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WO1996001630A1 - Medicament de prevention ou remede concernant le colon irritable ou la diarrhee - Google Patents

Medicament de prevention ou remede concernant le colon irritable ou la diarrhee Download PDF

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Publication number
WO1996001630A1
WO1996001630A1 PCT/JP1995/001365 JP9501365W WO9601630A1 WO 1996001630 A1 WO1996001630 A1 WO 1996001630A1 JP 9501365 W JP9501365 W JP 9501365W WO 9601630 A1 WO9601630 A1 WO 9601630A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
preventive
diarrhea
irritable bowel
bowel syndrome
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1995/001365
Other languages
English (en)
Japanese (ja)
Inventor
Kiyoshi Asano
Keiichiro Haga
Takeshi Kawakita
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsubishi Tanabe Pharma Corp
Original Assignee
Yoshitomi Pharmaceutical Industries 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.)
Filing date
Publication date
Application filed by Yoshitomi Pharmaceutical Industries Ltd filed Critical Yoshitomi Pharmaceutical Industries Ltd
Publication of WO1996001630A1 publication Critical patent/WO1996001630A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • Irritable bowel syndrome is a drug to prevent or treat diarrhea
  • the present invention relates to a medicament, especially a preventive or therapeutic agent for irritable bowel syndrome and diarrhea.
  • stomach hyperactivity In Japanese Patent Publication No. 5-73752 (corresponding English specification No. America Patent No. 488927282), there are stomach hyperactivity, antiemetic effect and Z or serotonin-13 receptor blockade. It is active and prevents and treats digestive disorders such as indigestion, delayed gastric emptying, and peptic ulcer, and / or administration of anticancer drugs such as migraine, cluster headache, arrhythmia, or cisplatin or radiation therapy
  • benzoxazine compounds Disclosed are benzoxazine compounds, optically active forms thereof, and pharmaceutically acceptable salts thereof, which are useful for treating central nervous system disorders such as nausea or vomiting, anxiety, or mental illness induced by the disease.
  • irritable bowel syndrome has attracted attention as a disease that presents with bowel symptoms such as defecation abnormalities such as diarrhea and constipation, abdominal pain, abdominal distention, abdominal discomfort, and wheezing.
  • the disease is based on abnormal motility and secretion of the gastrointestinal tract, particularly the colon, caused by autonomic nervous system imbalance. These symptoms are ameliorated by normalizing colon transit time.
  • Serotonin is a diarrhea-inducing substance. When ondansetron was administered to patients with carcinoid syndrome, a tumor of serotonin-producing cells, symptoms such as diarrhea disappeared. [Platt. Aj. (The Lancet) No. 339, pp. 14 16 (1992)].
  • An object of the present invention is to provide an agent for preventing and treating irritable bowel syndrome, in particular, various symptoms such as abnormal bowel movements, abdominal pain, abdominal distention, abdominal discomfort, wheezing, pitting, heartburn, and diarrhea. I do.
  • the present invention provides a compound represented by the general formula
  • R 1 and R 2 are the same or different and represent hydrogen or alkyl;
  • R 3 is hydrogen, alkyl, phenylalkyl, or halogen, alkoxy, alkyl, nitro, amino, trifluoromethyl, carboxy, 1 selected from alkoxycarbonyl
  • R 4 and R 5 are the same or different and each represents hydrogen, halogen, alkyl, alkoxy, amino, alkanoylamino, alkylamino, hydroxyl, nitro, and X represents oxygen or NH.
  • R 6 represents hydrogen, halogen, alkyl, alkoxy, amino, alkanoylamino, alkylamino, hydroxyl, nitro, and X represents oxygen or NH.
  • R is substituted by 1 to 3 substituents selected from alkyl, phenylalkyl, phenoxyalkyl or halogen, alkoxy, alkyl, nitro, amino, trifluoromethyl, carboxy, and alkoxycarbonyl. Phenylalkyl or phenoxyalkyl, R 8 represents hydrogen or alkoxy, and m represents 0 or 1.
  • R 9 is alkyl, phenylalkyl, or halogen, alkoxy, alkyl, M, n represents 0 or 1; phenylalkyl substituted by 1 to 3 substituents selected from nitro, amino, trifluoromethyl, carboxy, and alkoxycarbonyl; ).
  • a pharmaceutically acceptable salt thereof as an active ingredient which is for preventing or treating irritable bowel syndrome and diarrhea.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • alkyl examples include alkyl having 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl, and octyl.
  • alkoxy examples include alkoxy having 1 to 8 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy, and octyloxy.
  • alkanoylamino having 2 to 5 carbon atoms such as acetylamino, propionylamino, butyrylamino, and bivaloylamino.
  • c Alkylamino is mono- or di-substituted and has 1 to 8 carbon atoms in the alkyl portion.
  • C phenylalkyl include benzyl, dibutylamino, dihexylamino, and dioctylamino.
  • C phenylalkyl examples include benzyl, 1- or 2-phenylethyl, 3-phenylpropyl, and 4-phenylbutyl
  • phenyloxyalkyl examples include phenoxymethyl, 2-phenoxyshetyl, 3-phenoxypropyl, and 4-phenoxybutyl.
  • An optically active substance or a pharmaceutically acceptable salt is preferred.
  • (Sat) 1-6-chloro-3,4-dihydro-4-methyl-3-oxo —N— (3-quinuclidinyl) -12H—1,4-benzobenzodine-18-carboxamido hydrochloride (hereinafter sometimes referred to as compound A) is particularly preferred.
  • the compound used in the present invention suppressed the intestinal transport ability in the unrestrained state, and also showed an inhibitory effect on the enhanced intestinal transport ability in a test with animals loaded with restraint stress. It also reduced bowel movements and diarrhea and intestinal secretion induced by diarrhea-inducing substances. Therefore, the active ingredient compound of the present invention is useful for the prevention and treatment of various symptoms such as defecation abnormality, abdominal pain, abdominal distension, abdominal discomfort, anorexia, wheezing, vomiting, heartburn, and pitting in irritable syndrome. It can also be used to prevent and treat diarrhea.
  • the form of the medicament of the present invention includes tablets, capsules, troches, syrups, granules, powders, injections, suspensions and the like.
  • double-layer tablets and multi-layer tablets can be prepared together with other drugs.
  • the tablets may be tablets coated with a usual coating as required, such as sugar-coated tablets, enteric-coated tablets, and film-coated tablets.
  • excipients such as lactose, sucrose, crystalline cellulose, corn starch, calcium phosphate, sorbitol, glycine, carboxymethyl cellulose, acacia, polyvinylpyrrolidone, hydroxypropylcellulose, glycerin, polyethylene glycol, Magnesium stearate, silver, etc. are used.
  • additives such as sodium chloride, sorbitol, glycerin, olive oil, propylene glycol, and ethyl alcohol are used.
  • the amount of the compound used in the present invention in these preparations is from 0.1 to 100% by weight of the preparation, and suitably from 1 to 50% by weight for the preparation for oral administration. In the case of an injectable preparation, the content is 0.2 to 20% by weight.
  • the dose of the compound may vary depending on the patient's condition, weight, age, etc., but in the case of oral administration, it is usually 0.01 to 100 mg, preferably 0.3 to 60 mg per day for an adult. It is preferable to administer it once or in several divided doses.
  • Microcrystalline cellulose 2 8. Omg
  • the active ingredient compound A, lactose, corn starch and crystalline cellulose are mixed, a part of the corn starch is kneaded and granulated as a paste solution, and dried at 50 ° C for 3 hours. After the dried product is passed through a 24 mesh sieve, talc and magnesium stearate are added, and a 9 Omg tablet is manufactured using a 7. Omm diameter punch with a single-tablet tableting machine. Next, the tablets are coated with 5 mg per tablet using hydroxypropylmethyl cellulose and titanium oxide as film coating bases.
  • the active ingredient compound A, sodium pyrosulfite and sodium chloride (preliminarily sterilized by heating with 25 (TC for 30 minutes or more)) are dissolved in distilled water for injection to prepare a total amount of 200 Om1.
  • the solution was filtered under a nitrogen atmosphere with a membrane filter (pore size 0.45 lim), filled into 2 ml 1 ampules in 2 ml increments, air was replaced by nitrogen, removed, sealed, and sealed. Sterilize for 30 minutes at ° C.
  • test drug was orally administered to Wistar rats (13 to 16 rats / group) in which a silicone tube was inserted into the cecum as in Experimental Example 1, and 30 minutes later, Evansbull I solution (25 mg / m 1) was injected into the cecum.
  • the rat was immediately placed in a restraining cage, and after 45 minutes, the cecum and colon were removed and the transport rate to the dye tip was calculated.
  • the inhibition rate () was determined based on the control group (no treatment group), and the results are summarized in Table 2.
  • test drug was subcutaneously administered to d dY mice weighing about 25 g, and each of them was placed in an isolation box covered with filter paper. Change the filter paper every 2 hours and count the number of cases that showed defecation up to 4 hours later.At the same time, measured the wet weight and dry weight of feces and summarized the results in Table 3 c Table 3 Test drug administration Quantity 0-2 hours 0-4 hours
  • test drug was orally administered to d dY mice weighing about 25 g, and each of them was placed in an isolation box covered with filter paper. 30 minutes later, 5 mg Zkg of serotonin was subcutaneously administered, and one hour later, the number of animals excreted of diarrheal stool was determined. All were considered diarrhea stools, from loose stools with water on the filter paper to watery stools. Compare with the vehicle-administered group as a control group.
  • the numbers for the treatment group and the control group are (number of animals excreted diarrhea) / (number of animals used).
  • the asterisk indicates a significance level of less than 0.05%, and the asterisk indicates a significance level of less than 0.01%.
  • the medicament of the present invention is useful for the prevention or treatment of irritable bowel syndrome or diarrhea showing various symptoms such as bowel movement abnormality caused by abnormal movement of the large intestine.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à un médicament de prévention ou un remède concernant le côlon irritable ou la diarrhée et s'applique à un composé représenté par la formule générale (I) et comprenant 6-chloro-3,4-dihydro-4-méthyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide, un isomère optiquement actif, ou un sel médicalement acceptable utilisé comme principe actif.
PCT/JP1995/001365 1994-07-12 1995-07-07 Medicament de prevention ou remede concernant le colon irritable ou la diarrhee Ceased WO1996001630A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP15998594 1994-07-12
JP6/159985 1994-07-12
JP6/159984 1994-07-12
JP15998494 1994-07-12

Publications (1)

Publication Number Publication Date
WO1996001630A1 true WO1996001630A1 (fr) 1996-01-25

Family

ID=26486620

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1995/001365 Ceased WO1996001630A1 (fr) 1994-07-12 1995-07-07 Medicament de prevention ou remede concernant le colon irritable ou la diarrhee

Country Status (1)

Country Link
WO (1) WO1996001630A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01207290A (ja) * 1987-10-22 1989-08-21 Yoshitomi Pharmaceut Ind Ltd ベンズオキサジン化合物
JPH02218614A (ja) * 1989-02-17 1990-08-31 Yoshitomi Pharmaceut Ind Ltd 痴呆または認識障害に関する疾患の治療薬
JPH03255026A (ja) * 1990-03-01 1991-11-13 Yoshitomi Pharmaceut Ind Ltd 物質依存症に関する治療薬

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01207290A (ja) * 1987-10-22 1989-08-21 Yoshitomi Pharmaceut Ind Ltd ベンズオキサジン化合物
JPH02218614A (ja) * 1989-02-17 1990-08-31 Yoshitomi Pharmaceut Ind Ltd 痴呆または認識障害に関する疾患の治療薬
JPH03255026A (ja) * 1990-03-01 1991-11-13 Yoshitomi Pharmaceut Ind Ltd 物質依存症に関する治療薬

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