JPH11222433A - Prophylactic or therapeutic agent for sensitive bowel syndrome - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare a prophylactic or a therapeutic agent for sensitive bowel syndrome, especially various symptoms such as defecation abnormality, abdominalgia, abdominal distension feeling, abdominal unpleasant feeling, anorexia, borborygmus, emesis, ructus or pyrosis. SOLUTION: 2(4-Chlorophenyl)-5,6-dihydro-[1]benzothiepino[5,4-c]pyridazin-3(2 H)-one 7-oxide, its optical isomer or 2-(4-chlorophenyl)-5,6- dihydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one 7,7-dioxide is useful for the pyrophylaxis or therapy of sensitive bowel syndrome.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a medicament, especially a preventive or therapeutic agent for irritable bowel syndrome.

[0002]

2. Description of the Related Art Japanese Patent Publication No. 55509/1993 discloses 2- (4-chlorophenyl) -5 which has high affinity for benzodiazepine receptors, is highly safe, and is useful as a selective anxiolytic. , 6-Dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one 7-
Compounds such as oxides are disclosed. The compound is
For example, prevention of autonomic imbalance, neurogenic vomiting, neurogenic dermatitis, angina pectoris, nervous dyspnea, etc. or anxiety, tension, etc. It can be used for improvement or treatment, and is also useful as a neutralizing agent for overdose or intoxication of existing anxiolytics such as diazepam,
In addition, it has pharmacological actions such as leukocyte phagocytosis-enhancing action, macrophage phagocytosis-enhancing action and infection defense action,
It has also been shown to be useful as a biological defense enhancer. Irritable bowel syndrome has attracted attention as a disease in which abnormalities in colonic motility and secretion caused by ataxia in the autonomic nervous system exhibit bowel symptoms such as abnormal bowel movements, abdominal pain, abdominal distension, abdominal discomfort, and wheezing. These symptoms are ameliorated by normalizing the transit time of the large intestine, and a drug having a gastrointestinal motility-modulating action has been clinically used as such a drug.

[0003]

SUMMARY OF THE INVENTION The present invention relates to irritable bowel syndrome, and more particularly, to various symptoms such as abnormal bowel movements, abdominal pain, abdominal distention, abdominal discomfort, loss of appetite, vomit, vomiting, pitting, and heartburn. The purpose is to provide a prophylactic or therapeutic agent.

[0004]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have found that 2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5, 4-c] pyridazine-3 (2H) -one 7
-Oxide was found to significantly suppress colon transport ability, leading to the completion of the present invention. That is, the present invention provides 2- (4-chlorophenyl) -5,6-dihydro-
[1] Benzothiepino [5,4-c] pyridazine-3
(2H) -one 7-oxide, its optical isomer or 2- (4-chlorophenyl) -5,6-dihydro-
[1] Benzothiepino [5,4-c] pyridazine-3
The present invention relates to an agent for preventing or treating irritable bowel syndrome, which comprises (2H) -one 7,7-dioxide as an active ingredient. Preferably, 2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,
4-c] Pyridazin-3 (2H) -one 7-oxide is contained as an active ingredient, The prophylactic or therapeutic agent of irritable bowel syndrome characterized by the above-mentioned.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The compounds used in the present invention include:
2- (4-chlorophenyl) -5,6-dihydro-
[1] Benzothiepino [5,4-c] pyridazine-3
(2H) -one 7-oxide, its optical isomer, R-(-)-2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazine-3 ( 2H) -one 7-oxide, S-(+)-2
-(4-chlorophenyl) -5,6-dihydro- [1]
Benzothiepino [5,4-c] pyridazine-3 (2H)
-One 7-oxide and 2- (4-chlorophenyl)
-5,6-dihydro- [1] benzothiepino [5,4-
c] pyridazin-3 (2H) -one 7,7-dioxide. These compounds are disclosed in JP-B 5-55509.
And the method described in JP-A-3-251586. In order to clearly show that 2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one 7-oxide is a racemate, (±)
-2- (4-chlorophenyl) -5,6-dihydro-
[1] Benzothiepino [5,4-c] pyridazine-3
Although they may be referred to as (2H) -one 7-oxide, they are the same compound and are hereinafter referred to as Y-23684, which is their development number, in the present specification.

[0006] The compound used in the present invention showed an inhibitory effect on the large intestinal transport ability which was enhanced by the loading of restraint stress in animal tests. Therefore, it can also be used to improve various symptoms such as defecation abnormalities, abdominal pain, abdominal distention, abdominal discomfort, anorexia, abdominal vomit, vomiting, pitting, and heartburn in the irritable bowel group. The prophylactic or therapeutic agents of the invention are formulated in a form suitable for oral, parenteral or rectal administration. Pharmaceutical formulations include tablets, capsules, troches, syrups, granules, powders, injections,
Suspensions, suppositories and the like. In addition, a double-layer tablet or a multilayer tablet can be prepared together with other drugs. Further, the tablet may be a tablet coated with a usual coating, if necessary, for example, a sugar-coated tablet, an enteric-coated tablet, or a film-coated tablet.

In the case of a solid preparation, additives such as lactose, sucrose, crystalline cellulose, corn starch, calcium phosphate, sorbitol, glycine, carboxymethylcellulose, acacia, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, glycerin, polyethylene glycol , Magnesium stearate, talc and the like are used. When a semisolid preparation is used, animal and vegetable oils and fats such as olive oil, corn oil, castor oil and the like, mineral oils and fats such as petrolatum, white petrolatum, solid paraffin and the like, waxes such as jojoba oil, carnauba wax, beeswax and the like However, partially or totally synthesized glycerin fatty acid esters such as lauric acid, myristic acid, and palmitic acid are used. Examples of these commercially available products include Witepsol (manufactured by Dynamit Nobel), Pharmasol (manufactured by NOF Corporation) and the like. When a liquid preparation is used, additives such as sodium chloride, sorbitol, glycerin, olive oil, propylene glycol, and ethyl alcohol are used. Furthermore, it can also be made into an oral administration preparation using the mixed and crushed product described in Japanese Patent Publication No. 8-18985.

[0008] The amount of the active ingredient in these preparations is 0.1% of the preparation.
1 to 100% by weight, usually 1 to 50% by weight for preparations for oral administration and 0.2 to 20% by weight for preparations for injection. The dose may vary depending on the patient's condition, body weight, age, etc., but in the case of normal oral administration, it is about 0.01 to 100 mg, preferably about 0.03 to 60 mg, particularly preferably about 2 to 60 mg per day for an adult.
About 8 mg, and it is preferable to administer it once or in several divided doses.

[0009]

The following are prescription examples of the prophylactic or therapeutic agent of the present invention, but the present invention is not limited thereto. Formulation Example 1 Y-23684 10.0 mg Lactose 30.0 mg Corn starch 19.8 mg Crystalline cellulose 28.0 mg Talc 2.0 mg Magnesium stearate 0.2 mg Hydroxypropyl methylcellulose 4.0 mg Titanium oxide 1.0 mg ────────────────────────────── 95.0mg total amount

[0010] Y-23684, lactose, corn starch and crystalline cellulose are mixed, a part of the corn starch is kneaded and granulated as a paste liquid, and dried at 50 ° C for 3 hours. After the dried product was passed through a 24 mesh sieve, talc and magnesium stearate were added, and 90 m per tablet was obtained with a rotary tableting machine using a 6.0 mm diameter punch.
g tablets are produced. Next, the tablet is coated with 5 mg per tablet using hydroxypropylmethylcellulose and titanium oxide as film coating bases.

Formulation Example 2 Y-23684 10.0 mg Corn starch 20.0 mg Lactose 81.5 mg Crystalline cellulose 30.0 mg Hydroxypropylcellulose 3.0 mg Talc 5.0 mg Magnesium stearate 0.5 mg ──────────────────────────── 150.0mg

[0012] Y-23684 and corn starch are intensively mixed in a mortar in a dry system to obtain a mixed and crushed product. After sufficiently mixing the obtained powder mixture with lactose and crystalline cellulose in a kneading machine, a hydroxypropylcellulose paste solution is added and kneaded and granulated. After passing the granulated material through a 16-mesh sieve, the water content is 3 to 4% in a hot air dryer at 50 ° C.
After drying through a sieve of 24 mesh, talc and magnesium stearate were added, and 1 tablet per tablet was punched by a rotary tableting machine using a 7.5 mm diameter punch.
Make 50 mg tablets.

Formulation Example 3 Y-23684 0.3 g Witepsol H15 35.7 g ───── 36.0 mg of total amount 35.7 g of Witepsol H15 was melted at about 40 ° C., 0.3 g of active ingredient Y-23684 was added, and the mixture was stirred and dispersed. The uniformly mixed product was filled in a suppository mold to 1.2 g each, and Y-2368 was prepared in 1.2 g each.
4. Obtain suppositories containing 10 mg.

[0014]

Effects of the Invention In order to prove the pharmacological effects of Y-23684, the effects of Y-23684 on colon transport in rats were examined. EXPERIMENTAL EXAMPLE 1: Effect on restraint stress on colon transport The test drug was orally administered to Wistar rats (14 to 17 rats per group) in which a silicone tube was inserted into the cecum, and 30 minutes later, 0.4 ml of Evans blue solution ( 25 mg / ml) was injected into the cecum. The cecum and colon were removed 45 minutes after placing the rat in a restraining cage, and the ratio of the total colon length from the colon origin to the pigment tip was calculated as the transport rate. As a comparative example, 30 mg / kg of diazepam was similarly administered, and the transport rate was examined. The group not administered with the drug was used as a control group.
Table 1 summarizes the results.

Table 1 II. Test Drug Dose (mg / kg) Transport rate (%) 対 照 Control group 79.3 Y-23684 3 72.2 Control group 87.4 Y-23684 10 57.9 ** Control group 79.3 Y-23684 30 58.2 * ──────────────── Control group 79.3 Diazepam 30 68.2 ──────────────────────── ────────────

(In the table, the asterisk indicates a risk rate of 0.05% or less.
** indicates that significance is 0.01% or less. From the results in Table 1, it was revealed that Y-23684 significantly suppressed the colon transport ability enhanced by restraint stress at doses of 10 mg / kg and 30 mg / kg (oral administration). On the other hand, diazepam did not show a significant effect even at 30 mg / kg. From the above experimental examples, it was shown that the compounds used in the present invention are useful for the prevention and treatment of irritable bowel syndrome exhibiting various symptoms such as bowel movement abnormalities caused by dysmotility of the large intestine.

Claims (2)

[Claims] (1) 2- (4-chlorophenyl) -5,6-
Dihydro- [1] benzothiepino [5,4-c] pyridazin-3 (2H) -one 7-oxide, its optical isomer or 2- (4-chlorophenyl) -5,6-dihydro- [1] benzothiepino [5 , 4-c] pyridazine-
3 (2H) -one A preventive or therapeutic agent for irritable bowel syndrome, comprising 7,7-dioxide as an active ingredient. 2. The active ingredient is 2- (4-chlorophenyl).
-5,6-dihydro- [1] benzothiepino [5,4-
c) The preventive or therapeutic agent for irritable bowel syndrome according to claim 1, which is pyridazine-3 (2H) -one 7-oxide.