CN1200122A - Lubeluzole N-oxide - Google Patents
Lubeluzole N-oxide Download PDFInfo
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- CN1200122A CN1200122A CN96197774A CN96197774A CN1200122A CN 1200122 A CN1200122 A CN 1200122A CN 96197774 A CN96197774 A CN 96197774A CN 96197774 A CN96197774 A CN 96197774A CN 1200122 A CN1200122 A CN 1200122A
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- oxide
- lubeluzole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention is concerned with lubeluzole N-oxide(s), compositions containing the N-oxide(s), methods of preparing these and their use as a medicine, in particular in the treatment of conditions involving cerebral hypoxia.
Description
The present invention relates to neuroprotective Lubeluzole (lubeluzole) N-oxide compound, the composition that contains this N-oxide compound and their preparation method and as the application of medicine, in particular for treatment cerebral anoxia disease.
In patent US-4861786, once reported to have anti-hypoxia or active benzoxazole amine of anti-hypoxia disease and benzothiazole amino derivative.Patent WO-92/14731 has also disclosed some benzothiazole amino derivatives and has had the activity of useful anti-stroke.The injectable formulation of (S)-4-((2-[4-morpholinodithio base) methylamino-)-α-((3,4-two fluorophenoxies) methyl)-1-piperidines ethanol (being commonly referred to Lubeluzole) is disclosed in european patent application No.94203422.4 (November 24 1994 date of application).
The cerebral anoxia disease comprises apoplexy (especially hematencephalon under ischemic stroke, intracerebral hemorrhage, the spider retina) and head trauma.The method of current treatment cerebral anoxia disease mainly comprises neuroprotective and hematological methods of treatment.Better methods of treatment is still in exploration.Should preferred method for the treatment of anoxia be research theme of the present invention.Especially the present invention provides a new drug-lubeluzole N-oxide and pharmaceutically useful acid salt, solvate or their three-dimensional chemical isomer for treatment cerebral anoxia disease.This medicine is applicable to venoclysis and intracutaneous infusion, and concerning the cerebral anoxia patient, this is optimum route of administration, also can be taken orally, and keeps treatment and oral administration is the most suitable.The animal model test of acute apoplexy shows that the cis lubeluzole N-oxide is better than Lubeluzole to the provide protection of nerve.
Lubeluzole N-oxide means and comprises that one or more nitrogen-atoms are oxidized in the Lubeluzole structure, especially wherein the oxidized compound that obtains of nitrogen-atoms on the piperidine ring.
The invention particularly relates to lubeluzole N-oxide, its cis and trans forms, its structure is as follows:
(cis (S))
(trans (S))
Pharmaceutically useful acid salt comprises the form of the non-toxic salt with therapeutic activity, can make by free alkali and certain acid-respons, and described acid has mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid; Or organic acid such as acetate, propionic acid, hydroxyethanoic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, tartrate, citric acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid, cyclohexane sulfamic acid, Whitfield's ointment, para-aminosalicylic acid and two naphthalene Whitfield's ointment.The solvate of lubeluzole N-oxide has for example hydrate, alcohol adduct.
The lubeluzole N-oxide that preferably has cis-structure, and the most preferred with (-)-(suitable) lubeluzole N-oxide semihydrate.
The preparation of lubeluzole N-oxide is to be undertaken by the oxide compound already known processes for preparing nitrogenous compound.Lubeluzole is dissolved in the solvent, and adding the suitable oxygenant of capacity can make easily.The example of described oxygenant has hydrogen peroxide, peroxy acid such as metachloroperbenzoic acid, metal oxide such as sodium wolframate etc.The solvent that is suitable for has for example water and halohydrocarbon, especially methylene dichloride.
Except as otherwise noted, the amount of each composition is with its weight the per-cent of overall solution volume to be represented otherwise in the liquid composition.Except as otherwise noted, the amount of each composition is with its weight the per-cent of composition total weight to be represented otherwise in the solids composition.
The medicinal compositions that the present invention is suitable as the lubeluzole N-oxide of medicine comprises: pharmaceutically the activeconstituents of effective dose and one or more pharmaceutically useful in this technical field known vehicle or carrier.Described medicinal compositions is fit to by oral or non-through gi tract administration (comprising intramuscular, subcutaneous, intracutaneous and intravenously administrable).Described formulation most convenient be to exist with the discrete dosages unit.In general, the required pharmaceutically acceptable carrier aqueous solution (a) of preparation neuroprotective lubeluzole N-oxide transfusion comprising: water; Isotonic agent; Can regulate acid, alkali or the buffer substance of pH value of solution value scope between 2.5～3.6.
Should be noted that the concentration range of lubeluzole N-oxide is 0.005%～5% in the described solution (a), wherein better with 0.01%～1%, 0.02%～0.2% is better, and about 0.05% is best.
What be worth further specifying is that solution (a) can contain 1～10% isotonic agent.Using glucose is to obtain very clear soln as the advantage of isotonic agent.The glucose concn scope of using is 2～10% better, and concentration is about 5% best.
Solution (a) also contains acid and alkali, so that pH value of solution remains between 2.5～3.6, with better between 3.0～3.4, is preferably about 3.2.The pH value of solution (a) is preferably regulated with an amount of hydrochloric acid and sodium hydroxide.The buffering system of the mixture composition of also available an amount of other acid (as phosphoric acid, tartrate or citric acid) and alkali (especially sodium hydroxide) is regulated.
For increasing the solubleness of lubeluzole N-oxide in the described composition, can adopt solubilizing agent.Commonly used have cyclodextrin (CD) and a derivative thereof.Suitable cyclodextrin derivative have α-, β-, γ-Huan Hujing and ether or mixed ether, wherein the unitary one or more hydroxyls of the dextrose anhydrous of cyclodextrin are by C
1～6Alkyl (especially methyl, ethyl or sec.-propyl) replaces, for example any methylated β-CD; Hydroxyl C
1～6Alkyl (especially hydroxyethyl, hydroxypropyl or hydroxyl butyl)-CD; Carboxyl C
1～6Alkyl (especially carboxymethyl or propyloic)-CD; C
1～6Alkyl-carbonyl (especially ethanoyl)-CD; C
1～6Alkoxy carbonyl C
1～6Alkyl or carboxyl C
1～6Alkoxy C
1～6Alkyl (especially carboxymethoxyl propyl group or carboxylic ethoxycarbonyl propyl)-CD; C
1～6Alkyl carbonyl oxy C
1～6Alkyl (especially 2-acetoxyl group propyl group)-CD.Especially the solubilizing agent that is worth emphasizing is β-CD, 2,6-dimethyl-β-CD, any methylated β-CD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and (2-carboxymethoxyl) propyl group-β-CD more merit attention with 2-hydroxy propyl-Beta-CD again.
Term mixes ether and is meant that the oh group that wherein has two cyclodextrin at least carries out the cyclodextrin derivative that etherificate obtains with different groups (as hydroxypropyl, hydroxyethyl).
Molar average substitution value (M.S.) is the average mol that is used to weigh the oxyalkyl units of every mole of dextrose anhydrous.M.S. being worth available different analytical technology such as nucleus magnetic resonance (NMR), mass spectrum (MS) and infrared spectra (IR) measures.According to the difference of selected technology, the M.S. numerical value that a certain given cyclodextrin derivative is recorded may have difference slightly.The cyclodextrin hydroxyalkyl derivant that is used for the present composition is 0.125～10 with the M.S. scope of mass spectrometric determination, is generally 0.3～3, or 0.3～1.5.Preferred 0.3～0.8, be more preferably 0.35～0.5, preferably 0.4.The M.S. scope of measuring with NMR or IR is 0.3～1 better, especially with 0.55～0.75 for well.
Average substitution degree (D.S.) refers to the mean number of substituted hydroxyl in each anhydrous grape sugar unit.D.S. also available different analytical technology of value such as nucleus magnetic resonance (NMR), mass spectrum (MS) and infrared spectra (IR) record.According to selected technological method, also may be variant slightly to the D.S. numerical value that a certain given cyclodextrin derivative records.The cyclodextrin derivative that is used for the present composition is 0.125～3 with the D.S. scope of mass spectrometric determination, more commonly 0.2～2 or 0.2～1.5, and preferable range is 0.2～0.7, is more preferably 0.35～0.5, preferably 0.4.The D.S. scope of measuring by NMR or IR is 0.3～1 better, is more preferably 0.55～0.75.
Be used for the present composition more specifically β-and the γ-Huan Hujing hydroxyalkyl derivant be the substituted cyclodextrin derivative of part, wherein the hydroxyl of anhydrous grape sugar unit different positions by the average degree that alkyl replaces is respectively: 3 are about 0%～20%, 2 are about 2%～70%, 6 and are about 5%～90%.Unsubstituted β-or the amount of γ-Huan Hujing be no more than the 5% better of cyclodextrin total content, serve as better especially to be less than 1.5%.In addition, other useful especially cyclodextrin derivative are any methylated beta-cyclodextrins.
Being used for the better cyclodextrin derivative of the present composition is beta-cyclodextrin ether or the mixed ether with hydroxypropyl, the substituent part replacement of hydroxyethyl (especially 2-hydroxypropyl and/or 2-(1-hydroxypropyl)).
Be used for the best cyclodextrin derivative of the present composition and be the M.S. value between 0.35～0.5, and contain the hydroxypropyl-beta-cyclodextrin that is no more than 1.5% unsubstituted beta-cyclodextrin.Better between 0.55～0.75 with the M.S. value that NMR or IR method are measured.
For reduce the possibility that side reaction takes place as far as possible, intravenously administrable (or intradermal administration) preparation preferably contains the least possible composition.Therefore, preferably select the preparation of no solubilizing agent (as cyclodextrin) for use.In addition, the solution (a) with neuroprotective effect does not preferably contain sanitas.But then, oral liquid both can contain solubilizing agent (as cyclodextrin), also can contain one or more sanitass.
The invention particularly relates to neuroprotective agent solution (a), its composition is:
(i) 0.005～5% lubeluzole N-oxide or pharmaceutically useful additive salt or its solvate;
(ii) 1～10% isotonic agent;
(iii) be used for acid and/or the alkali of regulator solution pH value between 2.5～3.6;
(iv) add suitable quantity of water to 100%.
Neuroprotective agent solution (a) involved in the present invention preferably contains:
(i) 0.01～1% lubeluzole N-oxide or pharmaceutically useful additive salt or its solvate;
(ii) 2～10% glucose;
(iii) hydrochloric acid and the sodium hydroxide of regulator solution pH value between 3.0～3.4;
(iv) add suitable quantity of water to 100%.
Neuroprotective agent solution (a) involved in the present invention preferably contains has an appointment:
(i) 0.05% lubeluzole N-oxide or pharmaceutically useful additive salt or its solvate;
(ii) 5% glucose;
(iii) hydrochloric acid and sodium hydroxide, regulator solution pH value is about 3.2;
(iv) add suitable quantity of water to 100%.
Solution (a) is sterilized with known technology.
The solution that neuroprotective is arranged (a) that contains product of the present invention can be advantageously used in treating the acute anoxia patient.In general, be included in for effective treatment of acute anoxia disease in the 1st hour of treatment, give patient's infusion solution (a) 10～30ml or 5～10mg lubeluzole N-oxide.In 24 hours subsequently, should give the medicine of 4/3 or 133% above-mentioned dosage again.Also say so, their early stage will reduce then gradually with relatively large dosage.Also a couple of days gives the medicine of maintenance dose continuously simultaneously.
Treatment plan is preferably: give the solution or the 7.5mg effective constituent of patient's infusion 15ml effective constituent in the 1st hour of treatment, and gave the solution or the 10mg effective constituent of 20ml effective constituent again in 24 hours subsequently.Obviously, above-mentioned effective dose can be taken the circumstances into consideration increase and decrease to the evaluation of institute's format invention compound prescription according to the reaction of treatment target and/or according to the doctor.Above-mentioned effective dose only is to instruct suggestion, is not intended to limit the scope or application of this invention.
Lubeluzole N-oxide solution can use with physiological saline by known infusion methods easily.Also can with couplings such as its anti-hypoxia agent such as nmda receptor antagonist (as aptiganel, eliprodil, selfotel, for Li Lazha or remacemide) and antithrombotic agent such as tPA, streptokinase, staphylokinase, heparin.
Because the anoxic patient is many in emergency situation (as in ambulance, emergency room, intensive care unit) administration, so the present invention has also introduced common the most useful infusion device or the infusion bag of forming (pack) of treatment anoxia of the independently driver element that comprises medicine and easily dispose.As injector-actuated, the independent driving unit that especially drives the syringe of powder charge in advance can be divided into pneumatic and two kinds of vacuum driven.Especially useful is pneumatic intracutaneous delivery device, and it can accurately under the control carried medicine low speed, and they are at WO-75/13838 and corresponding patent US-5, narration in 527,288.This device comprises the syringe needle that has one or more drug reservoirs casees and a hollow; The syringe needle direction outwards has enough distances, with this device of box lunch when skin is pressurizeed syringe needle can pass stratum corneum and epidermis enters corium.This device is by standard type design, and it is by the removable storage unit that comprises the part of once using up (effective constituent, propulsion source) and comprise reusable driver elements such as described capsule case and electronic control part and form.
The present invention obviously also relates to the medicine of using described product treatment acute anoxia disease.Equally, as previously discussed, the present invention also relates to treat anoxic patient's method, this method comprises to described patient takes the pharmaceutically N-oxide products of effective dose.
Experimental section embodiment 1:(-)-(suitable) preparation of lubeluzole N-oxide semihydrate
In-10 ℃, to Lubeluzole (11.6g, 27mmol) in the stirred solution of methylene dichloride (700ml), add m-chlorobenzoic acid (6.7g, 31mmol).Reaction mixture stirred 24 hours, used 2% ammonia scrubbing 3 times then, washed with water 3 times again.Organic phase obtains the 9.6g crude product through dried over mgso, filtration and evaporation.Crude product carries out purifying with the methyl isopropyl Ketone recrystallization, gets product (-)-(suitable)-lubeluzole N-oxide semihydrate (mp.182.8 ℃), (yield 4.7g; 38.7%), [α]
D 20=-8.73 ° of (1% methanol solution) (compounds 1).Embodiment 2: pharmacology test
With the useful anti-hypoxia characteristic of the bright product of the present invention of following test card.
The treatment of photochemistry apoplexy rat model
Male Wistar rat, body weight 260-280g is with the N of fluothane
2O/O
2Mixture is anaesthetized.Rat is fixed on the stereotaxis device, peels off scalp, expose skull, conduit is inserted lateral tail vein.Keeping under the normal blood kinetics in 2 minutes rose-red (30mg/kg of internal jugular vein infusion; 0.9% normal saline solution of 15mg/ml) and blood gas.The cold white light focalization that sends with the intravital fiber optics bundle of diameter 1mm thing was skull surface irradiation 5 minutes.The hind leg district of the estheticokinetic neopallium of beam alignment right side parietal bone.Induce infraction after 5 minutes (being that power-off is after 5 minutes) to rat injection Lubeluzole or lubeluzole N-oxide (compound 1).Neurologic examination (comprising the limbs orienting response) infraction induce 24 hours at interval the back carry out 2 days of beginning, the sense of touch that the method that the back side or the side by rat mouse pawl contacts the desk edge is gently checked mouse forward with bypass orienting response (totally two inspections).Stretch that the mouse pawl contacts the desk edge so that stimulate limb portion's muscle and joint (totally two inspections) proprioceptive comprising with the bypass localization examination forward.Rat is placed on a high platform edges so that check proprioceptive adduction: the mouse pawl is pulled down gently from platform edges, upwards unclamp suddenly then, can check and recover and orienting response (inspection).
The standards of grading of each inspection are in above-mentioned 5 inspections: 0, can not locate, 1, not exclusively and/or locate slow; 2, fast, fully the location.Concerning each limbs, sense of touch/proprioceptive location score (comprising platform test) adds up altogether that score is up to 10 fens.The hind leg dysfunction that is caused by offside neopallium infraction is with the following table that the results are shown in of The compounds of this invention treatment
| Compound | Location scoring (on average) | Minimum | Maximum |
| The Lubeluzole lubeluzole N-oxide | ???????7.5 ???????9.5 | ????6 ????8 | ???10 ???10 |
Be not difficult to find out that from above data to being induced the experimental animal of apoplexy, the recovery effects of using the animal of lubeluzole N-oxide is better than taking the animal of Lubeluzole.
Claims (20)
1. lubeluzole N-oxide, its pharmaceutically useful acid salt, solvate or its three-dimensional chemical isomer.
2. the described N-oxide compound of claim 1, wherein the piperidines nitrogen-atoms is oxidized.
3. the described N-oxide compound of claim 2, cis and transly represent wherein with following formula,
(cis (S))
(trans (S))
4. the described N-oxide compound of claim 1, wherein said compound is (-)-(cis) lubeluzole N-oxide semihydrate.
5. the method for preparing lubeluzole N-oxide, this method comprise Lubeluzole be dissolved in the solvent, and to wherein adding the suitable oxygenant of q.s.
6. medicinal compositions, said composition contain any one described compound and pharmaceutically useful carrier in the claim 1～4 of significant quantity pharmaceutically.
7. the described composition of claim 6, it is suitable for oral or non-through gastrointestinal administration.
8. the described composition of claim 7, wherein said N-oxide compound is formulated in and contains water, isotonic agent, in the aqueous solution of acid, alkali or buffer material, described material is enough to regulate described pH value of solution scope between 2.5～3.6.
9. the described composition of claim 8, wherein neuroprotective agent solution (a) comprising:
(i) 0.005～5% lubeluzole N-oxide or its pharmaceutically useful additive salt or solvate;
(ii) 1～10% isotonic agent;
(iii) acid and/or the alkali of regulator solution pH value between 2.5～3.6;
(iv) add suitable quantity of water to 100%.
10. the described composition of claim 8, wherein neuroprotective agent solution (a) comprising:
(i) 0.01～1% lubeluzole N-oxide or its pharmaceutically useful additive salt or solvate;
(ii) 2～10% glucose;
(iii) hydrochloric acid and the sodium hydroxide of regulator solution pH value between 3.0～3.4;
(iv) add suitable quantity of water to 100%.
11. the described composition of claim 8, wherein said neuroprotective agent solution (a) comprising:
(i) 0.05% (w/v) lubeluzole N-oxide or its pharmaceutically useful acid salt or solvate;
(ii) 5% (w/v) glucose;
(iii) hydrochloric acid and the sodium hydroxide of regulator solution pH value about 3.2;
(iv) add suitable quantity of water to 100%.
12. the described composition of claim 8, the scope of the amount of wherein said neuroprotective agent solution (a) is 10～30ml, and contains the about 5～15mg of lubeluzole N-oxide.
13. the described composition of claim 8, the amount of wherein said neuroprotective agent solution (a) is about 15ml, and contains the about 7.5mg of lubeluzole N-oxide.
14. the described composition of claim 8, the amount of wherein said neuroprotective agent solution (a) is about 20ml, and contains the about 10mg of lubeluzole N-oxide.
15. the infusion device or the infusion bag of treatment apoplexy, they contain any one described N-oxide product in the claim 1～4 and easily dispose, driver element independently.
16. the described infusion bag of claim 15, wherein independently driver element is pneumatic or vacuum controlled.
17. any one described product in the claim 1～4 as medicine.
18. the described product that is used for the treatment of the cerebral anoxia disease of claim 17.
19. the described product that is used for the treatment of apoplexy and head injury of claim 17.
20. the described product that is used for the treatment of ischemic stroke, intracerebral hemorrhage and arachnoid hemorrhage of claim 17.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP95202887 | 1995-10-25 | ||
| EP95202887.6 | 1995-10-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1200122A true CN1200122A (en) | 1998-11-25 |
Family
ID=8220766
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96197774A Pending CN1200122A (en) | 1995-10-25 | 1996-10-21 | Lubeluzole N-oxide |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0843674A1 (en) |
| JP (1) | JPH11513699A (en) |
| CN (1) | CN1200122A (en) |
| AU (1) | AU7298296A (en) |
| CA (1) | CA2228054A1 (en) |
| IL (1) | IL123083A0 (en) |
| NO (1) | NO981687L (en) |
| WO (1) | WO1997015572A1 (en) |
| ZA (2) | ZA968961B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6355243B1 (en) † | 1999-11-13 | 2002-03-12 | Bayer Corporation | Method of thrombolysis by local delivery of active plasmin |
| US7544500B2 (en) | 1999-11-13 | 2009-06-09 | Talecris Biotherapeutics, Inc. | Process for the production of a reversibly inactive acidified plasmin composition |
| US9206410B2 (en) | 2009-03-03 | 2015-12-08 | Grifols Therapeutics Inc. | Compositions, methods and kits for preparing plasminogen and plasmin prepared therefrom |
| CN104955915B (en) | 2013-01-23 | 2017-06-13 | 株式会社Adeka | Antistatic additive, antistatic agent composition, antistatic resin compositions and formed body |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4306069A (en) * | 1980-06-19 | 1981-12-15 | Mead Johnson & Company | Encainide N-oxide |
| CA1260474A (en) * | 1984-12-03 | 1989-09-26 | Raymond A. Stokbroekx | Benzoxazol- and benzothiazolamine derivatives |
| ZW1992A1 (en) * | 1991-02-25 | 1993-09-22 | Janssen Pharmaceutica Nv | 4-/(2-benzotiazolyl)methylamino/-b-/(3,4-difluorephenoxy)methyl/-1-piperidine ethanol |
-
1996
- 1996-10-21 EP EP96934801A patent/EP0843674A1/en not_active Withdrawn
- 1996-10-21 JP JP9516279A patent/JPH11513699A/en active Pending
- 1996-10-21 IL IL12308396A patent/IL123083A0/en unknown
- 1996-10-21 AU AU72982/96A patent/AU7298296A/en not_active Abandoned
- 1996-10-21 CA CA002228054A patent/CA2228054A1/en not_active Abandoned
- 1996-10-21 WO PCT/EP1996/004608 patent/WO1997015572A1/en not_active Application Discontinuation
- 1996-10-21 CN CN96197774A patent/CN1200122A/en active Pending
- 1996-10-24 ZA ZA9608961A patent/ZA968961B/en unknown
- 1996-10-24 ZA ZA9608952A patent/ZA968952B/en unknown
-
1998
- 1998-04-15 NO NO981687A patent/NO981687L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO981687D0 (en) | 1998-04-15 |
| MX9803272A (en) | 1998-09-30 |
| ZA968952B (en) | 1998-04-24 |
| EP0843674A1 (en) | 1998-05-27 |
| IL123083A0 (en) | 1998-09-24 |
| ZA968961B (en) | 1998-04-24 |
| AU7298296A (en) | 1997-05-15 |
| WO1997015572A1 (en) | 1997-05-01 |
| NO981687L (en) | 1998-04-15 |
| JPH11513699A (en) | 1999-11-24 |
| CA2228054A1 (en) | 1997-05-01 |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |