WO1996026209A1 - Stable hydrates of a cephalosporin chloride salt - Google Patents

Stable hydrates of a cephalosporin chloride salt Download PDF

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Publication number
WO1996026209A1
WO1996026209A1 PCT/GB1996/000373 GB9600373W WO9626209A1 WO 1996026209 A1 WO1996026209 A1 WO 1996026209A1 GB 9600373 W GB9600373 W GB 9600373W WO 9626209 A1 WO9626209 A1 WO 9626209A1
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WO
WIPO (PCT)
Prior art keywords
ceph
methoxyimino
acetamido
pyridinium
methylamino
Prior art date
Application number
PCT/GB1996/000373
Other languages
French (fr)
Inventor
Richard Andrew Bentley Webster
Original Assignee
Pfizer Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to US08/894,123 priority Critical patent/US6034076A/en
Priority to EP96903105A priority patent/EP0811009A1/en
Priority to JP8525483A priority patent/JPH11505514A/en
Publication of WO1996026209A1 publication Critical patent/WO1996026209A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • 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

  • the present invention relates to a novel compound, to a process for its manufacture and to its use in the treatment and/or prevention of bacterial infections in humans and animals caused by a wide range of organisms.
  • EP-A-O 416 814 (Beecham Group pic) describes certain cephalosporin compounds which are described to be useful in the treatment of bacterial infections in humans and animals caused by a wide range of organisms.
  • This particular form of the compound has unexpectedly superior stability properties over the freeze dried material of example 2 in EP-A-0416814.
  • the present invention provides [6R,7RJ-7-[2-(2-Amino-4-thiazolyl)-2- (Z)-(methoxyimino)acetamido]-3-[l-(methylamino)pyridinium-4-thiomethyI]-ceph- 3-em-4-carboxylic acid chloride hydrochloride as a mono, di or tri-hydrate.
  • the present invention provides [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)- (methoxyimino)acetamido]-3-[l-(methylamino)pyridinium-4-thiomethyl]-ceph-3-em- 4-carboxylic acid chloride hydrochloride as a tri-hydrate.
  • the present invention further provides a process for the preparation of [6R,7R]-7-[2- (2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[l- (methylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylic acid chloride hydrochloride as a mono, di or tri-hydrate said process comprising treating an aqueous solution of [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)- (methoxyimino)acetamido]-3-[l-(methylamino)pyridinium-4-thiomethyl]-ceph-3-em- 4-carboxylate with hydrogen chloride
  • [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[l- (methylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylate is dissolved in water and treated with aqueous hydrochloric acid for example a 2 molar solution thereof.
  • the resulting solution is suitably diluted with a water soluble organic solvent to precipitate the product; for example tetrahydrofuran.
  • the resulting mixture may then be cooled for example overnight to 0 to 5°C, suitably at around 4°C.
  • the resulting crystalline product may then be isolated for example by filtration, and dried for example in vacuo at ambient temperature. It should be appreciated that more rigorous drying conditions will remove the bound molecules of water of hydration. In this way drying conditions may be conventionally controlled to give [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)- (methoxyimino)acetamido]-3-[l-(methylamino)pyridinium-4-thiomethyl]-ceph-3-em- 4-carboxylic acid chloride hydrochloride as the mono, di or tri-hydrates.
  • [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)- (methoxyimino)acetamido]-3-[l-(methylamino)pyridinium-4-thiomethyl]-ceph-3-em- 4-carboxylic acid chloride hydrochloride mono, di or tri-hydrate is an active medicinal product and may be formulated into unit dose forms suitable for administration to humans or animals in need of treatment.
  • Such unit dose forms may be for example those contemplated in EP-A-416 814 and those generally known in the art, especially those particularly adapted for administration to animals.
  • Amounts of [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3- [1 -(methylamino)pyridinium-4-thiomethyl] -ceph-3-em-4-carboxy lie acid chloride hydrochloride mono, di or tri-hydrate suitable for formulation into a unit dose form and the number of unit dose forms administered to a human or animal patient is mentioned in EP-A-0416 814 and is hereincorporated by reference.
  • the types of bacterial infections which may be treated by [6R,7R]-7-[2-(2-Amino-4- thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[l-(methylamino)pyridinium-4- thiomethyl]-ceph-3-em-4-carboxylic acid chloride hydrochloride mono, di or tri- hydrate include those specifically mentioned in EP-A-416814 which are incorporated herein by reference. Such infections are hereinafter referred to as "the infections”.
  • the present invention therefore provides a method for the treatment and/or prevention of "the infections" which comprises administering an effective amount of [6R,7R]-7- [2-(2- Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[ 1 - (methylamino)pyridinium-4-thiomethyI]-ceph-3-em-4-carboxylic acid chloride hydrochloride mono, di or tri-hydrate to a sufferer in need thereof.
  • the present invention also provides the use of [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2- (Z)-(methoxyimino)acetamido]-3-[l-(methylamino)pyridinium-4-thiomethyl]-ceph- 3-em-4-carboxylic acid chloride hydrochloride mono, di or tri-hydrate in the 90 treatment and/or prevention of "the infections" in humans or animals.
  • the present invention also provides the use of [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2- (Z)-(methoxyimino)acetamido]-3-[ 1 -(methylamino)pyridinium-4-thiomethyl] -ceph- 3-em-4-carboxylic acid chloride hydrochloride mono, di or tri-hydrate in the 95 manufacture of a medicament for treating and/or preventing "the infections" in humans or animals.
  • the present invention also provides a pharmaceutical composition for use in the treatment and/or prevention of "the infections" in animals or humans which comprises 100 admixing [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3- [l-(methylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylic acid chloride hydrochloride mono, di or tri-hydrate with pharmaceutically acceptable excipients.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The cephalosporin compound [6R, 7R]-7-[2-(2-amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[1-(methylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylic acid chloride hydrochloride is provided as a mono-, di- or tri-hydrate. The hydrates are produced by treating an aqueous solution of the corresponding carboxylate with hydrogen chloride and have been found to possess unexpectedly superior stability properties over other forms of the compound. The hydrates may be used in the treatment and/or prevention of bacterial infections in humans and animals.

Description

STABLE HYDRATES OF A CEPHALOSPORIN CHLORIDE SALT
The present invention relates to a novel compound, to a process for its manufacture and to its use in the treatment and/or prevention of bacterial infections in humans and animals caused by a wide range of organisms.
EP-A-O 416 814 (Beecham Group pic) describes certain cephalosporin compounds which are described to be useful in the treatment of bacterial infections in humans and animals caused by a wide range of organisms.
One particular compound mentioned therein, ie, [6R,7R]-7-[2-(2-Amino-4-thiazolyl)- 2-(Z)-(methoxyimino)acetamido]-3-[l-(methylamino)pyridinium-4-thiomethylj- ceph-3-em-4-carboxylate (ie, example 2) has now been prepared as crystalline carboxylic acid chloride hydrochloride mono-, di- or tri-hydrate.
This particular form of the compound has unexpectedly superior stability properties over the freeze dried material of example 2 in EP-A-0416814.
Accordingly the present invention provides [6R,7RJ-7-[2-(2-Amino-4-thiazolyl)-2- (Z)-(methoxyimino)acetamido]-3-[l-(methylamino)pyridinium-4-thiomethyI]-ceph- 3-em-4-carboxylic acid chloride hydrochloride as a mono, di or tri-hydrate.
Preferably the present invention provides [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)- (methoxyimino)acetamido]-3-[l-(methylamino)pyridinium-4-thiomethyl]-ceph-3-em- 4-carboxylic acid chloride hydrochloride as a tri-hydrate.
The present invention further provides a process for the preparation of [6R,7R]-7-[2- (2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[l- (methylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylic acid chloride hydrochloride as a mono, di or tri-hydrate said process comprising treating an aqueous solution of [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)- (methoxyimino)acetamido]-3-[l-(methylamino)pyridinium-4-thiomethyl]-ceph-3-em- 4-carboxylate with hydrogen chloride
Suitably [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[l- (methylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylate is dissolved in water and treated with aqueous hydrochloric acid for example a 2 molar solution thereof. The resulting solution is suitably diluted with a water soluble organic solvent to precipitate the product; for example tetrahydrofuran. The resulting mixture may then be cooled for example overnight to 0 to 5°C, suitably at around 4°C. The resulting crystalline product may then be isolated for example by filtration, and dried for example in vacuo at ambient temperature. It should be appreciated that more rigorous drying conditions will remove the bound molecules of water of hydration. In this way drying conditions may be conventionally controlled to give [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)- (methoxyimino)acetamido]-3-[l-(methylamino)pyridinium-4-thiomethyl]-ceph-3-em- 4-carboxylic acid chloride hydrochloride as the mono, di or tri-hydrates.
[6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[l-
(methylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylate may be prepared according to the procedures mentioned in or outlined by EP-A-416 814.
It should be appreciated that [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)- (methoxyimino)acetamido]-3-[l-(methylamino)pyridinium-4-thiomethyl]-ceph-3-em- 4-carboxylic acid chloride hydrochloride mono, di or tri-hydrate is an active medicinal product and may be formulated into unit dose forms suitable for administration to humans or animals in need of treatment.
[6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[l- (methylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylic acid chloride hydrochloride mono, di or tri-hydrate is especially suitable for the treatment and/or prevention of bacterial diseases in animals.
Such unit dose forms may be for example those contemplated in EP-A-416 814 and those generally known in the art, especially those particularly adapted for administration to animals.
Amounts of [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3- [1 -(methylamino)pyridinium-4-thiomethyl] -ceph-3-em-4-carboxy lie acid chloride hydrochloride mono, di or tri-hydrate suitable for formulation into a unit dose form and the number of unit dose forms administered to a human or animal patient is mentioned in EP-A-0416 814 and is hereincorporated by reference.
The types of bacterial infections which may be treated by [6R,7R]-7-[2-(2-Amino-4- thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[l-(methylamino)pyridinium-4- thiomethyl]-ceph-3-em-4-carboxylic acid chloride hydrochloride mono, di or tri- hydrate include those specifically mentioned in EP-A-416814 which are incorporated herein by reference. Such infections are hereinafter referred to as "the infections".
The present invention therefore provides a method for the treatment and/or prevention of "the infections" which comprises administering an effective amount of [6R,7R]-7- [2-(2- Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[ 1 - (methylamino)pyridinium-4-thiomethyI]-ceph-3-em-4-carboxylic acid chloride hydrochloride mono, di or tri-hydrate to a sufferer in need thereof. The present invention also provides the use of [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2- (Z)-(methoxyimino)acetamido]-3-[l-(methylamino)pyridinium-4-thiomethyl]-ceph- 3-em-4-carboxylic acid chloride hydrochloride mono, di or tri-hydrate in the 90 treatment and/or prevention of "the infections" in humans or animals.
The present invention also provides the use of [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2- (Z)-(methoxyimino)acetamido]-3-[ 1 -(methylamino)pyridinium-4-thiomethyl] -ceph- 3-em-4-carboxylic acid chloride hydrochloride mono, di or tri-hydrate in the 95 manufacture of a medicament for treating and/or preventing "the infections" in humans or animals.
The present invention also provides a pharmaceutical composition for use in the treatment and/or prevention of "the infections" in animals or humans which comprises 100 admixing [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3- [l-(methylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylic acid chloride hydrochloride mono, di or tri-hydrate with pharmaceutically acceptable excipients.
The following example illustrates the present invention.
105
Example 1
[6R.7R] -7-[2-(2- Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[ 1 - (methylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylic acid chloride hydrochloride trihydrate
110
[6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[l- (methylamino)pyridinium-4-thiomethyI]-ceph-3-em-4-carboxylate (2.75g, 5Jmmol) was dissolved in H2O (lOmL) and acidified with 2M aqueous HC1 (15mL). The solution was diluted with THF (400mL) and the mixture stored at 4°C overnight. The
115 resulting crystalline material was collected by filtration, washed with THF (lOOmL) and dried in vacuo at 20°C. The title compound_(2.7 g) was isolated as a crystalline solid (needles): δ (DMSO-d6) 2.99(s, 3H), 3.55(d,J=18Hz, 1H), 3.80(dJ=18Hz, 1H), 3.95(s, 3H), 4.4 l(q, J=12.9Hz, 2H), 5.24(d, J=4.8Hz, 1H), 5.79(d.d, J=7.9Hz, 4.8Hz, 1H), 6.96(s, 1H), 8.01(d, J=7.3Hz, 2H), 8.92(d, J=7.2Hz, 2H), 9.87(d, J=7.9Hz, 1H);
120 H 0 8.9% (Theory 8.16%).

Claims

1 . [6R, 7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-
[1 -(methylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylic acid chloride hydrochloride as a mono-, di-, or tri- hydrate.
2. [6R, 7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3- [ 1 -(methylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylic acid chloride hydrochloride as a tri-hydrate.
3. A process for the preparation of Ϊ6R, 7R]-7-[2-(2-amino-4-thiazolyl)-2- (Z)-(methoxyimino)acetamido]-3-[1 -(methylamino)pyridinium-4-thiomethyl]- ceph-3-em-4-carboxylic acid chloride hydrochloride as a mono-, di or tri- hydrate, said process comprising treating an aqueous solution of [6R, 7R]-7- [2-(2-amino-4-thiazolyl)-2-(Z)-<methoxyimino)acetamido]-3-[1 -(methylamino) pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylate with hydrogen chloride.
4. The use of [6R, 7R]-7-.2-(2-amino-4-thiazolyl)-2-(Z)-(methoxyimino) acetamido]-3-[1-(methylamino)pyridinium-4-thiomethyl]-ceph-3-em-4- carboxylic acid chloride hydrochloride mono-, di- or tri-hydrate in the manufacture of a medicament for treating and/or preventing bacterial infections in humans or animals.
5. A pharmaceutical composition for use in the treatment and/or prevention of bacterial infections in humans or animals which comprises an admixture of [6R, 7R]-7-[2-(2-amino-4-thiazolyl)-2-(Z)-(methoxyimino) acetamido]-3-[1 -(methylamino)pyridinium-4-thiomethyl]-ceph-3-em-4- carboxγlic acid chloride hydrochloride mono-, di- or tri-hydrate with pharmaceutically acceptable excipients.
6. A method for the treatment and/or prevention of bacterial infections in humans or animals which comprises administering an effective amount of [6R, 7R]-7-[2-(2-amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[1 -
5 (methylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylic acid chloride hydrochloride mono-, di- or tri-hydrate to a sufferer in need thereof.
7. The use of [6R, 7R]-7-[2-(2-amino-4-thiazolyl)-2-(Z)-(methoxyimino) ° acetamido]-3-[ 1 -(methylamino)pyridinium-4-thiomethyl]-ceph-3-em-4- carboxylic acid chloride hydrochloride mono-, di- or tri-hydrate in the treatment and/or prevention of bacterial infections in humans or animals.
5
0
5
0
5
PCT/GB1996/000373 1995-02-24 1996-02-19 Stable hydrates of a cephalosporin chloride salt WO1996026209A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US08/894,123 US6034076A (en) 1995-02-24 1996-02-19 Stable hydrates of a cephalosporin chloride salt
EP96903105A EP0811009A1 (en) 1995-02-24 1996-02-19 Stable hydrates of a cephalosporin chloride salt
JP8525483A JPH11505514A (en) 1995-02-24 1996-02-19 Stable hydrate of the salt of cephalosporin chloride

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9503717.2 1995-02-24
GBGB9503717.2A GB9503717D0 (en) 1995-02-24 1995-02-24 Novel compounds

Publications (1)

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WO1996026209A1 true WO1996026209A1 (en) 1996-08-29

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US (1) US6034076A (en)
EP (1) EP0811009A1 (en)
JP (1) JPH11505514A (en)
GB (1) GB9503717D0 (en)
WO (1) WO1996026209A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6660745B1 (en) 1999-05-11 2003-12-09 Mitsubishi Chemical Corporation Purine derivative dihydrate, drugs containing the same as the active ingredient and intermediate in the production thereof
US6734187B1 (en) 1997-11-12 2004-05-11 Mitsubishi Chemical Corporation Purine derivatives and medicaments comprising the same as active ingredient

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4656798B2 (en) * 2002-02-05 2011-03-23 武田薬品工業株式会社 Cephem compound

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4146710A (en) * 1976-08-31 1979-03-27 Takeda Chemical Industries, Ltd. Solid cephalosporin salt
EP0416814A2 (en) * 1989-09-04 1991-03-13 Beecham Group Plc Cephalosporin compounds, process for their preparation, pharmaceutical compositions and intermediates
EP0638573A1 (en) * 1993-08-10 1995-02-15 Lucky Ltd. Crystalline hydrates of cephalosporin and process for preparation thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4035361A (en) * 1976-03-17 1977-07-12 Eli Lilly And Company Bis-trimethylsilyl cefamandole and process therefor
NZ187013A (en) * 1977-04-27 1985-04-30 Beecham Group Ltd 9-amino-9-deoxy-clavulanic acid derivatives and pharmaceutical compositions
IE60588B1 (en) * 1986-07-30 1994-07-27 Sumitomo Pharma Carbapenem compound in crystalline form, and its production and use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4146710A (en) * 1976-08-31 1979-03-27 Takeda Chemical Industries, Ltd. Solid cephalosporin salt
EP0416814A2 (en) * 1989-09-04 1991-03-13 Beecham Group Plc Cephalosporin compounds, process for their preparation, pharmaceutical compositions and intermediates
EP0638573A1 (en) * 1993-08-10 1995-02-15 Lucky Ltd. Crystalline hydrates of cephalosporin and process for preparation thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6734187B1 (en) 1997-11-12 2004-05-11 Mitsubishi Chemical Corporation Purine derivatives and medicaments comprising the same as active ingredient
US6660745B1 (en) 1999-05-11 2003-12-09 Mitsubishi Chemical Corporation Purine derivative dihydrate, drugs containing the same as the active ingredient and intermediate in the production thereof
US6919455B2 (en) 1999-05-11 2005-07-19 Mitsubishi Chemical Corporation Purine derivative dihydrate, drugs containing the same as the active ingredient and intermediate in the production thereof

Also Published As

Publication number Publication date
US6034076A (en) 2000-03-07
JPH11505514A (en) 1999-05-21
EP0811009A1 (en) 1997-12-10
GB9503717D0 (en) 1995-04-12

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