WO1994012178A1 - Antioxidant neuroprotective use of, and method of treatment using, hydroxycarbazole compounds - Google Patents
Antioxidant neuroprotective use of, and method of treatment using, hydroxycarbazole compounds Download PDFInfo
- Publication number
- WO1994012178A1 WO1994012178A1 PCT/US1993/011598 US9311598W WO9412178A1 WO 1994012178 A1 WO1994012178 A1 WO 1994012178A1 US 9311598 W US9311598 W US 9311598W WO 9412178 A1 WO9412178 A1 WO 9412178A1
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- Prior art keywords
- carbon atoms
- formula
- hydrogen
- compound
- lower alkyl
- Prior art date
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- 0 *c1c(c2c(*)c(*)c(*)c(*)c2[n]2)c2c(*)c(*)c1* Chemical compound *c1c(c2c(*)c(*)c(*)c(*)c2[n]2)c2c(*)c(*)c1* 0.000 description 1
Classifications
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
Definitions
- the present invention relates to a new medical use of, and method of treatment using, the hydroxycarbazole compounds of Formula I, as oxygen radical scavengers, or antioxidants, for protection of vital organs, particularly the central nervous system including the brain, from oxidative damage.
- the present invention provides a new use for such hydroxycarbazole compounds for making pharmaceutical compositions useful in prevention of organ reperfusion injury including related acute inflammation, particularly neuroprotection, that is, protection of the central nervous system from traumatic and post-traumatic injury associated with stroke, e. g., prevention of stroke and neurotrauma, and reduction of morbidity resulting from the sequelae of stroke.
- R7-R13 are independently -H or-OH.
- A is independently H, -OH, or a moiety of Formula II:
- Rj is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl;
- R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl;
- R3 is hydrogen or lower alkyl of up to 6 carbon atoms;
- R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2-O-;
- X is a valency bond, -CH2, oxygen or sulfur
- Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl;
- R5 and R ⁇ are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a - CONH2- group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms, lower alkysulphinyl of up to 6 carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms; or
- R5 and R6 together represent methylenedioxy; and pharmaceutically acceptable salts thereof.
- LPO and oxygen radicals in tissue damage associated with ischemia is further supported by the protective effect of natural and synthetic antioxidants such as vitamin E and the lazaroid U-74500A (Levitt, M.A., Clin. Res. (1991) 39, 265A) or antioxidant enzymes such as superoxide dismutase (SOD) and catalase in diverse ischemic models (for review see Halliwell and Gutteridge, 1989).
- natural and synthetic antioxidants such as vitamin E and the lazaroid U-74500A (Levitt, M.A., Clin. Res. (1991) 39, 265A) or antioxidant enzymes such as superoxide dismutase (SOD) and catalase in diverse ischemic models (for review see Halliwell and Gutteridge, 1989).
- the present invention provides a new medical use for the hydroxycarbazole compounds of Formula I as oxygen radical scavengers or antioxidants for protection of vital organs from oxidative damage.
- the present invention provides a new use for compounds preferably selected from the group consisting essentially of the compounds of Formula I wherein A is the moiety of Formula II wherein Rl is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and one of R7, R9, or RJQ is -OH, most preferably the compound of Formula I wherein A is the moiety of Formula II wherein Rl is - H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is - H, and R7 is -OH, or a pharmaceutically
- the present invention also provides a method of treatment for prevention of oxidative tissue damage to organs afflicted with disease-induced ischemic trauma, particularly neuroprotection, that is, prevention of stroke and reduction of morbidity resulting from the sequelae of stroke, in mammals comprising internally administering to a mammal, preferably a human, in need thereof an effective amount of a compound selected from the group consisting essentially of the compounds of Formula I, preferably selected from the group consisting essentially of the compounds of Formula I wherein A is the moiety of Formula II wherein Rl is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and one of R7, R9, or R1 Q is -OH, most preferably the compound of Formula I wherein A is the moiety of Formula II wherein Rl is -H, R2 is -H, R3 is -H
- R ⁇ is hydrogen, lower alkanoyl of up to 6 carbon atoms or aroyl selected from benzoyl and naphthoyl;
- R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benzyl, phenylethyl and phenylpropyl;
- R3 is hydrogen or lower alkyl of up to 6 carbon atoms
- R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2-O-;
- X is a valency bond, -CH2, oxygen or sulfur
- Ar is selected from phenyl, naphthyl, indanyl and tetrahydronaphthyl;
- R5 and R ⁇ are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, lower alkyl of up to 6 carbon atoms, a - CONH2- group, lower alkoxy of up to 6 carbon atoms, benzyloxy, lower alkylthio of up to 6 carbon atoms, lower alkysulphinyl of up to 6 carbon atoms and lower alkylsulphonyl of up to 6 carbon atoms; or R5 and R6 together represent methylenedioxy; and pharmaceutically acceptable salts thereof.
- This patent further discloses a compound of Formula HI, better known as carvedilol ( 1 -(carbazol-4-yloxy-3- [[2- (o-methoxyphenoxy )ethyl] amino] -2- propanol), having the structure shown in Formula IV:
- Carvedilol is known to be both a competitive ⁇ - adrenoceptor antagonist and a vasodilator, and is also a calcium channel antagonist at higher concentrations .
- the vasodilatory actions of carvedilol result primarily from ocj -adrenoceptor blockade, whereas the ⁇ -adrenoceptor blocking activity of the drug prevents reflex tachycardia when used in the treatment of hypertension.
- These multiple actions of carvedilol are responsible for the antihypertensive efficacy of the drug in animals, particularly in humans, as well as for utility in the treatment of angina and CHF.
- ischemic organ trauma as in stroke, a high proportion of ischemic organ cells become irreversibly damaged and necrotic, the extent of injury being dependent upon the length of time that the trauma, e.g. the arterial occlusion, persists.
- the protection of central nervous system neurons from such damage and necrosis during occlusion occurring in stroke and post-traumatic reperfusion is essential to achieving the therapeutic goal of restoration of neurological function; here and throughout this application this property is referred to by the term "neuroprotection" and its synonyms.
- ⁇ -adrenoceptor antagonists for instance propranolol
- carbazolyl-(4)-oxypropanolamine compounds of Formula I are effective cardioprotective agents at antihypertensive doses which unexpectedly minimize these consequences.
- ⁇ -adrenoceptor blocking and vasodilatory properties of carvedilol provides cardioprotection during and after acute myocardial infarction.
- Some of the compounds of Formula I are known to be metabolites of carvedilol in human and other mammalian (e.g. gerbil) systems.
- the preferred compounds of the present invention that is, the compounds of Formula I wherein A is the moiety of Formula ⁇ wherein Rl is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and one of R7, R9, or R1 Q is -OH are known to be metabolites of carvedilol.
- the hydroxycarbazole compounds of Formula I are oxygen radical scavengers.
- oxygen scavengers the above- described compounds act to inhibit LPO, and further that the hydroxycarbazole compounds of Formula I are surprisingly effective protective agents in generally preventing a wide variety of disease states associated with oxidative tissue damage to the organs due to LPO following ischemic traumas.
- the compounds of the present invention are especially useful in neuroprotection, that is, prevention of stroke, and reduction of morbidity resulting from the sequelae of stroke.
- the compounds of Formula I preferably selected from the group consisting essentially of the compounds of Formula I wherein A is the moiety of Formula H wherein Rl is -H, R2 is -H, R3 is -H, R4 is - H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and one of R7, R9, or RJQ is -OH, most preferably the compound of Formula I wherein A is the moiety of Formula H wherein Rl is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and R7 is -OH, exhibit neuroprotection, and are especially useful for protecting cerebral tissue from stroke and neurotrauma as well as for preventing oxidative tissue damage of ischemic human cerebral tissue following occurence of an ischemic event such as stroke or cerebral trauma.
- chronic administration of these compounds can both reduce the risk of cerebral ischemia or stroke in individuals at risk thereof as well as provide adjunctive therapy by reducing the magnitude of oxidative tissue damage following an ischemic cerebral event. Because hypertensive individuals are at increased risk of stroke, the neuroprotective use of the present compounds at appropriate dosing regimens in combination with antihypertensive therapy significantly reduces the risk of stroke, and the sequelae of stroke in such patients.
- the compounds of Formula I preferably those selected from the group consisting essentially of the compounds of Formula I wherein A is the moiety of Formula H wherein Rl is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and one of R7, R9, or R ⁇ is -OH, most preferably the compound of Formula I wherein A is the moiety of Formula H wherein Rl is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and R7 is -OH, are useful for neuroprotection in humans according to the present invention at dosages ranging from about 1-3 mg kg i.v. b.i.d. and 3-30 .mg/kg p.o. b.i.d.
- the present invention also provides a method of treatment for prevention of oxidative tissue damage to organs afflicted with disease-induced ischemic trauma in mammals comprising internally administering to a mammal, preferably a human, in need thereof an effective amount of a compound selected from the group consisting essentially of the compounds of Formula I, preferably those selected from the group consisting essentially of the compounds of Formula I wherein A is the moiety of Formula H wherein Rl is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is -H, and one of R7, R9, or RJQ s -OH, most preferably the compound of Formula I wherein A is the moiety of Formula H wherein Rl is -H, R2 is -H, R3 is -H, R4 is -H, X is O, Ar is phenyl, R5 is ortho -OH, and R6 is
- compositions of the compounds of Formula I for neuroprotective use according to the present invention may be formulated as solutions or lyophilized powders for parenteral administration.
- Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
- the liquid formulation is generally a buffered, isotonic, aqueous solution.
- suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
- Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as ethanol, polyvinyl- pyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
- these compounds may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration.
- Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
- Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, ethanol, and water.
- Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
- the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
- the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit
- the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
- a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
- Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU57323/94A AU673882B2 (en) | 1992-12-01 | 1993-12-01 | Antioxidant neuroprotective use of, and method of treatment using, hydroxycarbazole compounds |
KR1019950702200A KR950703950A (en) | 1992-12-01 | 1993-12-01 | Antioxidant Neuroprotective Use of, and Method of Treatment Using, Hydroxycarbazole Compounds |
EP94903351A EP0671914A1 (en) | 1992-12-01 | 1993-12-01 | Antioxidant neuroprotective use of, and method of treatment using, hydroxycarbazole compounds |
JP6513451A JPH08503711A (en) | 1992-12-01 | 1993-12-01 | Antioxidant neuroprotective use of hydroxycarbazole compounds and methods of treatment using same |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US98392092A | 1992-12-01 | 1992-12-01 | |
US07/983,920 | 1992-12-01 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08446792 A-371-Of-International | 1995-05-30 | ||
US88977497A Continuation | 1995-05-30 | 1997-07-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1994012178A1 true WO1994012178A1 (en) | 1994-06-09 |
Family
ID=25530181
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1993/011598 WO1994012178A1 (en) | 1992-12-01 | 1993-12-01 | Antioxidant neuroprotective use of, and method of treatment using, hydroxycarbazole compounds |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0671914A1 (en) |
JP (1) | JPH08503711A (en) |
KR (1) | KR950703950A (en) |
CN (1) | CN1042795C (en) |
AU (1) | AU673882B2 (en) |
CA (1) | CA2150695A1 (en) |
WO (1) | WO1994012178A1 (en) |
ZA (1) | ZA938897B (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998002157A1 (en) * | 1996-07-13 | 1998-01-22 | Roche Diagnostics Gmbh | Pharmaceutical formulations for topical application containing as an active ingredient a carbazolyl-(4)-oxy-propanol amine derivate |
WO1998038985A2 (en) * | 1997-03-06 | 1998-09-11 | Roche Diagnostics Gmbh | Use of carvedilol for the manufacture of a medicament for preventive and therapeutic treatment of inflammatory diseases |
EP0907318A1 (en) * | 1996-04-29 | 1999-04-14 | Smithkline Beecham Corporation | Antioxidant compound |
EP1242070A2 (en) * | 1999-12-27 | 2002-09-25 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Treatment of ischemic brain injuries with brain targetted antioxidant compounds |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR035455A1 (en) * | 2001-04-23 | 2004-05-26 | Hoffmann La Roche | TRICYCLE DERIVATIVES OF ALQUILHIDROXAMATO, PROCESSES FOR THEIR DEVELOPMENT, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND THE USE OF SUCH COMPOUNDS IN THE PREPARATION OF MEDICINES |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4503067A (en) * | 1978-04-13 | 1985-03-05 | Boehringer Mannheim Gmbh | Carbazolyl-(4)-oxypropanolamine compounds and therapeutic compositions |
-
1993
- 1993-11-29 ZA ZA938897A patent/ZA938897B/en unknown
- 1993-12-01 CN CN93120406A patent/CN1042795C/en not_active Expired - Fee Related
- 1993-12-01 CA CA002150695A patent/CA2150695A1/en not_active Abandoned
- 1993-12-01 EP EP94903351A patent/EP0671914A1/en not_active Ceased
- 1993-12-01 KR KR1019950702200A patent/KR950703950A/en not_active Application Discontinuation
- 1993-12-01 JP JP6513451A patent/JPH08503711A/en active Pending
- 1993-12-01 WO PCT/US1993/011598 patent/WO1994012178A1/en not_active Application Discontinuation
- 1993-12-01 AU AU57323/94A patent/AU673882B2/en not_active Ceased
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4503067A (en) * | 1978-04-13 | 1985-03-05 | Boehringer Mannheim Gmbh | Carbazolyl-(4)-oxypropanolamine compounds and therapeutic compositions |
Non-Patent Citations (4)
Title |
---|
CHEMICAL ABSTRACTS, Vol. 118, No. 11, issued 1992, LYSKO et al., "Neuroprotective Effects of Carvedilol a New Antihypertensive, at the N-methyl-D- Aspartate Receptor", see Abstract No. 94036w, Neurosci. Lett. 148(1-2), 34-8. * |
CHEMICAL ABSTRACTS, Vol. 118, No. 7, issued 1992, LYSKO et al., "Neuroprotective Effects of Carvedilol a New Antihypertensive Agent, in Cultured Rat Cerebellar Neurons and in Gerbil Global Brain Ischemia", Stroke 23(11), 1630-6. * |
See also references of EP0671914A4 * |
The Journal of Pharmacology and Experimental Therapeutics, Vol. 263, No. 1, issued 1992 (USA), YUE et al.; "Carvedilol, a New Vasodilator and Beta Adrenoreceptor Antagonist, is an Antioxidant and Free Radical Scavenger", pages 92-98, see the Abstract particularly. * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0907318A1 (en) * | 1996-04-29 | 1999-04-14 | Smithkline Beecham Corporation | Antioxidant compound |
EP0907318A4 (en) * | 1996-04-29 | 2000-02-02 | Smithkline Beecham Corp | Antioxidant compound |
WO1998002157A1 (en) * | 1996-07-13 | 1998-01-22 | Roche Diagnostics Gmbh | Pharmaceutical formulations for topical application containing as an active ingredient a carbazolyl-(4)-oxy-propanol amine derivate |
WO1998038985A2 (en) * | 1997-03-06 | 1998-09-11 | Roche Diagnostics Gmbh | Use of carvedilol for the manufacture of a medicament for preventive and therapeutic treatment of inflammatory diseases |
WO1998038985A3 (en) * | 1997-03-06 | 1998-12-23 | Boehringer Mannheim Gmbh | Use of carvedilol for the manufacture of a medicament for preventive and therapeutic treatment of inflammatory diseases |
EP1242070A2 (en) * | 1999-12-27 | 2002-09-25 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Treatment of ischemic brain injuries with brain targetted antioxidant compounds |
EP1242070A4 (en) * | 1999-12-27 | 2003-05-28 | Yissum Res Dev Co | Treatment of ischemic brain injuries with brain targetted antioxidant compounds |
Also Published As
Publication number | Publication date |
---|---|
AU5732394A (en) | 1994-06-22 |
CN1042795C (en) | 1999-04-07 |
EP0671914A4 (en) | 1995-10-25 |
KR950703950A (en) | 1995-11-17 |
CN1098908A (en) | 1995-02-22 |
EP0671914A1 (en) | 1995-09-20 |
JPH08503711A (en) | 1996-04-23 |
ZA938897B (en) | 1994-08-01 |
CA2150695A1 (en) | 1994-06-09 |
AU673882B2 (en) | 1996-11-28 |
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