EP0000005A1 - Nouveaux dérivés de céphalosporines, leurs préparations et leurs compositions pharmaceutiques - Google Patents

Nouveaux dérivés de céphalosporines, leurs préparations et leurs compositions pharmaceutiques Download PDF

Info

Publication number
EP0000005A1
EP0000005A1 EP78100078A EP78100078A EP0000005A1 EP 0000005 A1 EP0000005 A1 EP 0000005A1 EP 78100078 A EP78100078 A EP 78100078A EP 78100078 A EP78100078 A EP 78100078A EP 0000005 A1 EP0000005 A1 EP 0000005A1
Authority
EP
European Patent Office
Prior art keywords
salts
methyl
compounds
formula
hydrates
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.)
Granted
Application number
EP78100078A
Other languages
German (de)
English (en)
Other versions
EP0000005B1 (fr
Inventor
Marc Dr. Montavon
Roland Dr. Reiner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Original Assignee
F Hoffmann La Roche AG
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 F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Publication of EP0000005A1 publication Critical patent/EP0000005A1/fr
Application granted granted Critical
Publication of EP0000005B1 publication Critical patent/EP0000005B1/fr
Expired legal-status Critical Current

Links

Classifications

    • 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
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms
    • 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 new acyl derivatives of the general formula in which R is furyl, thienyl or phenyl which is optionally substituted by halogen, hydroxy, lower alkoxy or lower alkyl, R 1 is lower alkyl or aminocarbonylmethyl and X is a group of the formulas in which one of the two radicals R 2 and R 3 or R 4 and R 5 is hydrogen and the other is lower alkyl, carboxymethyl or sulfomethyl, and salts of these compounds and hydrates of these salts.
  • salts of the compounds of formula I are alkali metal salts such as the sodium and potassium salt; the ammonium salt; Alkaline earth metal salts such as the calcium salt; Salts with organic bases, such as salts with amines, e.g. Salts with N-ethyl-piperidine, procaine, dibenzylamine, N, N'-dibenzylethyl-ethylenediamine, alkylamines or dialkylamines, and salts with amino acids, such as e.g. Salts with arginine or lysine.
  • the salts can be mono-salts or also disalts.
  • the second salt formation takes place on the tautomeric enol form of the triazine residue b, which has an acid character.
  • the compounds of formula I also form addition salts with organic or inorganic acids.
  • salts are hydrohalides, for example hydrochlorides, hydrobromides, hydroiodides, and also other mineral acid salts, such as sulfates, nitrates, phosphates and the like such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.
  • the salts of the compounds of formula I can be hydrated.
  • the hydration can take place in the course of the production process or can occur gradually as a result of hygroscopic properties of an initially anhydrous salt of a compound of the formula I.
  • lower alkyl groups are either straight chain or branched and can contain up to 7 carbon atoms, e.g. Methyl, ethyl, n-propyl, isopropyl, n-pentyl, n-heptyl.
  • Lower alkoxy groups have an analogous meaning.
  • Halogen represents all four halogens, i.e. Fluorine, chlorine, bromine and iodine; chlorine and bromine are preferred.
  • Preferred R groups are furyl, thienyl and phenyl, especially furyl. Methyl is preferred as R 1 .
  • Preferred X groups are group (c) and groups (a) and (b), in which one of the two radicals R 2 and R 3 or R 4 and R 5 is hydrogen and the other is methyl. Particularly preferred X groups are the 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl and the 1,4,5,6-tetrahydro-4-methyl -5,6-dioxo-as-triazin-3-yl group.
  • Preferred compounds are (7R) -7- [2- (2-furyl) -2- (methoxyimino) acetamido] -3 - / [(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo -as-triazin-3-yl) thio] methyl / -3-cephem-4-carboxylic acid and its salts and the hydrates of these salts.
  • the compounds of formula I and their salts or hydrates of the salts can be in the syn-isomeric form or in the anti-isomeric form or as mixtures of these two forms.
  • the syn-isomeric form or mixtures in which the syn-isomeric form predominates is preferred.
  • the carboxy groups present in the starting compounds of formulas II and IV can optionally be protected, e.g. by esterification to an easily cleavable ester such as a silyl ester, e.g. the trimethylsilyl ester.
  • the carboxy group can also be protected by salt formation with an inorganic or tertiary organic base such as triethylamine.
  • Suitable reactive functional derivatives of acids of the formula III are e.g. Halides, i.e. Chlorides, bromides and fluorides; Azides; Anhydrides, especially mixed anhydrides with stronger acids; reactive esters, e.g. N-hydroxysuccinimide esters, and amides, e.g. Imidazolides.
  • Halogens e.g. Chlorine, bromine or iodine
  • acyloxy residues e.g. lower alkanoyl radicals, such as acetoxy, lower.
  • Alkyl or arylsulfonyloxy radicals such as mesyloxy or tosyloxy, or the azidorest in question.
  • the reaction of a compound of formula II with an acid of formula III or a reactive functional derivative thereof can be carried out in a manner known per se. So you can e.g. condense a free acid of the formula III with one of the esters corresponding to the formula II using a carbodiimide, such as dicyclohexylcarbodiimide, in an inert solvent, such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide and then split off the ester group.
  • oxazolium salts e.g. Use N-ethyl-5-phenyl-isoxazolium-3'-sulfonate.
  • a salt of an acid of formula II e.g. a trialkylammonium salt
  • a reactive functional derivative of an acid of formula III as mentioned above in an inert solvent, e.g. one of the above to.
  • an acid halide preferably the chloride of an acid of the formula III
  • the amine of the formula II is reacted with the amine of the formula II.
  • the reaction takes place - preferably in the presence of an acid-binding agent, for example in the presence of aqueous alkali, preferably sodium hydroxide solution, or also in the presence of an alkali metal carbonate, such as potassium carbonate, or in the presence of a lower alkylated amine, such as triethylamine.
  • Water is preferably used as the solvent; but it can also be carried out in an aprotic organic solvent, such as, for example, dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric triamide.
  • reaction of a compound of the formula II with a compound of the formula III or a reactive functional derivative thereof can expediently take place at temperatures between about -40 ° C. and room temperature, for example at about 0-10 ° C.
  • reaction of a compound of formula IV with a thiol of formula V can be carried out in a manner known per se, e.g. at a temperature between about 40 and 80 ° C, suitably at about 60 ° C, in a polar solvent, for example in an alcohol, e.g. in a lower alkanol such as ethanol, propanol and the like, in dimethylformamide or dimethyl sulfoxide, preferably in water or in a buffer solution with a pH of about 6 to 7, preferably 6.5.
  • a polar solvent for example in an alcohol, e.g. in a lower alkanol such as ethanol, propanol and the like, in dimethylformamide or dimethyl sulfoxide, preferably in water or in a buffer solution with a pH of about 6 to 7, preferably 6.5.
  • the protective group is a silyl group (silyl ester), this group can be split off particularly easily by treating the reaction product with water. If the carboxyl group of an acid of formula IV is protected by salt formation (e.g. with triethylamine), this salt-forming protective group can be split off by treatment with acid.
  • acid e.g. Hydrochloric acid, sulfuric acid, phosphoric acid or citric acid can be used.
  • the 7-amino compounds of the formula II used as starting products can be started from a compound of the formula in which Y represents a leaving group and the carboxy group can be in protected form, be prepared with a thiol of formula V.
  • the reaction can be carried out under the same conditions as those of the starting compounds IV and V.
  • syn / anti mixture of a compound of the formula I obtained can be separated into the corresponding syn and anti forms in a customary manner, for example by recrystallization or by chromatographic methods using a suitable solvent or solvent mixture.
  • the compounds of formula I, their salts and the hydrates of these salts are antibiotic, in particular bactericidally active. They have a broad spectrum of activity against Gram-positive and Gram-negative microorganisms, including ⁇ -lactamase-forming staphylococci and various ⁇ -lactamase-forming Gram-negative bacteria, such as e.g. Haemophilus influenzae, - Escherichia coli, Proteus and Klebsiella species.
  • the compounds of formula I and the pharmaceutically acceptable salts and hydrated forms thereof can be used for the treatment and prophylaxis of infectious diseases.
  • a daily dose of approximately 1 g to approximately 4 g is suitable for the adult.
  • the parenteral administration of the compounds according to the invention is particularly preferred.
  • mice are infected intraperitoneally with an aqueous suspension of Proteus mirabilis.
  • the test substance is applied subcutaneously one hour after the infection.
  • the number of surviving animals is determined on the 4th day.
  • Different doses are applied and the dose at which 50% of the test animals survived (CD50, mg / kg) is determined by interpolation.
  • compositions can contain the compounds of formula I, their salts or hydrated forms of these salts, possibly in a mixture with another therapeutically valuable substance. They are expediently mixed with a pharmaceutical, inorganic or organic inert carrier material which is particularly suitable for parenteral administration, such as, for example, water, gum arabic.
  • a pharmaceutical, inorganic or organic inert carrier material which is particularly suitable for parenteral administration, such as, for example, water, gum arabic.
  • the pharmaceutical preparations are preferably in liquid form, for example as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.
  • This compound is prepared analogously to Example 1 from 3.4 g of 2-methoxyimino-2-furyl-acetic acid (syn / anti mixture 80:20) and 7.46 g of (7R) -7-amino-3-deacetoxy-3- [ (1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl) thio] cephalosporanoic acid.
  • R f value 0.34 (TLC on silica gel F 254 finished plates in the butanol / glacial acetic acid / water 4: 1: 1 system; visualization with UV light).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (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)
  • Saccharide Compounds (AREA)
EP78100078A 1977-06-03 1978-06-01 Nouveaux dérivés de céphalosporines, leurs préparations et leurs compositions pharmaceutiques Expired EP0000005B1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
LU77485 1977-06-03
LU77485 1977-06-03
CH3142/78 1978-03-22
CH314278 1978-03-22

Publications (2)

Publication Number Publication Date
EP0000005A1 true EP0000005A1 (fr) 1978-12-20
EP0000005B1 EP0000005B1 (fr) 1980-10-29

Family

ID=25692293

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100078A Expired EP0000005B1 (fr) 1977-06-03 1978-06-01 Nouveaux dérivés de céphalosporines, leurs préparations et leurs compositions pharmaceutiques

Country Status (26)

Country Link
EP (1) EP0000005B1 (fr)
JP (1) JPS5412394A (fr)
AR (1) AR225134A1 (fr)
AT (2) AT362501B (fr)
AU (1) AU518648B2 (fr)
BR (1) BR7803565A (fr)
CA (1) CA1114808A (fr)
CU (1) CU21118A (fr)
DE (2) DE2860248D1 (fr)
DK (1) DK246878A (fr)
ES (2) ES470442A1 (fr)
FI (1) FI781754A7 (fr)
FR (1) FR2393000A1 (fr)
GB (1) GB1599232A (fr)
GR (1) GR73554B (fr)
HU (1) HU182498B (fr)
IE (1) IE46903B1 (fr)
IL (1) IL54803A (fr)
IT (1) IT1098306B (fr)
MC (1) MC1195A1 (fr)
NL (1) NL7805715A (fr)
NO (1) NO781934L (fr)
NZ (1) NZ187392A (fr)
PH (1) PH14653A (fr)
PT (1) PT68134A (fr)
SE (1) SE7806465L (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0002605A1 (fr) * 1977-12-20 1979-06-27 Eli Lilly And Company Dérivés de céphalosporine et compositions pharmaceutiques les contenant utilisables dans le traitement des infections bactériennes et la préparation des dérivés de cephalosporine
DE2912829A1 (de) * 1978-03-31 1979-10-04 Roussel Uclaf O-substituierte oximderivate der 7-aminotiaoyl-acetamido-cephalosporansaeure, ihre herstellung und pharmazeutische zusammensetzungen
EP0045525A3 (en) * 1978-05-30 1982-02-17 F. Hoffmann-La Roche & Co. Aktiengesellschaft Cephalosporin derivatives and process for their preparation
EP0065748A1 (fr) * 1981-05-22 1982-12-01 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Procédé pour la préparation d'un dérivé de céphalosporine
EP0233780A3 (fr) * 1986-02-19 1989-02-01 Eli Lilly And Company Céphalosporines oximino O-substituées

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NO782998L (no) * 1978-07-19 1980-01-22 Hoffmann La Roche Cephalosporinestere og -etere.

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2137899A1 (fr) * 1971-05-14 1972-12-29 Glaxo Lab Ltd
FR2275215A1 (fr) * 1974-06-21 1976-01-16 Hoffmann La Roche Nouveaux derives heterocycliques de desacetoxycephalosporine, procede pour leur preparation et application en tant que medicament
FR2280381A1 (fr) * 1974-08-02 1976-02-27 Lilly Co Eli Nouveaux derives de cephalosporines

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1555471A (en) * 1975-06-19 1979-11-14 Glaxo Lab Ltd 7 carbamoylalkoxyimino acetamido 3 em 4 carboxylic acidsand derivatives thereof
GB1576625A (en) * 1976-04-12 1980-10-08 Fujisawa Pharmaceutical Co Syn isomer 3,7 disubstituted 3 cephem 4 carboxylic acid compounds and processes for the preparation thereof
GB1596278A (en) * 1976-11-30 1981-08-26 Glaxo Operations Ltd 7-(-oxyimino-acetamino)cephalosporin derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2137899A1 (fr) * 1971-05-14 1972-12-29 Glaxo Lab Ltd
FR2275215A1 (fr) * 1974-06-21 1976-01-16 Hoffmann La Roche Nouveaux derives heterocycliques de desacetoxycephalosporine, procede pour leur preparation et application en tant que medicament
FR2280381A1 (fr) * 1974-08-02 1976-02-27 Lilly Co Eli Nouveaux derives de cephalosporines

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0002605A1 (fr) * 1977-12-20 1979-06-27 Eli Lilly And Company Dérivés de céphalosporine et compositions pharmaceutiques les contenant utilisables dans le traitement des infections bactériennes et la préparation des dérivés de cephalosporine
DE2912829A1 (de) * 1978-03-31 1979-10-04 Roussel Uclaf O-substituierte oximderivate der 7-aminotiaoyl-acetamido-cephalosporansaeure, ihre herstellung und pharmazeutische zusammensetzungen
EP0045525A3 (en) * 1978-05-30 1982-02-17 F. Hoffmann-La Roche & Co. Aktiengesellschaft Cephalosporin derivatives and process for their preparation
EP0065748A1 (fr) * 1981-05-22 1982-12-01 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Procédé pour la préparation d'un dérivé de céphalosporine
US4472574A (en) * 1981-05-22 1984-09-18 Hoffman-La Roche Inc. Process for the manufacture of a cephem carboxylic acid derivative
EP0233780A3 (fr) * 1986-02-19 1989-02-01 Eli Lilly And Company Céphalosporines oximino O-substituées

Also Published As

Publication number Publication date
PT68134A (en) 1978-07-01
FI781754A7 (fi) 1978-12-04
EP0000005B1 (fr) 1980-10-29
AT362501B (de) 1981-05-25
HU182498B (en) 1984-01-30
IE46903B1 (en) 1983-11-02
AT365197B (de) 1981-12-28
ATA345980A (de) 1981-05-15
IL54803A0 (en) 1978-07-31
NL7805715A (nl) 1978-12-05
DE2860248D1 (en) 1981-01-29
IE781056L (en) 1978-12-03
ES470442A1 (es) 1979-10-01
GR73554B (fr) 1984-03-14
CA1114808A (fr) 1981-12-22
CU21118A (es) 1983-04-06
AR225134A1 (es) 1982-02-26
NZ187392A (en) 1984-05-31
JPS5412394A (en) 1979-01-30
AU518648B2 (en) 1981-10-15
FR2393000A1 (fr) 1978-12-29
DE2824065A1 (de) 1978-12-14
DK246878A (da) 1978-12-04
GB1599232A (en) 1981-09-30
IT1098306B (it) 1985-09-07
FR2393000B1 (fr) 1982-10-29
SE7806465L (sv) 1978-12-04
BR7803565A (pt) 1979-02-20
ES478115A1 (es) 1979-06-01
IT7824165A0 (it) 1978-06-02
IL54803A (en) 1982-01-31
NO781934L (no) 1978-12-05
MC1195A1 (fr) 1979-02-23
ATA403578A (de) 1980-10-15
AU3658878A (en) 1979-12-06
PH14653A (en) 1981-10-14

Similar Documents

Publication Publication Date Title
DE2462736C2 (de) 7-Aminothiazolylacetamido-3-cephem-4-carbonsäuren und Verfahren zur Herstellung derselben
DE2727753C2 (fr)
EP0088320B1 (fr) Dérivés de céphalosporine et procédé pour leur préparation
DE2805655C2 (de) 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxyaminoacetamido]-3-cephem-4-carbonsäuren, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
CH630632A5 (de) Verfahren zur herstellung neuer cephalosporinderivate.
EP0030294B1 (fr) Procédé de préparation de dérivés de céphalosporine; intermédiaires et leur préparation
DE2922036C2 (de) 7-[2-(2-Amino-4-thiazolyl)-2-methoxyimino-acetamido]- cephalosporansäure-Derivate
CH633558A5 (de) Verfahren zur herstellung neuer cephalosporinderivate.
CH655118A5 (de) Cephalosporinverbindungen, verfahren zu ihrer herstellung und antibakterielle mittel, die diese verbindungen enthalten.
CH641468A5 (de) Cephemderivate.
DE2736471C2 (fr)
DE3307550C2 (fr)
CH644129A5 (de) 3-unsubstituierte-3-cephemverbindungen, sowie verfahren zu ihrer herstellung.
EP0000005B1 (fr) Nouveaux dérivés de céphalosporines, leurs préparations et leurs compositions pharmaceutiques
EP0049855A2 (fr) Dérivés de céphalosporine, leur préparation, compositions pharmaceutiques les contenant et intermédiaires pour leur préparation
DE69109913T2 (de) Cephalosporinzwischenverbindungen, Verfahren zu ihrer Herstellung sowie zur Herstellung ihrer Endprodukte.
DE2527291C2 (fr)
EP0029966A2 (fr) Dérivés de céphalosporine, leurs préparations et compositions pharmaceutiques qui les contiennent
EP0553792B1 (fr) Procédé pour la préparation de l'hémiheptahydrate du sel disodé de ceftriaxone
EP0036652A2 (fr) Dérivés de céphalosporine, leur préparation, leurs compositions, leur utilisation dans le traitement contre des maladies et leurs intermédiaires
CH666037A5 (de) Verfahren zur herstellung von cephalosporin-syn-isomeren.
EP0008372B1 (fr) Esters et éthers de céphalosporines facilement hydrolysables, leur préparation et compositions les contenant
CH634326A5 (de) 2-hydroxyiminoacetamido-cephemcarbonsaeuren und ihre herstellung.
DD201142A5 (de) Verfahren zur herstellung von bistetrazolyl-methylsubstituierten cephalosporiantibiotika
DE2760488C2 (de) Cephalosporinderivate, Verfahren zu ihrer Herstellung und sie enthaltende Arzneimittel

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): BE CH DE FR LU NL SE

17P Request for examination filed
GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): BE CH DE FR LU NL SE

REF Corresponds to:

Ref document number: 2860248

Country of ref document: DE

Date of ref document: 19810129

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19810630

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19821220

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 19831212

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 19840104

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 19840507

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19840630

Year of fee payment: 7

Ref country code: NL

Payment date: 19840630

Year of fee payment: 7

Ref country code: BE

Payment date: 19840630

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19850602

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Effective date: 19850630

Ref country code: BE

Effective date: 19850630

BERE Be: lapsed

Owner name: F. HOFFMANN-LA ROCHE & CO. A.G.

Effective date: 19850601

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Effective date: 19860101

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19860228

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19860301

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee
REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 19911230

Year of fee payment: 6

EUG Se: european patent has lapsed

Ref document number: 78100078.1

Effective date: 19860728

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT