EP0000200B1 - N-Amidino-3,5-Diamino-6-substituierte-2-pyrazinecarboxamide und ein Verfahren zu ihrer Herstellung - Google Patents

N-Amidino-3,5-Diamino-6-substituierte-2-pyrazinecarboxamide und ein Verfahren zu ihrer Herstellung Download PDF

Info

Publication number
EP0000200B1
EP0000200B1 EP78100264A EP78100264A EP0000200B1 EP 0000200 B1 EP0000200 B1 EP 0000200B1 EP 78100264 A EP78100264 A EP 78100264A EP 78100264 A EP78100264 A EP 78100264A EP 0000200 B1 EP0000200 B1 EP 0000200B1
Authority
EP
European Patent Office
Prior art keywords
diamino
amidino
methyl
reaction
pyrazinoate
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.)
Expired
Application number
EP78100264A
Other languages
English (en)
French (fr)
Other versions
EP0000200A1 (de
Inventor
Otto William Woltersdorf, Jr.
Susan Jane Desolms
Edward Jethro Cragoe, Jr.
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.)
Merck and Co Inc
Original Assignee
Merck and Co 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 Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0000200A1 publication Critical patent/EP0000200A1/de
Application granted granted Critical
Publication of EP0000200B1 publication Critical patent/EP0000200B1/de
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
    • A01N31/02—Acyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics

Definitions

  • This invention relates to new N-amidino-3,5-diamino-6-substituted-2-pyazinecarboxamides and process for preparing same.
  • N-Amidino-3,5-diamino-6-substituted-2-pyrazinecarboxamides particularly the N-amidino-3,5-diamino-6-chloro-2-pyrazinecarboxamide which is commercially known as amiloride are described by the general formula in Column 1 of U.S. Patent 3,313,813. All of the compounds disclosed in U.S. Patent 3,313,813 possess diuretic and natriuretic properties; they selectively enhance the excretion of sodium ions without causing an increase in excretion of potassium ions.
  • the present invention also relates to several novel N-amidino-3,5-diamino-6-substituted -2-pyrazinecarboxamides. These compounds are also useful because they possess diuretic and natriuretic properties and selectively enhance the excretion of sodium ions without causing an increase in excretion of potassium ions.
  • the potassium loss which is caused by most known diuretics, often results in a severe muscular weakness. Since the compounds of this invention are essentially free of this potassium depletion, they have this decided advantage as diuretics.
  • diuretic agents they can be used for the treatment of edema, hypertension and other diseases known to be responsive to this therapy.
  • the products of this invention can be administered to man or animals in the form of pills, tablets, capsules, elixirs, injectable preparations and the like and can comprise one or more of the compounds of this invention as the only essential active ingredient of the pharmaceutical formulation or the novel compound(s) can be combined in pharmaceutical formulations with other diuretic agents or, indeed, other therapeutic agents.
  • the compounds of this invention are advantageously administered at a dosage range of from about 5 mg./day to about 750 mg./day or at a somewhat higher or lower dosage at the physician's discretion, preferably in subdivided amounts on a 2 to 4 times a day regimen.
  • This reaction can be run in a solvent, particularly an inert organic solvent and preferably hexamethylphosphoramide or dimethylformamide.
  • the reaction temperature is not critical and the reaction can be run at anywhere from 25-100°C.
  • the length of time the reaction is carried out is not critical either and can be run anywhere from 0.1 to 10 hours.
  • Isolation of the reaction product which is N-amidino-3,5-diamino-6-X-2-pyrazinecarboxamide from the reaction mixture is performed by methods known in the art such as by adding crushed ice and water to the reaction mixture to precipitate the desired product.
  • An alternative route to the compounds of this invention involves the reaction of CuX wherein X is as defined above with methyl-3,5-diamino-6-iodo-(or bromo)-pyrazinoate which in turn under similar reaction conditions as discussed for the first reaction above will provide methyl-3,5-diamino-6- substituted pyrazinoate.
  • This is shown in the above flow sheet as a reaction of IV to III.
  • Compound IV is known from the literature particularly U.S. Patent 3,313,813.
  • the methyl- 3,5-diamino-6-X-pyrazinoate (Compound III) can then be reacted with guanidine to yield the desired product Compound I.
  • This latter reaction is preferably carried out under anhydrous conditions with or without a solvent such as methanol, ethanol, isopropyl alcohol or other solvents.
  • the reaction may be carried out at room temperature or by heating on a steam bath for 1 minute to 2 hours or longer.
  • the desired product usually is recovered from the cooled reaction mixture by trituration with water. Purification frequently is carried out by converting the product to a salt which can be recrystallized or the base can be regenerated by addition of aqueous alkali.
  • N-Amidino-3,5-diamino-6-iodo-2-pyrazinecarboxamide hydrochloride (3.50 g., 0.01 mole), cuprous cyanide (2.15 g., 0.024 mole) and hexamethylphosphoramide (30 ml.) are combined and heated at 100°C. for 15 minutes. After cooling to ambient temperature the reaction mixture is added to aqueous sodium cyanide solution (100 ml.), stirred at 25°C for 1/2 hour and the solid precipitate is collected by suction filtration, washed with water, then chloroform. On dissolving the product in boiling water (50 ml.), treating with 6N HCI and cooling one obtains 1.43 g. of N-amidino-3,5-diamino-6-cyano-2-pyrazinecarboxamide hydrochloride m.p. 350°C.
  • Methyl 3,5-diamino-6-iodo-2-pyrazinoate (370 mg., 0.0012 mole), cuprous cyanide (215 mg., 0.0024 mole) and hexamethylphosphoramide (10 ml.) are combined and heated at 100°C. for 15 minutes. After cooling to 25°C. the reaction mixture is added to aqueous sodium cyanide solution, stirred at 25°C. for 1 hour and extracted with CHC1 3 . The CHC1 3 layer was washed with dilute NaCN solution, then with H 2 0, and dried (MgS0 4 ). After evaporation of the CHCI 3 , the residual oil was treated with hexane to give 75 mg. of methyl 3,5-diamino-6-cyano-2-pyrazinoate hemihydrate melting at 284-5°C.Elemental analysis for C 7 H 7 N 5 O 2 ⁇ 1/2 H 2 0;
  • Step A Methyl 3,5-diamino-6-trifluoromethylthio-2-pyrazinoate
  • Methyl 3,5-diamino-6-iodo-2-pyrazinoate (3.70 g., 0.0012 mole), cuprous trifluoromethylmer- captide (5.0 g., 0.0025 mole) and hexamethylphosphoramide (100 ml.) are combined and heated at 100°C. for 15 minutes.
  • the reaction mixture is added to crushed ice-H 2 0 and extracted with CHC1 3 , the CHCl 3 layer washed with water, dried (MgS0 4 ) then concentrated to give an amber oil.
  • Step B N-Amidino-3,5-diamino-6-trifluoromethylthio-2-pyrazinecarboxamide hydrate
  • Guanidine hydrochloride (3.34 g., 0.035 mole) is added to a solution of sodium methoxide (1.67 g., 0.032 mole) in methanol (20 ml.) with stirring at 25°C. After 15 minutes, methyl 3,5-diamino-6-trifluoromethylthio-2-pyrazinoate (1.85 g., 0.007 mole) is added, and the mixture is heated on a steam bath for 15 min. Crushed ice-H 2 0 (20 ml.) is added to the reaction mixture to precipitate 390mg. of N-amidino-3,5-diamino-6-trifluoromethylthio-2-pyrazinecarboxamide, m.p. 195°C. Elemental analysis for C 7 H 8 F 3 N 7 OS ⁇ H 2 O;
  • Step A Methyl 3,5-diamino-6-trifluoromethylthio-2-pyrazinoate
  • Methyl 3,5-diamino-6-trifluoromethylthio-2-pyrazinoate is prepared from methyl 3,5-diamino-6-iodo-2-pyrazinoate following essentially the same procedure described in Example 3, Step A except that dimethylformamide is used as the solvent.
  • Step A Methyl 3,5-diamino-6-trifluoromethylthio-2-pyrazinoate
  • Methyl 3,5-diamino-6-trifluoromethylthio-2-pyrazinoate is prepared from methyl 3,5-diamino-6-iodo-2-pyrazinate following essentially the same procedure described in Example 3, Step A except that bis(trifluoromethylthio)-mercury and copper are used to generate cuprous trifluoromethyl- thiomercaptide in situ.
  • N-Amidino-3,5-diamino-6-trifluoromethylthio-2-pyrazinecarboxamide is prepared from N-amidino-3,5-diamino-6-iodo-2-pyrazinecarboxamide hydrochloride by essentially the same procedure described in Example 1 using trifluoromethylthiocopper in place of cuprous cyanide.
  • Step A Methyl 3,5-diamino-6-phenylthiopyrazinoate
  • Step B N-Amidino-3,5-diamino-6-phenylthio-2-pyrazinecarboxamide hemihydrate
  • Guanidine hydrochloride (5.2 g., 0.055 mole) is added to an solution of sodium methoxide (2.7 g., 0.50 mole) in methanol (40 ml) stirred for five minutes and filtered free of sodium chloride.
  • the guanidine solution is evaporated to a volume of 20 ml. then treated with methyl 3,5-diamino-6-phenylthiopyrazinoate (2.5 g., 0.009 mole), heated on a steam bath for ten minutes then poured into water (200 mi.) to give 2.2 g. N-amidino-3,5-diamino-6-phenylthio-2-pyrazinecarboxamide hemihydrate which melts at 238°C. after being washed with methanol.

Landscapes

  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Plant Pathology (AREA)
  • Pest Control & Pesticides (AREA)
  • Dentistry (AREA)
  • Agronomy & Crop Science (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Diabetes (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)
  • Liquid Crystal Substances (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Claims (5)

1. Verbindung mit der Formel
Figure imgb0021
worin X Cyano, CF3S oder C6H5S ist, und ihre Salze mit pharmazeutisch brauchbaren Säuren.
2. Verfahren zur Herstellung von Verbindungen der Formel
Figure imgb0022
worin X Cyano, CF3S oder C6H5S ist, durch Reaktion einer Verbindung mit der Formel
Figure imgb0023
mit CuX,
worin X wie vorstehend definiert ist und Y I oder Br ist.
3. Verfahren nach Anspruch 2, bei dem die Reaktion im dem Lösungsmittel Hexamethylphosphoramid oder Dimethylformamid bei 25-100°C durchgeführt wird.
4. Verfahren zur Herstellung von Verbindungen mit der Formel
Figure imgb0024
durch
a) Reaktion einer Verbindung mit der Formel
Figure imgb0025
mit CuX, worin X Cyano, CF3S oder C6H5S ist, und Y oder Br ist, unter Bildung einer Verbindung mit der Formel
Figure imgb0026
worin X wie vorstehend definiert ist und
b) Umsetzen des Produkts der Stufe a) mit Guanidin unter Bildung der gewünschten Verbindungen.
5. Verfahren nach Anspruch 4, bei dem die Reaktion der Stufe
a) in Anwesenheit von Hexamethylphosphoramid oder Dimethylformamid bei 25-100°C durchgeführt wird.
EP78100264A 1977-06-29 1978-06-28 N-Amidino-3,5-Diamino-6-substituierte-2-pyrazinecarboxamide und ein Verfahren zu ihrer Herstellung Expired EP0000200B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US811011 1977-06-29
US05/811,011 US4196292A (en) 1977-06-29 1977-06-29 6-Substituted amiloride derivatives

Publications (2)

Publication Number Publication Date
EP0000200A1 EP0000200A1 (de) 1979-01-10
EP0000200B1 true EP0000200B1 (de) 1982-03-24

Family

ID=25205286

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100264A Expired EP0000200B1 (de) 1977-06-29 1978-06-28 N-Amidino-3,5-Diamino-6-substituierte-2-pyrazinecarboxamide und ein Verfahren zu ihrer Herstellung

Country Status (12)

Country Link
US (1) US4196292A (de)
EP (1) EP0000200B1 (de)
JP (1) JPS5412389A (de)
AT (1) AT362795B (de)
DE (1) DE2861684D1 (de)
DK (1) DK290278A (de)
ES (1) ES471244A1 (de)
FI (1) FI781966A (de)
HU (1) HU178302B (de)
IT (1) IT1105454B (de)
NO (1) NO782230L (de)
PL (1) PL119097B1 (de)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4362724A (en) * 1980-05-19 1982-12-07 Merck & Co., Inc. Method of treating edema and hypertension and pharmaceutical composition therefor in which the active ingredient comprises a novel substituted pyrazinyl-1,2,4-oxadiazole and a kaliuretic diuretic
US4594349A (en) * 1982-01-04 1986-06-10 Beyer Jr Karl H Hyperuretic agents
US4952582A (en) * 1982-01-04 1990-08-28 Beyer Jr Karl H Pyrazinoylguanidine and derivatives thereof having few polar substituents and being useful as hyperuretic agents
WO1990009792A1 (en) * 1989-03-03 1990-09-07 The General Hospital Corporation Topical application of amiloride or analogues thereof for treatment of inflammation
US6858614B2 (en) * 2002-02-19 2005-02-22 Parion Sciences, Inc. Phenolic guanidine sodium channel blockers
US6858615B2 (en) 2002-02-19 2005-02-22 Parion Sciences, Inc. Phenyl guanidine sodium channel blockers
US6903105B2 (en) * 2003-02-19 2005-06-07 Parion Sciences, Inc. Sodium channel blockers
US7745442B2 (en) 2003-08-20 2010-06-29 Parion Sciences, Inc. Methods of reducing risk of infection from pathogens
US20090253714A1 (en) * 2003-08-20 2009-10-08 Johnson Michael R Methods of reducing risk of infection from pathogens
US20070021439A1 (en) * 2005-07-25 2007-01-25 Parion Sciences, Inc. Methods of reducing risk of infection from pathogens with soluble amide and ester pyrazinoylguanidine sodium channel blockers
AR086745A1 (es) 2011-06-27 2014-01-22 Parion Sciences Inc 3,5-diamino-6-cloro-n-(n-(4-(4-(2-(hexil(2,3,4,5,6-pentahidroxihexil)amino)etoxi)fenil)butil)carbamimidoil)pirazina-2-carboxamida
BR112015014178A2 (pt) 2012-12-17 2017-07-11 Parion Sciences Inc compostos de 3,5-diamino-6-cloro-n-(n-(4-fenilbutil)carbamimidoil) pirazina-2- carboxamida
BR112015014349A2 (pt) 2012-12-17 2017-07-11 Parion Sciences Inc derivados de cloro-pirazina carboxamida úteis para o tratamento de doenças favorecidas por hidratação mucosa insuficiente
US9102633B2 (en) 2013-12-13 2015-08-11 Parion Sciences, Inc. Arylalkyl- and aryloxyalkyl-substituted epithelial sodium channel blocking compounds

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB286896A (en) * 1927-03-29 1928-03-15 Arthur William Howarth Improvements in smokers' pipes
US3305552A (en) * 1965-11-22 1967-02-21 Merck & Co Inc 3-aminopyrazinoic acids and process for their preparation
US3507865A (en) * 1967-04-27 1970-04-21 Merck & Co Inc 3-hydroxy- and 3-mercaptopyrazinamidoguanidines the corresponding ethers and thioethers and processes for their preparation
US3573306A (en) * 1969-03-05 1971-03-30 Merck & Co Inc Process for preparation of n-substituted 3,5-diamino-6-halopyrazinamides

Also Published As

Publication number Publication date
PL119097B1 (en) 1981-11-30
FI781966A (fi) 1978-12-30
NO782230L (no) 1979-01-02
US4196292A (en) 1980-04-01
EP0000200A1 (de) 1979-01-10
DE2861684D1 (en) 1982-04-29
DK290278A (da) 1978-12-30
JPS5412389A (en) 1979-01-30
PL207947A1 (pl) 1979-10-22
AT362795B (de) 1981-06-10
ES471244A1 (es) 1979-10-01
IT7849984A0 (it) 1978-06-22
IT1105454B (it) 1985-11-04
ATA469078A (de) 1980-11-15
HU178302B (en) 1982-04-28

Similar Documents

Publication Publication Date Title
EP0000200B1 (de) N-Amidino-3,5-Diamino-6-substituierte-2-pyrazinecarboxamide und ein Verfahren zu ihrer Herstellung
FR2554719A1 (fr) Medicaments a base de nouveaux derives de la vinyl-6 furo-(3,4-c)-pyridine
RU2162081C2 (ru) Способ получения ламотриджина и промежуточное соединение, используемое при его получении
EP1098891B1 (de) Polycyclische thiazolidin-2-yliden amine, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
JPH0150698B2 (de)
JPS61183286A (ja) ２‐アルコキシ‐ｎ‐（１‐アザビシクロ〔２，２，２〕オクタン‐３‐イル）アミノベンズアミドの製法
SK14672001A3 (sk) Spôsob syntézy a kryštalizácie zlúčenín obsahujúcich piperazínový kruh
US3948896A (en) N-mono(alkoxymethyl) phenobarbitals, process therefor and therapeutic composition and method containing same
US4609659A (en) 2,6-disubstituted derivatives of 3-nitropyrazines useful as adjuncts to radiation therapy
JPS61106574A (ja) オキサ（またはチア）ジアジン誘導体
JPS6399057A (ja) グリシン誘導体
CA1132562A (en) Halogeno derivatives of isopropylamino pyrimidine, their preparation and therapeutic use
US4162257A (en) N,N-dimethyl-5-phenyl-2-furamides
US4511577A (en) Derivatives of benzoic acid
IE43311B1 (en) 1-methyl-2-(pyridyloxmyethyl)-5-nitroimidazoles and process for preparing them
JPH0551584B2 (de)
JPH0615523B2 (ja) Ｓ−アルキルチオ−ｌ−システインスルフオキサイド化合物及びその製造方法並びにこれを含有する抗高脂血症及び強肝剤
CH666688A5 (fr) Procede de preparation des derives de la furo-(3,4-c)-pyridine substituees en position 6.
US4346100A (en) Phenoxy acetic acid derivative, its preparation and therapeutic use
US4182890A (en) Ethyl 2-oxo-3-phenylethylaminopiperidine-4-carboxylate hydrochloride
RU2039046C1 (ru) Способ получения 5-бромникотиновой кислоты
JPS6317869A (ja) ２−低級アルキル−４−アミノ−５−ホルミルピリミジンの製造法
EP0111151A1 (de) Substituierte Nitropyrazinverbindungen, Verfahren zu deren Herstellung und diese enthaltende pharmazeutische Zusammenstellungen
JPS5829059B2 (ja) 家禽の飼料組成物とその製法
JPS61268688A (ja) ２，６−ジアミノベンゾ−〔１，２−ｄ：４，５−ｄ′〕−ビスチアゾ−ルの製造法

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 GB 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 GB LU NL SE

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

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

Ref country code: FR

Payment date: 19820423

Year of fee payment: 5

REF Corresponds to:

Ref document number: 2861684

Country of ref document: DE

Date of ref document: 19820429

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

Ref country code: LU

Payment date: 19820622

Year of fee payment: 5

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: 19820630

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

Ref country code: CH

Payment date: 19820630

Year of fee payment: 5

Ref country code: SE

Payment date: 19820630

Year of fee payment: 5

Ref country code: BE

Payment date: 19820630

Year of fee payment: 5

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

Ref country code: NL

Effective date: 19830101

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19830301

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

Ref country code: BE

Effective date: 19830628

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

Ref country code: SE

Effective date: 19830629

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

Ref country code: CH

Effective date: 19830630

GBPC Gb: european patent ceased through non-payment of renewal fee
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: 19840229

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

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

Ref country code: GB

Effective date: 19881117

EUG Se: european patent has lapsed

Ref document number: 78100264.7

Effective date: 19850610

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

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230522