JP3064027B2 - Angiogenesis inhibitor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to N- [4 (3-aminopropane) aminobutyl] -2- (7-guanidinoheptanamide) -2-hydroxyethanamide (15-deoxyspagarine) or its pharmacology. The present invention relates to an angiogenesis inhibitor containing a permissible salt as an active ingredient, and as a drug, a disease accompanied by abnormal growth of blood vessels, for example, rheumatoid arthritis, diabetic retinopathy, various tumors, prematurity retinopathy, and the elderly It is expected as a prophylactic or therapeutic agent for macular degeneration, excessive scar formation during wound healing, and abnormal cell proliferation.

[0002]

BACKGROUND OF THE INVENTION Substances having angiogenesis inhibitory activity include, for example, protamine, indomethacin, medroxyprogesterone, a combination of cortisone and heparin, bovine cartilage,
A crude extract of the aortic wall and the like are known.

[0003]

However, there is no substance having an inhibitory effect on angiogenesis which is currently in practical use as a drug, and development of a new angiogenesis inhibitor is expected.

[0004]

The inventors of the present invention have conducted various studies and found that 15-deoxyspagarin has a new angiogenesis inhibitory action. That is, the present invention relates to a novel angiogenesis inhibitor comprising 15-deoxyspagarin or a pharmacologically acceptable salt thereof (hereinafter abbreviated as the present compound) as an active ingredient.

This compound is a known compound (JP-A-58-1983).
No. 62152) and its antitumor activity and immunosuppressive action are also known (European Patent No. 83).
No. 104 712.1 and No. 85 114 04
2.6). 15-Deoxyspagarin forms a salt with an acid, and the acid for forming the salt may be any of an inorganic acid and an organic acid as long as it is pharmacologically acceptable.
As the inorganic acid, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like are preferable, and hydrochloric acid is more preferable. Examples of the organic acid include acetic acid, propionic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, glutaric acid, citric acid, benzylsulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and propanesulfonic acid. , Aspartic acid, glutamic acid and the like.

When the present compound is used as an angiogenesis inhibitor, it is administered as an injection, oral preparation, suppository or the like, alone or in combination with an excipient or carrier. Pharmaceutically acceptable excipients and carriers are selected, and their type and composition are determined by the administration route and administration method. For example, water, alcohols or animal and vegetable oils such as soybean oil, peanut oil, sesame oil, and mineral oil as liquid carriers; sugars such as maltose and sucrose as solid carriers; amino acids; cellulose derivatives such as hydroxypropyl cellulose; magnesium stearate; And the like are used. In the case of injections, physiological saline, various buffers, sugar solutions such as glucose, inositol and mannitol; and glycols such as ethylene glycol, propylene glycol and polyethylene glycol are generally desirable. In addition, a lyophilized preparation is prepared together with excipients such as inositol, mannitol, glucose, mannose, maltose, lactose, sucrose and the like; anomiic acid such as phenylalanine and the like, and then used as a lyophilized preparation at the time of administration. Alternatively, it can be administered by dissolving in a liquid for intravenous administration such as physiological saline, glucose solution, electrolyte solution and 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, the active ingredient is usually contained in an amount of 0.1 to 50% by weight, preferably 1 to 10% by weight. In the case of oral administration, it is used in the form of tablets, capsules, powders, granules, liquids, dry syrups and the like together with the solid carrier or liquid carrier. Capsules, tablets, granules, powders generally contain 1 to 100% by weight, preferably 3 to 95% by weight, of the compound.

The dose is determined according to the patient's age, body weight, symptoms, treatment purpose and the like. The therapeutic dose is generally 1 to 100 mg / kg / day for parenteral administration and 5 to 500 mg / kg for oral administration.
・ It is day. The compound is characterized by relatively low toxicity and low accumulation of toxicity upon continuous administration.
The 50% lethal dose LD50 when the compound is administered once intraperitoneally to mice is 25 to ₅₀ mg / kg.

[0009]

EFFECT OF THE INVENTION The angiogenesis inhibitory effect of the present compound was proved by a test of the suprachondrial vascular network using fertilized chicken eggs. Hereinafter, a description will be given using test examples.

Test Example [Method] One silicon ring (inner diameter 3 mm, outer diameter 5 mm) was placed on the chorioallantoic membrane of a fertilized chicken egg (four days after fertilization), and a fixed amount of the compound (0.1 each) was placed in the ring. 1, 1, 10 μg / eg
g) was dissolved in 1% methylcellulose (20-30 cps) / physiological saline and added. Two days later, a 20% fat emulsion (trade name, Intralipos-Midori Cross) was injected into the chorioallantoic membrane. The vascular network on the chorioallantoic membrane is observed under a microscope, and an avascular zone (a part without blood vessels) with a diameter of 3 mm or more.
Indicates that the angiogenesis inhibitory activity was positive. [Results] ID ₅₀ (50% inhibition rate); 0.48 μg / egg

[0011]

The present invention will be specifically described below with reference to examples. Example 1 Lyophilized Injection Purified water was added to 30 parts by weight of the present compound (hydrochloride) to make the total amount 2000 parts, and the mixture was dissolved.
It is sterilized and filtered using S type. 2 g of this filtrate is 10 ml
And freeze-dried to give a freeze-dried injection containing 30 mg of the present compound (hydrochloride) in one vial.

Example 2 Granules 50 parts by weight of the present compound (hydrochloride), 600 parts of lactose, 330 parts of crystalline cellulose and hydroxypropyl cellulose 2
0 parts were mixed well, compressed using a roll-type compactor (Roller Compactor ^™ ), crushed and mixed with 16 mesh and 60 mesh.
Filtration was performed so as to enter between meshes to obtain granules.

Example 3 Tablets 30 parts by weight of the present compound (hydrochloride), 120 parts of crystalline lactose, 147 parts of crystalline cellulose and magnesium stearate 3
The part was tableted with a V-type mixer to obtain a tablet of 300 mg per tablet.

Claims (1)

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