CA2117435A1 - Preparation of 2-amino-6-chloropurine - Google Patents
Preparation of 2-amino-6-chloropurineInfo
- Publication number
- CA2117435A1 CA2117435A1 CA002117435A CA2117435A CA2117435A1 CA 2117435 A1 CA2117435 A1 CA 2117435A1 CA 002117435 A CA002117435 A CA 002117435A CA 2117435 A CA2117435 A CA 2117435A CA 2117435 A1 CA2117435 A1 CA 2117435A1
- Authority
- CA
- Canada
- Prior art keywords
- chloropurine
- amino
- acyl group
- guanine
- phase transfer
- 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.)
- Abandoned
Links
- RYYIULNRIVUMTQ-UHFFFAOYSA-N 6-chloroguanine Chemical compound NC1=NC(Cl)=C2N=CNC2=N1 RYYIULNRIVUMTQ-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 10
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical class O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000007062 hydrolysis Effects 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 4
- 239000012320 chlorinating reagent Substances 0.000 claims abstract 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- NIUZJTWSUGSWJI-UHFFFAOYSA-M triethyl(methyl)azanium;chloride Chemical group [Cl-].CC[N+](C)(CC)CC NIUZJTWSUGSWJI-UHFFFAOYSA-M 0.000 claims description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical group ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims 4
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 claims 1
- 229960004396 famciclovir Drugs 0.000 claims 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 claims 1
- 229960001179 penciclovir Drugs 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- WJSVJNDMOQTICG-UHFFFAOYSA-N 2-amino-1-[(2-methyl-4-methylidene-5-oxooxolan-2-yl)methyl]-7h-purin-6-one Chemical compound NC1=NC=2N=CNC=2C(=O)N1CC1(C)CC(=C)C(=O)O1 WJSVJNDMOQTICG-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- GHPYJLCQYMAXGG-WCCKRBBISA-N (2R)-2-amino-3-(2-boronoethylsulfanyl)propanoic acid hydrochloride Chemical compound Cl.N[C@@H](CSCCB(O)O)C(O)=O GHPYJLCQYMAXGG-WCCKRBBISA-N 0.000 description 1
- JYUXDXWXTPSAEL-UHFFFAOYSA-N 1,4-dioxane;oxolane Chemical compound C1CCOC1.C1COCCO1 JYUXDXWXTPSAEL-UHFFFAOYSA-N 0.000 description 1
- MWBWWFOAEOYUST-UHFFFAOYSA-N 2-aminopurine Chemical compound NC1=NC=C2N=CNC2=N1 MWBWWFOAEOYUST-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- RCJVRSBWZCNNQT-UHFFFAOYSA-N dichloridooxygen Chemical compound ClOCl RCJVRSBWZCNNQT-UHFFFAOYSA-N 0.000 description 1
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- QNXFUWFRTWSSOK-UHFFFAOYSA-N n-acetyl-n-(6-oxo-3,7-dihydropurin-2-yl)acetamide Chemical compound O=C1NC(N(C(C)=O)C(=O)C)=NC2=C1NC=N2 QNXFUWFRTWSSOK-UHFFFAOYSA-N 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical group [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for preparing 2-amino-6-chloropurine comprises reacting a 2,9-diacylated derivative of guanine with a chlorinating agent in the presence of a phase transfer catalyst containing chloride ions, and thereafter removing the 9-acyl group and the 2-acyl group by hydrolysis.
Description
CA21 i 7435 W O 93/15075 Pc~r/GB93/00185 Preparatton of 2-am~no-6-chloropurtne This invention relates to a process for the pr~pardl;on of a compound usetul 5 as an i" -", in the pr~:pd, n of phd""aceutical compounds.
The compound 2-amino-6-chloropurine of formula (I):
a <NX~ N
H N NHz 1 0 (1) is a useful i" ". in the pr.ra. ) of nucleoside analogue antiviral agents such as penciclu~i. and fdlllci(.luJi. described in EP-A-141927 (Example 1) and EP-A-182024 (Example 2). The illl~:r",e.lidlt~ is 15 9-s~ with an d~plupridle side chain precursor followed by conversion of the 6-chloro moiety to a hydroxy (a guanine) or hydrogen (a 2-aminopurine).
EP-A-203685 (Beecham Group p.l.c.) describes a process for preparing a 20 compound of fommula (I) as he,_;.,L.~ful~ defined which process cu",plises reacting guanine with a cl,lu,i,,dling agent in the presence of a phase transfer catalyst containing chloride ions. EP-A-433846 (Hoechst A~iengesel sul,dfl) describes a .;ur,~,:,uoncling process for preparing the 2-acylated derivative involving cl,lor", .~ of 2 9-diacylguanine and subsequent removal of the 9-25 acyl group by hydrolysis.
The reaction is preferably carried out in a polar inert organic solvent such asace~u,,it,ild tetrahydrofuran dioxan nil~u,,,~ll,ane diglyme dimethoxyethane ordicl,lo,u,,,~ll,ane. Acetonitrile is highly preferred.
CA 2 ~ 17~35 W O 93/15075 P(~r/G B93/00185 Suitable phase transfer catalysts include tetr~c~ Ihs~it~ d ammonium chlorides. Examples of ammonium substituents include C2-1 2 alkyl, usually C2 4 alkyl, or phenyl or benzyl. Other possible phase transfer catalysts include tetra-sl l~ - I ' pho:,,uhonium chlorides wherein examples of the 5 sl l~ l Itb are as defined above for ammonium chlorides. Fl ~ferdu' y the phase transfer catalyst is tetraethylammonium chloride.
The phase-transfer catalyst is preferably present in an amount of from 1 to 3 equivalents of the compound of formula (Il) and preferably from 1 to 2 1 0 equivalents.
A preferred chlu,i,ldtil,9 agent is phosphonus oxychloride.
Preferably the ~;hlo,i,l ,9 agent is present in an amount of from 2-10 15 preferably from 3-6 molar equivalents of the guanine derivative.
The reaction may be effected in the presence of a weak base, such as a tertiary amine, for example N,N-dimethylaniline or diethylaniline or triethylamine. The base is usually present in an d~,uru,~i".~2~1y molar 20 equivalent amount with respect to the guanine derivative. A!:_r" ' ~/~,ly, a catalytic amount of water may be added to the reaction mixture. When ac.i~u,,il,ile is the solvent, added base may not be necessary, but is preferred.
25 The reaction is preferably carried out at an elevated temperature of from 30-1 00~C, most preferably under reflux and/or with u lt d~onicdtion at 50-70~C.
Preferably the reaction is allowed to proceed for a period of greater than half 30 an hour, usually less than 30 hours.
We have now discovered that the compound of formula (I) may be prepared from 2,9-diacylguanine.
W O 93/15075 PC~r/G B93/0018S
The compound 2-amino-6-chloropurine of formula (I):
a <NX~ N
H N NHz 1 0 (1) is a useful i" ". in the pr.ra. ) of nucleoside analogue antiviral agents such as penciclu~i. and fdlllci(.luJi. described in EP-A-141927 (Example 1) and EP-A-182024 (Example 2). The illl~:r",e.lidlt~ is 15 9-s~ with an d~plupridle side chain precursor followed by conversion of the 6-chloro moiety to a hydroxy (a guanine) or hydrogen (a 2-aminopurine).
EP-A-203685 (Beecham Group p.l.c.) describes a process for preparing a 20 compound of fommula (I) as he,_;.,L.~ful~ defined which process cu",plises reacting guanine with a cl,lu,i,,dling agent in the presence of a phase transfer catalyst containing chloride ions. EP-A-433846 (Hoechst A~iengesel sul,dfl) describes a .;ur,~,:,uoncling process for preparing the 2-acylated derivative involving cl,lor", .~ of 2 9-diacylguanine and subsequent removal of the 9-25 acyl group by hydrolysis.
The reaction is preferably carried out in a polar inert organic solvent such asace~u,,it,ild tetrahydrofuran dioxan nil~u,,,~ll,ane diglyme dimethoxyethane ordicl,lo,u,,,~ll,ane. Acetonitrile is highly preferred.
CA 2 ~ 17~35 W O 93/15075 P(~r/G B93/00185 Suitable phase transfer catalysts include tetr~c~ Ihs~it~ d ammonium chlorides. Examples of ammonium substituents include C2-1 2 alkyl, usually C2 4 alkyl, or phenyl or benzyl. Other possible phase transfer catalysts include tetra-sl l~ - I ' pho:,,uhonium chlorides wherein examples of the 5 sl l~ l Itb are as defined above for ammonium chlorides. Fl ~ferdu' y the phase transfer catalyst is tetraethylammonium chloride.
The phase-transfer catalyst is preferably present in an amount of from 1 to 3 equivalents of the compound of formula (Il) and preferably from 1 to 2 1 0 equivalents.
A preferred chlu,i,ldtil,9 agent is phosphonus oxychloride.
Preferably the ~;hlo,i,l ,9 agent is present in an amount of from 2-10 15 preferably from 3-6 molar equivalents of the guanine derivative.
The reaction may be effected in the presence of a weak base, such as a tertiary amine, for example N,N-dimethylaniline or diethylaniline or triethylamine. The base is usually present in an d~,uru,~i".~2~1y molar 20 equivalent amount with respect to the guanine derivative. A!:_r" ' ~/~,ly, a catalytic amount of water may be added to the reaction mixture. When ac.i~u,,il,ile is the solvent, added base may not be necessary, but is preferred.
25 The reaction is preferably carried out at an elevated temperature of from 30-1 00~C, most preferably under reflux and/or with u lt d~onicdtion at 50-70~C.
Preferably the reaction is allowed to proceed for a period of greater than half 30 an hour, usually less than 30 hours.
We have now discovered that the compound of formula (I) may be prepared from 2,9-diacylguanine.
W O 93/15075 PC~r/G B93/0018S
Accordingly, the present invention provides a process for preparing 2-amino-6-chloropurine, which process comprises reacting a 2,9-diacylated derivative of guanine with a cl,loli"dli,)g agent in the presence of a phase transfer catalyst co"' , ,9 chloride ions, and thereafter removing the 9-acyl group 5 and the 2-acyl group by hydrolysis.
The reaction is described in EP-A-203685 and EP-A-433846, which are illcor~ordtdd herein by reference, except that methyltriethylammonium chloride is a preferred phase transfer catalyst; the amount of phosphorus 10 oAychlorida may be reduced to 2-4 equivalents, and the reaction time can be reduced.
If the removal of the 9-acyl group generally occurs at ambient temperature (below 30~C), but higher temperatures and reaction times (80-100~C, 1 -2 15 hours) are needed for removal of the 2-acyl group. Aqueous sodium hydroxide is a suitable basic medium for the hydrolysis.
The following example illustrates the invention.
Example Diacetyl guanine (8.09, 0.034 moles), triethylmethylammonium chloride (15.459, 0.102 moles), and llit:lllyldlll;ne (4.74 mls, 0.034 moles) were 25 heated together with stirring in ac~lu,,il~ild (70mls) to 50~C. Phosphorus o,~y~ loride (6.34 mls, 0.068 moles) was then added and stirring continued for 4 hours. The reaction mixture was cooled and then added to aqueous sodium hydroxide solution (209 in 300mls water). The reaction mixture was heated to 80~C for 2 hours and then the volume made up to 300 mls with 30 water. The mixture was cooled to 25~C and the pH adjuster to 7 using 10~/O
hJd~ hloiic acid. The resulting slurry was stirred for fifteen minutes and the product filtered off and washed with water 30 mls and then dried at 80~C
under vacuum to give a cream/off white coloured product.
35 Weight 2-amino-6-chloropurine 4.69 9 (74.6% yield).
The reaction is described in EP-A-203685 and EP-A-433846, which are illcor~ordtdd herein by reference, except that methyltriethylammonium chloride is a preferred phase transfer catalyst; the amount of phosphorus 10 oAychlorida may be reduced to 2-4 equivalents, and the reaction time can be reduced.
If the removal of the 9-acyl group generally occurs at ambient temperature (below 30~C), but higher temperatures and reaction times (80-100~C, 1 -2 15 hours) are needed for removal of the 2-acyl group. Aqueous sodium hydroxide is a suitable basic medium for the hydrolysis.
The following example illustrates the invention.
Example Diacetyl guanine (8.09, 0.034 moles), triethylmethylammonium chloride (15.459, 0.102 moles), and llit:lllyldlll;ne (4.74 mls, 0.034 moles) were 25 heated together with stirring in ac~lu,,il~ild (70mls) to 50~C. Phosphorus o,~y~ loride (6.34 mls, 0.068 moles) was then added and stirring continued for 4 hours. The reaction mixture was cooled and then added to aqueous sodium hydroxide solution (209 in 300mls water). The reaction mixture was heated to 80~C for 2 hours and then the volume made up to 300 mls with 30 water. The mixture was cooled to 25~C and the pH adjuster to 7 using 10~/O
hJd~ hloiic acid. The resulting slurry was stirred for fifteen minutes and the product filtered off and washed with water 30 mls and then dried at 80~C
under vacuum to give a cream/off white coloured product.
35 Weight 2-amino-6-chloropurine 4.69 9 (74.6% yield).
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing 2-amino-6-chloropurine, which process comprises reacting a 2,9-diacylated derivative of guanine with a chlorinating agent in the presence of a phase transfer catalyst containing chloride ions, and thereafter removing the 9-acyl group and the 2-acyl group by hydrolysis.
2. A process according to claim 1, wherein the chlorinating agent is phosphorus oxychloride and the phase transfer catalyst is methyltriethylammonium chloride.
3. A process according to in claim 2, wherein the amount of phosphorus oxychloride is 2-4 equivalents with respect to the 2,9-acylated guanine.
4. A process according to claim 1, wherein aqueous sodium hydroxide is used as the basic medium for the hydrolysis.
5. Famciclovir or penciclovir whenever prepared from 2-amino-6-chloropurine prepared according to the process of claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9201961.1 | 1992-01-30 | ||
| GB929201961A GB9201961D0 (en) | 1992-01-30 | 1992-01-30 | Pharmaceuticals |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2117435A1 true CA2117435A1 (en) | 1993-08-05 |
Family
ID=10709516
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002117435A Abandoned CA2117435A1 (en) | 1992-01-30 | 1993-01-28 | Preparation of 2-amino-6-chloropurine |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0625154A1 (en) |
| JP (1) | JPH07503246A (en) |
| KR (1) | KR950700299A (en) |
| AU (1) | AU669874B2 (en) |
| CA (1) | CA2117435A1 (en) |
| GB (1) | GB9201961D0 (en) |
| MX (1) | MX9300482A (en) |
| NZ (1) | NZ246677A (en) |
| WO (1) | WO1993015075A1 (en) |
| ZA (1) | ZA93615B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4231036A1 (en) * | 1992-09-17 | 1994-03-24 | Basf Ag | Process for the preparation of 2-amino-6-halopurines |
| JPH07133276A (en) * | 1993-09-17 | 1995-05-23 | Jiyuuzen Kagaku Kk | Production of 2-acetylamono-6-chloropurine |
| DE4415196C1 (en) * | 1994-04-30 | 1995-04-27 | Boehringer Ingelheim Kg | Improved process for the preparation of 2-amino-6-chloropurine and 2-acylamino-6-chloropurines |
| CA2189088C (en) * | 1995-11-09 | 2005-09-20 | Masatoshi Sakai | 2-amino-6-chloropurine and method for preparing the same |
| EP1490369B1 (en) * | 2002-04-04 | 2007-11-14 | Sumitomo Chemical Company, Limited | Production method of 2,6-dihalopurine |
| CN102336755B (en) * | 2011-09-30 | 2013-03-27 | 浙江工业大学 | Chemical synthesis method of 6-chloropurine |
| CN113214260B (en) * | 2021-05-10 | 2022-04-01 | 上海凌凯医药科技有限公司 | Synthesis method of 2-acetamido-9-acetyl purine |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3485225D1 (en) | 1983-08-18 | 1991-12-05 | Beecham Group Plc | ANTIVIRAL GUANINE DERIVATIVES. |
| EP0182024B1 (en) | 1984-09-20 | 1991-04-03 | Beecham Group Plc | Purine derivatives and their pharmaceutical use |
| GB8507606D0 (en) * | 1985-03-23 | 1985-05-01 | Beecham Group Plc | Process |
| DE3941658A1 (en) * | 1989-12-16 | 1991-06-20 | Hoechst Ag | METHOD FOR PRODUCING 2-ACYLAMINO-9-ACYL-6-HALOGEN PURIN |
| DE3941657A1 (en) | 1989-12-16 | 1991-06-20 | Hoechst Ag | METHOD FOR PRODUCING 2-ACYLAMINO-6-HALOGEN PURINE FROM 2,9-DIACYLGUANINE |
| GB9102127D0 (en) * | 1991-01-31 | 1991-03-13 | Smithkline Beecham Plc | Pharmaceuticals |
-
1992
- 1992-01-30 GB GB929201961A patent/GB9201961D0/en active Pending
-
1993
- 1993-01-28 AU AU33654/93A patent/AU669874B2/en not_active Ceased
- 1993-01-28 CA CA002117435A patent/CA2117435A1/en not_active Abandoned
- 1993-01-28 WO PCT/GB1993/000185 patent/WO1993015075A1/en not_active Ceased
- 1993-01-28 JP JP5513055A patent/JPH07503246A/en active Pending
- 1993-01-28 NZ NZ246677A patent/NZ246677A/en unknown
- 1993-01-28 ZA ZA93615A patent/ZA93615B/en unknown
- 1993-01-28 EP EP93902481A patent/EP0625154A1/en not_active Withdrawn
- 1993-01-28 KR KR1019940702650A patent/KR950700299A/en not_active Withdrawn
- 1993-01-28 MX MX9300482A patent/MX9300482A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0625154A1 (en) | 1994-11-23 |
| NZ246677A (en) | 1996-02-27 |
| KR950700299A (en) | 1995-01-16 |
| MX9300482A (en) | 1994-07-29 |
| GB9201961D0 (en) | 1992-03-18 |
| ZA93615B (en) | 1993-11-26 |
| JPH07503246A (en) | 1995-04-06 |
| AU669874B2 (en) | 1996-06-27 |
| AU3365493A (en) | 1993-09-01 |
| WO1993015075A1 (en) | 1993-08-05 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |