JP2834512B2 - Disease therapeutic agent containing lipoxin derivative as active ingredient - Google Patents

Description

BACKGROUND OF THE INVENTION <FIELD OF THE INVENTION> The present invention relates to leukotriene B ₄ antagonist as an active ingredient lipoxin derivatives. More specifically, the present invention relates to an anti-allergic agent, an anti-inflammatory agent, an anti-psoriatic agent, and a therapeutic agent for myocardial infarction containing a lipoxin A derivative as an active ingredient.

<Prior Art> Arachidonic acid is converted into various leukotrienes (LTs) in vivo by the action of lipoxygenase. These leukotrienes have various physiological activities, for example, LTB ₄ is chemotactic activity of leukocytes, infiltration, aggregation,
Involved in degranulation, superoxide anion production, increased adhesion to vascular endothelium, etc. (The Leukotrienes, A. Biologica
l Council Symposium, PJPiper, Raven Pres (New Yor
k)). Currently, leukotriene B ₄ asthmatic exhibiting these various physiological activities, nasal allergy, ocular inflammation, and allergic diseases such as atopic dermatitis, rheumatoid arthritis, gout, colitis, hepatitis, inflammatory nephritis, etc. It is known to be one of the causes of the disease. On the other hand, LTB ₄ in the lesions of psoriasis and acute myocardial infarction are revealed in the even of recent research that found a large amount.

The present inventors <object of the present invention>, for compounds that antagonize leukotriene B ₄ produced by lipoxygenase, Ripoxy A
As a result of intensive studies focusing on related compounds, the present inventors have found that the compound of the present invention can achieve such an object, and have reached the present invention.

<Structure and Effect of the Invention> That is, the present invention relates to the following formula [I] [Wherein, R ¹ represents a hydrogen atom or a methyl group. A leukotriene B ₄ antagonist containing an lipoxin A derivative represented by the following as an active ingredient, and an anti-allergic agent, an anti-inflammatory agent,
It is an anti-psoriatic agent and a therapeutic agent for myocardial infarction.

The compound represented by the above formula [I] in the present invention has been prepared by Ikegami et al.
It is a compound that has already been announced for its synthesis at the 108th Annual Meeting [(1988 Hiroshima) Abstracts 6E 08-11-2), but its biological activity is not known at all.

The lipoxin A derivative represented by the above formula [I] thus obtained has a leukotriene B ₄ antagonistic action,
For example suppressing migration by leukotriene B ₄ of peritoneal exudate cells obtained by casein stimulation in rats was demonstrated in the present invention.

Therefore, the compounds of the present invention are useful as leukotriene B ₄ antagonists, specifically, allergic diseases in which leukotriene B ₄ is said to be one of the causes of the disease, such as bronchial asthma,
Nasal allergies, ocular inflammation, atopic dermatitis; inflammatory diseases such as rheumatoid arthritis, gout, colitis, hepatitis, nephritis and the like; and psoriasis and acute myocardial infarction in which a large amount of leukotriene B ₄ are found in the lesions It is useful for treatment and prevention of diseases such as.

The compounds of the present invention may be administered orally or parenterally, such as rectally, subcutaneously, intramuscularly, intravenously, transdermally, or by inhalation, for the above purpose.

For oral administration, the preparation can be a solid preparation or a liquid preparation. Examples of solid preparations include tablets, pills, powders, and granules. In such solid dosage forms, the one or more active substances include at least one pharmaceutically acceptable carrier, such as commonly used sodium bicarbonate, calcium carbonate, potato starch,
It is mixed with sucrose, mannitol, carboxymethyl cellulose and the like. The preparation operation is performed according to a conventional method, and may contain additives other than those described above for preparation of the preparation, for example, lubricants such as calcium stearate, magnesium stearate, and glycerin.

Liquid preparations for oral administration include, for example, emulsions, solutions, suspensions, syrups or xyls. These formulations contain commonly used pharmaceutically acceptable carriers, such as water or liquid paraffin.

An oily base such as coconut oil, split coconut oil, soybean oil, and corn oil can also be used as a carrier.

Formulations for oral administration include, for example, solid preparations such as those described above, and enteral preparations such as, for example, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl alcohol phthalate, styrene maleic anhydride copolymer or methacrylic acid, methyl methacrylate copolymer. An enteric coating can be applied by spraying a solution of a soluble substance in an organic solvent or water to form an enteric preparation. Enteric solid preparations such as powders and granules can also be encapsulated.

Pharmaceutically acceptable carriers include other adjuvants, fragrances, stabilizers, or preservatives commonly used as needed.

The liquid formulations may also be administered in capsules made of an absorbable substance such as gelatin.

Solid preparations for rectal administration include suppositories, which contain one or more active substances and which are prepared in a manner known per se.

Formulations for parenteral administration are provided as sterile aqueous or water-insoluble formulations, suspensions, or emulsions. Non-aqueous solutions or suspensions include, for example, vegetable oils such as propyl glycol, polyethylene glycol or olive oil;
Injectable organic esters, such as ethyl oleate, are pharmaceutically acceptable carriers. Such formulations may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, and stabilizing agents. These solutions, suspensions and emulsions can be sterilized by appropriate treatment such as filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. In addition, a sterile solid preparation can be produced and dissolved in sterile water or a sterile solvent for injection immediately before use.

For inhalation, solutions or suspensions of the compounds according to the invention with conventional pharmaceutical excipients are also employed. For example, it is used as an inhalable aerosol spray. The compounds can also be administered by inhalation or other devices that allow the active compound in dry powder form to be in direct contact with the lungs.

The external preparation of the present invention can be produced in the form of an ointment, gel ointment, cream, patch or the like.

As the base used in the present invention, ointment bases generally used in external preparations, such as gel ointment bases, liquid bases and patch bases, such as white petrolatum, paraffin,
Lanolin, wax, macrogol, carboxyvinyl polymer, natural rubber-based pressure-sensitive adhesive, pressure-sensitive adhesive composed of acrylic acid ester-acrylic acid copolymer, and the like can be used.

As the dissolution aid used in the present invention, one that dissolves the main drug and promotes percutaneous absorption is used, for example, alcohols such as ethanol, isopropanol and benzyl alcohol; glycols such as propylene glycol and ethylene glycol; Propylene carbonate; fatty acid esters such as ethyl lactate, diisopropyl adipate, diethyl sebacate, isopropyl myristate, and triacetin; vegetable oils such as eucalyptus oil; and N-methylpyrrolidone. These compounds can be used alone or as a mixture of two or more.

Examples of the absorption promoter used in the present invention include pyroglutamic esters such as dodecyl pyroglutamate.

The dose of the compound of the present invention varies depending on the condition, age, sex, body weight, administration route and the like of the subject to be administered.
Usually, it can be administered in an amount of about 0.1 mg to 1000 mg-body weight / day. Such a dose can be administered once or several times a day, for example, divided into 2 to 6 times.

 Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1 Peritoneal exudate cells were collected from SD male rats (8 weeks old) by casein stimulation, and the number of leukocytes migrating for 4 hours was measured using LTB4 at ₁ mcg / ml.

1- (7-Carboxy-3,4-dihydroxy-1E-heptenyl) -2- (1-hydroxyhexyl) benzene is
6.3, 14.3, 30.9% at 10 ^-7 , 10 ^-6 and 10 ^-5 M, respectively
Showed an inhibitory effect on leukocyte migration.

Example 2 One tablet was prepared as a tablet having the following composition.

Active ingredient 1mg or 5mg Lactose 280mg Potato starch 80mg Polyvinylpyrrolidone 11mg Magnesium stearate 5mg 377mg or 381mg Mix active ingredient, lactose and potato starch,
This was uniformly wetted with a 20% solution of polyvinylpyrrolidone in ethanol, passed through a 20 mm mesh sieve, dried at 45 ° C., and again passed through a 15 mm mesh sieve.
The granules thus obtained were mixed with magnesium stearate and compressed into tablets.

1- (7-Carboxy-3,4-dihydroxy-1E-heptenyl) -2- (1-hydroxyhexyl) benzene was used as the active ingredient.

Example 3 Hard gelatin capsules were produced, one capsule containing the following composition:

Active ingredient 1 mg or 5 mg Microcrystalline cellulose 195 mg Amorphous silicic acid 5 mg 201 mg or 205 mg Finely powdered active ingredient, microcrystalline cellulose and powdered amorphous silicic acid were thoroughly mixed and filled into hard gelatin capsules.

1- (7-Carboxy-3,4-dihydroxy-1E-heptenyl) -2- (1-hydroxyhexyl) benzene was used as an active ingredient.

Example 4 A 1% cream was produced.

Take 2 g of glycerin monostearate and 400 mg of polyoxyethylene glycerin palmitate and place on a water bath
The mixture was stirred while being kept at 0 ° C, and 100 mg of the active ingredient and 20 mg of butylhydroxytoluene were added thereto and mixed well. 15 mg of methyl paraoxybenzoate was dissolved in about 6 ml of purified water, and 700 mg of glycerin was added. Add the oil layer created earlier to this aqueous layer little by little, stir well, add a small amount of purified water, and add 10 g
And

1- (7-Carboxy-3,4-dihydroxy-1E-heptenyl) -2- (1-hydroxyhexyl) benzene was used as an active ingredient.

Example 5 A 0.5% ointment was prepared as follows.

A hydrophilic ointment was manufactured according to the method of the Japanese Pharmacopoeia,
Omg was taken, and 100 mg of propylene glycol in which 50 mg of the active ingredient was dissolved was added thereto and mixed well to prepare an ointment. Hydrophilic ointment is white petrolatum 25g, sterial alcohol 22g, propylene glycol 12g, sodium lauryl sulfate 1.5g, ethyl and propyl paraoxybenzoate 0.025g each,
A product prepared by adding purified water to 0.013 g to make the total amount 100 g is used.

1- (7-Carboxy-3,4-dihydroxy-1E-heptenyl) -2- (1-hydroxyhexyl) benzene was used as an active ingredient.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Ikuo Nagata 4-2-2 Asahigaoka, Hino-shi, Tokyo Inside the Tokyo Research Center, Teijin Limited (72) Keiji Komoriya 4-2-2 Asahigaoka, Hino-shi, Tokyo No. Teijin Limited Tokyo Research Center (72) Inventor Shiro Ikegami 4-1-11 Kitanodai, Hachioji-shi, Tokyo (58) Field surveyed (Int. Cl. ⁶ , DB name) A61K 31/20 A61K 31 / 23 CA (STN) MEDLINE (STN)

Claims (5)

(57) [Claims] (1) The following formula [I] [Wherein, R ¹ represents a hydrogen atom or a methyl group. Leukotriene B ₄ antagonist as an active ingredient lipoxin A derivative represented by the. 2. An antiallergic agent comprising the lipoxin A derivative represented by the above formula [I] as an active ingredient. 3. An anti-inflammatory agent comprising the lipoxin A derivative represented by the above formula [I] as an active ingredient. 4. An anti-psoriatic agent comprising a lipoxin A derivative represented by the above formula [I] as an active ingredient. 5. A therapeutic agent for myocardial infarction comprising a lipoxin A derivative represented by the above formula [I] as an active ingredient.