WO1991009864A1 - Medicament pour le traitement d'affections ischemiques du c×ur ou du cerveau - Google Patents

Medicament pour le traitement d'affections ischemiques du c×ur ou du cerveau Download PDF

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Publication number
WO1991009864A1
WO1991009864A1 PCT/JP1990/000001 JP9000001W WO9109864A1 WO 1991009864 A1 WO1991009864 A1 WO 1991009864A1 JP 9000001 W JP9000001 W JP 9000001W WO 9109864 A1 WO9109864 A1 WO 9109864A1
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WO
WIPO (PCT)
Prior art keywords
compound
adenosine
brain
heart
blood flow
Prior art date
Application number
PCT/JP1990/000001
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English (en)
Japanese (ja)
Inventor
Kentaro Kogi
Toichi Abiru
Toyofumi Yamaguchi
Original Assignee
Yamasa Shoyu Kabushiki Kaisha
Toa Eiyo Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yamasa Shoyu Kabushiki Kaisha, Toa Eiyo Ltd. filed Critical Yamasa Shoyu Kabushiki Kaisha
Priority to PCT/JP1990/000001 priority Critical patent/WO1991009864A1/fr
Priority to CA002041648A priority patent/CA2041648A1/fr
Publication of WO1991009864A1 publication Critical patent/WO1991009864A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals

Definitions

  • 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.
  • 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.
  • adenosine derivatives were studied for the purpose of improving pharmacological activity, imparting adenosine denase resistance, and reducing side effects, and attempted to develop them as pharmaceuticals.
  • 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.
  • adenosine 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.
  • 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].
  • 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).
  • ischemic heart diseases such as angina pectoris, heart failure, and myocardial infarction
  • ischemic brain diseases such as cerebral circulatory disorders.
  • 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.
  • 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.
  • 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.
  • 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)
  • n 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.
  • 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.
  • 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.
  • n is in the range of 2 to 13 and more preferably ⁇ 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 [ ⁇ ]
  • n represents an integer of 2 to 15
  • n represents an integer of 2 to 15
  • the alkyne is selected from those having the corresponding n number according to the kind of the compound of the present invention.
  • a basic solvent is used.
  • a mixed solvent of triethylamine and N, N-dimethylformamide can be used.
  • 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.
  • 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
  • the compound of the present invention 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • '' these powders and condyles Tablets may be tabletted as is, or with the addition of a lubricant such as magnesium stearate or talc.
  • 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.
  • an enteric base such as hydroxypropylmethylcell mouth-sphthalate, methyl methacrylate copolymer and the like
  • an enteric preparation or ethyl cellulose, carnaupa wax, hydrogenated oil, etc.
  • a sustained-release preparation can be obtained.
  • 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.
  • 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.
  • 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.
  • Flavoring agents, coloring agents, preservatives and the like may be added to these liquid preparations, if desired.
  • 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.
  • a pH adjuster such as sodium
  • an isotonic agent such as sodium chloride and glucose
  • mannitol, dextrin, cyclodextrin, gelatin, etc. may be added, and the mixture may be freeze-dried under vacuum to give a ready-to-use injection.
  • 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.
  • 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.
  • 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.
  • 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.
  • a pressure-sensitive adhesive such as rosin and alkyl acrylate polymer
  • 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.
  • a propellant such as front gas
  • 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 may be administered in single or divided doses Desirable.
  • 6-black mouth-2-hand-9-(2,3,5-tri-0-acetinole--D-ribofuranosyl) purine 6.
  • Japanese white male male egrets weighing 2.0 to 2.5 kg were used.
  • Platelet aggregation was measured using an aggregometer using a platelet aggregator (380 ⁇ l 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.
  • 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.
  • 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 °% ⁇
  • 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 °% ⁇
  • 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.
  • Hypoxia low oxygen conditions
  • 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.
  • 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).
  • mice 8-week-old male ICR mice (Clear Japan Ltd.) in groups of 13 to 15 mice.
  • 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.
  • Atmospheric pressure low-oxygen method compound Alkynyl dose Number of patients Average survival time (rag / kg)
  • Prussic acid reammosis-induced anoxia (anoxic condition) method Compound Alkynyl Amount administered Number of subjects Average survival time Group type-(mg / kg) (animal) (sec)
  • test drug dispensed proximate dynamic within the renal artery is expressed as ID 5Q value (amount bloodstream by administration of study drug is reduced by 50%), the results of Table 4 (A ) Column.
  • 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.
  • 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.
  • 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.
  • 2-alkynyladenosine an active ingredient of the drug of the present invention
  • it has an effect, and the appearance of an atrioventricular block in the myocardium of adenosine and adenosine derivatives known in the past. Things.
  • 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 ⁇ ⁇ renal blood flow ⁇ reduced effect, i.e., o
  • the safety margin is compared with conventional compounds 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.
  • 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).
  • 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.
  • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
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  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Médicament permettant de traiter ou de prévenir les affections ischémiques du c÷ur ou du cerveau, comprenant en tant qu'ingrédient principal une 2-alkynyladénosine représentée par la formule générale (I), dans laquelle n représente un nombre entier compris entre 2 et 15.
PCT/JP1990/000001 1990-01-04 1990-01-04 Medicament pour le traitement d'affections ischemiques du c×ur ou du cerveau WO1991009864A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/JP1990/000001 WO1991009864A1 (fr) 1990-01-04 1990-01-04 Medicament pour le traitement d'affections ischemiques du c×ur ou du cerveau
CA002041648A CA2041648A1 (fr) 1990-01-04 1990-01-04 Agent therapeutique - prophylactique pour les maladies ischemiques du coeur ou du cerveau

Applications Claiming Priority (1)

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PCT/JP1990/000001 WO1991009864A1 (fr) 1990-01-04 1990-01-04 Medicament pour le traitement d'affections ischemiques du c×ur ou du cerveau

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002536300A (ja) * 1999-02-01 2002-10-29 ユニバーシティ オブ バージニア パテント ファウンデーション 炎症反応を治療するための組成物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0219876A2 (fr) * 1985-10-25 1987-04-29 Yamasa Shoyu Kabushiki Kaisha Agents antihypertensifs contenant des adénosines-2-alkynyle comme ingrédients actifs

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0219876A2 (fr) * 1985-10-25 1987-04-29 Yamasa Shoyu Kabushiki Kaisha Agents antihypertensifs contenant des adénosines-2-alkynyle comme ingrédients actifs

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002536300A (ja) * 1999-02-01 2002-10-29 ユニバーシティ オブ バージニア パテント ファウンデーション 炎症反応を治療するための組成物
JP4837831B2 (ja) * 1999-02-01 2011-12-14 ユニバーシティ オブ バージニア パテント ファウンデーション 炎症反応を治療するための組成物

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