EP0804201A1 - Procede de traitement des infections opportunistes avec des azaspiranes - Google Patents
Procede de traitement des infections opportunistes avec des azaspiranesInfo
- Publication number
- EP0804201A1 EP0804201A1 EP95928072A EP95928072A EP0804201A1 EP 0804201 A1 EP0804201 A1 EP 0804201A1 EP 95928072 A EP95928072 A EP 95928072A EP 95928072 A EP95928072 A EP 95928072A EP 0804201 A1 EP0804201 A1 EP 0804201A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- opportunistic infections
- formula
- pharmaceutically acceptable
- carbon atoms
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
-
- 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
- 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
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
Definitions
- This invention relates to a method of treating opportunistic infections in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a substituted azaspirane.
- Opportunistic infections are an increasing problem in medicine. Opportunistic infections can be caused by a wide variety of bacteria, viruses, fungi and protozoa, as described in Microbiology 16th edition. Appleton Crofts. NY, 1976, p 405. Of particular interest are e.g. Candida sp.. Pseudomonas sp.. Listeria sp.. Pneumocvstis carinii. Pneumococci. Neisseria sp.. Salmonella sp.. Mvcobacteria sp.. Cryptococcus sp.. Aspergillis sp.. Cryptosporidium sp.. Herpes simplex.
- Herpes zoster Cytomegalovirus and Toxoplasma sp. These organisms, which are often part of the normal flora, are rarely a cause for concern in normal hosts but, under certain circumstances, can cause serious disease. These circumstances include but are not limited to: prolonged high dose antibiotic therapy, cancer chemotherapy, transplantation and acquired immunodeficiency syndrome (AIDS) .
- a Biologic Response Modifier i.e., compounds with immunostimulatory activity, e.g. muramylpeptides
- immunostimulation may be contraindicated.
- a Biologic Response Modifier would be expected to exacerbate graft rejection of graft versus host disease.
- simple immunostimulation may accelerate disease progression.
- Immunomodulatory agents are, in general, not known for their ability to treat opportunistic infections. Further, there is presently no acceptable means for predicting whether a particular class of immunomodulatory agents will have utility in treating opportunistic infections.
- Badger I discloses compounds of Formula I as a class of novel compounds which induce an immunomodulatory effect which is characterized by the stimulation of suppressor cell activity.
- This invention relates to a method of treating opportunistic infections in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a compound of the formula
- R-- and R2 are the same or different and are selected from hydrogen or straight or branched chain alkyl, provided that the total number of carbon atoms contained by Rl and R-2 when taken together is 5-10; or R- ⁇ and R-2 together form a cyclic alkyl group having 3-7 carbon atoms;
- R3 and R are the same or different and are selected from hydrogen or straight chain alkyl having 1-3 carbon atoms; or R- and R ⁇ are joined together with the nitrogen atom to form a heterocyclic group having 5-8 atoms; or a pharmaceutically acceptable salt or hydrate or solvate thereof.
- a preferred compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) where Rl and R-2 are propyl, R ⁇ and R 4 are methyl, m is 1 and n is 3 which is N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2- propanamine dihydrochloride.
- a particularly preferred compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) where R 1 and R2 are propyl, R3 and R 4 are ethyl, m is 1 and n is 3 which is N,N-diethyl-8,8-dipropyl-2- azaspiro[4.5]decane-2-propanamine dihydrochloride.
- a particularly preferred compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) where R and R-2 are propyl, R3 and R 4 are joined together with the nitrogen to form a piperidine ring, m is 1 and n is 3 which is 8,8-dipropyl-2-azaspiro[4.5]decane-2-piperidinopropyl dihydrochloride.
- compound A refers to the dihydrochloride salt of a compound of Formula (I) where Rl and R2 are propyl, R3 and R4 are methyl, m is 1 and n is 3 which is N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2- propanamine dihydrochloride.
- Compound A was tested for its in vivo ability to treat opportunistic infections in Experiment 1.
- Compound A was dissolved in saline- and administered to CBA/J mice, at 0, 1.5, or 15 mg/kg, by daily intraperitoneal injection for 14 days.
- Control mice received saline.
- all mice received an intravenous injection of 1x10 ⁇ Candida Albicans (Strain B311). Survival was monitored daily until all mice died or were sacrificed for humane reasons. There was a significant increase in the mean survival time in the mice that received 15 mg/kg.
- mice that received intraperitoneal 5 doses of dexamethasone (an immunosuppressive steriod) at 50 mg/kg showed a significant decrease in mean survival time.
- Compound A was tested in an £i vivo experiment (Experiment 2) for its ability to treat opportunistic infections.
- Lewis rats received oral doses of 20 mg/kg of Compound A dissolved in 0.5% Tragacanth (5 doses/wk) for 16 days. On day 23 the rats were sacrificed and alveolar macrophages were collected by brochoalveolar lavage. The cells were dispensed into 24 well dishes and their ability to kill Candida albicans evaluated.
- This invention relates to a method of treating opportunistic infections in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof.
- a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof can be administered to such mammal including a human, in a conventional dosage form prepared by combining a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof, with a conventional pharmaceutically acceptable carrier or diluent according to known techniques, such as those described in Badger (I), U.S. Patent No.4,963,557.
- a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof is administered to a mammal, including a human in an amount sufficient to treat opportunistic infections.
- the route of administration of the Formula (I) ("active ingredient") compound is not critical but is usually oral or parenteral, preferably oral.
- parenteral as used herein includes intravenous, intramuscular, subcutaneous, intranasal, intrarectal, transdermal, intravaginal or intraperitoneal administration.
- the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
- the daily parenteral dosage regimen will preferably be from about 0.01 mg/kg to about 10 mg/kg of total body weight, most preferably from about 0.1 mg/kg to about 1 mg/kg.
- each parenteral dosage unit will contain the active ingredient in an amount of from about 0.1 mg to about 100 mg.
- the compounds of Formula (I) which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
- a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carriers) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agent.
- a suitable liquid carriers for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agent.
- a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
- a composition in the form of a capsule can be prepared using routine encapsulation procedures.
- pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carriers), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
- suitable pharmaceutical carriers for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
- the daily oral dosage regimen will preferably be from about 0.01 mg/kg to about 10 mg/kg of total body weight.
- each oral dosage unit will contain the active ingredient in an amount of from about 0.1 mg to about 100 mg.
- an active ingredient While it is possible for an active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation.
- the optimal quantity and spacing of individual dosages of a compound of formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof given per day and duration of therapy, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
- the method of this invention of treating opportunistic infections in a mammal, including a human comprises administering to a subject in need of such treatment an effective amount of a pharmaceutically active compound of the present invention.
- the invention also provides for the use of a compound of Formula (I) in the manufacture of a medicament for use in the treatment of opportunistic infections in a mammal, including a human.
- the invention also provides for a pharmaceutical composition for use in the treatment of opportunistic infections in a mammal, including a human.
- the invention also provides for a process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and a compound of Formula I which comprises bringing the compound of Formula I into association with the pharmaceutically acceptable carrier of diluent.
- FIGURE 1 The effect of N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2- propanamine dihydrochloride (Compound A ) on treating opportunistic infections in vivo from Experiment 1.
- FIGURE 1 The effect of N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2- propanamine dihydrochloride (Compound A ) on treating opportunistic infections in vivo from Experiment 1.
- FIGURE 1 The effect of N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2- propanamine dihydrochloride (Compound A ) on treating opportunistic infections in vivo from Experiment 1.
- FIGURE 1 The effect of N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2- propanamine dihydrochloride
- the compounds of the present invention can be co-administered with further active ingredients, such as compounds known to treat opportunistic infections
- EXAMPLE 1 - CAPSULE COMPOSITION An oral dosage form for administering Formula (I) compounds is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table II, below.
- An injectable form for administering Formula (I) compounds is produced by stirring 1.5% by weight of N,N-diethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2- propanamine dihydrochloride in 10% by volume propylene glycol in water.
- sucrose, calcium sulfate dihydrate and Formula (I) compound shown in Table III below are mixed and granulated in the proportions shown with a 10% gelatin solution.
- the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Tropical Medicine & Parasitology (AREA)
- Virology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9414902A GB9414902D0 (en) | 1994-07-23 | 1994-07-23 | Methods |
GB9414902 | 1994-07-23 | ||
PCT/US1995/008915 WO1996003126A1 (fr) | 1994-07-23 | 1995-07-14 | Procede de traitement des infections opportunistes avec des azaspiranes |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0804201A1 true EP0804201A1 (fr) | 1997-11-05 |
EP0804201A4 EP0804201A4 (fr) | 2000-04-26 |
Family
ID=10758802
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP95928072A Withdrawn EP0804201A4 (fr) | 1994-07-23 | 1995-07-14 | Procede de traitement des infections opportunistes avec des azaspiranes |
Country Status (15)
Country | Link |
---|---|
EP (1) | EP0804201A4 (fr) |
JP (1) | JPH10503202A (fr) |
KR (1) | KR970704446A (fr) |
CN (1) | CN1157564A (fr) |
AU (1) | AU684384B2 (fr) |
BR (1) | BR9508332A (fr) |
CA (1) | CA2195778A1 (fr) |
CZ (1) | CZ286482B6 (fr) |
GB (1) | GB9414902D0 (fr) |
HU (1) | HUT77379A (fr) |
MX (1) | MX9700626A (fr) |
NO (1) | NO310096B1 (fr) |
NZ (1) | NZ290974A (fr) |
WO (1) | WO1996003126A1 (fr) |
ZA (1) | ZA956098B (fr) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BR9601909A (pt) * | 1995-07-13 | 1999-10-13 | Smithkline Beecham Corp | N,n-dietil-8,8-dipropil-2-azaspiro(4,5)decano-2-propan amina dimaleato |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992014462A1 (fr) * | 1991-02-19 | 1992-09-03 | Smithkline Beecham Corporation | Inhibiteurs de cytokines |
WO1992022294A1 (fr) * | 1991-06-07 | 1992-12-23 | Smithkline Beecham Corporation | Azaspiranes immunomodulateurs |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4963557A (en) * | 1987-09-28 | 1990-10-16 | Smithkline Beecham Corporation | Immunomodulatory azaspiranes |
-
1994
- 1994-07-23 GB GB9414902A patent/GB9414902D0/en active Pending
-
1995
- 1995-07-14 BR BR9508332A patent/BR9508332A/pt not_active Application Discontinuation
- 1995-07-14 CA CA002195778A patent/CA2195778A1/fr not_active Abandoned
- 1995-07-14 EP EP95928072A patent/EP0804201A4/fr not_active Withdrawn
- 1995-07-14 CN CN95195052A patent/CN1157564A/zh active Pending
- 1995-07-14 NZ NZ290974A patent/NZ290974A/xx unknown
- 1995-07-14 CZ CZ1997209A patent/CZ286482B6/cs not_active IP Right Cessation
- 1995-07-14 AU AU31909/95A patent/AU684384B2/en not_active Ceased
- 1995-07-14 WO PCT/US1995/008915 patent/WO1996003126A1/fr not_active Application Discontinuation
- 1995-07-14 HU HU9700201A patent/HUT77379A/hu unknown
- 1995-07-14 MX MX9700626A patent/MX9700626A/es not_active IP Right Cessation
- 1995-07-14 JP JP8505798A patent/JPH10503202A/ja active Pending
- 1995-07-14 KR KR1019970700433A patent/KR970704446A/ko not_active Application Discontinuation
- 1995-07-21 ZA ZA956098A patent/ZA956098B/xx unknown
-
1997
- 1997-01-22 NO NO19970284A patent/NO310096B1/no not_active IP Right Cessation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992014462A1 (fr) * | 1991-02-19 | 1992-09-03 | Smithkline Beecham Corporation | Inhibiteurs de cytokines |
WO1992022294A1 (fr) * | 1991-06-07 | 1992-12-23 | Smithkline Beecham Corporation | Azaspiranes immunomodulateurs |
Non-Patent Citations (4)
Title |
---|
BADGER A M ET AL.: "Effects of SK&F 105685, a novel anti-arthritic agent, on immune function in the dog" INT. J. IMMUNOPHARMACOL., vol. 15, no. 2, 1993, pages 113-123, XP002106846 * |
BADGER A M ET AL: "BENEFICIAL EFFECTS OF SK&F 105685 IN RAT ADJUVANT ARTHRITIS: PROPHYLACTIC AND THERAPEUTIC EFFECTS ON DISEASE PARAMETER PROGRESSION" INTERNATIONAL JOURNAL OF IMMUNOPHARMACOLOGY, vol. 15, no. 3, 1 January 1993 (1993-01-01), pages 343-347, 349 - 35, XP000677832 * |
BADGER A M ET AL: "THERAPEUTIC ACTIVITY OF SK&F 105685, A NOVEL AZASPIRANE WITH SUPPRESSOR-CELL INDUCING ACTIVITY" CLINICAL AND EXPERIMENTAL RHEUMATOLOGY, vol. 11, no. SUPPL. 08, 1 March 1993 (1993-03-01), pages S107-S109, XP000677527 * |
See also references of WO9603126A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO1996003126A1 (fr) | 1996-02-08 |
BR9508332A (pt) | 1997-11-04 |
CA2195778A1 (fr) | 1996-02-08 |
NO970284D0 (no) | 1997-01-22 |
AU3190995A (en) | 1996-02-22 |
JPH10503202A (ja) | 1998-03-24 |
CN1157564A (zh) | 1997-08-20 |
NZ290974A (en) | 1999-08-30 |
CZ286482B6 (en) | 2000-04-12 |
HU9700201D0 (en) | 1997-04-28 |
MX9700626A (es) | 1997-05-31 |
GB9414902D0 (en) | 1994-09-14 |
ZA956098B (en) | 1996-05-23 |
CZ20997A3 (en) | 1997-10-15 |
KR970704446A (ko) | 1997-09-06 |
EP0804201A4 (fr) | 2000-04-26 |
AU684384B2 (en) | 1997-12-11 |
NO970284L (no) | 1997-03-19 |
NO310096B1 (no) | 2001-05-21 |
HUT77379A (hu) | 1998-04-28 |
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