JPH03287537A - Antiarteriosclerosis - Google Patents

Abstract

PURPOSE:To obtain an antiarteriosclerosis containing 2-alkynyladenosine as an active ingredient and reduced in problems such as side effects. CONSTITUTION:The aimed agent containing a compound, e.g. 2-octyladenosine, expressed by the formula (n is 0-15), having depressing action and antiallergic action and useful as a treating and preventing agent for ischemic heart or brain disease as an active ingredient. The agent can be orally or parenterally administered in order to treat or prevent arteriosclerosis of mammal including human and the dose is normally in the range of 0.1-100mg/day.body.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention relates to an anti-arteriosclerotic agent (arteriosclerotic agent) containing 2-alkynyladenosine as an active ingredient. 2-, which is an integer from ○ to 15]
Alkynyladenosine has a hypotensive effect [(A) JP-A-62-99395 (JP-A-1-33477), (B) JP-A-62-99330] and an anti-allergic effect [(C) Chem. ,Pharm,Bull
, 33 (4), 1766-69 (1985
)].

In addition, the present inventors have discovered that 2-alkynyladenosine is useful as a therapeutic/preventive agent for ischemic diseases of the heart or brain, and have filed a patent application (PCT/JP 8
9101158), these documents do not describe that 2-alkynyladenosine is useful as an anti-arteriosclerosis agent, nor do they contain any statement suggesting this.

On the other hand, several compounds are known as adenosine derivatives and adenosine analogs that have anti-arteriosclerotic effects (
JP-A-47-10383, JP-A-60-69496, JP-A-63-135384, JP-A-63-2011
No. 96, JP-A No. 1-1265100, JP-A No. 2-69
496 publications), these documents contain
Compounds having an alkynyl group in this position are not disclosed.

The main anti-arteriosclerotic agents currently used as pharmaceuticals include clofibrates (clofibrate, simfibrate, alfibrate, etc.), nicotinic acids (comol, tocopherol nicotinate, etc.), dextran sulfate, pantethine, Sitosterol preparations (such as soysterol), anabolic steroids (
Flazabol, oxandrolone, etc.) are known, but they are not necessarily satisfactory in terms of side effects.

Therefore, the problem to be solved by the present invention is to find a compound among adenosine derivatives that has few problems such as side effects and is useful as an anti-arteriosclerotic agent, and to find a compound that is useful as an anti-arteriosclerotic agent, and to The objective is to find new uses for alkynyl adenosine.

[Means for solving problems]

In the course of various studies on the biological activities of adenosine derivatives, the present inventors discovered a hitherto unknown anti-arteriosclerosis effect of 2-alkynyladenosine represented by formula (1) and completed the present invention. It's arrived.

That is, the present invention provides a 2-
The present invention provides an anti-arteriosclerosis agent characterized by containing alkynyl adenosine or a salt thereof as an active ingredient.

2-alkynyladenosine represented by the general formula (1) (hereinafter sometimes referred to as the "compound of the present invention"), which is the active ingredient of the drug of the present invention, is a known compound, for example, the above-mentioned documents (A), (B), The base can be formed according to the method described in (C).

A drug containing the compound of the present invention as an active ingredient is used as a drug for treating or preventing arteriosclerosis in mammals including humans.

The compounds of the present invention can be administered orally or parenterally together with conventional pharmaceutically acceptable carriers for treatment or prevention.

Oral dosage forms include powders, granules, and capsules.

It can be a solid preparation such as a tablet or a liquid preparation such as a syrup or elixir. In addition, parenteral preparations include injections, rectal preparations, skin external preparations, and inhalation preparations. These preparations are prepared according to conventional methods by adding pharmaceutically acceptable formulation auxiliaries to the compound of the present invention.

Furthermore, it is also possible to prepare a long-lasting preparation using known techniques.

To produce a solid preparation for oral administration, the compound of the present invention is mixed with excipients such as lactose, starch, crystalline cellulose, calcium lactate, calcium hydrogen phosphate, magnesium aluminate metasilicate, and silicic anhydride to form a powder. or
Furthermore, if necessary, a binder such as sucrose, hydroxypropylcellulose, or polyvinylpyrrolidone, or a disintegrant such as carboxymethylcellulose or carboxymethylcellulose calcium is added, and wet or dry granulation is performed to obtain granules. To manufacture tablets, these powders and granules may be compressed as they are or with the addition of a lubricant such as magnesium stearate or talc;
These granules or tablets can also be coated with an enteric base such as hydroxypropyl methylcellulose phthalate or methyl methacrylate copolymer to form an enteric-coated formulation, or coated with ethylcellulose, carnauba wax, hydrogenated oil, etc. to form a sustained-release formulation. . Furthermore, in order to manufacture capsules, powders or granules can be filled into hard capsules, or the compound of the present invention can be dissolved in glycerin, polyethylene glycol, sesame oil, olive oil, etc., and then coated with a gelatin film, and soft capsules can be prepared. You can also.

To produce a liquid preparation for oral administration: 1. The compound of the present invention and a sweetener such as white sugar, sorbitol, or glycerin are dissolved in water to form a clear syrup, or essential oils, ethanol, etc. are added to form an elixir. Alternatively, gum arabic, tragacanth, polysorbate 80, sodium carboxymethylcellulose, etc. may be added to form an emulsion or suspension. Flavoring agents, coloring agents, preservatives, etc. may be added to these liquid preparations as desired.

To produce an injection, the compound of the present invention may be mixed with hydrochloric acid, sodium hydroxide, lactic acid, sodium lactate, phosphoric acid, etc. as necessary.
pH 1 of sodium hydrogen, sodium dihydrogen phosphate, etc.
11 Dissolved in distilled water for injection with tonicity agents such as sodium chloride and glucose, filtered aseptically and filled into ampoules, or further added with mannitol, dextrin, cyclodextrin, gelatin, etc. and vacuum non-freeze-dried. However, it may also be used as an injection that dissolves before use. It is also possible to add lecithin, polysorbate 80, polyoxyethylene hydrogenated castor oil, etc. to the compound of the present invention and emulsify it in water to prepare an emulsion for injection.

To produce a rectal preparation, 1. The present invention is heated and melted together with a base material such as tri-, di-, or mono-glyceride of cocoa fatty acids, polyethylene glycol, etc., poured into a mold and cooled, or the compound of the present invention is After dissolving it in polyethylene glycol, soybean oil, etc., it may be covered with a gelatin film.

To produce a skin external preparation, the compound of the present invention is added to white petrolatum, beeswax, liquid paraffin, polyethylene glycol, etc., and if necessary, heated and kneaded to form an ointment, or rosin, acrylic acid alkyl ester, etc. After kneading it with an adhesive such as a polymer, it is spread on a nonwoven fabric such as polyethylene to form a tape.

To produce an inhalant, the compound of the present invention is dissolved or dispersed in a propellant such as chlorofluorocarbon gas, and the mixture is filled into a pressure-resistant container to form an aerosol.

The dosage of the compound of the present invention varies depending on the patient's age, weight, and pathological condition, but is usually about 0.1 to 1 per patient per day.
00■, and is preferably administered in a single dose or divided into several doses.

[Action and effect of the invention]

The compound of the present invention has anti-arteriosclerotic activity. That is, in an animal experiment using experimental animals in which arteriosclerosis was artificially induced (see Experimental Example 1), a symptom-improving effect was observed. It is generally accepted that the effectiveness of such experiments can be similarly applied to arteriosclerosis in mammals including humans (Jayakocly, L.
, Br, J., Pharmacol.

94, 335-346 (1988);
ne, J.

A. et al., Am. J. Physiol.
256: C591-C597 (1989)). Furthermore, it has been confirmed that the compound of the present invention has extremely low toxicity in an acute toxicity test (see Experimental Example 2).

Experimental Example 1 Anti-arteriosclerotic effect Male Wistar rats (6 rats per group) were fed a high-cholesterol diet (feed supplemented with 2% cholesterol and 0.5% cholic acid) and raised for 8 weeks (high-cholesterol vinegar).

On the other hand, male Wistar rats (6 rats per group) were raised in the same manner on a high-cholesterol diet, and 2-octynyladenosine (-formula (1), n=5) 1 .mu./kg was orally administered once a day (drug administration group).

In addition, as a control group, rats were fed a normal diet without the addition of cholesterol and cholic acid, and were raised in the same manner.

The thoracic aortas of each group of rats raised as described above were removed, ring specimens were prepared, and vascular reactivity was examined using the following method. That is, each ring specimen was suspended in an organ bath containing Krebs-Henseleit solution to which a mixed gas of 95% oxygen and 5% carbon dioxide was aerated.
Ring specimens precontracted with norepinephrine solution were relaxed by adding 10-1 to 10-''M acetylcholine solution, and the relaxing effects of each group of specimens were compared by measuring the isometric arc force at that time. The results are shown in Figure 1.

As is clear from FIG. 1, the relaxing effect of acetylcholine was reduced in the high cholesterol group compared to the control group, but no difference was observed in the drug-administered group compared to the control group.

Experimental Example 2 Acute Toxicity Slc: An acute toxicity test of 2-octynyladenosine and 2-hexadecynyladenosine (general formula (1)*n=13) was conducted using ICR mice (7 to 8 weeks old). No deaths were observed for any of the compounds during drug preparation and oral administration at the physically administrable maximum dose of 1000 .mu./-, and the LD and tl values were each estimated to be 1000 .mu./kg or more.

〔Example〕

Example 1 2-decynyl adenosine (general formula (13, n=7) Potato starch 150 ■ Light silicic anhydride 50 ■ Magnesium stearate 10 ■ Lactose
765 ■ Total amount
1,000 ml The above ingredients were mixed uniformly and filled into hard capsules in an amount of 200 ml each.

Example 2 2-octynyladenosine 2511 g Potato starch 150 ■ Crystalline cellulose 60 ■ Light silicic anhydride
50■Hydroxypropylcellulose 30■Magnesium stearate
15■ Lactose
670■ Total amount 1000g 2-octynyladenosine, lactose, potato starch, crystalline cellulose, and 25μ of light anhydrous silicic acid were mixed, and a 10% methanol solution of hydroxypropylcellulose was added to the mixture and granulated to give a diameter of 0.8-mm. Granules were prepared by extrusion through a screen, and after drying, magnesium stearate was added and compression molded to form 200 square tablets.

Example 3 2-hexynyl adenosine 25■ (General formula [1], n=3) Propylene glycol Total amount 1c) + j12
-Hexynyladenosine was dissolved in propylene glycol, filtered aseptically, and then filled into ampoules at a rate of 0.2-hexynyl adenosine.

Example 4 2-nonynyladenosine 25■ (general formula (1), n=6) Polyethylene glycol 1500 3000■ Polyethylene glycol 6000 1975 g Total amount 5000■ The above components were heated and melted at 60°C to uniformly melt them. After mixing, the mixture was poured into a plastic mold and cooled to give 1 g of molding agent.

[Brief explanation of the drawing]

11th! 1 shows the results of comparing the relaxing effects of acetylcholine at various concentrations on rat aorta ring preparations for the drug-administered group, high-cholesterol group, and control group. In the figure, 10 indicates the control group, 1 indicates the high cholesterol group, and 2 indicates the drug administration group.

Claims (1)

[Claims] 1) General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, n represents an integer from 0 to 15] 2-
An anti-arteriosclerosis agent characterized by containing alkynyl adenosine or a salt thereof as an active ingredient.