WO1991009864A1 - Drug for treating or preventing ischemic diseases of heart or brain - Google Patents

Abstract

This invention relates to a drug for treating or preventing ischemic diseases of a heart or brain comprising as the active ingredient 2-alkynyladenosine represented by general formula (I), wherein n represents an integer of 2 to 15.

Description

 Akira 细

Treatment and prevention of ischemic diseases of the heart or brain

 The present invention relates to a therapeutic or preventive agent for ischemic disease of the heart or brain, comprising 2-alkynyladenosine as an active ingredient.

 Background Technology-Adenosine, a physiologically active substance in the body, has a variety of physiological effects and is known to play an important role in maintaining tissue and nerve functions and, thus, homeostasis. I have. However, adenosine given from outside the body is quickly deaminated by adenosine deaminase and immediately inactivated.

Under these circumstances, the synthesis of adenosine derivatives was studied for the purpose of improving pharmacological activity, imparting adenosine denase resistance, and reducing side effects, and attempted to develop them as pharmaceuticals. Has been popularized. Various compounds have also been synthesized with respect to 2-substituted adenosine derivatives, such as 2-methoxyphenyladenosine (Hirata. M., Kawazoe, K., Tanabe. M. and Kikuchi. K .: Japan J. Pharmacol. _S 27, 689 (1977)) and 2-phenylaminoinoadenosine (Marumoto, R .. Yoshioka. Y .. Miyashi ta. 0 .. Shima. S., I mai. K., Kavazoe, K. and Hon jo. M .: Chem. Pharm. Bu 1 1.

23, 75.9 (19775)), and other biological activities such as adenosine kinase inhibitory activity, coronary vasodilatory activity, platelet aggregation inhibitory activity, and antiviral activity. Have been.

 Since adenosine has a potent vasodilator action and platelet aggregation inhibitory action, adenosine has been used for the treatment of ischemic heart disease, ischemic brain disease, etc. Attempts have been made to synthesize syn derivatives. As with adenosine, the action of conventional adenosine derivatives has not been separated from side effects such as atrioventricular conduction inhibition and reduction of renal blood flow, and no excellent compound has yet been found.

 On the other hand, 2-alkynyl adenosine, in which a substituent is introduced at the 2-position of adenosine by a carbon-carbon bond, is disclosed in Japanese Patent Application Laid-open Nos. Sho 62-93995 and Sho 62-93. — No. 9 333 0]. However, their specifications only describe their usefulness as an antihypertensive agent.Other pharmacological effects, in particular, platelet aggregation inhibitory effect, coronary blood flow increasing effect, cerebral vascular blood flow No mention is made of ameliorating effects on ischemic diseases such as increasing effects and cerebral protective effects (for example, cerebral protective effects such as anti-hypoxia effect and anti-anoxia effect).

In general, treatment and treatment of ischemic heart diseases such as angina pectoris, heart failure, and myocardial infarction, and ischemic brain diseases such as cerebral circulatory disorders. It is desired that the compound used for the prevention and prevention of the platelet be a compound having both a platelet aggregation-inhibiting effect and a blood flow-increasing effect or a brain-protective effect at the site of injury. Under the above circumstances, an adenosine derivative which has a potent platelet aggregation inhibitory action, coronary blood flow increasing action, cerebrovascular blood flow enhancing action or cerebral protective action and has no side effects as described above Is extremely significant in the treatment of ischemic diseases of the heart or brain.

The present inventors examined the effects of 2-alkynyladenosine on increasing blood flow in various blood vessels (such as coronary arteries and bone arteries), inhibiting platelet aggregation, and protecting the brain in a hypoxic condition. In addition, as a result of intensive studies on the presence or absence of atrioventricular block in the heart and the degree of renal blood flow from the viewpoint of side effects, the compound represented by the following formula (I) showed strong platelet aggregation It has both an inhibitory effect, an effect of increasing blood flow in various blood vessels, and a cerebral protective effect, and the appearance of an atrioventricular block, which is linked to the side effects of conventionally known adenosine and adenosine derivatives. ゃ The effect of reducing renal blood flow is weak. The present inventors have found that they exhibit excellent characteristics for prevention and treatment of various ischemic diseases (ischemic heart disease and ischemic brain disease), and completed the present invention. That is, the present invention relates to the general formula (I)

[Wherein, n represents an integer of 2 to 15] .A therapeutic or prophylactic agent for ischemic disease of the heart or brain characterized by containing 2-alkynyladenosine represented by the formula: What to provide.

 Further, the present invention provides a therapeutic or prophylactic agent for treating ischemic heart or brain disease, comprising a safe and effective amount of the above-mentioned 2-alkynyladenosine and a pharmaceutically acceptable carrier. Things.

 Further, the present invention provides a method for treating or preventing a heart or brain ischemic disease in a mammal, which comprises administering a safe and effective amount of the above-mentioned 2-alkynyladenosine to a patient having a heart or brain ischemic disease. The present invention still further relates to the use of the above 2-alkynyl adenosine for the manufacture of a medicament for the treatment or prevention of ischemic disease of the heart or arm.

BEST MODE FOR CARRYING OUT THE INVENTION 2-Alkynyl adenosine represented by the general formula [I] In view of the biological activity and the like to be described later, it is preferable that n is in the range of 2 to 13 and more preferably η is in the range of 3 to 7 as the active ingredient. It is suitable. 2-Alkynyl adenosine (hereinafter sometimes simply referred to as the compound of the present invention), which is an active ingredient of the drug of the present invention, has the general formula [Π]

[Π]

H

[Wherein X represents iodine or bromine] in the presence of bis (triphenylphosphine) palladium dichloride and cuprous iodide in a solvent. General formula (m)

CH≡ C (CH ₂ ) n CH cm)

[Wherein n represents an integer of 2 to 15] can be synthesized by a method of reacting with an alkyne represented by the following formula: —

No. 9 395). The alkyne is selected from those having the corresponding n number according to the kind of the compound of the present invention.

 As the reaction solvent, a basic solvent is used. For example, a mixed solvent of triethylamine and N, N-dimethylformamide can be used. Instead of triethylamine, tributylamine, trioctylamine, N, N, Ν ', Ν'-tetramethyl-1, 8-naphthalenediamine, dimethylethylaniline, dimethylethylaniline, pyriamine Tertiary amines such as gin, and non-protocols such as ,, Ν-dimethyl acetate, dimethyl sulfoxide, and acenitrile instead of ,, Ν-dimethylformamide. Polar solvents can be used.

 The reaction is completed within several hours from room temperature to a solvent reflux temperature. The compound of the present invention may be isolated by a conventional separation and purification method, and for example, techniques such as adsorption chromatography, ion exchange chromatography, extraction, and recrystallization are applied.

 The agent of the present invention is used for ischemic heart disease such as angina pectoris, heart failure or myocardial infarction or cerebral circulation disorder based on sequelae of cerebral infarction or sequelae of cerebral hemorrhage, acute cerebral bleeding due to hypoxic (absence) oxygenation of the brain, It is used for the prevention of ischemic brain disease and for the purpose.

When the compound of the present invention is used as a medicament, the compound of the present invention is in free form or an acid addition salt thereof with a pharmaceutically acceptable acid. Used as Examples of the acid addition salt include an inorganic acid salt such as a hydrochloride, a sulfate, and a hydrobromide, and an organic acid salt such as an oxalate, a citrate, and a phosphate.

 Further, the compound of the present invention can be orally or parenterally administered together with a pharmaceutically acceptable carrier for treatment or prevention.

 Oral preparations can be solid preparations such as powders, granules, capsules and tablets, or liquid preparations such as syrups and elixirs. Parenteral preparations include injections, rectum, external preparations for the skin, and inhalants. These preparations are produced in a conventional manner by adding a pharmaceutically acceptable auxiliary to the compound of the present invention. It is also possible to prepare a sustained-release preparation by a known technique.

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 metasilicate aluminate, and maleic anhydride. Powders, and, if necessary, binders such as sucrose, hydroxyquine propylcellulose, and polyvinyl viridone; and disintegrants such as carboxymethylcellulose and carboxymethylcellulose. Granulate by wet or dry granulation. To make tablets, '' these powders and condyles Tablets may be tabletted as is, or with the addition of a lubricant such as magnesium stearate or talc. Also, these granules or tablets are coated with an enteric base such as hydroxypropylmethylcell mouth-sphthalate, methyl methacrylate copolymer and the like, and coated with an enteric preparation, or ethyl cellulose, carnaupa wax, hydrogenated oil, etc. As a result, a sustained-release preparation can be obtained. In addition, capsules are prepared by filling powders or granules into hard capsules, or dissolving the compound of the present invention in glycerin, polyethylene glycol, sesame oil, olive oil, and the like. It can be coated with a gelatin film to make capsules.

 To prepare a liquid preparation for oral administration, the compound of the present invention and a sweetener such as white $ 1, sorbitol, or glycerin can be dissolved in water to give a clear syrup, or an essential oil or essence can be obtained. Elixir by adding Ethanol, etc., or an emulsion or suspension by adding arabic gum, tragacanth, polysorbate 80, carboxymethylcellulose sodium, etc. May be. Flavoring agents, coloring agents, preservatives and the like may be added to these liquid preparations, if desired.

In order to manufacture an injection, the compound of the present invention may be added, if necessary, to hydrochloric acid, sodium hydroxide, lactic acid, sodium lactate, sodium phosphate-hydrogen, sodium phosphate dihydrogen. Dissolve in distilled water for injection together with a pH adjuster such as sodium and an isotonic agent such as sodium chloride and glucose, and aseptically fill the sample with i. Alternatively, mannitol, dextrin, cyclodextrin, gelatin, etc. may be added, and the mixture may be freeze-dried under vacuum to give a ready-to-use injection. Further, lecithin, polysorbate 8 °, polyoxyethylene hydrogenated castor oil, and the like can be added to the compound of the present invention, and the mixture can be emulsified in water to give an emulsion for injection.

 In order to manufacture a rectal preparation, the compound of the present invention is used together with a suppository base such as cocoa fatty acid tri-, di- or monoglyceride, or polyethylene glycol. The compound of the present invention may be dissolved in polyethylene glycol, soybean oil, or the like, and then coated with a gelatin film.

 To prepare an external preparation for the skin, the compound of the present invention is added to white cellulose, beeswax, liquid paraffin, polyethylene glycol, etc., and if necessary, heated and kneaded to prepare a plaster. After being kneaded with a pressure-sensitive adhesive such as rosin and alkyl acrylate polymer, it is spread on a nonwoven fabric such as polyethylene to form a tape.

 In order to produce an inhalant, the compound of the present invention is dissolved or dispersed in a propellant such as front gas and filled into a pressure-resistant container to give an aerosol.

 The dose of the compound of the present invention varies depending on the age, body weight and disease state of the patient, but is generally 0.1 to 1 per individual per day.

100 and may be administered in single or divided doses Desirable.

 (Synthesis example of compound)

 6-black mouth-2-hand-9-(2,3,5-tri-0-acetinole--D-ribofuranosyl) purine 6. 〇 g of methanol Z ammonia (0.C (Saturated with) and added to 60 ml, and reacted in 6 CTC for 17 hours in a sealed tube. After cooling the reaction solution, the gas was removed, and the mixture was concentrated under reduced pressure. The residue was crystallized from water to give 2-odoadenosine 3.94- (yield 90%).

 Melting point 1 4 1 to 144 ° C

Dissolve 3-3 mg (I mmole) of 2-chloride adenosine in dimethylformamide (10 ml)-triethylamine (3 ml), and add bis (triphenylphosphine) palladium dichloride 2. 1 mg and cuprous iodide (12 mg) were added, and each alkyne (1.1 equivalent) was added in an argon stream, followed by heating and stirring at 80 ° C. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol, hydrogen sulfide was passed through for 1 minute, and the deposited precipitate was removed by filtration.The filtrate was concentrated under reduced pressure to dryness, and the residue was subjected to silica gel column chromatography. Purification by chromatography and recrystallization from methanol or methanol-water gave 2-alkynyl adenosine. The reaction time, yield, melting point and infrared absorption spectrum are as shown in Table 1.

〔薬理試験の実施例〕

(Example of pharmacological test)

Example 1. Platelet aggregation inhibitory action

 Japanese white male male egrets weighing 2.0 to 2.5 kg were used.

 Blood was collected from the carotid artery under anesthesia with Pentobarbi Luna Trium and mixed with 1 Z 7 volumes of anticoagulant dextrose citrate solution. Next, the mixture was centrifuged at 140 X g for 15 minutes, and supernatant (platelet-rich plasma: PRP) was collected. PRP was centrifuged at 1300 xg for 7 minutes, and the obtained platelet pellet was washed with HEPES buffer (pH 6.5) for washing platelets, and centrifuged at 1300 xg for 7 minutes. did. The platelet pellet washed twice under the same conditions was used as a suspension (1.0% human, fibrinogen, 1.8 mM calcium chloride, 1.2 mM magnesium chloride in the platelet washing buffer). Was added, and a platelet suspension was prepared so as to have 5-8 × 10 u Zml.

 Platelet aggregation was measured using an aggregometer using a platelet aggregator (380 μl of the test drug was added, and 3 minutes later, a platelet agglutinating substance (a final concentration of 10 adenosine-5%) was added. '-Diphosphate) was added at 1 ◦ ^ to induce aggregation.

The platelet aggregation inhibitory effect of the test drug is represented by the Ic5 _{) value (the concentration of the test drug that inhibits platelet aggregation by 50%), and the results are shown in column (A) of Table 2. Example 2. Coronary artery blood flow increasing action

 Adult mongrel dogs weighing 9 to 15 kg were anesthetized with sodium pentobarbital and thoracotomy was performed under mechanical ventilation. After pericardiectomy, the left descending coronary artery is separated from the surrounding tissue, a blood flow measurement probe is installed under heparin sodium treatment, and the coronary artery blood flow is measured using an electromagnetic blood flow meter. did.

Incidentally, test drug dispensed proximate dynamic into the coronary artery, acts increase coronary blood flow ED _{5 Q} value (the blood flow to 1 5 seconds blocking of the coronary artery., After which the reactive hyperemia of blood flow that occurs when resuming The increase was defined as 100%, and the increase in blood flow was increased by 50% due to the administration of the test drug), and the results are shown in column (B) of Table 2.

Example 3. Vertebral artery blood flow increasing action

 Adult male and female mongrel dogs weighing 8 to 1.3 kg were anesthetized by intravenous administration of pentobarbital sodium, the chest was opened along the midline under artificial respiration, and the left vertebral artery was exposed. After introducing a polyethylene tube into the left vertebral artery under parina stream treatment, a probe for blood flow measurement was installed at the other end, which was guided from the left femoral artery. The blood port diversion tube was connected, and the vertebral artery blood flow was measured using an electromagnetic blood flow meter.

The test drug was injected into the vertebral artery by close intraarterial injection, and the effect of increasing vertebral artery blood flow was ED5 ₍₎ value (the blood flow increase due to the administration of papaverine hydrochloride 100 ^ g / kg into the vertebral artery Is 100%, and blood flow is 5 °% 增 The result is shown in (C) 撋 in Table 2.

Two

(A) Platelet aggregation inhibitory action

Compound number Type of alkynyl group IC ₅₀ (M)

2 C C H

 o 2) 3 36.1 X 10 -8-

4 C C H

 2) 5 3 1. 4 10 -7

5 C O C H -7

 2.1 X 10

2) 6 3

 6 C C (C H C H

 2) 7 7.2 x 10 -7

 Three

 12 C ^ C (C H

2) 13 CH 3.1 X 10 " ⁶ <

 Three

 Adenosine control ο 3.2 X 1 0-6

(B) Increased coronary blood flow

 Compound number Kind of alkynyl group E D 50 (II ϊΛε

2-C then (Cilno H ^> 0.002

4 1 C (CH) ₅ CH ₃ 0.008

5 One C ^ C (CH ₂ ) ₆ CH ₃ 0.075

6-C and (I and I 7

 12-C ― C, xi ii ii 0.1 <adenosine control agent 0.1

"(C) Vertebral artery blood flow increasing compound No. Kin of alkynyl group E D 5 o (nAg)

2 1 C 0.14

4 One C (one) ₅ CH ₃ 0.4

5 1 C (CH) ₆ CH ₃ 1.2

 6 One C = C (L H) y C H 3 <

12 C = C (CH 2) 3 <Adenosine control agent 0.52 Example 4. Cerebral Protective Effect in Hypoxic (No) Oxygen State When the brain becomes hypoxic due to impaired cerebral circulation, its function is rapidly and irreversibly lost. Therefore, drug efficacy was determined using the change in gas phase components or the prolonged effect of the test drug on the survival time of the animal in the hypoxic (oxygen-free) state induced by the drug as an index.

Experiment 1 Normobaric hypoxia methods Determination of the drug efficacy by the normobaric hypoxia method was performed by Yasuda et al. (Arch. Int. Pharmacodyn. 23 3, 13 6—144 (1788) ) Was performed in the following manner. The animals used were 7-week-old male ICR mice (Clear Nippon, Ltd.) as groups 8 to 1 L.

Mice were placed in a glass desiccator Isseki one, elicited low oxygen conditions (Hypoxia) by bubbling _{9 6% N 2, 4%} 0 2 mixed gas of 5 £ min flow rate. The time from when the gas was ventilated into the container until the mouse stopped breathing was measured and defined as the survival time.

 The test drug was administered intraperitoneally 30 minutes before the start of gas ventilation. The average survival time of the control group and the group to which the test drug was administered was calculated, and the results are shown in column (A) of Table 3.

The test drug was suspended in a physiological saline solution containing ◦ .5% CMC (carboxymethyl cell mouth), and the administration volume was 0.1 ml per 10 g body weight. The mice in the control group were similarly administered only 0.5% CMC physiological saline. Statistical processing is It was performed by t test (student's t-test).

 (Result)

 Administration of 1-mg / kg of 2-hexynyladenosine (compound 2) and 1 mg / kg of 2-octynyladenosine (compound 4) significantly increased survival time.

Experiment 2 Ca-cyanide (KCN)-induced anoxya (oxygen-free) method.

 Judgment of the drug efficacy by the KCN-induced anoxia method was carried out according to the method of Arasava, et al. (J. Pharmcobio-Dyn. 5, 295-300 (1982)).

 The animals used were 8-week-old male ICR mice (Clear Japan Ltd.) in groups of 13 to 15 mice.

 The test drug was intraperitoneally administered at a dose of 1 ml per 10 g body weight, and 30 minutes later, 1 ^ 2, 5 mgZkg was rapidly administered into the tail vein to measure the survival time until respiratory arrest. The test drug was prepared in the same manner as in Experiment 1.

The average survival time of the control group and the group to which the test drug was administered was calculated, and the results are shown in column (B) of Table 3. Mice that did not show respiratory arrest for more than 18 seconds after KCN administration were regarded as survivors, and the survival time was calculated as 180 seconds when calculating the average survival time. (Result) ·

 Administration of 2-hexynyladenosine (compound 2) IragZkg and administration of 2-hexadecinyladenosine (compound 12) 30 ^ Zkg compared the survival time of each control group. It showed a significant prolongation effect.

Three

 (A) Atmospheric pressure low-oxygen method compound Alkynyl dose Number of patients Average survival time (rag / kg)

2 -CC (CH ₂ ) ₃ CH ₃ 0.19 m.'9 (± 22.1) ^a )

 0.3 9 169.2 (± 23.5)

1.09.217,3 (± 26.2) **

4 -Cho C (CH ₂ ) ₅ CH ₃ 0.3 9 128.7 (± 4.8)

 1. 0 9 222.9 (± 25.9) **

3.09 30.6 (± 26.7) Control of moss 1 1 126.8 (± 10.7)

(B) Prussic acid reammosis-induced anoxia (anoxic condition) method Compound Alkynyl Amount administered Number of subjects Average survival time Group type-(mg / kg) (animal) (sec)

2 -Cho C (CH ₂ ) ₃ CH ₃ 1.01 5 50.5 (± 3.8) * Control (1) 1 5 39.8 (± 2.4)

12 -C≡C (CH2) i3CH3 30 1 5 76.7 (± 11.7) Control (2) 1 3 41.8 (± 1.9)

a) Standard error (S.E.) UP <0.01

Book P Example 5. Effect on renal blood flow

 Adult male and female mongrel dogs weighing 10 to 15 kg were anesthetized intravenously with 30 mg Z kg of bentobarpital sodium, fixed in the dorsal position, incised in the lower left abdomen under artificial ventilation, and left The renal artery was exposed. A polyethylene tube was introduced into the renal arteries under heparin natrium treatment, and a blood flow measurement probe was installed at the other end. The blood flow from the left femoral artery was then flowed through the port using a tube for port flow, and the renal artery blood flow was measured using an electromagnetic flowmeter.

Incidentally, test drug dispensed proximate dynamic within the renal artery, renal blood flow '减少for work is expressed as ID _5Q value (amount bloodstream by administration of study drug is reduced by 50%), the results of Table 4 (A ) Column.

Example 6. Effect on atrioventricular conduction

Body weight: 360-600 g: Male guinea pig, anesthetized by intraperitoneal injection of urethane (1.4 g Zkg), fixed in dorsal position, incised in trachea to secure airway The ren tube was introduced. Blood pressure was measured via a carrier amplifier by connecting a force transducer inserted into the left common carotid artery to a pressure transducer. Electrocardiograms were recorded using a bioelectric amplifier in the second lead method, and PQ intervals were measured from the electrocardiogram. The test drug was administered through the left femoral vein, and the presence or absence of an atrioventricular block was expressed as the rate of the second-degree atrioventricular block due to the administration of the test drug (number of appearing animals Z number of animals used). So Are shown in column (B) of Table 4.

Four

(A) Renal blood flow reduction compound No.Type of alkynyl group

2-C C (H) C H 0.15

4 One C ≡ C (CH) ₅ CH 3 <

5 1 C ≡ C (CH) ₆ CH 3 <

6 1 C ^≡ C, then ii ^) 7 then 3

12 g C = C CH) | gu H 3 adenosine comparator 0.2

(B) Appearance rate of atrioventricular block

 * Number of Appearing Animals / Compound No.Type of Alkynyl Group Number of Animals Used

2 One C, C, H, and H 6/6

4 One C (C) ₅ CH ₃ 1/6

5 1 C ≡ C (CH) ₆ CH 0/6

6 One C ― C (C H) 7 ri 1/6

1 2 CC (CH) 丄_n CH 0/6 Adenosine control agent 6/6 300 / z gZkg IV Example 7. Acute toxicity

S 1 c: An acute toxicity test of compound 4 (η = 5) and compound 12 (η = 13) was performed using ICR mice (7 to 8 weeks old). Both compounds, deaths Te oral odor of drugs prepared and physically administrable maximum amount 1 0 0 0 mgZkg is not observed, LD _5Q value was estimated to be respectively 1 0 0 0 mgZkg more.

(Example of formulation)

Example 1.

 Compound 6 2 Dig White starch Starch 150 mg

 I

 Light Caic anhydride 50 mg Magnesium stearate 10 nig Lactose 765 mg Total 100 000 mg The above components were mixed uniformly, and 20 mg of hard capsules were filled.

Example 2.

Compound 4 25 mg Parsley starch 150 mg Crystalline cellulose 60 mg Light calcium anhydride 50 mg Hydroxypropyl cellulose 30 mg Magnesium stearate15 mg Lactose 6 7 0

 100 nig total amount Compound 4, lactose, potato starch, crystalline cellulose, and light gay anhydride are mixed together, and a 1 methanol solution of hydroxypropylcellulose is added, and the mixture is kneaded and granulated. Extruded with a 8πππ screen to prepare a condylar, dried, then added with magnesium stearate and compressed and formed into tablets of 20 mg.

Example 3.

 Compound 2.25 nig Total amount of propylene glycol 10 ml

,

 Compound 2 was dissolved in propylene glycol, aseptically filtered, and then filled into ampoules (2 ml each). Example 4.

 Compound 5 2 5 mg Polyethylene glycol 1 500 00 300 mg Polyethylene glycol 6000 1 75 m

 The total amount was 500 mg. The above components were heated and melted at 60 ° C, mixed uniformly, poured into a plastic mold and cooled to give 1 g of suppositories.

As described above, 2-alkynyladenosine, an active ingredient of the drug of the present invention, has a potent platelet aggregation inhibitory effect, a blood flow enhancing effect on various blood vessels (coronary artery and vertebral artery), and a cerebral protection. In addition, it has an effect, and the appearance of an atrioventricular block in the myocardium of adenosine and adenosine derivatives known in the past. Things. More specifically, 2-alkynyl adenosine, an active ingredient of the drug of the present invention, has a main effect such as a platelet aggregation inhibitory effect, a blood flow increasing effect of various blood vessels, a cerebral protective effect, and an atrioventricular protein. The ratio to the side effects such as the appearance of ク ク renal blood flow 减 reduced effect, i.e., o The safety margin is compared with conventional compounds o

It is extremely wide. For example, coronary o-arterial blood flow increasing action as main effect and renal blood flow decreasing effect as side effect u

 o

The safety margin (coefficient) of 2-alkynyl adenosine calculated based on the results of Tables 2 and 4 is shown in Table 5 below. From Table 5, it can be understood that 2-alkynyladenosine is a compound with a wider safety margin than adenosine.

5 Compound No. Kind of alkynyl group Safety agent (Region)

2 C = C (C Jti) H 7 5

4 One C ^ C 3 7 5 <

5 1 C ≡ C 4 0 <

6 i C

2 0 <

2 0 <

1 2 1 CC (x xi) i3 and Jti 3 0 Adenosine control 2 Also, from Tables 2 and 4, 2-alkynyl adenosine has one of the side effects of atrioventricular block, which is one of the side effects, although its main effect is equal to or greater than that of adenosine. Is kept low. The frequency of atrioventricular block of compound No. 2 was the same as that of the control adenosine, but this was caused by a large dose of 300 ^ g Z kg (intravenous administration). Considering the strength of the main action of the compound, it is considered that the administration of an effective amount for the expression of the activity of the main action can suppress the appearance of an atrioventricular block to a low level. '

 Industrial applicability

 The present invention provides, for the first time, a drug that is extremely excellent in preventing and treating ischemic heart diseases such as angina pectoris, heart failure and myocardial infarction, and ischemic brain diseases such as cerebral circulatory disorders based on sequelae of cerebral infarction and cerebral hemorrhage. O it became possible to do

Claims

The scope of the claims —General formula (I) (CH ₂ ) ―

[Wherein, n represents an integer of 2 to 15] A therapeutic agent for heart or brain ischemic disease, characterized by containing 2-alkynyladenosine as an active ingredient.  2. The method according to claim 1, wherein n is in the range of 2 to 13.  3. The therapeutic / preventive agent according to claim 1 or 2, wherein n is in the range of 3-7. '  4. A cardiac or cerebral nervous system comprising a safe and effective amount of a 2-alkynylade'nosin represented by the general formula [I] according to claim 1 and a pharmaceutically acceptable carrier. Treatment and prevention of ischemic diseases. 5. 2-α represented by the general formula [I] according to claim 1 in an amount that is safe and effective for patients with ischemic disease of the heart or brain. A method for treating or preventing cardiac or cerebral ischemic disease in a mammal, which comprises administering ruquinyl adenosine. - 6. Use of the 2-alkynyl adenosine represented by the general formula [I] according to claim 1 for the manufacture of a medicament for treating or preventing ischemic disease of the heart or brain.