
  • heterocycloalkyl radicals include piperidinyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolinyl, morpholinyl, pyrrolidinyl, oxazolidinonyl, bipiperidinyl and the like and substituted piperidinyl, pipe Ferazinyl, pyrrolidinyl, imidazolinyl, morpholinyl, pyrrolidinyl, oxazolidinonyl, bipiperidinyl, and the like.
  • Aryl means an aromatic hydrocarbon which may be phenyl or optionally substituted with hydroxy, cyano, alkyl, alkoxy, halogen, nitro, alkoxycarbonyl, amino, dialkylamino, aminocarbonyl, carbonylamino .
  • aryl are phenyl or hydroxy, cyano, alkyl, alkoxy, halogen, nitro, alkoxycarbonyl, amino, dialkylamino, aminocarbonyl, phenyl substituted from 1 to 5 by substituents of carbonylamino, etc. .
  • Heteroaryl is one or more independently N, optionally substituted with hydroxy, cyano, alkyl, alkoxy, halogen, nitro, alkoxycarbonyl, amino, dialkylamino, aminocarbonyl, carbonylamino A radical containing at least one of O and S elements and having at least one aromatic hydrocarbon ring phase.
  • heteroaryl examples include pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridinyl substituted with pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiophenyl, phthalimidyl, indolyl, benzimidazolyl and the like Ophenyl, phthalimidyl, indolyl, benzimidazolyl, and the like.
  • Halogen means radical fluoro, bromo, chloro, and / or iodo.
  • Formula (I) compounds of the invention are preferably compounds of formula (I-A):
  • R 1 , R 2 and L are as defined in formula (I) above.
  • the compound of the present invention is preferably a compound wherein the 3,4 position of the piperidine ring of formula (I) is a cis isomer or a pharmaceutically acceptable salt thereof and a hydrate thereof, more preferably formula (I) Is a (3S, 4R) isomer, or a pharmaceutically acceptable salt thereof and a hydrate thereof.
  • L is formula (a);
  • X is a direct bond and R 6 is C 1-10 alkyl, an isomer thereof, or a pharmaceutically acceptable salt thereof and a hydrate thereof.
  • the compounds of the present invention are preferably compounds of formula (I), isomers thereof, or pharmaceutically acceptable salts thereof and hydrates thereof, wherein in formula (I) L is formula (b); More preferably formula (b) is formula (e), and in formula (e) X is a direct bond; R 8 is selected from cycloC 3-8 alkyl, heterocycloC 3-8 alkyl, C 3-8 aryl, arylC 1-4 alkyl or heteroC 3-12 allyl, wherein the heteroatoms are S, N, A compound of formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof and a hydrate thereof, wherein the atom is one or more selected from O.
  • the compounds of the present invention are preferably compounds of formula (I), isomers thereof, or pharmaceutically acceptable salts thereof and hydrates thereof, wherein in formula (I) L is formula (c); Even more preferably in formula (c), Y is a hydroxy group, R is morpholine, a compound of formula I, an isomer thereof, or a pharmaceutically acceptable salt thereof and a hydrate thereof.
  • Preferred compounds among the compounds of formula (I) of the present invention are as follows.
  • the compounds of formula (I) of the present invention are not limited to the compounds of formula (I) prepared by the methods mentioned below.
  • a method for preparing a compound of formula (I-1) comprising the step of obtaining a compound of formula (I-1) by reacting a compound of formula (VIII) with a compound of formula (VII) prepared in step 3. to provide:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , m are as defined in formula (I), A is integer 1, B is halogen or sulfonate, D is halogen.
  • the piperidine-benzamide compound (II) used in Scheme 1 can be simply synthesized by a known method (EP 0076530).
  • a protecting group (tert-butyl acetate) is introduced at the amine position of piperidine of the compound of formula (III), and the reaction is preferably performed at room temperature using di-tert-butyl dicarbonate.
  • the step of replacing hydroxy of the compound of formula (IV) with halogen or sulfonate it is preferable to use N-bromosuccinimide, carbon tetrabromide or methanesulfonyl chloride as the halogen reagent, and the reaction is 0 ° C. It is preferable to start at and gradually raise the temperature to room temperature.
  • the second step is to react the compound of formula (II) with the compound of formula (V) to obtain a compound of formula (VI).
  • Potassium carbonate and potassium iodide can be used, and the solvent is N, N-dimethylformamide. Or ethanol can be used, the reaction is preferably carried out at 120-130 °C.
  • the third step reaction is a reaction in which the protecting group (tert-butyl acetate) of the amine is separated with trifluoroacetic acid in the compound of formula (VI), and is preferably stirred under reflux under a dichloromethane solvent.
  • the fourth step is to obtain a derivative (I-2) by reacting a compound of formula (VII) with a compound of formula (VIII), using potassium carbonate and potassium iodide, and the solvent is N, N-dimethylformamide. Or N, N-dimethylacetamide, and the reaction is preferably carried out at 120-140 ° C.
  • compound (VIII) it is also possible to use a compound which can be simply synthesized by a known method or can be easily obtained commercially.
  • the present invention is the nucleophilic substitution reaction of the compound of formula (III) represented by Scheme 2 and the compound of formula (X) (represented by a. And b. Obtaining a compound; (2) substituting the hydroxy of the compound of formula (XI) prepared in the first step with halogen or sulfonate to obtain a compound of formula (XII); And (3) reacting the compound of formula (XII) prepared in step 2 with a compound of formula (II) to obtain a compound of formula (I-2). to provide:
  • the first stage reaction is a step of introducing a substituent to the amine position of the piperidine of the compound of formula (III) can be synthesized by the following two methods.
  • the piperidine derivative (XI) is synthesized using diisopropylethylamine reagent in dichloromethane solvent using derivative (a).
  • the derivative (a) is a compound which can be simply synthesized by a known method, and the reaction preferably starts at 0 ° C. and gradually raises the temperature to room temperature.
  • pyridine derivative (XI) can be synthesized using derivative (b).
  • the second step is to replace the hydroxy of the compound of formula (XI) with sulfonate, methanesulfonyl chloride and the like can be used, the reaction is preferably started at 0 °C gradually raise the temperature to room temperature.
  • the third step is to obtain a derivative (I-2) by reacting a compound of formula (II) with a compound of formula (II).
  • Potassium carbonate and potassium iodide can be used, and the solvent is N, N-dimethylform.
  • Amides can be used and the reaction is preferably carried out at 120-140 ° C.
  • the present invention comprises the steps of (1) to obtain a compound of formula (XIV) by nucleophilic substitution reaction of the compound of formula (XIII) and the compound of formula (IX) represented by Scheme 3; (2) substituting hydroxy of the compound of formula (XIV) prepared in the first step with halogen or sulfonate to obtain a compound of formula (XV); And (3) reacting the compound of formula (XV) prepared in the second step with the compound of formula (II) to obtain a compound of formula (I-3).
  • the first stage reaction synthesizes the compound of formula (XIV) using general substituted carboxylic acid hydrochloric acid or substituted chloroformate substituted by introducing a substituent at the amine position of piperidine of the compound of formula (XIII). .
  • the second stage reaction is a step of substituting the hydroxy group of the compound of formula (XIV) with sulfonate, and methanesulfonyl chloride may be used, and the reaction is preferably started at 0 ° C. and gradually raised to room temperature.
  • the third step is to obtain a derivative (I-3) by reacting a compound of formula (II) with a compound of formula (XV).
  • Potassium carbonate and potassium iodide can be used, and the solvent is N, N-dimethylform.
  • Amide may be used, and the reaction is preferably performed at 120-130 ° C.
  • the present invention (1) the nucleophilic substitution reaction of the compound of formula (XVI) and the compound of formula (XVII) represented by Scheme 4 to obtain a formula (XVIII) (first step); And (2) reacting the compound of formula (XVIII) prepared in the first step with a compound of formula (II) to obtain a compound of formula (I-4). do:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R are as defined in formula (I).
  • the first step of the reaction is to prepare the compound of formula (XVIII) by substituting epichlorohydrin (XVII) in water solvent using sodium hydroxide at the amine position of the heterocycloalkyl (R) of the compound of formula (XVI).
  • the furnace temperature preferably starts at 0 ° C. and gradually raises the temperature to room temperature.
  • the compound (I-4) is obtained by reacting the compound of formula (II) with the compound of formula (XVIII), using ethanol as a solvent. It is preferable to perform reaction at 80-90 degreeC.
  • the compound of formula (XVI) and compound of formula (XVII) may be used as a commercially available compound.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R are as defined in Formula I, m 'is defined as 1-6, D "is a halogen of Br or I is , D 'is chloride (Cl).)
  • the first step is to replace D ′′ of the compound of formula (XIX) with R.
  • Sodium hydride and N, N-dimethylformamide can be used as a solvent, and the type of halogen is preferably bromo or chloro. It is preferable that the reaction starts at 0 ° C. and gradually raises the temperature to room temperature.
  • the second step reaction is to obtain a derivative (I-5) by reacting a compound of formula (II) with a compound of formula (XX).
  • Potassium carbonate and potassium iodide can be used, and the solvent is N, N-dimethylformamide. It can be used and it is preferable to perform reaction at 120-140 degreeC.
  • the present invention provides a composition for the efficacy of 5-HT 4 receptor containing the above-mentioned compound of formula (I) of the present invention as an active ingredient.
  • composition for 5-HT 4 receptor efficacy is reflux esophagitis, gastrointestinal disease, gastric dyskinesia, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, postoperative bowel obstruction, gastrointestinal insufficiency,
  • IBS irritable bowel syndrome
  • the present invention by administering the above-mentioned compound of formula (I) of the present invention to mammals, including humans, reflux esophagitis, gastrointestinal diseases, gastrointestinal disorders, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome ( IBS), constipation, postoperative intestinal obstruction, gastric insufficiency, indigestion, esophagitis, gastroesophageal disease, motion sickness, central nervous system disease, Alzheimer's disease, cognitive disorders, vomiting, migraine, nerve disease, pain, cardiovascular disorders, heart failure, deep vein, diabetes And a method for preventing or treating one disease selected from apnea syndrome.
  • mammals including humans, reflux esophagitis, gastrointestinal diseases, gastrointestinal disorders, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome ( IBS), constipation, postoperative intestinal obstruction, gastric insufficiency, indigestion, esophagitis, gastroesophageal disease, motion
  • the present invention also provides the use of the aforementioned compounds of formula (I) of the invention in the preparation of 5-HT 4 receptor agonists.
  • 5-HT 4 receptor agonists include reflux esophagitis, gastrointestinal disorders, gastrointestinal disorders, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, postoperative bowel obstruction, gastric ataxia, indigestion, esophagitis, Means drugs to prevent or treat gastroesophageal disease, motion sickness, central nervous system disease, Alzheimer's disease, cognitive impairment, vomiting, migraine, neurological disease, pain, cardiovascular disorders, heart failure, deep vein, diabetes and apnea syndrome do.
  • composition of the present invention may contain one or more active ingredients exhibiting the same or similar functions in addition to the benzamide derivative.
  • composition of the present invention can be prepared by including one or more pharmaceutically acceptable carriers in addition to the above-described active ingredient for administration.
  • Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, if necessary, as an antioxidant, buffer And other conventional additives such as bacteriostatic agents can be added.
  • Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like.
  • it may be preferably formulated according to each disease or component by a suitable method in the art or using a method disclosed in Remington's Pharmaceutical Science (Recent Edition), Merck Publishing Company, Easton PA.
  • compositions of the present invention may be administered parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) or orally, depending on the desired method, and the dosage may be based on the weight, age, sex, health status, The range varies depending on the diet, the time of administration, the method of administration, the rate of excretion and the severity of the disease.
  • the daily dosage is preferably 5 to 300 mg / kg of the benzamide derivative, more preferably 83 to 167 mg / kg, and preferably divided once to several times a day.
  • 50% lethal dose (LD 50 ) of the benzamide derivative was found to be 1 g / kg or more, which is considered a safe substance.
  • Compounds of the present invention have the same or superior affinity for 5-HT 4 receptors compared to cisapride, improved ventricular tachycardia, ventricular fibrillation, ventricular arrhythmias and prolongation of QT interval, which are disadvantages of cisapride, Due to its low toxicity, it can be used as a therapeutic agent for diseases of the digestive system.
  • reagents used below were purchased from Aldrich, TCI, Kanto chemical, Samchun (domestic), Daejung (domestic), Duksan (domestic), and the like.
  • cis-norcisapride 6.07 g of cis-4-amino-5-chloro-2-methoxy-N- (3-methoxypiperidin-4-yl) benzamide (hereinafter referred to as "cis-norcisapride") is added to N, N- 5 g of tert-butyl 4- (bromomethyl) piperidine-1-carboxylate prepared in (2) after dissolving in 40 ml of dimethylformamide (DMF), 3.744 g of potassium carbonate (K 2 CO 3 ), potassium 642 mg of iodide (KI) was added sequentially. The reaction mixture was stirred at 120 ° C. for 2 hours.
  • DMF dimethylformamide
  • K 2 CO 3 potassium carbonate
  • KI iodide
  • Example 301 mg of the title compound was prepared in the same manner as in Example 1 (5), except that butyl 2-chloroacetate (633 ⁇ l) was used instead of ethyl 2-bromoacetate in Example (5) as a starting material.
  • butyl 2-chloroacetate (633 ⁇ l) was used instead of ethyl 2-bromoacetate in Example (5) as a starting material.
  • Example 4 550 mg of the title compound was obtained in the same manner as in Example 4 except for using piperidine 1 g instead of morpholine as a starting material in Example 4 (1).
  • Example 4 (1) Except for using 1 g of 1,4'-bipiperidine instead of morpholine as a starting material in Example 4 (1) was prepared in the same manner as in Example 4 to obtain 400 mg of the title compound.
  • Example 5 250 mg of the title compound was obtained by the same method as Example 5, except that 5.078 g of pyrrolidin-2-one was used instead of oxazolidin-2-one as a starting material in Example 5 (1).
  • Example 9 469 mg of the title compound was obtained in the same manner as in Example 9, except that 4.7 ml of cyclohexanecarbonyl chloride was used instead of benzoyl chloride as a starting material in Example 9 (1).
  • Example 9 In the same manner as in Example 9, except that 4.9 ml of benzyl chloroformate was used instead of benzoyl chloride as the starting material in Example 9 (1) to obtain 180 mg of the title compound.
  • Example 9 317 mg of the title compound was obtained in the same manner as in Example 9, except that 3.7 ml of thiophen-2-carbonyl chloride was used instead of benzoyl chloride as a starting material in Example 9 (1).
  • Example 9 290 mg of the title compound was obtained in the same manner as in Example 9, except that 4.2 ml of cyclopentanecarbonyl chloride was used instead of benzoyl chloride as a starting material in Example 9 (1).
  • Example 9 As in Example 9, except that 2 g of 4-hydroxypiperidine and 4.14 ml of isobutyryl chloride were used instead of piperidin-4-ylmethanol and benzoyl chloride as starting materials in Example 9 (1). The method gave 50 mg of the title compound.
  • Example 9 686 mg of the title compound was obtained in the same manner as in Example 9 except that 4.35 ml of piperidine-1-carbonyl chloride was used instead of benzoyl chloride as a starting material in Example 9 (1).
  • Example 9 430 mg of the title compound was obtained in the same manner as in Example 9, except that 3.2 ml of cyclopropanecarbonyl chloride was used instead of benzoyl chloride as a starting material in Example 9 (1).
  • Example 9 236 mg of the title compound was obtained in the same manner as in Example 9, except that 4.1 ml of morpholine-4-carbonyl chloride was used instead of benzoyl chloride as a starting material in Example 9 (1).
  • Example 9 30 mg of the title compound was obtained in the same manner as in Example 9, except that 15.5 g of nicotinoyl chloride hydrochloride was used instead of benzoyl chloride as a starting material in Example 9 (1).
  • Binding affinity assessment for human derived 5-HT 4 receptors is described by Wyngaert et al. The procedure was described in the Journal of Neurochemistry, (1997) 69, 1810-1819.
  • COS-7 cells purchased from ATCC
  • the collected cells were pulverized to obtain a membrane pulverization and used in the binding experiment.
  • the experimental material compound 1-19, cisapride
  • 4 ⁇ 0.0625 uM and [H3] -GR113808 manufactured by Amersham Biosciences. The mixture was incubated for 40 minutes at 37 degrees Celsius.
  • Cisapride used as a reference, is purchased from the shamrock company in India.
  • the compounds described in the present invention inhibit the specific binding of the radioligand to the 5-HT 4 receptor at a concentration equal to or lower than that of the comparator cisapride, thus exhibiting a strong binding force to 5-HT 4 . It can be seen that.
  • tablets were prepared by tableting according to a conventional method for producing tablets.
  • the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.
  • a sterilized 20 ml vial was filled with a benzamide derivative, citrate sodium salt, citric acid and dextrose and sealed with an aluminum cap. It was prepared by dissolving the above mixture using distilled water for injection and then diluting with an appropriate volume of distilled water for injection.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un composé de la formule chimique (I), des isomères de celui-ci ou des sels pharmaceutiquement acceptables de ce composé et ses isomères; un procédé de production du composé et de ses isomères et une composition pharmaceutique qui est efficace sur des récepteurs 5-HT4 et qui contient le composé ou un isomère de celui-ci comme principe actif.
PCT/KR2009/004754 2008-09-01 2009-08-26 Nouveau composé dérivé de benzamide et son procédé de fabrication WO2010024586A2 (fr)

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KR1020080085718A KR20100026641A (ko) 2008-09-01 2008-09-01 신규한 벤즈아미드 유도체 화합물 및 그의 제조방법
KR10-2008-0085718 2008-09-01

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018081513A1 (fr) 2016-10-31 2018-05-03 Biocryst Pharmaceuticals, Inc. Promédicaments d'inhibiteurs de la kallicréine
WO2021225968A1 (fr) * 2020-05-04 2021-11-11 Takeda Pharmaceutical Company Limited Dérivés de n-(pipéridin-4-yl)benzamide à action luminale

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998016511A1 (fr) * 1996-10-15 1998-04-23 Janssen Pharmaceutica N.V. Synthese de cisapride
US5783702A (en) * 1994-10-07 1998-07-21 Torcan Chemical Ltd. Preparation of cisapride
WO1999002496A1 (fr) * 1997-07-11 1999-01-21 Janssen Pharmaceutica N.V. (+)-norcisapride utiles pour traiter les troubles a mediation 5-ht3 et 5-ht4
WO2001093849A2 (fr) * 2000-06-07 2001-12-13 Aryx Therapeutics Materiaux et methodes permettant de traiter le reflux gastro-oesophagien
WO2002036113A1 (fr) * 2000-11-01 2002-05-10 Respiratorius Ab Composition comprenant des agonistes (5ht-4) et des antagonistes (5ht-2, 5ht-3) recepteurs de la serotonine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5783702A (en) * 1994-10-07 1998-07-21 Torcan Chemical Ltd. Preparation of cisapride
WO1998016511A1 (fr) * 1996-10-15 1998-04-23 Janssen Pharmaceutica N.V. Synthese de cisapride
WO1999002496A1 (fr) * 1997-07-11 1999-01-21 Janssen Pharmaceutica N.V. (+)-norcisapride utiles pour traiter les troubles a mediation 5-ht3 et 5-ht4
WO2001093849A2 (fr) * 2000-06-07 2001-12-13 Aryx Therapeutics Materiaux et methodes permettant de traiter le reflux gastro-oesophagien
WO2002036113A1 (fr) * 2000-11-01 2002-05-10 Respiratorius Ab Composition comprenant des agonistes (5ht-4) et des antagonistes (5ht-2, 5ht-3) recepteurs de la serotonine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018081513A1 (fr) 2016-10-31 2018-05-03 Biocryst Pharmaceuticals, Inc. Promédicaments d'inhibiteurs de la kallicréine
WO2021225968A1 (fr) * 2020-05-04 2021-11-11 Takeda Pharmaceutical Company Limited Dérivés de n-(pipéridin-4-yl)benzamide à action luminale

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KR20100026641A (ko) 2010-03-10

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