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WO1997035862A1 - Derives azaspiro - Google Patents

Derives azaspiro Download PDF

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Publication number
WO1997035862A1
WO1997035862A1 PCT/EP1997/001406 EP9701406W WO9735862A1 WO 1997035862 A1 WO1997035862 A1 WO 1997035862A1 EP 9701406 W EP9701406 W EP 9701406W WO 9735862 A1 WO9735862 A1 WO 9735862A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
formula
hydrogen
oxygen
compound
Prior art date
Application number
PCT/EP1997/001406
Other languages
English (en)
Inventor
Laramie Mary Gaster
Paul Adrian Wyman
Original Assignee
Smithkline Beecham Plc
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 Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to EP97915403A priority Critical patent/EP0889893A1/fr
Priority to JP9534010A priority patent/JP2000507254A/ja
Publication of WO1997035862A1 publication Critical patent/WO1997035862A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/42—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of mineralocorticosteroids

Definitions

  • the present invention relates to novel piperidine derivatives, processes for their preparation, and pharmaceutical compositions containing them.
  • EPA 0 533 266/7/8 disclose a series of benzanilide derivatives which are said to possess 5HT 1 D receptor antagonist activity. These compounds are said to be of use in the treatment of various CNS disorders.
  • the 5HT 1 D ⁇ receptor has now been reclassif ⁇ ed as the 5HT 1 B receptor (P.R Hartig et al Trends in Pharmacological Science, 1996, 17, 103 - 105.
  • the present invention therefore provides a compound of formula (I) or a salt or N-oxide thereof:
  • R 1 is hydrogen, halogen, C 1 -6 alkyl, C 3-6 cycloalkyl, COC 1-6 alkyl, C 1 -6 alkoxy, hydroxy, hydroxy C 1 -6 alkyl, hydroxyC 1-6 alkoxy, C 1 -6 alkoxy C 1 -6 alkoxy, acyl, nitro,
  • R 2 and R 3 are independently hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl,
  • B is oxygen or sulphur
  • D is nitrogen, carbon or a CH group
  • R 8 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl or C 1 -6 alkylC 3-6 cycloalkyl;
  • R 9 and R 10 are independently hydrogen or C 1-6 a lkyl;
  • E is oxygen, CR 18 R 19 or NR 20 where R 18 , R 19 and R 20 are independently hydrogen or C 1 -6 alkyl or E is S(O) v where v is 0, 1 or 2;
  • D is nitrogen
  • R 6 is hydrogen
  • G, X, Y and CR 9 R 10 are all CH 2 groups.
  • C 1 -6 alkyl groups may be straight chain or branched.
  • aryl includes phenyl and naphthyl.
  • Heteroaryl groups include thienyl, furyl, pyridyl, pyrimidyl and pyrazinyl groups.
  • Optional substituents for aryl and heteroaryl groups include those groups listed above for R 2 /R 3 .
  • R 1 is hydrogen, halogen, C 1 -6 alkyl, C 3-6 cycloalkyl, COC 1-6 alkyl, C ⁇ alkoxy, hydroxy, hydroxyC 1-6 alkyl, hydroxyC 1-6 alkoxy, C 1 -6 alkoxyC 1 -6 alkoxy, acyl, nitro, trifluoromethyl, cyano, SR 9 , SOR 9 , SO 2 R 9 , SO 2 NR 10 R H , CO 2 R 10 , NR 10 SO 2 R 1 1 , CONR 10 R 11 , CO 2 NR 10 R 1 1 , CONR 10 (CH 2 ) p CO 2 R 11 ,
  • R 1 is a 5 to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur
  • suitable heterocyclic rings include thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrrolidinyl and pyrazinyl.
  • the heterocyclic rings can be linked to the remainder of the molecule via a carbon atom or, when present, a nitrogen atom.
  • Suitable substituents for these rings include R 2 and R 3 groups as defined above.
  • R 1 is optionally substituted triazolyl, thiazolyl, isoxazolyl, pyrazinyl or oxadiazolyl.
  • R 1 is optionally substituted oxadiazolyl.
  • Preferred substituents include C 1-6 alkyl such as methyl.
  • R 1 is a 5-methyl-1,2,4-oxadiazol-3-yl group.
  • R 2 and R 3 are independently hydrogen, halogen, C 1 -6 alkyl,
  • R 10 CONR 10 R 11 , NR 10 R 11 where R 10 and R 1 1 are independently hydrogen or C 1-6 alkyl, or R 2 and R 3 together form a group -(CH 2 ) r R 14 -(CH 2 ) s - where R 14 is O, S, CH 2 or NR 15 where R 15 is hydrogen or C 1-6 alkyl and r and s are independently 0, 1 or 2.
  • R 2 group is ortho with respect to the biphenyl linkage.
  • R 2 is hydrogen or C 1-6 alkyl, in particular methyl.
  • R 3 is hydrogen.
  • B is oxygen or sulphur.
  • B is oxygen.
  • D is nitrogen, carbon or a CH group.
  • D is nitrogen.
  • R 6 together with R 7 forms a group -A- where A is (CR 16 R 17 ) t where t is 2 or 3 and R 16 and R 17 are both hydrogen.
  • R 8 is hydrogen, C 1 -6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl or
  • R 8 is C 1-6 alkylC 3-6 cycloalkyl.
  • R 8 is C 1-6 alkyl, most preferably R 8 is methyl.
  • R 9 and R 10 are independently hydrogen or C 1-6 alkyl.
  • R 9 and RIO are both hydrogen.
  • m is 2 forming part of a spiro-piperidine ring.
  • E is oxygen, CR 18 R 19 or NR 20 where R 18 , R 19 and R 20 are independently hydrogen or C 1 -6 alkyl or E is S(O) v where v is 0, 1 or 2.
  • E is oxygen.
  • R 21 and R 22 are independently hydrogen or C 1 -6 alkyl.
  • G is CH 2 .
  • X and Y are independently CR 9 R 10 where R 9 and R 10 are as defined above.
  • R 9 and R 10 are as defined above.
  • X and Y are both CH 2 .
  • Particularly preferred compounds of the invention include:
  • Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts. These include acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalatcs, methanesulphonates and p-toluenesulphonates.
  • acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalatcs, methanesulphonates and p-toluenesulphonates.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and the mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the invention.
  • the present invention provides a process for the preparation of a compound of formula (I) which comprises.
  • R 1 , R 2 and R 3 are groups as defined in formula (I) or protected derivatives thereof and L is a leaving group
  • R 6 , R 7 , R 8 , R 9 , R 10 , E, G, X, Y, and m are groups as defined in formula (I) or protected derivatives thereof and optionally thereafter in any order:
  • Suitable activated carboxylic acid derivatives of formula (II) include acyl halides and acid anhydrides. Activated compounds of formula (II) can also be prepared by reaction of the corresponding carboxylic acid with a coupling reagent such as
  • the group L is halo, particularly chloro.
  • a compound of formulae (II) and (III) are typically reacted together in an inert organic solvent such as DMF, THF or dichloromethane at ambient or elevated temperature in the presence of a base such as an alkali metal hydroxide, triethylamine or pyridine.
  • L is an ester forming group such that the resulting esters of formula (II) can be reacted with compounds of formula (III) in the presence of an organo- aluminium reagent such as trimethylaluminium.
  • an organo- aluminium reagent such as trimethylaluminium.
  • Such a reaction is typically carried out in the presence of an inert solvant such as toluene.
  • Carboxylic acid groups can be protected as esters.
  • Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection is achieved using standard conditions.
  • 5HT 1 B receptor antagonists and in particular the compounds of the present invention, are expected to be of use in the treatment of CNS disorders such as mood disorders, including depression, seasonal affective disorder and dysthymia, anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnestic disorders and age-associated memory impairment; and disorders of eating behaviours, including anorexia nervosa and bulimia nervosa.
  • CNS disorders include motor disorders such as Parkinson's disease, dementia in
  • Parkinson's disease neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders.
  • 5HT 1 B receptor antagonists may also be of use in the treatment of endocrine disorders such as hyperprolactinaemia, in the treatment of vasospasm (particularly in the cerebral vasculature) and hypertension, as well as disorders in the gastrointestinal tract where changes in motility and secretion are involved. They may also be of use in the treatment of sexual dysfunction and
  • the present invention provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in therapy.
  • the present invention also provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of the
  • the invention provides the use of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of the aforementioned disorders.
  • the invention provides a method of treating the aforementioned disorders which comprises administering an effective amount to a patient in need of such treatment of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the invention provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment or prophylaxis of depression.
  • the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitu table powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.
  • 6-Nitroindoline (15.63g, 0.095 mol) was refluxed for 0.25 h in acetic anhydride (100 ml), cooled, and the precipitate filtered and washed with water, before drying in vacuo.
  • This material (16.6g, 0.08 mol) was hydrogenated in ethanol (500 ml) over 10% palladium on charcoal (3.4g of 50% paste in water). The catalyst was removed by filtration and the filtrate was evaporated to leave the title compound as an off-white/cream powder (12.59g; 89%).
  • the title compound was prepared from 1-acetyl-5-bromo-6-[(1-methyl-1,2,5,6- tetrahydropyridin-4-yl)methoxy]indoline (D4) using a similar procedure to Description 8b in WO96/ 19477, but with toluene at 80°C in place of refluxing benzene.
  • the product was obtained from the acid/base purification as a beige solid (94%).
  • the title compound was prepared from 7-acetyl-1'-methyl-2,3,5,6- tetrahydrospiro[furo[3,2-f]indole-3,4'-piperidine] (D5) using the procedure of Description 8c in W096/19477.
  • the product was recry stall ised from ethyl acetate/60-80 petrol (44%).
  • Lawesson's reagent (117 mg, 0.288 mmol) and the suspension was heated under reflux for 3 hrs until a yellow solution resulted. The reaction mixture was allowed to cool to room temperature, then concentrated in vacuo and loaded onto a neutral alumina column and eluted with DCM, to remove excess Lawesson's reagent. Elution with 1%

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Psychiatry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention porte sur des composés de formule (I), où B est O ou S, D est C ou N, et E est O, CR?18R19 ou NR20¿, qui présentent une activité antagoniste du récepteur 5HT1B.
PCT/EP1997/001406 1996-03-27 1997-03-19 Derives azaspiro WO1997035862A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP97915403A EP0889893A1 (fr) 1996-03-27 1997-03-19 Derives azaspiro
JP9534010A JP2000507254A (ja) 1996-03-27 1997-03-19 アザスピロ誘導体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9606396.1 1996-03-27
GBGB9606396.1A GB9606396D0 (en) 1996-03-27 1996-03-27 Novel compounds

Publications (1)

Publication Number Publication Date
WO1997035862A1 true WO1997035862A1 (fr) 1997-10-02

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ID=10791079

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/001406 WO1997035862A1 (fr) 1996-03-27 1997-03-19 Derives azaspiro

Country Status (4)

Country Link
EP (1) EP0889893A1 (fr)
JP (1) JP2000507254A (fr)
GB (1) GB9606396D0 (fr)
WO (1) WO1997035862A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9241942B2 (en) 2007-06-08 2016-01-26 Mannkind Corporation IRE-1α inhibitors

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1403458B1 (it) 2010-12-28 2013-10-17 Scarpa Calzaturificio Spa Scarpone da sci
ITTV20130204A1 (it) 2013-12-06 2015-06-07 Scarpa Calzaturificio Spa Scarpone da sci
ITTV20130205A1 (it) 2013-12-06 2015-06-07 Scarpa Calzaturificio Spa Scarpone da sci
ITUB20160158A1 (it) 2016-01-15 2017-07-15 Scarpa Calzaturificio Spa Scarpone da sci

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0533267A1 (fr) * 1991-09-18 1993-03-24 Glaxo Group Limited Dérivés de benzanilide comme 5-HT1D antagonistes
WO1995017401A1 (fr) * 1993-12-21 1995-06-29 Smithkline Beecham Plc Carboxamides de dihydrobenzofuranyle-biphenyle presentant une activite antagoniste du 5ht¿1d?
WO1996011934A1 (fr) * 1994-10-18 1996-04-25 Smithkline Beecham Plc Composes spiro tricycliques, leur procede de preparation et leur utilisation en tant qu'antagonistes du recepteur de 5ht1d
WO1996019477A1 (fr) * 1994-12-22 1996-06-27 Smithkline Beecham Plc Composes spiro tetracycliques, procedes de preparation et utilisation comme antagonistes du recepteur 5ht1d

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0533267A1 (fr) * 1991-09-18 1993-03-24 Glaxo Group Limited Dérivés de benzanilide comme 5-HT1D antagonistes
WO1995017401A1 (fr) * 1993-12-21 1995-06-29 Smithkline Beecham Plc Carboxamides de dihydrobenzofuranyle-biphenyle presentant une activite antagoniste du 5ht¿1d?
WO1996011934A1 (fr) * 1994-10-18 1996-04-25 Smithkline Beecham Plc Composes spiro tricycliques, leur procede de preparation et leur utilisation en tant qu'antagonistes du recepteur de 5ht1d
WO1996019477A1 (fr) * 1994-12-22 1996-06-27 Smithkline Beecham Plc Composes spiro tetracycliques, procedes de preparation et utilisation comme antagonistes du recepteur 5ht1d

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9241942B2 (en) 2007-06-08 2016-01-26 Mannkind Corporation IRE-1α inhibitors
US9546149B2 (en) 2007-06-08 2017-01-17 Mannkind Corporation IRE-1α inhibitors

Also Published As

Publication number Publication date
JP2000507254A (ja) 2000-06-13
EP0889893A1 (fr) 1999-01-13
GB9606396D0 (en) 1996-06-05

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