JPH04283514A - Blood vessel neogensis inhibitor - Google Patents

Abstract

PURPOSE:To obtain a blood vessel neogensis inhibitor effective preventing and treating diseases caused by abnormal multiplication of blood vessel, having relatively low toxicity, small accumulation of toxicity by continuous administration, comprising 15-deoxyspagalin or a salt thereof as an active ingredient. CONSTITUTION:A blood vessel neogensis inhibitor comprising N-[4-(3- aminopropane)aminobutyl]-2-(7-guanidinoheptanamido)-2-hydroxyethanamide (15-deoxyspergualin) or a pharmaceutically acceptable salt thereof as an active ingredient. The compound is administered or blended with an excipient or a carrier, made into an injection, oral agent or suppository and administered and a dose is 1-100mg/kg day in the case of parenteral administration and 5-500mg/kg day in oral administration.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to N-[4(3-aminopropane)aminobutyl]-2-(7-guanidinoheptanamide)-2-hydroxyethanamide (15-deoxyspergarin) or its pharmacology. This drug relates to an angiogenesis inhibitor containing an acceptable salt as an active ingredient.As a pharmaceutical, it can be used to treat diseases accompanied by abnormal growth of blood vessels, such as rheumatoid arthritis, diabetic retinopathy, various tumors, retinopathy of prematurity, and the elderly. It is expected to be a preventive or therapeutic agent for sexual macular degeneration, excessive scar formation during wound healing, and abnormal cell proliferation.

0002

BACKGROUND OF THE INVENTION Known substances having an angiogenesis inhibiting effect include, for example, protamine, indomethacin, medroxyprogesterone, a combination of cortisone and heparin, bovine cartilage, and a crude extract of aortic wall.

0003

[Problems to be Solved by the Invention] However, there are currently no substances that have an angiogenesis inhibitory effect that have been put into practical use as pharmaceuticals, and the development of new angiogenesis inhibitors is expected.

0004

[Means for Solving the Problems] As a result of various studies, the present inventors discovered that 15-deoxyspargarin has a new angiogenesis inhibitory effect. That is, the present invention relates to a novel angiogenesis inhibitor characterized by containing 15-deoxyspargarin or a pharmacologically acceptable salt thereof (hereinafter abbreviated as the present compound) as an active ingredient.

[0005] This compound is already a known compound (Japanese Unexamined Patent Publication No. 1988-
62152) and is also known for its antitumor activity and immunosuppressive effect (European Patent No. 83).
104 712.1 and 85 11
4 042.6). 15-deoxyspargarin forms a salt with an acid, and the acid for forming the salt may be either an inorganic acid or an organic acid as long as it is pharmacologically acceptable. As the inorganic acid, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc. are preferable, and hydrochloric acid is more preferable. Examples of organic acids include acetic acid, propionic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, glutaric acid, citric acid, benzelsulfonic acid, toluenesulfonic acid, methanesulfonic acid,
Ethanesulfonic acid, propanesulfonic acid, aspartic acid, glutamic acid, etc. are preferred.

When the present compound is used as an angiogenesis inhibitor, it is administered alone or mixed with an excipient or carrier as an injection, oral preparation, or suppository. Pharmaceutically acceptable excipients and carriers are selected, and their types and compositions are determined by the route and method of administration. For example, as a liquid carrier water, alcohols or animal or vegetable oils such as soybean oil, peanut oil, sesame oil, mineral oil;
Further, as solid carriers, sugars such as maltose and sucrose; amino acids, cellulose derivatives such as hydroxypropyl cellulose, and organic acid salts such as magnesium stearate are used. In the case of injections, physiological saline, various buffer solutions, saccharide solutions such as glucose, inositol, and mannitol; and glycols such as ethylene glycol, propylene glycol, and polyethylene glycol are generally preferred. In addition, it can be made into a lyophilized preparation with excipients such as saccharides such as inositol, mannitol, glucose, mannose, maltose, lactose, and sucrose; and amino acids such as phenylalanine, and then administered in a suitable injection solvent such as sterile water. , physiological saline, glucose solution,
It can also be administered by dissolving it in a liquid for intravenous administration, such as an electrolyte solution or an amino acid solution.

The content of the present compound in the preparation varies depending on the preparation, but is usually 0.1 to 100% by weight, preferably 1 to 98% by weight. For example, in the case of an injection solution, the active ingredient content is usually 0.1 to 50% by weight, preferably 1 to 10% by weight. When administered orally, it is used in the form of tablets, capsules, powders, granules, liquids, dry syrups, etc. together with the solid carrier or liquid carrier. Capsules, tablets, granules and powders generally contain from 1 to 100% by weight, preferably from 3 to 95% by weight of the compound.

[0008] The dose is determined depending on the patient's age, weight, symptoms, therapeutic purpose, etc., but the therapeutic dose is generally 1 to 100 mg/kg/day for parenteral administration and 5 to 500 mg/kg for oral administration.
g/kg/day. This compound has relatively low toxicity;
It is also characterized by low toxicity accumulation upon continuous administration. The 50% lethal dose LD50 when this compound is intraperitoneally administered once to mice is 25 to 50 mg/kg.

[0009]

[Effect of the Invention] The angiogenesis inhibitory effect of this compound was demonstrated by a test on the epichorioallantoic vascular network using fertilized chicken eggs. This will be explained below using test examples.

Test Example [Method] One silicone ring (inner diameter 3 mm, outer diameter 5 mm) was placed on the chorioallantoic membrane of a fertilized chicken egg (4 days after fertilization), and a certain amount of the present compound (0. 1, 1, 10μg/
egg) to 1% methylcellulose (20-30cps
)/dissolved in physiological saline and added. 20 days later
% fat emulsion (trade name, Intralipos-Midori Juji) was injected into the chorioallantoic membrane. The vascular network on the chorioallantoic membrane was observed under a microscope, and the avascular network with a diameter of 3 mm or more was detected.
When ne (part without blood vessels) was shown, the angiogenesis inhibitory activity was determined to be positive. [Results] ID50 (50% inhibition rate); 0.48 μg/e
gg

[0011]

[Examples] The present invention will be specifically explained below using examples. Example 1 Freeze-dried injection Purified water was added to 30 parts by weight of the present compound (hydrochloride) to make a total volume of 2,000 parts. After dissolving the solution, it was filtered through a Millipore filter G.
Filter for sterilization using S type. 2g of this filtrate
The mixture was placed in a 1-liter vial and lyophilized to obtain a lyophilized injection containing 30 mg of the present compound (hydrochloride) per vial.

Example 2 Granules: 50 parts by weight of the present compound (hydrochloride), 600 parts of lactose, 330 parts of crystalline cellulose, and 2 parts of hydroxypropyl cellulose.
0 parts were mixed well, compressed using a roll compactor (Roller CompactorTM), and crushed to form 16 mesh and 6
It was filtered to fit between 0 mesh and made into granules.

Example 3 Tablet 30 parts by weight of the present compound (hydrochloride), 120 parts of crystalline lactose, 147 parts of crystalline cellulose, and 3 parts of magnesium stearate.
A portion of the mixture was compressed into tablets using a V-type mixer to obtain tablets each weighing 300 mg.

Claims (1)

[Claims] 1. A novel angiogenesis inhibitor comprising 15-deoxyspargarin or a pharmacologically acceptable salt thereof as an active ingredient.