JPH0361646B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a vasodilator effective for treating angina pectoris, hypertension, etc., which contains purine derivatives and pharmaceutically acceptable salts thereof as active ingredients. Conventionally, adenosine and its derivatives have been known as compounds having a vasodilatory effect and having a purine skeleton. These dilate blood vessels, especially the coronary arteries [circulation
Research (Circ.Res.) 45, p468-478, (1979)]
However, it also showed a negative chronotropic effect (decreased heart rate) [Eur. J. Pharmacol. 19, p246-250,
[Biochem. -col.) 18, p43, (1969)].
Furthermore, among adenosine derivatives, it is known that N6-substituted adenosine derivatives in particular have a stronger negative chronotropic effect than adenosine, and this effect lasts for a significantly longer time. On the other hand, the ribose group of adenosine is thought to be essential for adenosine's effects, including vasodilatory effects, and adenine, which has the same purine skeleton as adenosine but does not have a ribose group, either does not exhibit vasodilatory effects or exhibits no vasodilatory effects. For example, Physiology and Pharmacology of Adenosine Derivatives, published by Raven Press, New York (ph)
−ysiology and pharmacology of Adenosine
Derivatives, Raven Press, New York), p113
~18, (1983), etc. Under these circumstances, adenosine, its derivatives, and adenine have not been put to practical use as vasodilators, and the emergence of more effective drugs is desired. The present inventors have conducted extensive studies to improve the drawbacks of adenosine, its derivatives, and adenine, and have discovered that a specific adenine derivative that does not have the ribose group, which was thought to be essential, has unexpectedly excellent vasodilation properties. The present inventors have discovered that the present invention has a positive chronotropic effect and does not exhibit negative chronotropic effects, leading to the completion of the present invention. That is, the present invention is based on the general formula (wherein R is a chlorine atom, a methoxy group, a methylamino group, a dimethylamino group, a furfurylamino group, or a cyclohexylamino group) and at least one of their pharmaceutically acceptable salts. It is a vasodilator characterized by containing it as a component. The purine derivative of the present invention can exist in the following tautomerism. (In the formula, R is as described above.) The purine derivative according to the present invention has the physical properties as shown in the following table, and is better than 6-chloropurine, which is known as a reagent, and has the properties shown in the following table. It can be synthesized by a method.

【table】

[Table] Synthesis Example Synthesis of 6-cyclohexylaminopurine 150 mg of 6-chloropurine was dissolved in 1.2 ml of cyclohexylamine and stirred at 100°C for 1 hour. After the reaction was completed, water was added, extracted with chloroform, and the extracted layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain crude crystals. This product was recrystallized in a mixed solvent of chloroform-ether to obtain 152 mg of the desired product having a melting point of 209-212°C. Next, the pharmacological effects of the purine derivative according to the present invention,
Acute toxicity, dosage and method of administration will be described. (1) Pharmacological Effect Test Example 1 (Relaxation Effect on Rabbit Coronary Artery Specimens) Female and male rabbits weighing 2 to 3 kg were fixed in a fixator, and the carotid artery was cut to kill them. The heart was then quickly removed and placed in a Krebs-Henseleit (Krebs-Henseleit) aeration with 95% O ₂ -5% CO _{2 .}
Henselite) solution (NaCl118mM, KCl4.7mM,
_MgSO4 1.2mM, _CaCl2 2.5mM, _{kH2PO4 1.2mM} ,
NaHCO ₃ 25mM, glucose 11mM).
Thereafter, a penicillin injection needle with a diameter of 1/4 was inserted from the aorta into the left circumflex coronary artery in the liquid, and the coronary artery was removed together with the injection needle. The myocardium of the extracted coronary artery was removed under a magnifying glass, with a width of approximately 1 mm and a length of approximately 10 mm.
A spiral specimen was prepared. The specimen was heated to a _Krebs - _Henselite (Krebs-Hens-
elite) solution was suspended in a Magnus tube filled with 20 ml, and a load of 0.5 g was applied. After equilibrating for 60-120 minutes, the specimen was slightly contracted with KCl (8mM-20mM), each test compound was cumulatively added, and the tension change was measured via a strain gauge transducer. Measurements were recorded on an ink oscillograph. The maximum relaxation response was defined as the relaxation response upon treatment with 10 ^-4 M Papaverine, and the ED ₅₀ value (-LCG M) of each test compound was determined, and the results shown in Table 1 were obtained. Table 1 Test compound No. ED ₅₀ (-LOG M) 1 4.89±0.08 2 4.12±0.09 3 4.10±0.05 4 4.38±0.04 5 3.61±0.09 6 3.38±0.05 Adenine (comparison group) 3.27±0.02 Test example 2 (Relaxation effect on rabbit aorta specimen) The aorta was removed in the same manner as in Test Example 1 to prepare a spiral specimen with a width of about 4 mm and a length of about 20 mm. Suspend this in a 20ml Magnus tube and load 1.5
gave g. The test compounds were Compound No. 1,
Compound No. 3 and adenosine were used as a comparison group. The test was conducted in the same manner as in Test Example 1 except for the conditions described above, and as a result, Compound No. 1 and Compound 3 showed a relaxing reaction about 5 times and 3 times stronger than adenosine, respectively. . In addition, the vasodilatory effect on the proximal blood vessels such as the aorta was stronger than that of adenosine. Test Example 3 [Test by Langendolf method] 1000 units/Kg of heparin was intravenously injected into female and male rabbits weighing 2 to 3 kg, and after 20 to 30 minutes, they were fixed in a fixator and the carotid artery was cut. and caused death. The heart was then quickly removed and placed in a cooled Krebs-Henselite in an ice bath.
immersed in liquid. A cannula was then inserted into the heart through the aorta according to the Langendorf method, and the heart was perfused. Irrigation fluid has a PH
A Krebs-Henseleit solution adjusted to 7.4 and constantly aerated with 95% O ₂ -5% CO ₂ was used. The perfusion pressure is
The perfusion temperature was maintained at 60 cm water pressure and 37°C. After equilibration for about 60 minutes or more, 0.5 ml of an aqueous solution in which a predetermined amount of each test compound was dissolved was administered into the perfusion cannula, and the perfusion flow rate and heart rate were measured. The flow rate is
The heart rate was measured using a pressure transducer and a cardiometer using a balloon inserted into the right ventricle from the pulmonary artery. Although a transient decrease in heart rate was observed for 60 to 120 minutes or more with 6-cyclohexyladenosine, no decrease in heart rate was observed with Compound No. 1 of the present invention. Test Example 4 (Effect on blood pressure and heart rate) Urethane 1.0 g/Kg was intraperitoneally administered to female Wistar rats weighing 300 to 400 g, a cannula was inserted into the left femoral artery, and a pressure transducer and cardiometer were attached. Blood pressure and heart rate were recorded using an ink oscillograph. Compound No. 1 was used as the test compound, and administration was performed through the right femoral vein. As a result, Parts 4 to 6 below
As shown in the figure, blood pressure decreased by 20-35%, but there was almost no effect on heart rate. (2) Acute toxicity Compound No. Route of administration LD ₅₀ value (mg/Kg) 1. Intraperitoneal 125-250 6. Intravenous 250 or more (3) Dose and method of administration The dose of the vasodilator of the present invention depends on the subject, Although it cannot be definitively defined due to differences in administration conditions such as age, medical condition, and individual differences, in general when targeting humans,
As an active ingredient, 0.01-100mg per day per kg of body weight.
Preferably, 0.1 to 10 mg is administered in one to four divided doses. In some cases, amounts outside the above range may be administered. Moreover, drug administration can be carried out by oral, intravenous, intramuscular, subcutaneous routes, and the like. The vasodilator of the present invention is formulated in the same manner as conventional pharmaceuticals, for example, from an active ingredient and a pharmaceutically acceptable diluent, and can be administered orally or parenterally. The formulation may take various forms such as powders, granules, tablets, sugar-coated tablets, capsules, suppositories, suspensions, solutions, emulsions, ampoules, and injection solutions. The diluent used in the above formulation includes solid, liquid, semi-solid, or ingestible capsules, such as excipients, fillers, binders, wetting agents, disintegrants, surfactants, and dispersants. agents, buffering agents, fragrances, preservatives, solubilizing agents, solvents, etc., and these may be used alone or in combination of two or more. It can also be used in the form of a mixture with other drugs. Next, formulation examples of the vasodilator of the present invention will be described. Formulation example 1 (1) Compound No. 1 0.6 parts by weight (2) Ethylenediamine 0.3 parts by weight (3) Nonionic surfactant 2.1 parts by weight (4) Physiological saline 97.0 parts by weight (1) to (4) heated After mixing, the mixture was sterilized and made into an injection. Formulation example 2 (1) Compound No. 1 10 parts by weight (2) Glucose 20 parts by weight (3) Cornstarch 60 parts by weight (4) 5% cornstarch paste 9 parts by weight (5) Magnesium stearate 1 part by weight (1) - (4) were mixed uniformly and made into granules by a wet method, and then (5) was added and compressed into tablets.

[Brief explanation of drawings]

Figures 1, 2 and 3 are graphs showing the heart rate and perfusion flow rate of Compound No. 1 of the present invention, adenosine and 6-cyclohexyladenosine, respectively; The figures and FIG. 6 show the respective dosages (0.1 mg/Kg, 1
This is a graph showing the heart rate and blood pressure at 3 mg/Kg and 3 mg/Kg.

Claims (1)

[Claims] 1. General formula (wherein R is a chlorine atom, a methoxy group, a methylamino group, a dimethylamino group, a furfurylamino group, or a cyclohexylamino group) and at least one of their pharmaceutically acceptable salts. A vasodilator characterized by containing it as an ingredient.