JPH0881374A - Skin pruritus preventive/therapeutic agent - Google Patents

Abstract

PURPOSE: To obtain an agent containing a compound having serotonin-3 receptor antagonistic activity and useful for preventing/therapeutic skin pruritus involved in systemic diseases such as chronic renal failure, hepatic cholestasia or hematopoietic disorder. CONSTITUTION: This skin pruritus preventive/therapeutic agent contains, as active ingredient, a benzoxazine compound of formula I [R<1> and R<2> are each H or an alkyl; R<3> is H, a phenylalkyl, alkyl, etc.; R<4> and R<5> are each H, a halogen, alkyl, alkoxyl, amino, etc.; R<6> is a group of formula II ((m) is 0 or 1) or formula III (R<7> is an alkyl, phenylalkyl, phenoxyalkyl, etc.; R<8> is H or an alkoxyl), etc.], an optically active form or a medicinally permissible salt thereof, e.g. 6-chloro-3,4-dihydro-4-methyl-3-oxo-N-(3-quinuclidinyl)-2H-1,4- benzoxazine-8-carboxamide. It is preferable that the active ingredient content of this medicinal agent be 1-50wt.% or 0.2-20wt.% for oral administration or injection, respectively.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a medicine, especially a preventive or therapeutic drug for pruritus cutanea.

[0002]

2. Description of the Related Art Japanese Patent Publication No. 5-73752 discloses gastric hyperactivity, anti-emetic action and / or serotonin-3.
It has receptor-blocking activity and prevents or treats gastrointestinal disorders such as dyspepsia, delayed gastric emptying, peptic ulcer, and / or migraine, cluster headache, arrhythmia, or administration of anticancer drugs such as cisplatin. Benzoxazine compounds useful for the treatment of radiation-induced nausea or vomiting, or disorders of the central nervous system such as anxiety or psychosis,
The optically active forms or pharmaceutically acceptable salts thereof are disclosed.

By the way, chronic renal failure, hepatic cholestasis,
Pruritus is known to be associated with systemic diseases such as hematopoietic disorders, endocrine disorders, and malignant tumors [Lorette, G. et al., Drugs, Vol. 39, 2].
18-223 (1990)]. Although histamine is considered as one of the causative agents of pruritus, antihistamines are clinically effective for some pruritus but cannot suppress all of them. Serotonin is known to cause itching by intradermal administration (Journal of Dermatol. Sci.)
No. 4, p. 55 (1992)]. Recently, when pruritus-associated chronic hepatitis patients were treated with the serotonin-3 receptor antagonist ondanserotone, it was observed that pruritus disappeared [The Lancet No. 341, 1,
277 (1993)]. From this, the involvement of serotonin as a pruritus-causing substance is presumed, and serotonin-
The usefulness of 3 receptor antagonists was shown.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a preventive or therapeutic drug for pruritus dermatitis associated with systemic diseases such as chronic renal failure, hepatic cholestasis, hematopoietic disorders, endocrine diseases and malignant tumors. The purpose is to do.

[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 with 1 to 3 substituents selected from R ³ , R ⁴ 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]

[Chemical 5]

(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.). ] It is related with the prophylactic or therapeutic agent of the pruritus dermatitis, which contains as an active ingredient the benzoxazine compound represented by these, its optically active substance, and a pharmaceutically acceptable salt.

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 and suppositories. 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]

The compound used in the present invention suppressed the pruritus-induced scratching behavior in the animal test.
Therefore, the medicament of the present invention is useful for pruritus dermatitis associated with systemic diseases such as chronic renal failure, hepatic cholestasis, hematopoietic disorders, endocrine diseases, and malignant tumors, and the prevention or treatment of such symptoms. It can be used as a medicine.

[0020]

[Examples] Formulation examples of the drug of the present invention will be illustrated below.

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.

[0024]

The efficacy and pharmacological effect of compound A will be explained by the following experiments.

Experimental Example Effect on Serotonin-Induced Scratching Behavior 10 μg of serotonin was intradermally administered to ddY mice weighing about 30 g, and the number of scratching behavior on the hind limb to the administration site was measured until 60 minutes later. The test drug was administered to the same site at the same time as serotonin.

──────────────────────────────────── Test drug Dose (pmol id) Number of scratching actions Suppression rate (%) ──────────────────────────────────── Non-administration group 52.1 ± 9. 1 Compound A 10 34.8 ± 5.3-33 Compound A 100 28.7 ± 5.7 ^* -45 ───────────────────────── ──────────── (Numerical values in the table represent mean ± standard error. * Indicates significance at a risk rate of 0.05% or less.)

From the results in the table, 100 pmol of compound A
It was clarified that the intradermal administration of erythrocytes suppressed the serotonin-induced scratching behavior. Therefore, the medicament of the present invention is useful for the prevention or treatment of pruritus dermatitis associated with systemic diseases such as chronic renal failure, hepatic cholestasis, hematopoietic disorders, endocrine diseases and malignant tumors.

─────────────────────────────────────────────────── ─── 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 prophylactic or therapeutic drug for pruritus dermatitis, which comprises as an active ingredient a benzoxazine compound represented by the following formula, an optically active substance thereof, or a pharmaceutically acceptable salt thereof. 2. 6-Chloro-3,4-dihydro-4-methyl-3-oxo-N- (3-quinuclidinyl) -2H
A prophylactic or therapeutic drug for pruritus dermatitis, which comprises -1,4-benzoxazine-8-carboxamide, an optically active substance thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.