JPS606616A - Vasodilator - Google Patents

Abstract

PURPOSE:To obtain the titled drug effective to stenocardia, hypertension, etc., free from the negative chronotropism, and containing a purine derivative or its salt as an active component. CONSTITUTION:The objective vasodilator contains at least one compound of formula (R is Cl, methoxy, methylamino, dimethylamino, furfurylamino or cyclohexylamino) or its salt, as an active component. Dose: 0.1-100mg, preferably 0.1 -10mg of the active component per kg daily in 1-4 divided doses. It is administered e.g. by oral administration, intravenous injection, intramuscular injection, subcutaneous injection, etc. in the form of powder, granule, capsule, suppository, liquid, injection, etc. The active compound of formula can be prepared by reacting 6-chloropurine with the compound of formula RH.

Description

[Detailed description of the invention]

The present invention is based on pudding! 51! The present invention relates to a vasodilator effective for angina pectoris, high blood pressure, etc., which contains IJI form II and its 41 pharmaceutically acceptable IJIs as an active ingredient. Conventionally, p-denosine and its 1111 compound are known as compounds having a vasodilatory effect and having a purine skeleton. Go Jl et al. show the dilation effect of the II arterial artery in blood vessels, poetry.

[Circushi - Shicon Research (C1rc
. Res, )45. ρ468～478. <1979)] also showed a negative chronotropic effect (decreased heart rate) [Eurobitonji! - Null of Pharmacology (Eur, J. Pharmscol,) 19. p246-250. (+
972>1. Also, under physiological conditions, p-denosine deaminase]! It is known that it is activated by absorption into the +ll lit tissue, and the effect is significantly weakened [41]
Biochemical Pharmaco Ocy (Blochem)
Phsrma-eot, >IL p43+ (+969
)]s Furthermore, Todenosine! Among the 11 conductors, Ne-
It is also known that the negative chronotropic effect of ttp denosine derivatives is stronger than that of ttp denosine, and the effect lasts for a significantly longer time. On the other hand, the ribose group of adenosine is thought to be essential for the vasodilatory effect, including the vasodilatory effect. For example, Physio O.C. and Pharmaco O.C. of p-Denosine Derivatives, New York, Published by Ray Ambres Co., Ltd. (ph-
yslaloay and Pharmscolooy
of Adsnosln@Dsrlvstlv@s+
Raven Pr@ms, New York) + al
l3~+18. (+983) etc.41. Due to this negative current situation, denosine, its derivatives, and adenine have not been put to practical use as vasodilators, and there is a desire for a more effective rIWI agent. The present inventors have made extensive studies to improve the drawbacks of p-denosine, its derivatives, and adenine, and considering the psychological reasons (and surprisingly, there are certain adenine derivatives that do not have a ribose group). The present invention has been completed by discovering that it has a self-propagating effect on Yu J1 and does not exhibit negative chronotropic effects.That is, the present invention is based on the general formula (wherein RLt, methoxy group, methyl Contains as an active ingredient at least one purine compound represented by a tomino group, a dimedyl tomino group, a furfurylamino group, or a Schiff O hexylamino group, and a pharmaceutically acceptable salt thereof. The purine!1ul1 body of the present invention can exist in the following tautomeric form. The reduced product has the physical properties shown in the following table, and can be synthesized from 6-ri00 purine, which is known as a reagent, by a known method as described in the synthesis example below. 150 ma!, 1.2 ml of cyclohexylamine was added to FflM and incubated at 100° C. for 1 hour. After the reaction was completed, water was added, extracted with chloroform, and the extracted waste was washed with brine, then dried over anhydrous Wat sodium. This was then recrystallized in a mixed solvent of 209-212° C. to give a target #I52maeI with a melting point of 209-212°C. Next, a purine conductor according to the present invention was obtained. (1) Pharmacological effect test example 1. (Relaxation effect in rabbit coronal ligament specimen) Female and male rabbits weighing 2-3 - - Fasten the blood by cutting the artery, then quickly take out the blood vessels, add 95% 0.-5% CO, and ventilate with a cloth.
ml (NsC1118mM, C14,7mM, MgS
O4 1,2mM, CaCl52.5mM, Ku, Po4
1.2mM, N5HCO325mM, glucose I1m
Then, in the liquid, a 1/4-diameter henigilin injection needle was inserted from the aorta into the 0th branch of the left coronary artery, and the coronary artery was removed with the injection port ↑. The myocardium of the coronary artery was removed under a magnifying glass, with a width of approximately 1 mm and a length of approximately 10 mm.
A spiral-shaped specimen of mm was prepared. In this case, Klebsu-Henseleit (Ni r@bs-H@ns-@
1its) A solution of 20 n+ l r- was suspended in a magmes tube to give a negative ljO, 5u. 60-120
After incubating for minutes, the specimen was slightly contracted with C1 (8mM to 20mM), 1 ml of each test compound was added cumulatively, and the tension changes were measured isometrically using a strain gauge and tramp user. The maximum relaxation response was recorded in ink on an oscillograph.
verin@) treatment, and the EDSO value of each test compound (-LOG Request #, 1614-m in Table 1)
1m1 table test example 2. (Relaxation effect in rabbit aorta specimen) The aorta was excised with the same wound as in Trial Example 1, and the width #14f was removed.
fIm, ate-like specimen of length approximately 201nffI*(11
I did 4. This product was suspended in a 20 ml Magnus tube, and a load of 1.5 g was applied. Compound ? Adenosine was used as the compound Yang 3 and Hijiku. Except for the above-mentioned conditions, the test was carried out under the same conditions as Test Example 1, and mlA fruit, Compound 1kl and Compound 4 were tested.
jlNL3° is about 5 times and H
It showed a strong relaxation anti-aS of 8. Furthermore, the six-tube dilation effect in blood vessels at the base of the aorta etc. It was also stronger than adenosine. Test example 3. [Langendorff
) Test according to law] Body! Heparin 10 for 2-3 to 9 female and male rabbits
Q was intravenously injected into 00 units/unit, and 20 to 30 minutes later, the animals were fixed in a fixator, and the feeding door was cut to kill them. Then, quickly take out the specimen and soak it in the cooled Busssllit solution in a water bath.
f) Insert a cannula into the public office through the aorta in accordance with the law;
Shinchen em *t, *, w wing liquid tt, 1llL in pH 7,4
Krebs-Henseleit solution, always aerated at 95 rm, %0 snow-5% CO, 1, was used. **Pressure is 60cm water pressure, perfusion temperature is 37
After equilibrating for about 60 minutes or more, incubate at 100°C.
0.5 kl of an aqueous solution in which a predetermined amount of each test compound was dissolved was administered into the I-flow cannula, and irrigation flow and heart rate were measured. The flow rate is determined through the l1Itlytya needle and the heart rate is
As a result of measuring the heart rate using a pressure transducer and a cardiometer from a balloon inserted into the right ventricle from the pulmonary artery, as shown in Figures 1A1-3 below, adenosine showed a transient response, while 6-cyclohexyladenosine showed a 60-60% increase in heart rate. 1
A decrease in heart rate was observed for 20 minutes or more, but no decrease in heart rate was observed with 1 kl of the compound of the present invention. Test example 4. (Effect on blood pressure and heart rate) 300~
Urethane 1. on a 400g female Wistar rat. Oa
/g was administered intraperitoneally, a cannula was inserted into the left aorta, and h pressure and σ heart rate were recorded in ink on an oscillograph via a pressure transducer and cardiometer. Compound ELL NLI was used and administered through the right vena cava.As shown in Figures 4 to 6 below, the pressure L fell by 120-35%, but there was almost no effect on the heart rate. 41 and 71M. (2) Acute toxicity 6 Intravenous 250 or more (3) Dose and σ Administration method Differences in administration conditions such as administration of the vasodilator of the present invention, administration voltage, age, medical condition, and -individual differences Generally speaking, when using a person as a counter current, the active ingredient must be 1 lb/kg of body weight.
Q, 0.01-100mg per day, preferably 0
．． Administer 1-10 mg in 10-4 divided doses. In some cases, on &! The vasodilator of the present invention may be administered outside the range. IIImjm□411.1e,□□ II
Formulated with IWs-acceptable diluents, this tI5 can be administered orally or non-lactamally. As a formulation! It can take the form of various types of drugs, such as tablets, sugar-coated tablets, capsules, suppositories, suspensions, solutions, emulsions, tablets, and injections. The diluent used in the above formulation may be solid, liquid, semi-solid or (1 includes ingestible capsules, etc.), such as m-shape, filler, binder, wetting agent, disintegrant, interface. These include activators, dispersants, stimulants, fragrances, preservatives, 11-lysis aids, and solvents. It can also be used in the 4s form.Next, a formulation example of the vasodilator of the present invention will be described.Formulation example 1゜(1) Compound ljl & I O, 6-fold 11i?(2) Ethylenediamine o, 31 parts by weight (3 ) nonionic surfactant
2.11111B(4)1111ijl water 97.01
t18B(1) to (4) are combined with vibration and sterilization to prepare an injection. One drug example 2゜(1) Compound 1'kl 10111 01l Glucose 201M1111 (3):]-:/Starch 601M1111(4)5
% cornstarch paste liquid 9mjfi part (5) magosium stearate I! Parts (1) to (4) were uniformly mixed and made into granules by a wet method, and then (5) was added and the mixture was crushed into tablets.

[Brief explanation of drawings]

Figure 11, Figure 2 and Figure 3 respectively show the compounds of the present invention.
This is a graphical representation of the heart rate of k+, 7' denosine and 7'chlorohexyladenosine. Administration! (0.1mQ/Ka, I n
This is a graph showing the heart rate and Mri at +a/nio+3n+a/ni9). Junjin Ishi Mlgyo Co., Ltd. Deaf 11 yen % 2B Akira 3 Figure IQ-' m oJL, 10-"fnamata, 10-'
? qaoJ,. 4th II Akira 50th 61st Σ +1! ! 1411 Maki (8/issue) 1ω J” JFl, - Immediately 011 Wednesday, 31bet to L

Claims (1)

[Scope of Claims] Purine salt conductor represented by the general formula (wherein R is a chlorine atom, a methoxy group, a methyltomino group, a dimedylamino group, a furfuryltomino group, or a cyclohexyltomino group) and the pharmaceutical use of Sowara. 1. A vasodilator containing as an active ingredient at least one salt acceptable to .