JPH0827000A - Drugs for the prevention or treatment of various symptoms due to emesis - Google Patents

Abstract

(57) [Summary] [Purpose] To provide a preventive or therapeutic drug for various symptoms caused by emesis. Composition: 6-chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H-
A medicine comprising a benzoxazine compound such as 1,4-benzoxazine-8-carboxamide.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medicine, and more particularly to a medicine for preventing or treating various symptoms caused by emesis.

[0002]

2. Description of the Related Art Japanese Patent Publication No. 5-73752 discloses gastric hyperactivity, anti-emetic action and / or 5-HT ₃ receptor blocker activity, indigestion, delayed gastric emptying, peptic ulcer. Prevention and treatment of diseases of the digestive system such as and / or central nervous system such as migraine, cluster headache, arrhythmia, nausea or vomiting induced by administration of anticancer drug such as cisplatin or radiation therapy, or anxiety, psychosis Disclosed are benzoxazine compounds, optically active forms or pharmaceutically acceptable salts thereof, which are useful for the treatment of disorders such as

By the way, it was reported that when ondansetron, which is a serotonin-3 receptor blocker, was administered to a patient with emesis who could not eat because of severe vomiting, a remarkable improvement effect was shown [The Lancet (The Lancet ) No. 340, 1
223 (1992) and ibid. 341, 185.
There is a page (1993).

[0004]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a preventive or therapeutic drug for various symptoms due to emesis.

[0005]

The present inventors have completed the present invention as a result of intensive studies to solve the above problems. That is, the present invention has the general formula

[0006]

[Chemical 4]

[Wherein R ¹ and R ² are the same or different and each represents hydrogen or alkyl, and R ³ is hydrogen, alkyl, phenylalkyl, halogen, alkoxy, alkyl, nitro, amino, trifluoromethyl, carboxy or alkoxycarbonyl. Phenylalkyl substituted by 1 to 3 substituents selected from R ⁴ , R ⁵ are the same or different and are hydrogen, halogen, alkyl, alkoxy, amino, alkanoylamino, alkylamino, hydroxyl group, nitro, Is oxygen or NH, R ⁶ is

[0008]

Embedded image

(R ⁷ is phenylalkyl substituted with 1 to 3 substituents selected from alkyl, phenylalkyl, phenoxyalkyl or halogen, alkoxy, alkyl, nitro, amino, trifluoromethyl, carboxy, alkoxycarbonyl, or Phenoxyalkyl, R ⁸ is hydrogen, alkoxy, m is 0,1
Indicates. ) Or

[0010]

[Chemical 6]

(R ⁹ is m, phenylalkyl or phenylalkyl substituted with 1 to 3 substituents selected from halogen, alkoxy, alkyl, nitro, amino, trifluoromethyl, carboxy and alkoxycarbonyl; , N is 0 or 1.). ] A benzoxazine compound represented by the following, an optically active substance thereof, and a pharmaceutically acceptable salt thereof as active ingredients, and a preventive or therapeutic agent for various symptoms due to emesis.

Explaining the above definitions, halogen is fluorine, chlorine, bromine, iodine, and alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, etc. Alkoxy having 1 to 8 carbon atoms, and alkoxy is 1 to 8 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the like. Alkoxy is an acylamino with an alkanoylamino having 2 to 5 carbon atoms such as acetylamino, propionylamino, butyrylamino, pivaloylamino, etc. Has a carbon number,
Examples thereof include methylamino, ethylamino, propylamino, isopropylamino, butylamino, hexylamino, octylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, dihexylamino and dioctylamino. Examples of phenylalkyl are benzyl, 1- or 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, and examples of phenoxyalkyl are phenoxymethyl, 2-phenoxyethyl, 3-phenoxypropyl, 4-phenoxybutyl. Can be given.

As the compound of the general formula (I), 6-chloro-3,4-dihydro-4-methyl-3-oxo-N-
(3-Quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide, its optically active substance or a pharmaceutically acceptable salt thereof is preferable, and among them, (±) -6-chloro-3,4-dihydro-4. -Methyl-3-oxo-N
-(3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide monohydrochloride (hereinafter referred to as compound A
Sometimes)) is preferred.

The medicament of the present invention is formulated in a form suitable for oral, parenteral or rectal administration. The form of the pharmaceutical preparation includes tablets, capsules, troches, syrups, granules, powders, injections, suspensions, suppositories and the like. Further, it can be made into a double-layer tablet or a multi-layer tablet together with other drugs. Further, the tablets may be tablets coated with a usual coating as necessary, for example, sugar-coated tablets, enteric-coated tablets and film-coated tablets.

In the case of a solid preparation, additives such as lactose, sucrose, crystalline cellulose, corn starch, calcium phosphate, sorbitol, glycine, carboxymethyl cellulose, gum arabic, polyvinylpyrrolidone, hydroxypropyl cellulose, glycerin, polyethylene glycol, magnesium stearate. , Talc, etc. are used.

In the case of a semi-solid preparation, animal and vegetable oils and fats such as olive oil, corn oil and castor oil are mineral oils and fats such as petrolatum and white petrolatum.
As solid paraffin and the like, waxes such as jojoba oil, carnauba wax, beeswax and the like, and partially or totally synthetic glycerin fatty acid ester such as lauric acid, myristic acid and palmitic acid are used. Examples of these commercially available products include Witepsol (manufactured by Dynamit Nobel) and Pharmasol (manufactured by NOF Corporation).

In the case of liquid preparations, additives such as sodium chloride, sorbitol, glycerin, olive oil, propylene glycol, ethyl alcohol and the like are used.

The amount of active ingredient in these preparations depends on the formulation.
1-100% by weight, suitably 1-50% by weight for formulations for oral administration and 0.2-20% by weight for injectable formulations. The dose may vary depending on the patient's symptoms, body weight, age and the like, but usually, in the case of oral administration, it is 0.01 to 100 mg, preferably 0.03 to 60 mg per day for an adult, and this is administered once or several times. It is preferable to administer separately.

[0019]

ACTION AND EFFECT OF THE INVENTION The medicament of the present invention is useful as a prophylactic or therapeutic drug for various symptoms due to emesis.

[0020]

[Examples] Formulation examples of the medicament of the present invention will be described below with formulation examples.

Formulation Example 1 Compound A 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 ──────────────── ───────────────────── Total amount 90.0 mg Active ingredient Compound A, lactose, corn starch and crystalline cellulose are mixed, and a part of the corn starch is used as a paste solution. Knead and granulate, and dry at 50 ° C. for 3 hours. The dried product is passed through a 24 mesh sieve, talc and magnesium stearate are added, and 90 mg of each tablet is produced using a rotary tableting machine and a punch having a diameter of 7.0 mm. Next, the tablets are coated with hydroxypropylmethylcellulose and titanium oxide as a film coating base at 5 mg per tablet.

Formulation Example 2 Compound A 10 g Sodium pyrosulfite 0.5 g Sodium chloride 18 g Distilled water for injection Total amount 2000 ml Active ingredient compound A, sodium pyrosulfite and 2 in advance
Sodium chloride, which has been sterilized by heating at 50 ° C. for 30 minutes or more, is dissolved in distilled water for injection to prepare a total volume of 2000 ml. The obtained solution was filtered through a membrane filter (pore size 0.45 μm) under a nitrogen atmosphere, 2 ml each was filled in 2 ml ampoules, air was replaced with nitrogen to remove, and after sealing, 115 ° C., 30 Sterilize for minutes.

Formulation Example 3 Compound A 0.3 g Witepsol H15 35.7 g ────────────────────────────────── ──── Total amount 36.0 g Witepsol H15 35.7 g was melted at about 40 ° C., active ingredient compound A 0.3 g was added, and the mixture was stirred and dispersed. A suppository type is prepared by uniformly mixing the suppository molds so that the weight of the suppository is 1.2 g each, to obtain a suppository containing 10 mg of Compound A in 1.2 g of each suppository.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display area // (C07D 413/12 211: 40 265: 36)

Claims (2)

[Claims] 1. A compound of the general formula [Wherein R ¹ and R ² are the same or different and each represents hydrogen or alkyl, and R ³ represents hydrogen, alkyl, phenylalkyl, or halogen, alkoxy, alkyl, nitro, amino,
Phenylalkyl substituted with 1 to 3 substituents selected from trifluoromethyl, carboxy and alkoxycarbonyl, R ⁴ and R ⁵ are the same or different and are hydrogen, halogen, alkyl, alkoxy, amino, alkanoylamino, alkyl Amino, hydroxyl, nitro, X
Is oxygen or NH, and R ⁶ is (R ⁷ is alkyl, phenylalkyl, phenoxyalkyl or halogen, alkoxy, alkyl, nitro,
Phenylalkyl or phenoxyalkyl substituted with 1 to 3 substituents selected from amino, trifluoromethyl, carboxy and alkoxycarbonyl,
R ⁸ represents hydrogen or alkoxy, and m represents 0 or 1. ) Or [Chemical 3] (R ⁹ is alkyl, phenylalkyl, or phenylalkyl substituted with 1 to 3 substituents selected from halogen, alkoxy, alkyl, nitro, amino, trifluoromethyl, carboxy, and alkoxycarbonyl, and m and n are 0, 1) is shown. ] A preventive or therapeutic agent for various symptoms due to emesis, which comprises a benzoxazine compound represented by the following formula, an optically active substance thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. 2. 6-Chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H
A preventive or therapeutic agent for various symptoms due to emesis, which comprises -1,4-benzoxazine-8-carboxamide, an optically active substance thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.