Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
  • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/40—Oxygen atoms
  • C07D211/44—Oxygen atoms attached in position 4
  • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• the present invention relates to an ischemic cardioplegic agent and a therapeutic agent for angina pectoris containing a molanolin derivative as an active ingredient.
• Surgical treatment for patients with severe angina includes PTCA.
• a special catheter with a balloon at the tip is inserted into the stenosis of the coronary artery, which is the artery that sends blood to the heart muscle, and the stenosis is inflated with a balloon to expand the blood vessel lumen and improve blood flow.
• the balloon blocks the blood flow in the coronary arteries, causing myocardium to become bloody, causing cardiomyocyte necrosis and pain.
• minimizing such damage to the myocardium is one of the very important conditions for reducing the invasion to the patient.
• there are no known drugs to control such damage It is expected from a medical point of view that protection of myocardium in blood, for example, damage caused by blood in PTCA surgery, is expected from a medical point of view, and development of a new drug is desired.
• the compound represented by the general formula [I] is known to have a brassin inhibitor inhibitory activity (Japanese Patent Publication No. 7-51505).
• Brasmin inhibitors can be used as thrombolytic agents because they activate brassmin.
• Jill thrombolytics restore blood flow by relieving thrombus and blood vessels such as acute myocardial infarction and pulmonary disease, and protect the myocardium itself during blood bleeding like the compound according to the present invention. It does not do.
• the compound according to the present invention has a glucosidase inhibitory activity (Japanese Patent Publication No. 59-43459, Japanese Patent Application Laid-Open No. 62-205455), but a substance having a glucosidase inhibitory activity has a protective effect on blood myocardium. No examples have been reported to have. Disclosure of the invention
• An object of the present invention is to provide a IS (IS ⁇ cardiomyocyte protective agent) and a compound useful as a therapeutic agent for angina based on its action.
• the present inventors diligently searched for a drug having an inhibitory action on myocardial necrosis. As a result, they found that the compound represented by the general formula [I] has a convenient protective action on blood myocardium as described below. Completed the invention. That is, the present invention relates to a protective agent for ischemic myocardium and a therapeutic agent for angina pectoris, which contains a compound represented by the following general formula [I] as an active ingredient.
• the protective effect on blood myocardium refers to an effect of suppressing the necrosis of spontaneous cardiomyocytes in the blood site, which occurs after the blood flow of the myocardium that has fallen into blood is restored.
• R 1, R 2, R 3 are the same or different, hydrogen, Ashiru number 1 1 2 carbons, hexane carbonyl to consequent opening, alkoxy ⁇ cetyl from 3 1 0 carbon atoms, 1 to 4 carbon atoms Is the alkyl or naphthylcarbonyl optionally substituted by halogen, the phenyl having 1 to 4 carbon atoms or the number of carbon atoms optionally substituted by halogen?
• A represents CH or N.
• R 4 represents hydroxy
• R 5 represents alkylamino optionally substituted by one or two hydroxy
• R s represents hydroxymethyl or acyloxymethyl.
• R 6 represents hydrogen, and represents hydroxymethyl or C 2-7 acyloxymethyl.
• R 5 is an alkyl group having 1 to 30 carbon atoms which may be substituted by hydroxy, or a carbon number in which the aryl moiety may be substituted by hydroxy, carboxy or alkoxycarbonyl?
• R 3 form a ring, and represent the following general formula [II].
• R 2 , R 3 up to 12 is a straight chain or a branched straight chain Can be mentioned.
• formyl, acetyl, propionyl, butyryl, norrelyl, isovaleryl, vivaloyl, lauroyl and the like can be mentioned.
• alkoxyacetyl having 3 to 10 carbon atoms represented by R l , R 2 and R 3 examples include straight-chain or branched-chain alkoxyacetyls.
• methoxyacetyl, ethoxyacetyl, bropoxyacetyl, isobutyloxyacetyl, neopentyloxyacetyl, isohexyloxyacetyl, and octyloxyacetyl can be exemplified.
• naphthylcarbonyl which may be substituted with alkyl or halogen having 1 to 4 carbon atoms include 7-methyl-11-naphthylcarbonyl, 8-chloro-12-naphthylcarbonyl, 6-ethyl-2-naphthylcarbonyl , 5-bromo-11-naphthylcarbonyl, 5-butyl-1-naphthylcarbonyl and the like.
• Examples of the pyridinecarbonyl which may be substituted with alkyl having 1 to 4 carbon atoms or halogen include 2-ethylpyridine-4-carbonyl, 3-butylpyridine_5-carbonyl, 2-cyclopyridine-14-carbonyl, 3-bromoviridine-15-carbonyl and the like.
• dihydropyridine carbonyl which may be substituted with alkyl having 1 to 10 carbon atoms
• dihydropyridine carbonyl which may be substituted with alkyl having 1 to 10 carbon atoms
• 2-ethyl-1,4-dihydroviridine-14-carbonyl N-butyl-1,4-dihydropyridine-14-carbonyl
• N-octyl-1,4-dihydropyridine-14-carbonyl and the like.
• Examples of thiophenecarbonyl which may be substituted with alkyl having 1 to 4 carbon atoms include 2-methylthiophene-3-carbonyl, 2-isopropylthiophene-14-carbonyl, and 3-t-butylthiophene-141 And carbonyl.
• furylcarbonyl which may be substituted with alkyl or halogen having 1 to 4 carbon atoms include 2-ethylfuryl-1-carbonyl, 2-propylfuryl-14-carbonyl, and 3-isobutylfuryl-4-carbonyl. And the like.
• Benzene ring is alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons, halogen, Rifle-methyl, C-4 alkylsulfonyl, C1-C4 alkylmer, butano, cyano or dimethylamino which may be substituted with 2-methylpentyl, 3-ethylbenzyl, 4-isobromide Pyrbenzyl, 4-isobutylbenzyl, 2-ethoxybenzyl, 3-propoxybenzyl, 4-butoxybenzyl, 4-chlorobenzyl, 3-fluorobenzyl, 2-bromobenzyl, 4-trifluoromethylbenzyl, 3-triflu Romethylpendyl, 2-trifluoromethylbenzyl, 4-ethylsulfonylbenzyl, 3-bromosulfonylbenzyl, 4-butylsulfonylpentyl, 2-methylmerbutobenzil, 3-ethylmerbutbutenyl, 4-
• the alkyl hydroxyalkyl optionally substituted with Amino represented by R 5 the number of carbon atoms of straight or branched] ⁇ 1 0 alkyl include et al are of, Examples thereof include 2-hydroxyethylamino, 2,3-dihydroxybutyrylamino, isopropyramino, and 2-hydroxy-11- (hydroxymethyl) ethylamino.
• acyloxymethyl represented by R 6 examples include linear or branched ones having 1 to 10 carbon atoms.
• formyl, acetyl, propionyl, butyryl, norrelyl, isovaleryl, vivaloyl, lauroyl and the like can be mentioned.
• examples of the acyloxymethyl represented by R 4 include straight or branched ones having 1 to 30 carbon atoms.
• formyl, acetyl, bropionyl, butyryl, valeryl, isovaleryl, vivaloyl, lauroyl and the like can be mentioned.
• A is a alkyl optionally substituted by hydroxy, represented by R 5, it may be mentioned straight-chain or branched alkyl having 1 to 30 carbon atoms.
• Unsubstituted alkyl ⁇ hydroxymethyl such as methyl, ethyl, propyl, cyclopropyl, 'isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, decyl, eicosyl, triacontyl, 2-hydroxyshethyl, 3-hydroxypropyl, 2-hydroxycyclopropyl, 1-hydroxymethylethyl, 4-hydroxybutyl, 2-hydroxymethylpropyl, 5-hydroxypentyl, 3-hydroxymethylbutyl, hexyl, 4-hydroxymethyl
• Examples include hydroxyalkyl such as pentyl, 9-hydroxynonyl and 10-hydroxydecyl.
• R s represents aryloxyalkyl in which the aryl moiety may be substituted with hydroxy, carboxy or alkoxycarbonyl.
• examples of the alkoxy moiety of the alkoxycarbonyl substituted at the aryl moiety include straight-chain or branched ones having 1 to 10 carbon atoms, such as methoxy, propoxy, pentoxy and hexoxy. And deshiki kishi.
• the alkyl moiety of aryloxyalkyl includes straight or branched ones having 1 to 10 carbon atoms, such as 4- (4-hydroxyphenoxy) butyl, 5- (3,5-dihydroxy). Phenoxy) pentyl, 3- (4-carboxyphenoxy) propyl, 2- (4-ethoxycarbonylphenoxy) ethyl and the like.
• R s represents aryl alkenyl having 8 to 14 carbon atoms in which the benzene ring may be substituted with cyano, carboxy, alkoxy, alkoxyalkoxy, or alkyl.
• alkoxy is a straight or branched C 1 to C 4 carbon atom, and includes methoxy, ethoxy, propoxy, butoxy and the like.
• alkoxyalkoxy include those having 3 to 10 carbon atoms, such as methoxetoxy, ethoxyethoxy, ethoxybroboxy, and propoxybutoxy.
• alkyl examples include straight or branched ones having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.
• the compound represented by the above general formula (h) can be produced, for example, by the method described in Japanese Patent Publication No. 59-43459, International Publication W095 3068, Japanese Patent Application Laid-Open No. Can be.
• the compound of the present invention can be used for treatment as it is in the form of free amine, but can be used in the form of a pharmaceutically acceptable salt by a known method.
• Salts include salts of mineral acids such as hydrochloric acid, hydrobromic acid, 3 ⁇ 43 ⁇ 4m, and phosphoric acid, acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, P-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid. And the like, and salts of organic acids.
• the hydrochloride of the compound according to the present invention can be obtained by dissolving it in an alcohol solution of hydrochloric acid.
• the present invention also includes solvates of the compound of the present invention or a salt thereof).
• the solution may be obtained by recrystallizing the chain to be dissolved from a corresponding solvent or a suitable mixed solvent containing the corresponding solvent.
• the ⁇ compound of the compound according to the present invention may be obtained by recrystallizing a hydrous alcohol.
• the compounds according to the present invention may be in a polymorphic form.
• the polymorph is also included in the present invention.
• the medicament of the present invention When the medicament of the present invention is administered, it may be administered alone, or may be applied in combination with or mixed with a drug that can be administered simultaneously.
• the conjugate of the present invention can be used as a pharmaceutical composition containing, for example, 0.016 to 99.5%, preferably 0.1% to 906 in a nontoxic and inert carrier which is pharmaceutically acceptable or not. It can be administered to animals containing it.
• Carriers include solid, semi-solid, or liquid diluents, fillers, and other One or more auxiliaries are used.
• the pharmaceutical composition is desirably administered in a unit dosage form.
• the pharmaceutical composition of the present invention can be administered by injection, intratissue administration, topical administration (such as transdermal administration), or rectally. Needless to say, it is administered in a dosage form suitable for these administration methods. For example, oral administration and intradermal administration (particularly intravenous administration) are preferred.
• the dose as an ischemic cardioplegic agent or a therapeutic agent for angina pectoris should be adjusted taking into account the patient's condition such as age and weight, the administration route, the nature and extent of the disease, etc.
• the amount of the active ingredient of the present invention per day is generally in the range of ( ⁇ to ⁇ days human, preferably lg to 5 gZ days / human. A dose less than this is sufficient, or conversely, a larger dose may be required, and it is preferable to administer the drug in 2 or 3 times a day. It is desirable.
• solid or liquid dosage units such as powders, powders, fine granules, tablets, dragees, films, capsules, granules, suspensions, liquids, syrups, drops, sublingual tablets It can be done with other dosage forms.
• Powders are prepared by comminuting the compound of the present invention to an appropriate degree. Powders are prepared by comminuting the compound of the present invention with a suitable finely divided material and then admixing it with a similarly finely divided pharmaceutical carrier, for example, edible carbohydrates such as batter, mannitol and the like. If necessary, flavoring agents, preservatives, dispersing agents, coloring agents, flavors and the like may be added.
• a suitable finely divided material for example, edible carbohydrates such as batter, mannitol and the like.
• a similarly finely divided pharmaceutical carrier for example, edible carbohydrates such as batter, mannitol and the like.
• flavoring agents, preservatives, dispersing agents, coloring agents, flavors and the like may be added.
• the force busel is prepared by filling the powdered powder, powder or tablet granulated as described above in a capsule shell such as gelatin capsule, as described in the section on powder.
• Lubricants and superplasticizers such as colloidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol are mixed with the powdered state, and then the filling operation is performed. You can also do it.
• Disintegrants and solubilizers such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, calcium carbonate, and sodium carbonate In addition, it can improve the efficacy of the medicament when ingested.
• the fine powder of the compound according to the present invention can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, or a surfactant, and wrapped with a gelatin sheet to form a soft capsule.
• Tablets are prepared by adding an excipient to form a powder mixture, granulating or slugging, and then adding a disintegrant or lubricant or by tableting the powder mixture directly.
• the powder mixture is made by mixing the appropriately powdered material with the above-mentioned diluents and bases and, if necessary, a binder (e.g., sodium carboxymethylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxybutyl propylmethylcellulose, gelatin, Polybutylpyrrolidone, polybutyl alcohol, etc.), dissolution retardant (eg, paraffin, wax, hydrogenated castor oil, etc.), resorbent (eg, quaternary salt) and adsorbent (eg, bentonite, kaolin, diphosphate) ) May also be used in combination.
• a binder e.g., sodium carboxymethylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxybutyl propylmethylcellulose, gelatin, Polybutylpyrrolidone, polybutyl alcohol, etc.
• dissolution retardant eg, paraffin, wax, hydrogenated castor oil, etc.
• the powder mixture can be first moistened with a mixing agent, for example, syrup, starch paste, gum arabic, a cellulose solution or a macromolecular substance solution, stirred and mixed with iR, dried and pulverized to obtain granules.
• a mixing agent for example, syrup, starch paste, gum arabic, a cellulose solution or a macromolecular substance solution
• iR i-molecular substance solution
• the granules thus produced can be prevented from adhering to each other by adding stearic acid, stearic acid salts, talc, mineral oil and the like as a lubricant.
• the mixture thus lubricated is then tableted.
• the uncoated tablets thus produced can be coated with a film-coated sugar coating.
• the compound according to the present invention may be directly tableted after mixing with a fluid inert carrier without going through the steps of granulating and slagging as in ⁇ ⁇ .
• a transparent or translucent protective coating consisting of a shellac hermetic coating, or alternatively or overlying a coating of sugar or a polymeric material, and a polishing surface consisting of a wax may also be used.
• oral dosage forms such as solutions, syrups, elixirs and the like can also be presented in dosage unit form so that a given quantity contains a fixed quantity of a compound according to the invention.
• the sylob is produced by dissolving the compound of the present invention in an aqueous solution containing a suitable sweetener.
• Xyl is produced by using a non-toxic alcoholic carrier.
• a clouding agent is formulated by dispersing the compound of the present invention in a non-toxic carrier.
• Solubilizers and emulsifiers eg, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters
• preservatives eg, ⁇ pamint oil, saccharin
• flavoring agents eg, ⁇ pamint oil, saccharin
• dosage unit formulations for oral administration can be microencapsulated.
• the formulation can also provide an extended period of action or sustained release by coating or embedding in polymers, waxes and the like.
• Intrathecal administration can be carried out using liquid dosage unit forms for subcutaneous or intramuscular or intravenous injection, for example, in the form of solutions or suspensions.
• a fixed amount of the compound of the present invention is suspended or dissolved in a non-toxic liquid carrier suitable for injection, such as an aqueous or oily medium, and the suspension or solution is sterilized. It is manufactured by Non-toxic salts or salt solutions may be added to make the injection solution isotonic.
• Rectal administration can be carried out by preparing the compound of the present invention as a solid soluble or insoluble in water having a low melting point and using a suppository.
• the compound of the present invention is N-methylapane 100 mg, lactose 25 mg, corn starch 10 mg, low-substituted hydroxybutyral cellulose 7.5 mg, hydroxypropyl propyl cellulose 2.5 mg, magnesium stearate Tablets were prepared according to a conventional method so as to contain 5 mg.
• An elution agent was prepared according to a conventional method using distilled water for injection to contain 100 mg of N-methylmoranoline and 45 mg of sodium chloride as the compound of the present invention per tube (5 ml). Ischemic myocardium protective action of the compound according to the present invention
• the occluder was tightened to occlude the left coronary artery and render the downstream area ischemic. 3 (3 ⁇ 43 ⁇ 4) After that, the occluder was loosened to reopen the coronary arteries, and the perfusion area was reperfused. Two trials were performed, one minute before and five minutes before resumption (Table 1).
• p-methylmoranoline was dissolved in physiological saline and used, and as a control, physiological saline was used.
• physiological saline was used.
• Two days after reperfusion the silk thread used for occlusion was loosely tied, and the chest was closed with negative pressure in the thoracic cavity.
• the cannula inserted into the jugular vein was removed, and the ligation was performed after hemostasis. ⁇ ⁇ After confirming that the heron awakened from anesthesia and breathed spontaneously, the tracheal tube was removed.
• the heron was intravenously administered with 1000 units of heparin, and three minutes later, pentobarbital was intravenously administered and euthanized.
• the chest was opened and the heart was excised and immersed in physiological saline. After ligating the coronary artery, a tube was inserted into the artery and 4% monastral blue was injected. The left ventricle was cut into 5 pieces, and the section was immersed in a 1% triphenyltetrazolium chloride (TTC) solution, photographed, and weighed.
• TTC triphenyltetrazolium chloride
• IN Infarct area volume
• AAR Danger area volume
• Intravenous administration The drug was dissolved in physiological saline, 1N HC1, and DMSO and administered to the femoral vein 3 mm before the occlusion of the left coronary artery.
• the rats were anesthetized with pentobarbital 60 mg kg ip, and 50 units of heparin was administered from the femoral vein.
• the heart is removed and immediately suspended on the Langendorff device Then, the blood was washed with heparinized saline (100 IU / ml) to wash out the blood. Then, the coronary artery was ligated with the remaining silk thread, and the circuit was switched to 3% monastral blue solution, and 0.25 ml of the solution was flown.
• Photomicrographs (volaroid camera, Olympus) of a section of the heart base of a formalin-fixed myocardial slice under a microscope and magnified approximately 5 times Left ventricle and danger zone (portion not stained with Monastral Bull) The infarct area (the area not stained by TC staining) was transferred to an OHP film, and the area of each area was measured using a digitizer and a computer. ) was calculated.
• Table 3 shows the ratio of the infarcted area to the critical area between the group to which the compound of the present invention was administered once (Compounds 1 to 6, Cast, BUCAS T) and the group to which only saline was administered as a control (Saline).
• the pharmacological effect of the compound according to the present invention was confirmed.
• the ratio was 31.0% for Compound 1, 66.8% for Compound 2, 65.1% for Compound 3, and 65.1% for Compound 3. 45.6%, 49.3% for compound 5, 29.3% for the compound 6, 419% for castanospermine, 21.3% for BUCAST, and the compound according to the present invention significantly reduces the proportion of the infarct area. It turned out to be.
• Table 4 shows the ratio of the infarcted area to the dangerous area in the group to which the compound according to the present invention was administered once (Compounds 1, 2, 4, 7, Cast, BUCAST) and the untreated group (Control) as a control. Comparison Then, the pharmacological effect of the compound according to the present invention was confirmed.
• the compound according to the present invention significantly reduced the proportion of the infarct area by 31.3% in the administration 3 hours before 41.3%, 21.3% in the administration 2 hours before administration of the compound 7, and 15.7% in the administration 1 hour before BUCAST. It turned out to be.
• the compound according to the present invention when administered to humans or animals in the form of a free form, a salt thereof or a solution thereof, has a remarkable protective effect on blood and myocardium and has a remarkably low toxicity. It is suitable as a cardiomuscular protective agent and a therapeutic agent for angina based on its action.
• the compound according to the present invention has a protective effect on blood myocardium, it is possible to secure a longer balloon dilatation time during PTCA, and more sufficient blood vessel dilation to reduce the incidence of restenosis. can do.

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• 1997
  • 1997-01-15 ZA ZA97324A patent/ZA97324B/xx unknown
  • 1997-01-17 WO PCT/JP1997/000071 patent/WO1997025987A1/ja active Application Filing
  • 1997-01-17 AU AU13989/97A patent/AU1398997A/en not_active Abandoned

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