Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
  • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
  • C07C57/03—Monocarboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

• the present invention relates to a prophylactic and therapeutic agent for thrombosis.
• Thrombosis is a pathological phenomenon in which blood clots are formed by coagulation of blood platelets due to the aggregation of platelets in the heart or blood vessels of a living body. It causes stenosis and occlusion of blood vessels, and causes ischemic lesions and infarcts in major organs such as the heart, brain, and lungs, causing dysfunction of these organs and causing clinically serious diseases. You The causes of the above-mentioned thrombus formation have not been clearly elucidated so far. Forces, basically changes in the properties of blood vessel walls, changes in blood flow, and changes in blood components are considered as factors.
• platelet adhesion / aggregation factors such as recent coagulation factors, fibrinolytic factors, and prostaglandin, as well as reticular system functions, etc., are considered to be involved in the above thrombus and intravascular blood coagulation. Attention is being given. However, thrombosis occurs when the above factors are abnormally closely related to each other and are intertwined.
• Anticoagulants have been introduced. Typical examples are sodium citrate, heparin, coumarin derivatives, Indion derivatives are known, and these anticoagulants are not suitable for thrombus that has already been produced in view of their mechanism of action. dissolve the Les Effect is rather than, Ri total of the improvement of the blood clot ⁇ 0 binary states to follow, not only Ru effective der to prevent stomach Shi prevent recurrence of thrombosis. or recent years thrombus actively Enzyme preparations such as oral kinase and streptokinase have been developed as agents that dissolve and improve blood flow, that is, thrombolytic agents, especially antigen-free. In addition, non-pyrogenic peroxidase has been widely used in clinical practice 5.
• platelet hyperactivity is closely related to the formation of thrombus. It has been pointed out that, for its prevention or treatment, platelet function inhibitors, so-called antiplatelet agents such as platelet membrane stabilizers, adenylyl cycle activators, Inhibition of sponge esterase, aspirin, and inhibition of LASS (labile aggregatio n st imulat ing-sub s tance) production of phosphorus, non-steroid anti-inflammatory agents, etc.
• LASS labile aggregatio n st imulat ing-sub s tance
• the present invention relates to (all-Z) -4,7,10,13,16,19-docosahexaenoic acid and pharmacologically acceptable salts and esters of the acid.
• Thrombosis prevention and treatment characterized by the fact that it contains at least one species selected from the group consisting of There is one remedy.
• the prophylactic and therapeutic agent for thrombosis of the present invention is based on the use of the above-mentioned specific polyunsaturated fatty acids and their derivatives as active ingredients, and is used for deep vein thrombosis, limb thrombosis, and embolism.
• S It has an excellent effect on the prevention and treatment of various thrombosis such as pulmonary embolism, retinal vein thrombosis, coronary artery thrombosis, cerebral thrombosis, etc. obtain.
• the above-mentioned erectile component compound of the present invention has good absorbability from the intestinal tract, can be used internally, and is safe in blood. Therefore, the effect lasts for a long time, and it can be taken for a long period of time. Is not shown much.
• Esters and amito's can be used as the active ingredient similarly to the above compounds.
• the pharmacologically acceptable salts and esters are typically sodium salts, potassium salts, potassium salts, aluminum salts.
• the prophylactic and therapeutic agent for thrombosis of the present invention can be administered alone as an active ingredient compound, but is usually administered in the form of a pharmaceutical composition together with a pharmaceutical carrier.
• a pharmaceutical carrier Used as a carrier; fillers, extenders, binders, humectants, humectants, disintegrants, surfactants, lubricants commonly used to prepare medicinal products according to their form And diluents or excipients.
• various forms can be selected according to the purpose, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, and granules. Preparations, capsules, suppositories, injections (solutions, suspensions, etc.) and the like.
• the carrier may be, for example, lactose, sucrose, sodium chloride, sodium pudose solution, urea, starch, calcium carbonate.
• $ & Says $ & ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ Sugar, glucose, glycerin, starch solution, gelatin solution ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ Binders such as phenolic cellulose, cellulose, phenolic cellulose, phenolic lime, polyvinyl pyrrolidone, starch, and aldol Sodium sodium formate, powdered zinc, powdered aluminum, powdered sodium carbonate, calcium carbonate, touin, sodium rauryl sulfate Disintegration
• the carrier may be, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, etc.
• the carrier may be, for example, polyethylene glycol, viscose, high-grade alcohol, or high-grade alcohol. Esters, gelatin, semi-synthetic glycerides, etc. can be used. Prepared as injection ij
• solutions and suspensions are preferably sterilized and isotonic with blood, and may be used in the form of solutions, emulsions, and suspensions.
• diluents such as water, ethyl alcohol, propylene glycol, and ethoxylate fetal isosteryl alcohol , Polio fiso d'isosteal real call, poliox ethylensolbito, solvitan ester, etc. can be used.
• glycerin may be contained in the preparation in an amount sufficient to prepare an isotonic solution, such as salt and glucose.
• antioxidants for example, butylated hydroxytoluene, propyl gallate, quinone , And-Tocopherol, etc., as well as conventional solubilizers, buffers, soothing agents, preservatives, coloring agents, flavors, flavors, sweeteners, and other pharmaceuticals Sase! This can be done, and certain antioxidants may promote anti-thrombotic effects.
• the amount of the active ingredient compound to be contained in the pharmaceutical composition is not particularly limited and may be widely selected, but is usually in the whole composition / weight.
• the active ingredient compound of 2 to / is almost equivalent to the free acid weight based on the weight of free acid when using the agent as an example. 1 included .
• the agent for preventing and treating thrombosis of the present invention is not particularly limited in its use, and may be administered in a method according to various forms.
• tablets, pills, solutions, suspensions, emulsions, granules In the case of injections, it is administered orally, and in the case of injections, it is administered as a simple mixture with normal replenisher such as glucose and amic acid and administered intravenously.
• Intramuscularly, intradermally, subcutaneously or intraperitoneally, alone as needed, rectally in the case of suppositories, and intracavity in the case of women Can be administered.
• the dosage of the preparation C is appropriately selected according to the administration method, the patient's symptoms, etc., and generally the active ingredient compound is expressed in terms of free acid in terms of free acid / / to so mg / k ⁇ -day. , Preferably ⁇ 2 ⁇ ⁇ . i73 ⁇ 4 3 ⁇ 4i.day, which is usually divided into j to j times per day o
• the present invention also provides a prophylactic and therapeutic agent for thrombosis in a food form containing such a specific fat or oil.
• a prophylactic and therapeutic agent for & thrombosis which is not considered a conventional example, is provided.
• FIG. 2 shows the inhibitory effect of the compounds of the present invention on platelet aggregation induced by ADP, collagen and arachidonic acid, respectively.
• the graphs show changes over time in the turbidity (absorbance) of the blood sample used in the experimental examples.
• (1) indicates the test compound concentration S00lA
• (2) indicates the test compound concentration. Same concentration 0
• a collagen to be used as a platelet aggregation inducer As a collagen to be used as a platelet aggregation inducer, a collagen reagent “Horm” manufactured by Hormon Chemie (Nishi-Ata) was used. In the form of saline solution, ADP and arachidonic acid are available from Sigma, respectively.
• OMPI ⁇ Use as a saline solution and an ethanol solution, respectively.
• the platelet count in the plasma obtained by the centrifugation at // ⁇ rpm above is determined by the following formula: and, the Re this diluted Let 's platelet count that Do the X / 0 8 or above P PP to prepare a PRP (platelet rich plasma).
• O PI i ADP solution i prepared with physiological saline or ethanol to a concentration that gives 20 jx9 / m for gen and 50 i9ZmT for arachidonic acid, and collagen Solution 20 Hi and arachidonic acid solution / ⁇ are respectively added to induce platelet aggregation.
• the platelet aggregation inhibitory effect of the test compound at each concentration is examined by continuously recording the turbidity change (absorbance change) caused by the above-mentioned stagnation. .
• FIG. 10 is a graph showing a similar platelet aggregation inhibitory effect at a time of / min.
• the horizontal axis represents time
• the vertical axis represents absorbance change.
• the middle curve (1) is the concentration of the test compound at SOO /
• the line (2) is 2S0fi9 / n
• the curve is 9 / m
• the curve is the control solution (with no test compound added, control), the curve (S) EPA for comparison
• the active compound of the present invention is susceptible to any platelet aggregation induced by ADP, collagen and arachidonic acid.
• ADP platelet aggregation induced by ADP, collagen and arachidonic acid.
• the preferred degree of application is slightly different, it is evident that it has a sufficient inhibitory effect.
• the active ingredient compound of the present invention has an inhibitory effect about ⁇ 2 times that of the active ingredient compound. It is found to be effective as a therapeutic agent.
• Fig. 7 shows the results of the inhibitory effect on ADP-induced platelet aggregation
• Fig. 7 shows the results of inhibition of collagen-induced platelet aggregation
• Fig. 7 shows the results of inhibition on collagen-induced platelet aggregation
• Fig. 7 shows the inhibition of arachidonic acid-induced platelet aggregation.
• the result of production II ? Each is shown in the figure. In each figure, curve (1) does not show the test compound, and the curve does not show the control raft (control).
• test compound 5 mid was used as the test compound, which was dissolved in soo-ethanol.
• OMPI («2 ri; am, inner diameter / 3 n).
• the extracorporeal circuit was filled with saline containing heparin (Z00 to ⁇ 00 units) and kept in a thermostat kept at soil / ° C.
• ADP / from the front of the above filter Administer 5 saline solutions in about 5 transfers to induce platelet aggregation. The force before and after the filter is measured, and the difference is calculated and used as an indicator of the degree of cohesion. After administration of ADP J times every minute, calculate the above difference, determine the degree of coagulation of the control ⁇ -l, and continue the test compound! ?

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Citations (2)

• 1980
  • 1980-06-27 JP JP8807280A patent/JPS5735512A/ja active Granted
• 1981
  • 1981-06-27 WO PCT/JP1981/000148 patent/WO1982000095A1/ja not_active Ceased
  • 1981-06-27 GB GB8204905A patent/GB2090529B/en not_active Expired

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