WO1992008461A1 - Inhibition specifique de la dihydrofolate reductase et composes prevus a cet effet - Google Patents
Inhibition specifique de la dihydrofolate reductase et composes prevus a cet effet Download PDFInfo
- Publication number
- WO1992008461A1 WO1992008461A1 PCT/US1991/008515 US9108515W WO9208461A1 WO 1992008461 A1 WO1992008461 A1 WO 1992008461A1 US 9108515 W US9108515 W US 9108515W WO 9208461 A1 WO9208461 A1 WO 9208461A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pyrimidine
- diamino
- benzyl
- methoxy
- bromo
- Prior art date
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- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 description 1
- 229960004448 pentamidine Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 235000008729 phenylalanine Nutrition 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 238000013022 venting Methods 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
Definitions
- This invention relates to pharmacology and the inhibition of enzymes specific to pathogens. More particularly, the invention relates to methods for spe ⁇ cifically inhibiting the enzyme dihydrofolate reductase in fungal pathogens, and compounds therefor.
- PCP Pneumocystis carinii pneumonia
- trimethoprim and pyrimethamine exhibit 50% inhibition concentrations (IC 50 ) of 8 and 2,500 nM for E. coli DHFR, while IC J QS for P. carinii DHFR are 39,600 and 2,400 nM, respectively.
- R x is 3-R 3 -4-R 4 -5-R 5 -benzyl or (N-R ⁇ - ⁇ -azabicycloI ⁇ .lloct-S-yl;
- R. and R 2 together form where R 3 .and Rj are
- compositions for treating a fungal infection such as P. carin ⁇
- a fungal infection such as P. carin ⁇
- a mammal comprising an effective amount of a compound of formula I in combination with a pharmaceutically acceptable excipient.
- Another aspect of the invention is the use of a compound of formula I to prepare a composition for treating a fungal infection (such as P. carin ⁇ ' ) in a mam ⁇ mal comprising an effective amount of a compound of formula I in combination with a pharmaceutically acceptable excipient
- fungal infection and "fungal pathogen” refer to the infection of a mammal with an organism of the Kingdom Fungi, for example Pneumocystis carin ⁇ . Aspergillus, Candida, Fusarium, and the like.
- the presently preferred method of the invention is the treatment of Pneumocystis carin ⁇ using the compounds of the invention.
- pharmaceutically acceptable refers to compounds and compo ⁇ sitions which may be administered to mammals without undue toxicity.
- Exem ⁇ plary pharmaceutically acceptable salts include mineral acid salts such as hydro- chlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like.
- the term "effective .amount” refers to an amount of compound sufficient to exhibit a detectable therapeutic effect.
- the therapeutic effect may include, for example, without ⁇ mitation, inhibiting the growth of pathogens, inhibiting or pre ⁇ venting the release of toxins by pathogens, killing pathogens, and preventing the estab ⁇ shment of infection (prophylaxis).
- the precise effective amount for a sub ⁇ ject will depend upon the subject's size and health, the nature of the pathogen, the severity of the infection, and the like. Thus, it is not possible to specify an exact effective amount in advance. However, the effective amount for a given situation can be determined by routine experimentation based on the information provided herein.
- lower alkyl refers to saturated straight or branched-chain rad ⁇ icals consisting of carbon and hydrogen having from 1 to 6 carbon atoms, inclu ⁇ sive, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-hexyl, and the like.
- Lower alkoxy refers to a radical of the form R-O-, where "R" is lower .alkyl as defined above. Suitable examples include methoxy, ethoxy, prop- oxy, butoxy, .and the like.
- lower alkylthio refers to radicals of the form R-S-
- lower alkylsulfinyl refers to groups of the form R-S(-O)-.
- methylthio ethylthio, methylsuhlnyl, t-butylsulfinyl, and the like.
- alkenyl refers to straight or branched-chain radicals consist- ing of carbon and hydrogen having 2-6 carbon atoms and at least one double bond between a pair of carbon atoms, such as ethenyl (vinyl), 2-propenyl, 1-methyl- ethenyl, 2-butenyl, 3-butenyl, and the like.
- carboxy-lower alkyl refers to radicals having the form -(CH 2 ) n -COOH, where n is an integer from 1 to 6 inclusive. "Dicarboxy-lower alkyl” indicates lower allcyl chains having two COOH groups attached.
- Aryl denotes cyc ⁇ c hydrocarbon radicals of 6-10 carbon atoms which exhibit aromatic character, for example phenyl and napthyl.
- halo refers to fluoro, chloro, bromo, and iodo.
- amino acid refers to any of the 20 or so commonly occurring amino acids, for example, glycine, alanine, arginine, phenylalanine, glutamic acid, va ⁇ ne, histidine, proline, ornithine, norleucine. and the like.
- R 8 When attached as R 8 in a radical of the form -O(CH 2 ) n -COR 8 , the amino acid will preferably be attached via a peptide bond, e ⁇ by a bond between the amino group of the amino acid and the acyl car ⁇ bon of the radical.
- coadministering means administration of a compound of the invention in combination with a second therapeutic agent.
- the second therapeutic agent is a dihydropteroate synthase inhibitor, preferably dapsone or a sulfa drug.
- Suitable sulfa drugs include, without limitation, sulfadiame, sulfamethoxazole, and the like.
- Coadministration may be simultaneous, for example by administer ⁇ ing a mixture of the therapeutic agents, or may be accomplished by administration of the agents separately within a short time period.
- the compounds of the invention are structurally related to the compound trimethoprim (2,4-diam o-5-(3,4,5-trimemoxybenzyl)pyrimidine), the synthesis for which is known in the ait. See for example U.S. Pat No. 2,909,522, which des- cribes the synthesis of trimethoprim and related compounds.
- Compounds of for ⁇ mula I may simflarly be synthesized by those of ordinary skill in the art. Syntheses of such compounds are described in the following U.S. patents: Hitchings ___ (2,658,897); Hitchings et_al.
- Presently preferred compounds of the invention are: ,4-diamino-5-[3,5-dimemoxy-4-(2-hydroxyprop-2-yl)benzyl]pyrimidine; 2,4-diamino-5-(3 ,5-dimethoxy-4-N-pyrrolylbenzyl)pyrimidine; 2,4-diamino-5-(3,5-diethoxy-4-N-pyrrolylbenzyl)pyrimidine; 2,4-diar no-5-(3,5-dipropoxy-4-N-py ⁇ olylben ⁇ l)pyrimidine; 2,4-diammo-5-(3,5-dibutoxy-4-N-pyrrolylbenzyl)pyrimidine; 2,4-diammo-5-(3,5-diethoxy-4-carboethoxyber ⁇ zyl)pyrimidine; 2,4-diammo-5-(3,5-divinyl-4-vinyloxybenzyl)pyrimidine;
- 2,2-dime yl-5-(2,4-dia ⁇ ninopyri ⁇ nidin-5-ylmethyl)-7-methoxybenz[b]dioxolane The most preferred compounds at present are 2,4-diamino-5-(3,5-diethoxy-4-N- pvrrolylbenzyl)pyrimidine and 2,4-diamino-5-[3 ⁇ -dimethoxy-4-(2-hydroxyprop-2- yl)benzyl]pyrimidine.
- compositions of the invention for administration will generaUy include an effective amount of a compound of formula I in addition to a pharmaceutically acceptable excipient.
- Suitable excipients include most carriers approved for oral or parenteral adininistration, including water, saline, Ringer's solution, H-ank's solution, and solutions of glucose, lactose, dextrose, ethanol, glycerol, albumin, and the like.
- These compositions may optionally include stabilizers, antioxidants, antimicrobials, preservatives, buffering agents, surfactants, and other accessory additives.
- a presently preferred vehicle comprises about 1 mg/mL serum albumin in phosphate-buffered saline (PBS).
- PBS phosphate-buffered saline
- an effective dose of compound of formula I will range from about 10 ⁇ g/Kg to about 50 mg Kg.
- Suitable ai ⁇ mal models include the mouse model illustrated in the Examples below. Rats and other rodents have DHFR very sim ⁇ ar to the human enzyme, and thus make suitable animal models.
- a group of experimental animals is inoculated with 10-100 LD so s of Pneumocystis carin ⁇ , foUowed by treatment with a solution of test compound.
- a negative con ⁇ trol group is left untreated, wh ⁇ e a positive control group is treated with a stan ⁇ dard therapy, such as trimethoprim.
- Administration of the compounds is prefer- ably per os (e.g.. using a gavage), but may be parenteral, for example by subcu ⁇ taneous or intramuscular injection, or by inhalation of an aerosol.
- the animals are monitored during treatment, and are sacrificed and examined after 60 days for presence of infection.
- Buffers were prepared as follows: 4xDHFR buffe ⁇ 200 mM Tes, 300 mM BME, 4 mM EDTA, pH 7.0. +DHF buffe ⁇ 2.5 mg mL BSA, 0.25 mM NADPH, 62.5 uM dihydrofolate, 2.5x DHFR buffer. -DHF buffer: 2.5 mg/mL BSA, 0.25 mM NADPH, 2.5x DHFR buffer. Enzyme buffe ⁇ 50 mM Tes, 5 mM DTT, 1 mM EDTA, 20% glycerol, 1 mg/mL BSA, pH 7.0.
- D ⁇ ution buffer 50 mM Tes, 5 mM DTT, 1 mM EDTA, 1 mg/mL BSA, pH 7.0.
- PcDHFR 5 ⁇ g/mL P. carin ⁇ DHFR in enzyme buffer.
- crude hDHFR crude recombinant human DHFR (obtained from Hoffmann-LaRoche) in enzyme buffer (9.9 mg mL total protein).
- purified hDHFR purified recombinant human DHFR (obtained from Hoffmann- LaRoche) in enzyme buffer (3.5 mg/mL total protein).
- Test compounds were prepared and provided by Hoffmann-L.aRoche. Stock solutions were prepared by dissolving 2-8 mg in dimethylsulfoxide (DMSO) to prepare 50 mM solutions. Compounds which did not dissolve at 50 mM were d ⁇ uted serially to 25, 16.6, or 12.5 mM.
- DMSO dimethylsulfoxide
- KK 2,4-dian_ ⁇ mo-5-(4,5,6-trimethoxy-2,3-dihydromd ⁇ n-l-yl)pyri ⁇ mdine; LL) 2,2-dimethyl-5-(2,4-diammopyrir din-5-ylmethyl)-7-methoxybenz[b]di- oxolane; MM) 2,4-diammcH5-(3,5-diethoxy-4-carboethoxybenzyl)pyrimidine; and NN) 2,4-diamino-5-(2,7-dimethylbenzpyrazol-5-y ethyl)pyrimidine. TABLE ⁇ :
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4502293A JPH07509215A (ja) | 1990-11-14 | 1991-11-14 | ジヒドロ葉酸還元酵素の特異的阻害およびそのための化合物 |
EP92900837A EP0639075A1 (fr) | 1990-11-14 | 1991-11-14 | Inhibition specifique de la dihydrofolate reductase et composes prevus a cet effet |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US61361990A | 1990-11-14 | 1990-11-14 | |
US613,619 | 1990-11-14 | ||
US73069191A | 1991-07-16 | 1991-07-16 | |
US730,691 | 1991-07-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992008461A1 true WO1992008461A1 (fr) | 1992-05-29 |
Family
ID=27087063
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1991/008515 WO1992008461A1 (fr) | 1990-11-14 | 1991-11-14 | Inhibition specifique de la dihydrofolate reductase et composes prevus a cet effet |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0639075A1 (fr) |
JP (1) | JPH07509215A (fr) |
AU (1) | AU657348B2 (fr) |
CA (1) | CA2095518A1 (fr) |
IE (1) | IE913974A1 (fr) |
PT (1) | PT99514B (fr) |
WO (1) | WO1992008461A1 (fr) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0629403A1 (fr) * | 1993-06-17 | 1994-12-21 | F. Hoffmann-La Roche Ag | Mélange d'antibiotiques |
WO1996016046A3 (fr) * | 1994-11-24 | 1996-07-25 | Hoffmann La Roche | Nouvelles benzylpyrimidines |
WO1997043277A1 (fr) * | 1996-05-15 | 1997-11-20 | F. Hoffmann-La Roche Ag | Derives de 2,4-diaminopyrimidine |
WO1998037898A1 (fr) * | 1997-02-24 | 1998-09-03 | Barclay Barry J | Agents antifongiques agissant en synergie, inhibiteurs du metabolisme du folate, plus specifiquement le methotrexate et le sulfamethoxazole |
WO2000071160A1 (fr) * | 1999-05-24 | 2000-11-30 | Sankyo Company, Limited | Compositions medicinales contenant un anticorps anti-fas |
RU2173164C2 (ru) * | 1996-10-14 | 2001-09-10 | Корея Инститьют Оф Сайенс Энд Текнолоджи | ЭКСТРАКТ ИЗ КОЖУРЫ ПЛОДОВ ЦИТРУСОВЫХ В КАЧЕСТВЕ ИНГИБИТОРА 3-ГИДРОКСИ-3-МЕТИЛГЛУТАРИЛ-СoА (ГМГ - СoА) -РЕДУКТАЗЫ |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8853228B2 (en) * | 2007-06-04 | 2014-10-07 | University Of Connecticut | Heterocyclic analogs of propargyl-linked inhibitors of dihydrofolate reductase |
Citations (8)
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---|---|---|---|---|
US3577543A (en) * | 1966-03-31 | 1971-05-04 | Ici Ltd | Insecticidal and fungicidal 2-aminopyrimidinyl-6-carbamate compositions |
US3852450A (en) * | 1971-12-23 | 1974-12-03 | Lepetit Spa | Antibacterial compositions containing rifampicin and a pyrimidine derivative |
US4374136A (en) * | 1980-10-27 | 1983-02-15 | May & Baker Limited | Pyrimidine derivatives |
US4501890A (en) * | 1983-09-26 | 1985-02-26 | Eli Lilly And Company | Trans-(±)-2,4,6-substituted-5,5a,6,7,8,9,9a,10-octahydro-pyrimido[4,5-g]quinolines |
EP0139613A1 (fr) * | 1983-08-29 | 1985-05-02 | Ciba-Geigy Ag | Dérivés de la N-(nitro-2 phényl) amino-4 pyrimidine, leur préparation et leur application |
US4640923A (en) * | 1984-05-10 | 1987-02-03 | Bayer Aktiengesellschaft | Methods of combatting fungi employing 2,4-diamino-6-halogeno-5-alkylthio-pyrimidines |
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US4996198A (en) * | 1988-07-11 | 1991-02-26 | Hoffmann-La Roche Inc. | Anticoccidial composition |
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GB1142654A (en) * | 1965-10-28 | 1969-02-12 | Wellcome Found | Cyano-acetals and their use in benzylpyrimidine synthesis |
FR94837E (fr) * | 1966-02-19 | 1969-11-28 | Wellcome Found | Procédé de préparation de dérivés de la pyrimidine. |
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DE3174994D1 (de) * | 1980-11-27 | 1986-08-28 | Wellcome Found | Antibacterial benzylpyrimidines |
US4451466A (en) * | 1982-07-02 | 1984-05-29 | Shell Oil Company | Use of pyrroloquinazolinediamines as pesticides |
CA1244028A (fr) * | 1983-04-14 | 1988-11-01 | Hans Maag | Derives de pyrimidine |
-
1991
- 1991-11-14 PT PT99514A patent/PT99514B/pt not_active IP Right Cessation
- 1991-11-14 JP JP4502293A patent/JPH07509215A/ja active Pending
- 1991-11-14 WO PCT/US1991/008515 patent/WO1992008461A1/fr not_active Application Discontinuation
- 1991-11-14 CA CA002095518A patent/CA2095518A1/fr not_active Abandoned
- 1991-11-14 IE IE397491A patent/IE913974A1/en not_active Application Discontinuation
- 1991-11-14 EP EP92900837A patent/EP0639075A1/fr not_active Ceased
-
1992
- 1992-08-31 AU AU22027/92A patent/AU657348B2/en not_active Ceased
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US3577543A (en) * | 1966-03-31 | 1971-05-04 | Ici Ltd | Insecticidal and fungicidal 2-aminopyrimidinyl-6-carbamate compositions |
US3852450A (en) * | 1971-12-23 | 1974-12-03 | Lepetit Spa | Antibacterial compositions containing rifampicin and a pyrimidine derivative |
US4374136A (en) * | 1980-10-27 | 1983-02-15 | May & Baker Limited | Pyrimidine derivatives |
EP0139613A1 (fr) * | 1983-08-29 | 1985-05-02 | Ciba-Geigy Ag | Dérivés de la N-(nitro-2 phényl) amino-4 pyrimidine, leur préparation et leur application |
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Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0629403A1 (fr) * | 1993-06-17 | 1994-12-21 | F. Hoffmann-La Roche Ag | Mélange d'antibiotiques |
AU685449B2 (en) * | 1993-06-17 | 1998-01-22 | F. Hoffmann-La Roche Ag | Antibiotic combination |
US5721242A (en) * | 1993-06-17 | 1998-02-24 | Hoffmann-La Roche Inc. | Antibiotic combination |
CN1054745C (zh) * | 1993-06-17 | 2000-07-26 | 霍夫曼-拉罗奇有限公司 | 抗菌组合物 |
WO1996016046A3 (fr) * | 1994-11-24 | 1996-07-25 | Hoffmann La Roche | Nouvelles benzylpyrimidines |
WO1997043277A1 (fr) * | 1996-05-15 | 1997-11-20 | F. Hoffmann-La Roche Ag | Derives de 2,4-diaminopyrimidine |
US5866583A (en) * | 1996-05-15 | 1999-02-02 | Hoffmann-La Roche Inc. | Substituted 2,4-diaminopyrimidines |
RU2173164C2 (ru) * | 1996-10-14 | 2001-09-10 | Корея Инститьют Оф Сайенс Энд Текнолоджи | ЭКСТРАКТ ИЗ КОЖУРЫ ПЛОДОВ ЦИТРУСОВЫХ В КАЧЕСТВЕ ИНГИБИТОРА 3-ГИДРОКСИ-3-МЕТИЛГЛУТАРИЛ-СoА (ГМГ - СoА) -РЕДУКТАЗЫ |
WO1998037898A1 (fr) * | 1997-02-24 | 1998-09-03 | Barclay Barry J | Agents antifongiques agissant en synergie, inhibiteurs du metabolisme du folate, plus specifiquement le methotrexate et le sulfamethoxazole |
WO2000071160A1 (fr) * | 1999-05-24 | 2000-11-30 | Sankyo Company, Limited | Compositions medicinales contenant un anticorps anti-fas |
US6746673B2 (en) | 1999-05-24 | 2004-06-08 | Sankyo Company, Limited | Pharmaceutical compositions containing anti-Fas antibody |
Also Published As
Publication number | Publication date |
---|---|
JPH07509215A (ja) | 1995-10-12 |
CA2095518A1 (fr) | 1992-05-15 |
EP0639075A4 (fr) | 1993-09-29 |
PT99514B (pt) | 1999-04-30 |
EP0639075A1 (fr) | 1995-02-22 |
AU2202792A (en) | 1994-04-28 |
AU657348B2 (en) | 1995-03-09 |
IE913974A1 (en) | 1992-05-20 |
PT99514A (pt) | 1992-10-30 |
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