WO1996001630A1 - Preventive or remedy for irritable bowel syndrome or diarrhea - Google Patents

Abstract

A preventive or remedy for irritable bowel syndrome or diarrhea containing a compound represented by general formula (I) including 6-chloro-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide, an optically active isomer thereof, or a medicinally acceptable salt thereof as the active ingredient.

Description

 Specification

 Irritable bowel syndrome is a drug to prevent or treat diarrhea

 Technical field

 The present invention relates to a medicament, especially a preventive or therapeutic agent for irritable bowel syndrome and diarrhea.

 Background art

 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 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.

 In recent years, in a stressful society, 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)]. These results indicate that serotonin-13 receptor antagonists are useful for improving symptoms of irritable bowel syndrome and treating diarrhea.

 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.

 Disclosure of the invention

The present inventors have conducted intensive studies in order to solve the above object, and as a result, completed the present invention. It has led to. That is, the present invention provides a compound represented by the general formula

Wherein 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. And R ⁶

(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; ). Or a pharmaceutically acceptable salt thereof as an active ingredient, which is for preventing or treating irritable bowel syndrome and diarrhea.

 The definitions of the above symbols are described below.

 Halogen includes fluorine, chlorine, bromine and iodine.

 Examples of the alkyl include alkyl having 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl, and octyl.

 Examples of the alkoxy include alkoxy having 1 to 8 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy, and octyloxy. Examples include 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. For example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, hexylamino, octylamino, dimethylamino, getylamino, dibupyramino, diisopropylamine Examples of C phenylalkyl include benzyl, dibutylamino, dihexylamino, and dioctylamino. Examples of C phenylalkyl include benzyl, 1- or 2-phenylethyl, 3-phenylpropyl, and 4-phenylbutyl, and phenyloxyalkyl includes Examples include phenoxymethyl, 2-phenoxyshetyl, 3-phenoxypropyl, and 4-phenoxybutyl.

As the active ingredient compound of the present invention, 6-chloro-3,4-dihydro-4-methyl-3_oxo_N— (3-quinuclidinyl) —2H—1,4-benzobenzoxazine-8-carboxamide, An optically active substance or a pharmaceutically acceptable salt is preferred. Among them, (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. In addition, double-layer tablets and multi-layer tablets can be prepared together with other drugs. Further, the tablets may be tablets coated with a usual coating as required, such as sugar-coated tablets, enteric-coated tablets, and film-coated tablets.

 For solid dosage forms, 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.

 When a liquid preparation is 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.

Hereinafter, formulation examples of the medicament of the present invention will be described with formulation examples. Formulation Example 1

 Compound A 10 Omg

 Lactose 3 0.0 mg

 Corn starch 19.8 mg

 Microcrystalline cellulose 2 8. Omg

 Talc 2.0 mg

 0.2 mg of magnesium stearate

 9 0.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.

Formulation Example 2

 Compound A 10 g

 Sodium pyrosulfite 0.5 g

 Sodium chloride 18 g

 Distilled water for injection

 2 0 0 0m l

 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.

The efficacy and pharmacological effect of the active ingredient compound of the present invention will be explained by the following experiments. Experimental example 1 Effect on uninhibited colon transport A silicone tube was chronically inserted into the cecum of Wistar rats weighing around 200 g (15 to 16 rats per group). About one week later, the test drug was orally administered, and 30 minutes later, an Evans blue solution (25 mg / m 1) was injected into the cecum. After 45 minutes, the cecum and the cervix were removed, and the transport rate (%) from the colon origin to the pigment tip for the entire colon was calculated. The inhibition rate (%) was determined based on the control group (no treatment group), and the results are summarized in Table 1.

 Table 1 Test drug dose (mgZkg) Transport rate Inhibition rate (%) Control group 49.9 ± 3.4

 Compound A 1 34.4 ± 3.0 * * 31

 Compound A 10 36.7 ± 1.8 * * 27

(The values in the table represent the mean soil standard error. The asterisk indicates a significance level of 0.05% or less, and the asterisk indicates a significance level of 0.01% or less.)

 From the results in Table 1, it was clarified that Compound A inhibited colon transport at a dose of 1 mgZkg or more (oral administration).

Experimental example 2 Effect of restraint stress on colon transport

The 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. Table 2 Test drug dose (mgZkg) Transport rate (%) Inhibition rate (%) Control group 77.4 ± 6.0

 Compound A 0.01 68.7 ± 6.4 11

 Compound A 0.1 56.7 ± 5.3 * 27

 Compound A1 57.2 ± 4.7 * 26

 Compound A 10 50.4 ± 6.3 * * 35

(The values in the table represent the mean soil standard error. The * mark indicates a significance level of 0.05% or less, and the ** mark indicates a significance level of 0.01% or less.)

 From the results in Table 2, it was revealed that Compound A, at a dose of 0.1 mgZkg or more (oral administration), suppressed the intestinal transport enhanced by the stress of restraint stress.

Experimental example 3 Effect on mouse defecation

The 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

(mg / kg) Control group 21/22 78 ± 11.5 31 ± 4.7 21/22 108 ± 14.5 48 ± 6.5 Compound A 0.01 19/22 59 ± 8.3 25 ± 3.7 20/22 90 ± 13.3 41 ± 6.8 Compound A 0.1 16 / 22 55 ± 10.9 20 ± 3.5 * 21/22 63 ± 9.5 ** 28 ± 3.3 ** Compound A 1 18/22 51 ± 7.6 20 ± 2.7 * 19/22 64 ± 8.2 28 ± 3.4 ** Compound A 10 21 / 22 53 ± 10.1 20 ± 3.0 * 21/22 64 ± 9.8 ** 26 ± 3.3 [The numerical values in the table represent the average value of (fecal excretion animals) / (number of animals used) and the average value of the fecal weight (mg) of feces excreted animals. The asterisk indicates a significance level of less than 0.05% and the asterisk indicates a significance level of less than 0.01%. ]

 From the results in Table 3, it became clear that Compound A suppressed defecation with a dose of 0.1 mgZkg or more.

Experimental Example 4 Effect on Serotonin-Induced Diarrhea in Mice

 The 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.

 Table 4 Test drug dose (mgZkg) Control group Treatment group Compound A 0.01 17/20 16/20

 Compound A 0.1 17/20 10/20 * Compound A 1 17/20 5/20 * * Compound A 10 17/20 5/20 * *

[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 results in Table 4 revealed that Compound A suppressed serotonin-induced diarrhea at doses of 0.1 mgZkg or more.

Experimental Example 5 Effect on cholera toxin-induced intestinal fluid secretion in rats

A loop of about 20 cm was created in the jejunum of urethane anesthetized Wistar rats weighing about 300 g (6 rats per group). Physiology of cholera toxin 3 g dissolved in the loop A saline solution (2 ml) was placed therein, and after 4 hours, the amount of liquid remaining in the loop was measured. From the change in the fluid volume, the secreted fluid volume per unit weight per hour was determined and summarized in Table 5 _c Table 5 Test Drug Dose (mgZkg) Secreted Volume (mgZh rZg) Control Group 0.45 ± 0.11

 Compound A 0.1 0.14 ± 0.15

 Compound A 1 0.15 ± 0.05 * 氺

(The numerical values in the table represent the mean soil standard error. The asterisks indicate that the significance level is significant at 0.05% or less.)

 The results in Table 5 revealed that Compound A suppressed cholera toxin-induced intestinal secretion at a dose of lmgZkg.

 From the above experimental examples and the like, 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.

Claims

The scope of the claims 1. General formula

[Wherein, R ¹ and R ² are the same or different and represent hydrogen or alkyl, and R ³ is hydrogen, alkyl, phenylalkyl, or halogen, alkoxy, alkyl, nitro, amino, trifluoromethyl, carboxy, or alkoxycarbonyl R ⁴ and R ⁵ may be the same or different and hydrogen, halogen, alkyl, alkoxy, amino, alkanoylamino, alkylamino, hydroxyl, nitro, X Is oxygen or NH, R ⁶ is

(R ⁷ is substituted by 1 to 3 substituents selected from alkyl, phenylalkyl, phenoxyalkyl or halogen, alkoxy, alkyl, nitro, amino, trifluoromethyl, carboxy, and alkoxypropyl. R ⁸ represents hydrogen or alkoxy, and m represents 0 or 1.) 1 (0) _m -NR ⁹ (CH ₂ ) „ (R ⁹ is alkyl, phenylalkyl, or phenylalkyl substituted by 1 to 3 substituents selected from halogen, alkoxy, alkyl, nitro, amino, trifluoromethyl, carboxy, alkoxycarbonyl, m, n Indicates 0 or 1.) Is shown. ] A preventive or therapeutic drug for irritable bowel syndrome, comprising as an active ingredient a benzoxazine compound represented by the formula: or an optically active form thereof or a pharmaceutically acceptable salt thereof.  2.6-Chloro-3,4-dihydro-l-methyl-1--3-oxo-N- (3-quinuclidinyl) -l2H-l, 4-benzoxazine-8-carboxamide, its optically active form or on pharmaceuticals An agent for preventing or treating irritable bowel syndrome or diarrhea, comprising an acceptable salt as an active ingredient.  3. The prevention or treatment according to claim 1, which is a preventive or therapeutic agent for irritable bowel syndrome. 4. The prevention or treatment according to claim 2, which is a preventive or therapeutic agent for irritable bowel syndrome. 5. The preventive or therapeutic agent _{c according to} claim 1, which is a preventive or therapeutic agent for diarrhea. 6. The preventive or therapeutic agent according to claim 2, which is a preventive or therapeutic agent for diarrhea c.