WO1994012497A1 - Heterocyclic compound - Google Patents
Heterocyclic compound Download PDFInfo
- Publication number
- WO1994012497A1 WO1994012497A1 PCT/JP1993/001484 JP9301484W WO9412497A1 WO 1994012497 A1 WO1994012497 A1 WO 1994012497A1 JP 9301484 W JP9301484 W JP 9301484W WO 9412497 A1 WO9412497 A1 WO 9412497A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- pharmaceutical composition
- serotonin
- receptor
- acid
- Prior art date
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- 150000002391 heterocyclic compounds Chemical class 0.000 title description 9
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- DCSUBABJRXZOMT-UHFFFAOYSA-N cisapride Natural products C1CC(NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)C(OC)CN1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-UHFFFAOYSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 208000006881 esophagitis Diseases 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- 210000001630 jejunum Anatomy 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 231100000668 minimum lethal dose Toxicity 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000418 oral toxicity Toxicity 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 239000001120 potassium sulphate Substances 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000004203 pyloric antrum Anatomy 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- OKXPYKHKJCATPX-UHFFFAOYSA-N quinazoline-2-carboxylic acid Chemical class C1=CC=CC2=NC(C(=O)O)=NC=C21 OKXPYKHKJCATPX-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 231100000191 repeated dose toxicity Toxicity 0.000 description 1
- JWHOQZUREKYPBY-UHFFFAOYSA-N rubonic acid Natural products CC1(C)CCC2(CCC3(C)C(=CCC4C5(C)CCC(=O)C(C)(C)C5CC(=O)C34C)C2C1)C(=O)O JWHOQZUREKYPBY-UHFFFAOYSA-N 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002562 urinalysis Methods 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
Definitions
- the present invention relates to a heterocyclic compound, and more specifically, has an effect of stimulating serotonin 4 receptor, and is effective for treating chronic gastritis, improving gastrointestinal symptoms associated with postgastrectomy syndrome and the like.
- New quinoline compounds and pharmaceutical uses thereof are also useful.
- Serotonin is a neurotransmitter widely distributed in living organisms and has various physiological activities. Conventionally, three subtypes of serotonin receptor, serotonin 1 receptor, serotonin 2 receptor, and serotonin 3 receptor are known. In addition to these, the potency of the serotonin 4 receptor was reported by Dumuis A et al.
- Serotonin 4 receptor is thought to be involved in guinea pig ileum, contraction of the ascending colon, relaxation of rat esophagus, etc., and is a stimulant of serotonin 4 receptor Cisapride, a drug that promotes gastrointestinal motility, improves gastrointestinal symptoms such as heartburn, anorexia, upper abdominal pain, and abdominal distension due to chronic gastritis and postgastrectomy syndrome, and reflux. Effective for treatment of esophagitis, pseudo bowel obstruction and constipation Retrepure (Alimentary Pharmacology and Therapeutics, Vol. 6, pp. 273, 1991).
- European Patent No. 0 586 836 A1 discloses a heterocyclic compound.
- a quinoline derivative having a nin 3 receptor antagonism is disclosed.
- an object of the present invention is to provide a novel heterocyclic compound having a strong stimulating action particularly on the serotonin 4 receptor and a pharmaceutical use thereof.
- An object of the present invention is to provide a compound of formula (I)
- Another object of the present invention is to provide a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier as an active ingredient, especially a serotonin 4 receptor.
- An object of the present invention is to provide a pharmaceutical composition for stimulating the body.
- Yet another object of the present invention is to stimulate the serotonin 4 receptor, comprising administering to a human an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. It is to provide a way to do this.
- Yet another object of the present invention is to provide a compound of formula (I) or a pharmaceutically acceptable compound thereof for use as an active ingredient of a pharmaceutical composition, especially for stimulating the serotonin 4 receptor. To provide the salt.
- Still another object of the present invention is to produce a pharmaceutical composition for stimulating a serotonin 4 receptor containing a compound of the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Or a salt thereof.
- Pharmaceutically acceptable salts of the compounds of formula (I) of the present invention include acid addition salts.
- Such acid addition salts are salts in which a pharmacologically acceptable acid has been added to the nitrogen atom in the molecule of the compound of formula (I), for example, hydrochloric acid, hydrobromic acid, Salts of mineral acids such as hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; oxalic acid, citric acid, tartaric acid, maleic acid, carboxylic acid, fumaric acid, p- O Salts of organic acids such as norensurenoleic acid, benzenesulphonic acid and methansulphonic acid, etc.
- the compound (compound (1)) represented by the formula (I) of the present invention can be produced, for example, by the method shown in the following production scheme.
- the starting compound (2) can be produced by the method described in J. Chem. So, p. 3462, p.
- the reductive ring closure reaction from compound (2) to compound (3) The reaction can be carried out under ordinary conditions for the reduction of the nitro group, and the compound (3) can be obtained by cyclization simultaneously with the reduction.
- the reduction reaction conditions are, for example,
- Examples of the solvent used in the reduction reaction of (1) include water; acetic acid; alcohols; hydrocarbons such as hexane; ethers such as getyl ether and tetrahydrofuran; , Non-protonic polar solvents such as N-dimethylformamide; or a mixed solvent thereof.
- Examples of the solvent used in the reduction reaction of (2) include water, acetic acid, methanol, ethanol, dioxane, and the like, or a mixed solvent thereof.
- the reaction temperature of the reduction reactions 1 and 2 is usually from 0 ° C to the boiling point of the solvent, and the reaction time is usually 30 minutes to 12 hours.
- the N-isopropylation of the compound (3) to the compound (4) can be carried out under the usual N-alkylation conditions of an acid amide group, for example, in a suitable solvent as a base.
- Metallic alkalis such as triumium and potassium; hydrogenated alkalis such as sodium hydride; sodium ethoxide, potassium sulphate, etc.
- Alkali hydroxide; sodium hydroxide, alkali hydroxide such as potassium hydroxide; sodium carbonate N-isopyl can be pilated using carbonates such as aluminum and potassium carbonate; and amines such as triethylamine and pyridine. .
- Examples of the solvent used herein include alcohols such as methanol and ethanol; ethers such as diethyl ether, dioxane, and tetrahydrofuran; Hydrocarbons such as benzene, benzene and the like; N, N—non-propyl polar solvents such as dimethylformamide; and a mixed solvent thereof.
- the reaction temperature is usually from 0 ° C to the boiling point of the solvent.
- An appropriate reaction time is usually 30 minutes to 12 hours.
- Examples of the reactive derivative for introducing an isopropyl group include a halogenated isopropyl such as an isopropyl iodide.
- Hydrolysis of compound (4) to compound (5) can be carried out under ordinary hydrolysis conditions, such as acidic hydrolysis using hydrochloric acid or acetic acid, or acid hydrolysis using sodium hydroxide or the like. Rehydration, etc.
- the reaction temperature is usually from 0 ° C to the boiling point of the solvent.
- the reaction time is usually 30 minutes to 12 hours.
- Amidation of the compound (5) to the compound (1) is carried out with the compound (5) or a reactive derivative thereof and the end-3-amino-8-methyl-8-azabicyclo [3.2.1]
- Compound (1) can be produced by reacting octane (compound (6)). This amidation reaction can be performed by a method known per se.
- a method of appropriately reacting a reactive derivative of the compound (5) for example, an acid halide, a lower alkyl ester, or an active ester, imidazolide, or a mixed acid anhydride, or the like.
- a method of directly bonding the compound (5) and the compound (6) using a condensing agent can be used.
- Solvents include, for example, ether, tetrahydrofuran dioxane, methylene chloride, form-of-closure, dichloroethane, benzene, toluene, xylene. Water, water, or mixtures thereof.
- potassium carbonate sodium hydroxide
- potassium hydroxide potassium hydroxide
- pyridin triethylamine
- N, N-dimethylaniline Anything can be used as the base.
- reaction time is usually 30 minutes to 12 hours.
- the compound (5) is reacted with the compound (6) in a solvent which is generally inert to the reaction, in the presence of the condensing agent, at a temperature from 0 ° C to the boiling point of the solvent.
- condensing agent for example, dicyclohexyl force rubodiy Mid, 2-black N-methyl pyridinium dye, diphenyl phosphoryl azide, etc. can be used.
- compound (4) or (5) can also be produced by the method shown below.
- the compound (7) is oxidized in a solvent such as dioxane with an oxidizing agent such as 2,3-dichloro-1,5,6-diano-1,4-dibenzoquinone (DDQ).
- DDQ 2,3-dichloro-1,5,6-diano-1,4-dibenzoquinone
- Compound (8) is converted to compound (4) or (5) by condensing with malonic acid or malonic ester in the presence or absence of a condensing agent. It can be.
- the condensing agent to be used for example, an alkali metal hydroxide, Carbonates, bicarbonates, alcohols or amines such as amides, ammonia, and pyridin; acetic acid, acetic anhydride or one of the reagents such as zinc chloride
- the compound of the present invention can be produced in the same manner as described above.
- the minimum lethal dose by oral administration was 12 as a result of a single dose toxicity test in mice (acute toxicity). 5 mg Z kg or more.
- the dose of the compound of the formula (1), which is the active ingredient of the pharmaceutical composition of the present invention varies depending on the condition. Usually, the daily dose for an adult is 0.1 l in the case of oral administration. ⁇ 100 mgZ human, Intravenous dose: 0.01 to 20 mg / human, usually once a day or divided into 2 to 4 times a day Can be done.
- the pharmaceutical composition of the present invention can be prepared and used in solid preparations such as tablets, pills, capsules, granules, injections, solutions, emulsions, suppositories, and the like.
- each of the above formulations are manufactured according to conventional formulation techniques, but if necessary, use commonly used additives such as auxiliaries, stabilizers, emulsifiers, and diluents. Can be done.
- the serotonin 4 receptor stimulating action of the compound of the formula (1) which is an active ingredient of the pharmaceutical composition of the present invention, and various digestive tracts Exercise activity and toxicity.
- a 25-cm proximal ileum is removed from the ileocecal region using a Nore-Trey monomoret, and the longitudinal muscles obtained from two strips of approximately 4 cm from the proximal ileum are removed.
- Specimens longitudinal muscle was suspended in Krebs solvent solution (3 2 ⁇ 3 4 ° C ), only if the load of about 0. 8 g, was bubbled through 9 5% 0 2, 5 9 C 02. Responses were recorded via a displacement transducer.
- the electrical stimulation conditions were 0.2 Hz, lmsec, and the system was left at a submaximal voltage for about 1 hour to stabilize. 1 0 - of 8 M concentration of 5 - After sure that the twitch response is enhanced by HT, were tested for effects of test samples. Test compounds were added cumulatively after the specimens had rested for at least 45 minutes.
- control compounds 2 to 5 having an alkyl group other than an isopropyl group as R shown in Table 1, U.S.P. Patent No. 5,106,851 and reference compound 6 described in European Patent Publication No. 0 586 836 A1.
- Control Compound The compound of the present invention showed much stronger serotonin 4 receptor stimulating activity than any of the compounds of 7.
- Test Example 2 Effect on rat stomach motility
- Wistar male rats (body weight 250-350) were fasted for 18 hours and used. The animals were laparotomized under ether anesthesia and a rubber balloon was inserted into the stomach rather than the forestomach. A force knurl for drug administration was placed intraperitoneally. After recovery from anesthesia, the balloon was connected to a low-pressure transducer to record gastric movements while awake.
- the compound of the present invention was suspended in physiological saline and administered intraperitoneally. The average value of contraction frequency and motor index over 10 minutes was calculated. It was shown as a percentage (%) of the value before administration (0 min). The value at 0 minutes was calculated by averaging the values for 30 minutes before administration. Lmg / kg (intraperitoneal administration) of the compound of the present invention showed a gastric motility promoting effect. On the other hand, no effect was observed with administration of the vehicle alone.
- Table 3 below shows the changes in contraction frequency and motor index caused by the administration of the compound of the present invention.
- Gastroenterologia Japonica The method described in Vol. 12, Vol. 27, Paragraph 197, 1977 was used.
- Pentobarbi A Luna Trim Under anesthesia, a beagle dog (male and female: 11-15 kg) was used to measure the motion of the pyloric antrum, duodenum, jejunum, ileum and colon in five places. The gauge force transducer was sewn. In addition, a power nail for drug administration was chronically attached to the external jugular vein. After recovery from surgery, conscious dogs in fasted and postprandial periods in unrestrained dogs The movement of each part of the gastrointestinal tract was measured.
- the compound of the present invention was administered by dissolving it in a 5% aqueous solution of lactic acid saline for intravenous administration, and suspended and administered in a 5% aqueous solution of arabia gum for oral administration.
- the motor index was calculated as an average value for 15 minutes and expressed as a percentage (%) of the value before administration (0 minutes). The value at 0 minutes was calculated by averaging the values for 30 minutes before administration.
- Intravenous and oral administration of the compounds of the present invention showed a promoting effect on gastrointestinal motility in the fasting and postprandial phases. On the other hand, administration of the vehicle alone had no effect.
- Tables 4 and 5 below show the effects of intravenous administration of 0.3 mg Z kg and oral administration of 1 mg Z kg of the compound of the present invention on the motility index of postprandial gastric motility.
- Wistar male rats (weighing 170-220 g) were fasted for 24 hours before use. 30 minutes after the subcutaneous administration or 60 minutes after the oral administration, one oral administration of glass ball (500 / ⁇ ) was performed. After 30 minutes, the glass balls remaining in the stomach were collected, and their weight was measured to calculate the gastric remaining rate for control exercise.
- the compound of the present invention was administered after being suspended in physiological saline.
- ICR male mice (20--30 g body weight) were used after fasting for 18 hours. 15 minutes after subcutaneous administration or 30 minutes after oral administration, 5% charcoal powdered arabia rubber suspension was orally administered. Twenty minutes after this, the intestinal tract was excised, the total length of the intestinal tract and the movement distance of the charcoal powder were measured, and the transfer rate to control animals was calculated.
- Specimens were administered suspended in saline.
- general condition was observed and body weight was measured.At the end of the administration period, hematological tests, blood chemistry tests, urinalysis, dissection tests, organ weight measurements, histopathological tests, etc. were performed. .
- suppression of body weight gain was observed, and secondary changes associated with deterioration in general condition were observed in the liver, thymus, accessory genitalia, adrenal glands, and the like.
- no toxic change was observed in the 100 mg Z kg group, and it was inferred that the toxicity was weak considering the pharmacological activity of the compound of the present invention.
- a thionyl chloride 5 solution containing 0.5 g of 1-isopropyl-12 (1H) -quinolone-13-carboxylate was refluxed and stirred for 2 hours. After thionyl chloride was sufficiently distilled off under reduced pressure, benzene 3 was added. End 3—Amino 8—Methyl 1—Azabicyclo [3.2.1] Octane 3 containing 0.36 g of octane was cooled under ice-cooling. The solution was added dropwise to a benzene solution of acid chloride and stirred at room temperature for 2 hours.
- Compound of the present invention 20 g, lactose: 190 g, potato starch: 200 g, crystalline cellulose: 280 g, potassium carboxy cellulose: 200 g, hydroxymethyl cellulose: 100 g g, then pulverize with a pulverizer, and then enter a stirring granulator, add an appropriate amount of water to perform granulation, and then dry with a fluid bed drier, and stir 10 g of acid magnesium was added, and a tableting machine was used to obtain a tablet (100 m, 6 band diameter) containing 2 mg of the compound of the present invention.
- the compound of the present invention acts on the serotonin 4 receptor and has a serotonin-like receptor stimulating action.
- it has a gastrointestinal motility stimulating effect, improves gastrointestinal symptoms such as heartburn, anorexia, upper abdominal pain and abdominal distension associated with chronic gastritis, postgastrectomy syndrome, etc., and reflux esophagitis, pseudo It is effective in treating bowel obstruction and constipation.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/428,119 US5571820A (en) | 1992-11-20 | 1993-10-15 | Heterocyclic compound |
AU51615/93A AU5161593A (en) | 1992-11-20 | 1993-10-15 | Heterocyclic compound |
EP93922638A EP0670319A4 (en) | 1992-11-20 | 1993-10-15 | HETEROCYCLIC COMPOUNDS. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP31165392 | 1992-11-20 | ||
JP4/311653 | 1992-11-20 |
Publications (1)
Publication Number | Publication Date |
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WO1994012497A1 true WO1994012497A1 (en) | 1994-06-09 |
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1993/001484 WO1994012497A1 (en) | 1992-11-20 | 1993-10-15 | Heterocyclic compound |
Country Status (4)
Country | Link |
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US (1) | US5571820A (ja) |
EP (1) | EP0670319A4 (ja) |
AU (1) | AU5161593A (ja) |
WO (1) | WO1994012497A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0710662A1 (en) * | 1994-05-18 | 1996-05-08 | Taisho Pharmaceutical Co. Ltd | Quinolinecarboxylic acid derivative |
EP0748808A1 (en) * | 1994-02-28 | 1996-12-18 | Taisho Pharmaceutical Co. Ltd | Heterocyclic compound |
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US5864039A (en) * | 1994-03-30 | 1999-01-26 | Yoshitomi Pharmaceutical Industries, Ltd. | Benzoic acid compounds and use thereof as medicaments |
DK1689742T3 (da) * | 2003-11-24 | 2010-05-17 | Pfizer | Quinoloncarboxylsyreforbindelser med 5-HT-receptor-agonistisk aktivitet |
US7024155B2 (en) * | 2003-11-25 | 2006-04-04 | G Squared, Llc | Device and method for facilitating transmission, production, recording, sound reinforcement and real-time monitoring of audio and visual elements of a production |
TW200533348A (en) * | 2004-02-18 | 2005-10-16 | Theravance Inc | Indazole-carboxamide compounds as 5-ht4 receptor agonists |
TWI351282B (en) | 2004-04-07 | 2011-11-01 | Theravance Inc | Quinolinone-carboxamide compounds as 5-ht4 recepto |
US7728006B2 (en) * | 2004-04-07 | 2010-06-01 | Theravance, Inc. | Quinolinone-carboxamide compounds as 5-HT4 receptor agonists |
US8309575B2 (en) | 2004-04-07 | 2012-11-13 | Theravance, Inc. | Quinolinone-carboxamide compounds as 5-HT4 receptor agonists |
WO2006052640A1 (en) * | 2004-11-05 | 2006-05-18 | Theravance, Inc. | 5-ht4 receptor agonist compounds |
ES2327142T3 (es) * | 2004-11-05 | 2009-10-26 | Theravance, Inc. | Compuestos de quinolinona-carboxamida. |
CN101080406A (zh) * | 2004-12-22 | 2007-11-28 | 施万制药 | 吲唑-甲酰胺化合物 |
NZ560828A (en) * | 2005-03-02 | 2011-01-28 | Theravance Inc | Quinolinone compounds as 5-HT4 receptor agonists |
TWI377206B (en) * | 2005-04-06 | 2012-11-21 | Theravance Inc | Crystalline form of a quinolinone-carboxamide compound |
TWI384986B (zh) * | 2007-01-17 | 2013-02-11 | Lg Life Sciences Ltd | 抗病毒劑之順丁烯二酸單鹽以及含有該單鹽之醫藥組成物 |
US7648093B2 (en) * | 2007-03-27 | 2010-01-19 | Dennis Kruger | Pill crusher and pill pouch |
WO2010089993A1 (ja) | 2009-02-03 | 2010-08-12 | クミアイ化学工業株式会社 | 縮合環化した2-ピリドン誘導体及び除草剤 |
Citations (2)
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JPH03197462A (ja) * | 1989-02-06 | 1991-08-28 | Ist De Angeli Spa | ベンゾ融合―n―含有ヘテロ環誘導体 |
JPH04226980A (ja) * | 1990-05-23 | 1992-08-17 | Kyowa Hakko Kogyo Co Ltd | 複素環式化合物 |
-
1993
- 1993-10-15 EP EP93922638A patent/EP0670319A4/en not_active Withdrawn
- 1993-10-15 WO PCT/JP1993/001484 patent/WO1994012497A1/ja not_active Application Discontinuation
- 1993-10-15 US US08/428,119 patent/US5571820A/en not_active Expired - Fee Related
- 1993-10-15 AU AU51615/93A patent/AU5161593A/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03197462A (ja) * | 1989-02-06 | 1991-08-28 | Ist De Angeli Spa | ベンゾ融合―n―含有ヘテロ環誘導体 |
JPH04226980A (ja) * | 1990-05-23 | 1992-08-17 | Kyowa Hakko Kogyo Co Ltd | 複素環式化合物 |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0748808A1 (en) * | 1994-02-28 | 1996-12-18 | Taisho Pharmaceutical Co. Ltd | Heterocyclic compound |
EP0748808A4 (en) * | 1994-02-28 | 1998-10-07 | Taisho Pharmaceutical Co Ltd | HETEROCYCLIC COMPOUNDS |
EP0710662A1 (en) * | 1994-05-18 | 1996-05-08 | Taisho Pharmaceutical Co. Ltd | Quinolinecarboxylic acid derivative |
EP0710662A4 (en) * | 1994-05-18 | 1996-09-18 | Taisho Pharmaceutical Co Ltd | CHINOLINE CARBONIC ACID DERIVATIVES |
US5753673A (en) * | 1994-05-18 | 1998-05-19 | Taisho Pharmaceutical Co., Ltd. | Quinolinecarboxylic acid derivatives |
Also Published As
Publication number | Publication date |
---|---|
US5571820A (en) | 1996-11-05 |
EP0670319A1 (en) | 1995-09-06 |
EP0670319A4 (en) | 1996-01-17 |
AU5161593A (en) | 1994-06-22 |
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