EP0000151B1 - 1-substituted aminoindolines, process for their production and pharmaceutical compositions containing them - Google Patents

1-substituted aminoindolines, process for their production and pharmaceutical compositions containing them Download PDF

Info

Publication number
EP0000151B1
EP0000151B1 EP78100166A EP78100166A EP0000151B1 EP 0000151 B1 EP0000151 B1 EP 0000151B1 EP 78100166 A EP78100166 A EP 78100166A EP 78100166 A EP78100166 A EP 78100166A EP 0000151 B1 EP0000151 B1 EP 0000151B1
Authority
EP
European Patent Office
Prior art keywords
hydrogen
compound
formula
carbon atoms
alkyl
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
EP78100166A
Other languages
German (de)
French (fr)
Other versions
EP0000151A1 (en
Inventor
Gerhard Dr. Bormann
Richard Dr. Berthold
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.)
Sandoz AG
Original Assignee
Sandoz 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 Sandoz AG filed Critical Sandoz AG
Publication of EP0000151A1 publication Critical patent/EP0000151A1/en
Application granted granted Critical
Publication of EP0000151B1 publication Critical patent/EP0000151B1/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to 1-substituted aminoindoline derivatives.
  • Alkyl, alkoxy and alkylthio preferably contain 1 or 2, especially 1 carbon atom.
  • Halogen is preferably chlorine.
  • a compound of formula I may be obtained by a process comprising cyclizing a compound of formula II, wherein
  • the process according to the invention may be effected in a manner analogous to known methods for cyclizing analogous amino derivatives.
  • X is e. g. a group -NHR a , wherein R a is alkyl of 1 to 4 carbon atoms, especially methyl, or R a is hydrogen.
  • the reaction is preferably effected in an inert solvent such as methanol or ethanol, or, when the amine of formula IV (see below) is liquid at the reaction temperature, the reaction is conveniently effected in the absence of any additional solvent.
  • the reaction is preferably effected in the presence of a mineral acid such as hydrochloric or hydroiodic acid.
  • the reaction temperature may be from room temperature to about 150°C and is preferably at least 50° C, e. g. the boiling temperature of the reaction mixture.
  • the compounds of formula I may be isolated and purified in accordance with known methods.
  • the compounds of formula I may be present in free form, or in the form of acid addition salts.
  • Acid addition salt forms for example, the hydrochloride or hydrogen maleate, may be produced from the free form in known manner, and vice-versa.
  • the compounds of formula I may also be present in tautomeric form, i. e. with the double bond adjacent to one of the other two nitrogen atoms of the guanidine moiety, insofar as this nitrogen atom is not substituted by an alkyl group R i or R 2 . It is to be appreciated that such tautomeric forms also fall under the scope of formula I.
  • the production of the starting materials may be effected in known manner.
  • a compound of formula II may e. g. be produced by reacting a compound of formula III, wherein R 3 to R 5 and X are as defined above and the group -S-Y is a leaving group, with a compound of formula IV, wherein R i , R 2 and n are as defined above.
  • Y may e. g. be alkyl of 1 to 4 carbon atoms, preferably methyl.
  • the reaction conditions may be chosen such as to be identical with the conditions for cyclization according to the invention.
  • the compounds of formula III are then advantageously reacted with the compounds of formula IV to give directly the corresponding compounds of formula I, without intermediate isolation of the compounds offormula II.
  • the starting material is obtained as follows:
  • the compounds of formula I exhibit pharmacological activity.
  • the compounds possess vasoconstricting activity, as indicated by standard tests.
  • this activity may be observed in vivo in rats treated in accordance with the principles of J. S. Gillespie and T. C. Muir, Br. J. Pharmac. Chemother. (1967) 30, 78-87): a pressor effect is elicited following i. v. administration of from about 0.02 to about 50 ⁇ g/kg, particularly of from about 0.02 to about 0.5 ⁇ g/kg of the compounds.
  • the compounds are therefore indicated for use as vasoconstricting agents, e. g. for the prophylaxis and treatment of vascular headaches such as migraine, and of orthostatic disorders such as orthostatic hypotension and its symptoms, such as vertigo.
  • an indicated daily dose is from about 0.0025 to about 1 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.0005 to about 0.5 mg, or in sustained release form.
  • the activity of the compound of Example 1 is especially interesting.
  • the compounds of formula I may be administered in free form or in pharmaceutically acceptable acid addition salt form. Such forms exhibit the same order of activity as the free form.
  • the present invention also provides a pharmaceutical composition comprising a compound of formula I, in free form or in pharmaceutically acceptable salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a solution or a tablet.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
  • Peptides Or Proteins (AREA)

Description

  • The present invention relates to 1-substituted aminoindoline derivatives.
  • In accordance with the invention there are provided compounds of formula I,
    Figure imgb0001
    wherein
    • one of R1 and R2 is hydrogen and the other is hydrogen or alkyl of 1 to 4 carbon atoms,
    • R3 is hydrogen or alkyl of 1 to 4 carbon atoms, in the 2- or 3-position,
    • R4 and R5 independently are hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35, and
    • n is 2, 3 or 4.
  • Alkyl, alkoxy and alkylthio preferably contain 1 or 2, especially 1 carbon atom. Halogen is preferably chlorine.
    • Ri, R2, R3 and R5 are preferably hydrogen. R4 is preferably hydrogen, alkyl or halogen, especially hydrogen.
    • R3 is preferably in the 3 position of the indoline nucleus.
    • R4 is preferably in the 4,5 or 6, especially in the 4 or 5, preferably in the 4-position.
    • n is preferably 2.
  • In accordance with the invention, a compound of formula I may be obtained by a process comprising cyclizing a compound of formula II,
    Figure imgb0002
    wherein
    • R1 to R5 and n are as defined above and
    • X is a leaving group.
  • The process according to the invention may be effected in a manner analogous to known methods for cyclizing analogous amino derivatives. X is e. g. a group -NHRa, wherein Ra is alkyl of 1 to 4 carbon atoms, especially methyl, or Ra is hydrogen. The reaction is preferably effected in an inert solvent such as methanol or ethanol, or, when the amine of formula IV (see below) is liquid at the reaction temperature, the reaction is conveniently effected in the absence of any additional solvent. The reaction is preferably effected in the presence of a mineral acid such as hydrochloric or hydroiodic acid. The reaction temperature may be from room temperature to about 150°C and is preferably at least 50° C, e. g. the boiling temperature of the reaction mixture.
  • The compounds of formula I may be isolated and purified in accordance with known methods.
  • The compounds of formula I may be present in free form, or in the form of acid addition salts. Acid addition salt forms, for example, the hydrochloride or hydrogen maleate, may be produced from the free form in known manner, and vice-versa.
  • The compounds of formula I may also be present in tautomeric form, i. e. with the double bond adjacent to one of the other two nitrogen atoms of the guanidine moiety, insofar as this nitrogen atom is not substituted by an alkyl group Ri or R2. It is to be appreciated that such tautomeric forms also fall under the scope of formula I.
  • The production of the starting materials may be effected in known manner.
  • A compound of formula II may e. g. be produced by reacting a compound of formula III,
    Figure imgb0003
    wherein R3 to R5 and X are as defined above and the group -S-Y is a leaving group, with a compound of formula IV,
    Figure imgb0004
    wherein Ri, R2 and n are as defined above.
  • Y may e. g. be alkyl of 1 to 4 carbon atoms, preferably methyl. The reaction conditions may be chosen such as to be identical with the conditions for cyclization according to the invention. The compounds of formula III are then advantageously reacted with the compounds of formula IV to give directly the corresponding compounds of formula I, without intermediate isolation of the compounds offormula II.
  • When in the compounds of formula III Y is alkyl of 1 to 4 carbon atoms and X is a grcup -NH-Ra, the reaction conditions for producing compounds of formula I directly from corresponding compounds of formula III are analogous to known reaction conditions for the production of a 1-(indolin-1-yl)-guanidine derivative from a 1-(indolin-1-yl)-2-(lower)alkylisothiourea.
  • Insofar as the production of the starting materials is not described, these are known or may be produced and purified in accordance with known processes, or in a manner analogous to the processes described above or analogous to known processes.
  • In the following non-limitative Examples all temperatures are indicated in degrees Centigrade and are uncorrected.
    • Example 1 1-(Imidazolidin-2-ylidenamino)indoline
  • To 10 g 1-(indolin-1-yl)-2-methylisothiourea hydrochloride dissolved in 40 ml ethanol are added 8 ml ethylene diamine and the reaction mixture is boiled for 6 hours with stirring. The mixture is then evaporated to dryness and the residue is extracted from a 1 M solution of sodium hydroxide with methylene chloride. The organic phase is then dried over magnesium sulphate and evaporated. The title compound is obtained (M. P. of the hydrogen maleate 171―172° ― from ethanol/ether).
  • The starting material is obtained as follows:
    • 1-Aminoindoline is reacted with benzoyl isothiocyanate in boiling tetrahydrofurane and, after saponification of the product over 15 minutes with diluted sodium hydroxide under reflux, 1-(indolin-1-yl)thiourea (M. P. 225-227° - from methanol) is obtained. This product is converted into 1-(indolin-1-yl)-2-methylisothiourea hydroiodide by heating up for 1 hour with methyl iodide in methanol. The free base is obtained by addition of aqueous sodium hydroxide and is further reacted with a 2N methanolic solution of hydrochloric acid to give 1-(indolin-1-yl)-2-methylisothiourea hydrochloride (M. P. 227-229° - from methanol/ether).
  • The following compounds of formula I are obtained in a manner analogous to Example 1, using the corresponding starting materials of formula III, wherein Y is methyl and X is ―NH2 or ―NH―CH3, and of formula IV:
    Figure imgb0005
  • The compounds of formula I exhibit pharmacological activity. In particular, the compounds possess vasoconstricting activity, as indicated by standard tests. For example, this activity may be observed in vivo in rats treated in accordance with the principles of J. S. Gillespie and T. C. Muir, Br. J. Pharmac. Chemother. (1967) 30, 78-87): a pressor effect is elicited following i. v. administration of from about 0.02 to about 50 µg/kg, particularly of from about 0.02 to about 0.5 µg/kg of the compounds.
  • The compounds are therefore indicated for use as vasoconstricting agents, e. g. for the prophylaxis and treatment of vascular headaches such as migraine, and of orthostatic disorders such as orthostatic hypotension and its symptoms, such as vertigo.
  • For this use an indicated daily dose is from about 0.0025 to about 1 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.0005 to about 0.5 mg, or in sustained release form.
  • The activity of the compound of Example 1 is especially interesting.
  • The compounds of formula I may be administered in free form or in pharmaceutically acceptable acid addition salt form. Such forms exhibit the same order of activity as the free form. The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free form or in pharmaceutically acceptable salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a solution or a tablet.

Claims (11)

1. A process for the production of a compound of formula I,
Figure imgb0006
wherein
one of R1 and R2 is hydrogen and the other is hydrogen or alkyl of 1 to 4 carbon atoms,
R3 is hydrogen or alkyl of 1 to 4 carbon atoms, in the 2- or 3-position,
R4 and R5 independently are hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35, and
n is 2, 3 or 4,

or a tautomeric form thereof, which comprises cyclizing a compound of formula I
Figure imgb0007
wherein
R1 to R5 and n are as defined above and
X is a leaving group.
2. A compound of formula I, as defined in claim 1, or a tautomeric form thereof.
3. A compound of claim 2, wherein RI to R5 are hydrogen and n is 2.
4. A compound of claim 2, wherein Ri, R2 and R5 are hydrogen and n is 2.
5. A compound of claim 4, wherein R3 is hydrogen and R4 is 5-chloro, or R3 is 2-methyl and R4 is hydrogen.
6. A compound of claim 4, wherein R3 is 3-methyl and R4 is hydrogen, or R3 is hydrogen and R4 is 4-methyl.
7. A compound of claim 4, wherein R3 is hydrogen and R4 is 4-methoxy, or R3 is hydrogen and R4 is 7-methyl.
8. A compound according to any one of claims 2 to 7, in free form.
9. A compound according to any one of claims 2 to 7, in acid addition salt form.
10. A pharmaceutical composition comprising a compound according to any one of claims 2 to 7 in free form or in pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.
11. A compound of claim 2, for use in a method for treatment of the human or animal body by therapy.
EP78100166A 1977-06-28 1978-06-15 1-substituted aminoindolines, process for their production and pharmaceutical compositions containing them Expired EP0000151B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH791577 1977-06-28
CH7915/77 1977-06-28

Publications (2)

Publication Number Publication Date
EP0000151A1 EP0000151A1 (en) 1979-01-10
EP0000151B1 true EP0000151B1 (en) 1981-05-20

Family

ID=4332315

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100166A Expired EP0000151B1 (en) 1977-06-28 1978-06-15 1-substituted aminoindolines, process for their production and pharmaceutical compositions containing them

Country Status (13)

Country Link
EP (1) EP0000151B1 (en)
JP (1) JPS5412373A (en)
AU (1) AU3746878A (en)
CA (1) CA1094553A (en)
DE (1) DE2860709D1 (en)
DK (1) DK275278A (en)
ES (1) ES471125A1 (en)
FI (1) FI781947A7 (en)
IL (1) IL55005A (en)
IT (1) IT7850073A0 (en)
NZ (1) NZ187675A (en)
PT (1) PT68217A (en)
ZA (1) ZA783708B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2444035A1 (en) * 1978-12-13 1980-07-11 Sandoz Sa NEWS 1-AMINO-INDOLINS, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINES
EP0072954A3 (en) * 1981-08-22 1983-09-28 Beiersdorf Aktiengesellschaft Isoindolin-2-yl-amino-imidazolines and isoindolin-2-yl guanidines, process for their preparation and their use as medicines
EP0146787A3 (en) * 1983-12-03 1985-11-21 Dr. Karl Thomae Gmbh Indole derivatives, medicaments containing these compounds, and process for their preparation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3214757A1 (en) 2021-04-08 2022-10-13 Andreas Loew Multifuntional molecules binding to tcr and uses thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH529702A (en) * 1970-07-06 1972-10-31 Sandoz Ag Optically active benz(c,d)indole derivs - with vasoconstrictive and cns - smoothing activity
GB1408362A (en) * 1973-05-25 1975-10-01 Lepetit Spa 2-pyrrol-1-yl amino 4,5-dihydro-1-h-imidazole derivatives

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2444035A1 (en) * 1978-12-13 1980-07-11 Sandoz Sa NEWS 1-AMINO-INDOLINS, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINES
EP0072954A3 (en) * 1981-08-22 1983-09-28 Beiersdorf Aktiengesellschaft Isoindolin-2-yl-amino-imidazolines and isoindolin-2-yl guanidines, process for their preparation and their use as medicines
US4526897A (en) * 1981-08-22 1985-07-02 Beiersdorf Aktiengesellschaft Hypertensive isoindolin-2-yl-aminoimidazolines and isoindolin-2-yl-guanidines
EP0146787A3 (en) * 1983-12-03 1985-11-21 Dr. Karl Thomae Gmbh Indole derivatives, medicaments containing these compounds, and process for their preparation

Also Published As

Publication number Publication date
PT68217A (en) 1978-07-01
DE2860709D1 (en) 1981-08-27
DK275278A (en) 1978-12-29
NZ187675A (en) 1981-02-11
IT7850073A0 (en) 1978-06-28
IL55005A (en) 1981-12-31
EP0000151A1 (en) 1979-01-10
JPS5412373A (en) 1979-01-30
AU3746878A (en) 1980-01-03
IL55005A0 (en) 1978-08-31
ZA783708B (en) 1980-02-27
ES471125A1 (en) 1979-09-16
FI781947A7 (en) 1978-12-29
CA1094553A (en) 1981-01-27

Similar Documents

Publication Publication Date Title
US4059621A (en) Substituted benzamido propanolamines
WO2003074525A1 (en) Nitrogen-containing heterocyclic compound
CN101006090A (en) Hydrates and polymorphs of 4-[[(7r)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-4-6-oxo-2-piperidinyl]amino]-3-methoxy-n-(1-methyl-4-piperidinyl)-benzamide, methods for the production thereof
JPH0739387B2 (en) Novel 1-benzyl-aminoalkyl-pyrrolidinone compound and method for producing the same
US4575508A (en) 2-Substituted 1-(3'-aminoalkyl)-1,2,3,4-tetrahydro-β-carbolines, and their use as antiarrhythmic agents
GB2243832A (en) 2-substituted 4-acetamido-5-chloro-n-[2-(diethylamino)ethyl]-benzamide derivative
US3579524A (en) 2-aminoalkyl derivatives of phthalimidines
US4379160A (en) Carbazole compounds and medicinal use thereof
EP0000151B1 (en) 1-substituted aminoindolines, process for their production and pharmaceutical compositions containing them
IE46907B1 (en) Pyridobenzodiazepines
US4001271A (en) 3-(isopropyl amino alkoxy)-2-phenyl-isoindolin-1-ones
CZ327494A3 (en) Esters of nicotinic acid and process for preparing thereof
US3530140A (en) Certain pyridyl-hydrazino-2-yl-imidazolines
US5472966A (en) Antidepressant heteroarylaminoalkyl derivatives of naphthyl-monazines
US3972994A (en) Disubstituted azabicycloalkanes
CZ280490A3 (en) Pyridobenzoindole derivatives, process of their preparation and a pharmaceutical containing thereof
HK24194A (en) Pyrrolo[1,2-a][4,1]benzoxazepines, process for their preparation, pharmaceutical compositions containing these compounds and therapeutical use
NZ201642A (en) 1-phenylindazol-3-one derivatives and pharmaceutical compositions
KR100917041B1 (en) Novel Compounds Antagonistic to 5-HT7 Receptors
US3576811A (en) 1-alkyl-1-(beta-piperidino-ethyl)-1,2,3,4- tetrahydronaphthalen-2-ones
EP0338877A1 (en) Selective binding compounds for 5-hydroxytryptamine 1-A-receptors and pharmaceutical compositions containing them
EP0375536B1 (en) Derivatives of 1,7'-(imidazo-(1,2-a)pyridine) 5'-(6'H) ones and process for their preparation
US3635962A (en) 4 - bis-morpholino- and 2
HUT61760A (en) Process for producing bridged, bicyclic imides comprising 4-/4-(3-benzisothiazolyl)-1-piperazinyl/-butyl group and pharmaceutical compositions comprising such compounds
US3308133A (en) Novel alkylene diamine derivatives

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

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

Ref country code: BE

Effective date: 19810615

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

Ref country code: LU

Payment date: 19810619

Year of fee payment: 4

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

Ref country code: CH

Effective date: 19810630

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

Ref country code: NL

Payment date: 19810630

Year of fee payment: 4

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

Ref country code: SE

Payment date: 19810731

Year of fee payment: 4

REF Corresponds to:

Ref document number: 2860709

Country of ref document: DE

Date of ref document: 19810827

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: SE

Effective date: 19820616

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

Ref country code: NL

Effective date: 19830101

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

Ref country code: DE

Effective date: 19830201

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee
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: 19830331

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: 78100166.4

Effective date: 19850612

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