JPH03215421A - Disease treating agent containing aromatic derivative as active ingredient - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a therapeutic agent for diseases caused by hexadecimal extrinsic coagulation reaction, which contains an aromatic derivative as an active ingredient.

More specifically, tissue thromboplastin (tissue thromboplastin)
The present invention relates to a therapeutic agent for DIC containing an aromatic derivative as an active ingredient and having a release-inhibiting effect.

Prior art> Tissue thromboblastin can be used in most living tissues, especially the brain and lungs. It is present in large amounts in dense tissues of the circulatory system, such as the placenta. This tissue thromboplastin is a glycoprotein consisting of a lipid part and a protein part, and is a coenzyme protein that forms a complex with factor ①, which is involved in the blood coagulation system, and promotes the activation of factor X and factor ②.

Tissues affected by various diseases such as malignant tumors and trauma. Surgery. When this tissue thromboplastin is released into the blood due to severe hepatitis, acute leukemia (blood cell disorder), Durham-negative sepsis (endotoxin release), etc., blood coagulation becomes hexadecimal and DIC (disseiinated intravascuum) occurs.
It is a trigger for diseases that occur due to the acceleration of so-called extrinsic coagulation reactions such as lar coagulation and diffuse intravascular coagulation. Among these, DIC is a serious disease that causes damage to various organs, such as shock. Respiratory failure. kidney failure. Hepatic dysfunction, peripheral necrosis, and impaired consciousness. Involved in diseases such as digestive disorders.

<Objective of the Invention> As a result of intensive research into compounds that suppress the release of tissue thromboblastin, the present inventors discovered that the compound of the present invention can achieve this objective, and thus arrived at the present invention. .

<Structure and Effects of the Invention> The present invention relates to the following formula [I] [wherein R1 is a hydrogen atom]. Represents a methyl group. The present invention relates to a therapeutic agent for diseases caused by hexadecimal extrinsic coagulation reaction, which contains an aromatic derivative represented by the following as an active ingredient.

The compound represented by the above formula [I] in the present invention is a compound already proposed by the present inventors (Japanese Patent Laid-Open No. 63-270634), but it is not known that this compound inhibits the release of tissue thromboplastin (tissue factor). Not known at all.

According to the present inventors, it has been revealed that the compound represented by the above formula [I] suppresses the release of tissue thromboblastin from macrophages caused by LPS (lipobolysaccharide).

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

For oral administration, solid or liquid preparations can be provided. Examples of solid preparations include tablets. pills,
Available in powder or granule form. In such solid formulations, one or more active substances are present in at least one pharmaceutically acceptable carrier, such as the commonly used sodium bicarbonate. Carbonate, potato starch, sucrose. Mannitol. Mixed with carboxymethyl cellulose, etc. Preparation operations are carried out according to conventional methods.
It may also contain additives for formulation other than those mentioned above, such as lubricants such as calcium stearate, magnesium stearate, and glycerin.

Liquid preparations for oral administration include, for example, emulsions, solutions,
Contains suspending agents, thickening agents, and xyl agents. These formulations include commonly used pharmaceutically acceptable carriers such as water or liquid paraffin.

Coconut oil, split coconut oil. Oily bases such as soybean oil and corn oil can also be used as carriers.

For oral administration, formulations can be prepared, for example, in solid formulations such as those mentioned above, such as cellulose acetate phthalate, hydroxybuvir methylcellulose phthalate, polyvinyl alcohol phthalate. It is also possible to formulate an enteric preparation by applying an enteric coating by spraying an organic solvent or an aqueous solution of an enteric substance such as a styrene maleic anhydride copolymer or a methacrylic acid or methyl methacrylate copolymer. Powder. Enteric-coated solid preparations such as granules can also be wrapped in capsules.

The pharmaceutically acceptable carrier includes other adjuvants and fragrances that are normally used as necessary. Contains stabilizers or preservatives.

The liquid preparation may also be administered in a capsule made of an absorbable material such as gelatin.

Solid preparations for rectal administration include suppositories containing one or more active substances and prepared by methods known per se.

Preparations for parenteral administration are presented as sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Non-aqueous solutions or suspensions include, for example, probyl glycol. Polyethylene glycol or a vegetable oil, such as olive oil, and an injectable organic ester, such as ethyl oleate, are pharmaceutically acceptable carriers. Such preparations also contain preservatives. Auxiliary agents such as wetting agents, emulsifying agents, dispersing agents, and stabilizing agents may be included. These solutions, suspensions and emulsions can be prepared by, for example, filtration through bacteria retention filters;
Sterilization can be achieved by appropriately adding a disinfectant or performing treatments such as irradiation. Alternatively, a sterile solid preparation can be prepared and used by dissolving it in sterile water or a sterile injection solvent immediately before use.

Solutions or suspensions of the compounds of the invention with customary pharmaceutical excipients may also be used for inhalation. For example, it is used as an inhalable aerosol spray. The compound can also be administered by an inhaler or other device that brings the active compound in dry powder form into direct contact with the lungs.

The external preparation of the present invention is an ointment. Gel ointment. cream,
It can be manufactured in the form of a patch or the like.

The bases used in the present invention include ointment bases, gel ointment bases, liquid bases, and patch bases that are generally used for external preparations. For example, white petrolatum. Paraffin, lanolin, wax, macrogol. Carboxyvinyl polymer, natural rubber adhesive. An adhesive made of an acrylic acid ester-acrylic acid copolymer can be used.

The solubilizing agent used in the present invention dissolves crude drugs,
Substances that promote transdermal absorption are used, such as ethanol. Alcohols such as isopropanol and benzyl alcohol; glycols such as brobylene glycol and ethylene glycol; brobylene carbonate: ethyl lactate, diisoprovir adibate, diethyl sebacate. Isoprovil myristate. Fatty acid esters such as triacetin:
Vegetable oils such as eucalyptus oil; N-methylbiolidone and the like. These compounds can be used alone or as a mixture of two or more.

Examples of the absorption enhancer used in the present invention include biroglutamic acid esters such as biroglutamic acid dodecyl ester.

The amount of administration of the compound of the present invention varies depending on the condition, age, sex, body weight, route of administration, etc. of the subject to be administered, but it is usually administered in an amount of about 0.1III to 1000 η/K/day. can. Such a dose may be administered once or several times a day, for example, in 2 to 6 divided doses.

In the present invention, the aromatic derivative represented by the formula [I] is added to the aromatic derivative represented by the formula [I].
) was found to have the effect of suppressing the release of

The compounds of the present invention are therefore useful in treating such conditions where such inhibition would be beneficial. Tissue thromboblastin destroys tissues (malignant tumors).
Trauma, surgery, burns. Placental abruption, severe hepatitis. DI is released by pancreatic disease) and blood cell destruction (leukemia, Durham-negative sepsis, platelet destruction, hemolysis) and triggers DIC.DI
In G, the coagulation system becomes hexadecimal, causing thrombotic organ damage (brain, heart, kidneys, lungs, pancreas, intestines, liver), and on the other hand, coagulation system factors are consumed, causing bleeding symptoms. do. Therefore, the aromatic derivatives of the present invention are further useful in the treatment and prevention of diseases derived from DIC.

Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 (E)-N- (2-methoxycarbonylphenyl)-
8-(2-naphthyl)-5.6-trans-5.6-
methanol 7-octenamide 1×10″5M or 1
It was added to macrophages at a concentration of X10→M and incubated for 1 hour. Then LPS (1 μg/ad!
) and cultured for 6 hours. This compound suppresses the production of tiSSIIe lactor in a concentration-dependent manner,
0-5Mr56%. I X10-Mt' 100% inhibition.

Example 2 Tablets were manufactured, each having the following composition.

Active Ingredients Lactose Potato Starch Polyvinylpyrolidone 1IIIg or 5mg 280■ 80Ilg 111I9 Mix the active ingredient, lactose and potato starch, evenly wet it with a 20% ethanol solution of polyvinylpyrrolidone and pass through a 20IIM mesh sieve. through 4
It was dried at 5° C. and passed through a 15-diameter mesh sieve again. The granules thus obtained were admixed with magnesium stearate and compressed into tablets.

(E)-N-(2-methoxyluponinolephenyl)-8-(2-naphthinole)5,6-trans-5,6-methanol-7-octenamide was used as the active ingredient.

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

Active Ingredient Microcrystalline Cellulose 1 or 5 Ilg 1 95ay The active ingredient in finely powdered form, microcrystalline cellulose and unpressed amorphous silicic acid were thoroughly mixed and packed into hard Seratin capsules.

(E)-N-(2-methoxycarbonylphenyl)-8-(2-naphthyl)5.6-trans-5,6-methanol-7-octenamide was used as the active ingredient.

Example 4 A 0.5% ointment was prepared as follows.

Hydrophilic ointment is manufactured according to the manufacturing method of the Japanese Pharmacopoeia, and this is
0 #iF was taken, and 100 μl of brobylene glycol in which 50 μl of the active ingredient had been dissolved was added and mixed well to prepare an ointment. Hydrophilic soft blue is made from 25g of white petrolatum. 22 g of stearyl alcohol, 12 g of brobylene glycol, 1.59 g of sodium lauryl sulfate, 0.0259 g each of ethyl hydroxybenzoate and provil. 0.0139 and purified water to make a total amount of 100 g.

(E)-N-(2-methoxycarbonylphenyl)-8-(2-naphthyl)-5.6-trans-5.6-methanol-7-octenamide was used as the active ingredient.

Example 5 A 1% cream was produced by the following method.

Take 400 η of glycerin monostearate 21 polyoxyethylene glycerin balmitic acid ester, stir while keeping it at 60°C on a water bath, and add 100 j of the active ingredient to this.
lj and 20 μm of butylated hydroxytoluene were added and mixed well. Approximately 6a1 of purified water! Methyl oxybenzoate 1
5 μm was dissolved and 700 μg of glycerin was added. The previously prepared oil layer was added little by little to this aqueous layer and stirred well, and a small amount of purified water was added to bring the total amount to 109.

(E)-N-(2-methoxyluponylphenyl)-8-(2-naphthyl)-5.6-trans-5.6-methanol-7-octenamide was used as the active ingredient.

Claims (1)

[Claims] 1. The following formula [I] ▲There are numerical formulas, chemical formulas, tables, etc.▼...[I] [In the formula, R^1 represents a hydrogen atom or a methyl group. A therapeutic agent for diseases caused by enhancement of an extrinsic coagulation reaction, which contains an aromatic derivative represented by the following as an active ingredient. 2. DIC (disseminated intravasa) is a disease that develops due to enhancement of extrinsic coagulation reactions.
Claim 1
A therapeutic agent for the disease described. 3. The main action of the aromatic derivative represented by the above formula [I] in disease treatment is tissue thromboplastin (tissue thromboplastin).
3. The disease therapeutic agent according to claim 1 or 2, which has an effect of inhibiting the release of e factor.