EP0000452B1 - 1,2,4-oxadiazol derivatives, their preparation and application in pharmaceutical compositions - Google Patents

1,2,4-oxadiazol derivatives, their preparation and application in pharmaceutical compositions Download PDF

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Publication number
EP0000452B1
EP0000452B1 EP78400026A EP78400026A EP0000452B1 EP 0000452 B1 EP0000452 B1 EP 0000452B1 EP 78400026 A EP78400026 A EP 78400026A EP 78400026 A EP78400026 A EP 78400026A EP 0000452 B1 EP0000452 B1 EP 0000452B1
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Prior art keywords
formula
radical
compound
compounds
reacting
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EP0000452A1 (en
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Michael John Dimsdale
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Synthelabo SA
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Synthelabo SA
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Priority claimed from FR7817114A external-priority patent/FR2428034A2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to oxadiazole derivatives, their preparation and their therapeutic use.
  • Certain compounds of the invention form pharmaceutically acceptable acid addition salts; these salts are part of the invention.
  • R 1 and R 2 each represent, independently of one another, a chlorine atom, a fluorine atom or the methyl radical.
  • the compounds are prepared by reacting a compound of formula (II) with ammonia or an amine HNR 3 R 4 (III), then the intermediate obtained with hydroxylamine.
  • the reaction is carried out in a solvent such as a lower alcohol, acetone, benzene, an ether, chloroform, but preferably in methanol.
  • a solvent such as a lower alcohol, acetone, benzene, an ether, chloroform, but preferably in methanol.
  • the first part of the reaction is carried out in an alkalized mixture of water and acetone, at a temperature ranging from 0 to 10 ° C.
  • the second part of the reaction is carried out in a polar solvent, such as an alcohol, in the presence of a tertiary base, without isolation of the intermediate.
  • a polar solvent such as an alcohol
  • the reaction with the compound (IV) is carried out in a solvent such as an ether, chloroform, a hydrocarbon such as benzene, a lower alcohol, but preferably in chloroform.
  • a solvent such as an ether, chloroform, a hydrocarbon such as benzene, a lower alcohol, but preferably in chloroform.
  • the compounds (II) are new and form part of the invention.
  • the product is chromatographed on a silica column.
  • Example 2 [N, N-bis (2-hydroxyethyl) -formamidino] -3 (2,6-dichloro benzyl) -5 oxadiazole-1, 2, 4 and its hydrochloride.
  • the solid obtained is crystallized from a 70/30 isopropyl ether / isopropanol mixture.
  • the monohydrochloride melts at 257 ° C.
  • the crude intermediate is dissolved in 60 ml of ethanol and the solution obtained is added to a suspension of 10.75 g (0.15 mole) of hydroxylamine hydrochloride in 25 ml of pyridine.
  • the reaction is slow and very slightly exothermic.
  • the reaction is allowed to take place overnight.
  • the temperature generally stabilizes around 40 °.
  • the precipitated product is filtered off, then washed with ethanol and ether.
  • the filtrate is concentrated to dryness, then taken up in water and made alkaline with 2N sodium hydroxide.
  • a second jet of oxadiazole precipitates; it is drained and washed with ethanol and ether.
  • the 3-amino (2,6-dichloro-benzyl) -5 oxadiazole-1, 2, 4 is recrystallized from ethanol, which melts at 185 ° C.
  • the compounds of the invention have been subjected to pharmacological tests which have shown their activity as antihypertensive agents.
  • the toxicity of the compounds (I) was determined i.p., in the male CDI rat (Charles River) of 100 to 120 g, kept fasting for 18 hours.
  • the lethal dose 50% (LD 50) is shown in Table II.
  • Antihypertensive activity is evaluated in spontaneously hypertensive male rats according to the method of Gerold and Tschirky (Arzneim. Forsch. 1968, 18, 1285). Systolic pressure is measured by sensing the pulse at the caudal artery.
  • the invention therefore includes all pharmaceutical compositions containing at least one of the compounds (I) as active ingredient, in combination with any excipients suitable for their administration, mainly by the oral route, but also by the endorectal or parenteral route.
  • the daily oral dosage can vary from 4 to 100 mg.

Description

La présente invention concerne des dérivés d'oxadiazole, leur préparation et leur application en thérapeutique.The present invention relates to oxadiazole derivatives, their preparation and their therapeutic use.

Des dérivés d'oxadiazole ont déjà été décrits dans la littérature, en particulier dans les trois documents suivants :

  • - l'extrait de « Zeitschrift für Chemie », 1974, 14 (3) pages 94-95 décrit des dérivés d'oxadiazole de formule
    Figure imgb0001
    dans laquelle R est C6H5, CH2C6H5 ou CH(C6H5)2 ;
  • - la demande de brevet DE-A-2 461 882 est relative à un procédé de préparation de 3-amino-1,2,4-oxadiazoles dont plusieurs ont été antérieurement décrits dans la littérature comme produits chimiques et comme agents antiinflammatoires ;
  • - enfin la demande de brevet français n° 2100 914 concerne des 3-amino-5-benzyl (substitué ou non) -oxadiazoles, utiles comme antiinflammatoires.
Oxadiazole derivatives have already been described in the literature, in particular in the following three documents:
  • - the extract from "Zeitschrift für Chemie", 1974, 14 (3) pages 94-95 describes oxadiazole derivatives of formula
    Figure imgb0001
     wherein R is C 6 H 5 , CH 2 C 6 H 5 or CH (C 6 H 5 ) 2 ;
  • - Patent application DE-A-2 461 882 relates to a process for the preparation of 3-amino-1,2,4-oxadiazoles, several of which have previously been described in the literature as chemicals and as anti-inflammatory agents;
  • - finally French patent application n ° 2100 914 relates to 3-amino-5-benzyl (substituted or not) -oxadiazoles, useful as anti-inflammatory drugs.

La Demanderesse a trouvé que les composés répondant à la formule (I) définie ci-après possèdent une activité antihypertensive.The Applicant has found that the compounds corresponding to formula (I) defined below have antihypertensive activity.

Les composés de l'invention répondent à la formule (I)

Figure imgb0002
dans laquelle

  • R1 et R2 sont chacun indépendamment l'un de l'autre un atome d'halogène ou un radical alkyle,
  • R est
    • - soit un radical NR3R4 dans lequel R3 et R4 sont chacun, indépendamment l'un de l'autre, un atome d'hydrogène ou un radical alkyle ;
    • - soit un radical -N = CH-NR5R6dans lequel R5 et Ra sont chacun, indépendamment l'un de l'autre, un radical alkyle, un radical hydroxyalkyle ou NR5R6forment un radical
      Figure imgb0003
      les radicaux alkyles ayant de 1 à 4 atomes de carbone.
The compounds of the invention correspond to formula (I)
Figure imgb0002
 in which
  • R 1 and R 2 are each independently of the other a halogen atom or an alkyl radical,
  • R is
    • - Or an NR 3 R 4 radical in which R 3 and R 4 are each, independently of one another, a hydrogen atom or an alkyl radical;
    • - or a radical -N = CH-NR 5 R 6 in which R 5 and R a are each, independently of one another, an alkyl radical, a hydroxyalkyl radical or NR 5 R 6 form a radical
      Figure imgb0003
       alkyl radicals having from 1 to 4 carbon atoms.

Certains composés de l'invention forment des sels d'addition aux acides pharmaceutiquement acceptables ; ces sels font partie de l'invention.Certain compounds of the invention form pharmaceutically acceptable acid addition salts; these salts are part of the invention.

Un groupe particulier de composés est formé par ceux pour lesquels R1 et R2 représentent chacun, indépendamment l'un de l'autre, un atome de chlore, un atome de fluor ou le radical méthyle.A particular group of compounds is formed by those for which R 1 and R 2 each represent, independently of one another, a chlorine atom, a fluorine atom or the methyl radical.

Selon l'invention on prépare les composés en faisant réagir un composé de formule (II)

Figure imgb0004
avec de l'ammoniac ou une amine HNR3R4 (III), puis l'intermédiaire obtenu avec de l'hydroxylamine.According to the invention, the compounds are prepared by reacting a compound of formula (II)
Figure imgb0004
 with ammonia or an amine HNR 3 R 4 (III), then the intermediate obtained with hydroxylamine.

La réaction est effectuée dans un solvant tel que un alcool inférieur, l'acétone, le benzène, un éther, le chloroforme, mais de préférence dans du méthanol.The reaction is carried out in a solvent such as a lower alcohol, acetone, benzene, an ether, chloroform, but preferably in methanol.

On peut aussi préparer les composés de l'invention (I) dans lesquels R = NH2 en faisant réagir un composé de formule (V)

Figure imgb0005
avec le cyanamide NH2CN, puis l'intermédiaire obtenu avec de l'hydroxylamine.It is also possible to prepare the compounds of the invention (I) in which R = NH 2 by reacting a compound of formula (V)
Figure imgb0005
 with cyanamide NH 2 CN, then the intermediate obtained with hydroxylamine.

La première partie de la réaction est effectuée dans un mélange alcalinisé d'eau et d'acétone, à une température allant de 0 à 10°C.The first part of the reaction is carried out in an alkalized mixture of water and acetone, at a temperature ranging from 0 to 10 ° C.

La seconde partie de la réaction est réalisée dans un solvant polaire, tel qu'un alcool, en présence d'une base tertiaire, sans isolation de l'intermédiaire.The second part of the reaction is carried out in a polar solvent, such as an alcohol, in the presence of a tertiary base, without isolation of the intermediate.

Les composés dans lesquels R = -N = CH-NR5R6 sont préparés à partir du composé (I) correspondant dans lequel R = NH2 soit par réaction avec un composé

Figure imgb0006
ou avec le composé (alk0)3CH puis une amine R5R6NH.The compounds in which R = -N = CH-NR 5 R 6 are prepared from the corresponding compound (I) in which R = NH 2 either by reaction with a compound
Figure imgb0006
 or with the compound (alk0) 3 CH then an amine R 5 R 6 NH.

La réaction avec le composé (IV) est effectuée dans un solvant tel que un éther, le chloroforme, un hydrocarbure tel que le benzène, un alcool inférieur, mais de préférence dans du chloroforme.The reaction with the compound (IV) is carried out in a solvent such as an ether, chloroform, a hydrocarbon such as benzene, a lower alcohol, but preferably in chloroform.

Les schémas réactionnels sont les suivants :

Figure imgb0007
The reaction schemes are as follows:
Figure imgb0007

Les composés (II) sont nouveaux et font partie de l'invention.The compounds (II) are new and form part of the invention.

Ils sont obtenus par la méthode de F. Eloy et A. Van Oventraeten [Chimie Thér. 4,9 (1969)] à partir du chlorure d'acide correspondant.

Figure imgb0008
They are obtained by the method of F. Eloy and A. Van Oventraeten [Chimie Thér. 4.9 (1969)] from the corresponding acid chloride.
Figure imgb0008

Les composés (V) sont connus et décrits dans la littérature.The compounds (V) are known and described in the literature.

Ils sont obtenus à partir du toluène substitué de manière classique (passage par le bromure, le cyanure et l'acide).

Figure imgb0009
They are obtained from toluene substituted in a conventional manner (passage through bromide, cyanide and acid).
Figure imgb0009

Les exemples suivants illustrent l'invention.The following examples illustrate the invention.

Les analyses et les spectres IR et RMN ont confirmé la structure des composés.The analyzes and the IR and NMR spectra confirmed the structure of the compounds.

Exemple 1 : Méthylamino-3 (dichloro-2,6-benzyl)-5 oxadiazole-1, 2, 4.Example 1: Methylamino-3 (2,6-dichloro-benzyl) -5 oxadiazole-1, 2, 4.

Dans une solution de 6 g (0,019 mole) de N-[bis-diméthylthio]-méthylène (dichloro-2,6 phényl)-acétamide dans 15 cm3 de méthanol on ajoute 12 cm3 de méthylamine en solution dans du méthanol.In a solution of 6 g (0.019 mole) of N- [bis-dimethylthio] -methylene (2,6-dichloro phenyl) -acetamide in 15 cm 3 of methanol is added 12 cm 3 of methylamine dissolved in methanol.

On agite 2 heures. On verse cette solution dans une solution de 6,75 g (0,097 mole) de chlorhydrate d'hydroxylamine et de 19 cm3 d'une solution 5,08 molaire de méthanolate de sodium.Shake for 2 hours. This solution is poured into a solution of 6.75 g (0.097 mole) of hydroxylamine hydrochloride and 19 cm 3 of a 5.08 molar solution of sodium methanolate.

On laisse 48 heures à la température ambiante. On concentre à siccité. On reprend le solide formé par CH2Cl2.It is left for 48 hours at room temperature. Concentrate to dryness. The solid formed by CH 2 Cl 2 is taken up .

On chromatographie le produit sur une colonne de silice.

Figure imgb0010
The product is chromatographed on a silica column.
Figure imgb0010

Exemple 2 : [N,N-bis (hydroxy-2 éthyl)-formamidino]-3 (dichloro-2,6 benzyl)-5 oxadiazole-1, 2, 4 et son chlorhydrate.Example 2: [N, N-bis (2-hydroxyethyl) -formamidino] -3 (2,6-dichloro benzyl) -5 oxadiazole-1, 2, 4 and its hydrochloride. 1. (Ethoxyméthylène-amino)-3 (dichloro-2,6 benzyl)-5 oxadiazole-1, 2, 4.1. (Ethoxymethylene-amino) -3 (2,6-dichloro benzyl) -5 oxadiazole-1, 2, 4.

On chauffe à l'air libre à 150°C, pendant 3 heures, 1 g d'amino-3 (dichloro-2,6 benzyl)-5 oxadiazole-1, 2, 4 et quelques ml d'orthoformiate d'éthyle en quantité juste suffisante pour assurer une légère agitation. On chasse sous pression réduite l'excès d'orthoformiate d'éthyle. Le résidu est cristallisé dans de l'éther.

Figure imgb0011
1 g of amino-3 (2,6-dichloro-benzyl) -5 oxadiazole-1, 2, 4 and a few ml of ethyl orthoformate are heated in the open air at 150 ° C. for 3 hours. just enough to ensure gentle agitation. The excess ethyl orthoformate is removed under reduced pressure. The residue is crystallized from ether.
Figure imgb0011

2. [N,N-bis (hydroxy-2 éthyl)-formamidino]-3 (dichloro-2,6 benzyl)-5 oxadiazole-1, 2, 4 et son chlorhydrate.2. [N, N-bis (2-hydroxyethyl) -formamidino] -3 (2,6-dichloro benzyl) -5 oxadiazole-1, 2, 4 and its hydrochloride.

On dissout 5 g d'(éthoxyméthylène-amino)-3 (dichloro-2,6 benzyl)-5 oxadiazole-1, 2, 4 et 2 g de diéthanolamine dans 70 ml de THF.5 g of (ethoxymethylene-amino) -3 (2,6-dichloro-benzyl) -5 oxadiazole-1, 2, 4 and 2 g of diethanolamine are dissolved in 70 ml of THF.

Après un repos d'une nuit, le THF est évaporé.After an overnight rest, the THF is evaporated.

Le résidu est trituré dans de l'éther contenant 10% de chlorure de méthylène.The residue is triturated in ether containing 10% methylene chloride.

Le solide obtenu est cristallisé dans un mélange éther isopropylique/isopropanol 70/30.

Figure imgb0012
The solid obtained is crystallized from a 70/30 isopropyl ether / isopropanol mixture.
Figure imgb0012

Le monochlorhydrate fond à 257 °C.The monohydrochloride melts at 257 ° C.

Exemple 3 : Amino-3 (dichloro-2,6 benzyl)-5 oxiadiazole-1,2,4.Example 3: Amino-3 (2,6-dichloro benzyl) -5 oxiadiazole-1,2,4.

On dissout 4,2 g (0,1 mole) de cyanamide dans 96 ml d'eau et 9,6 ml de soude concentrée. On refroidit à 0-5 °C dans un bain de glace et de sel et on ajoute lentement une solution de 23,5 g (0,1 mole) du chlorure de l'acide (dichloro-2,6 phényl)-2 acétique dans 50 ml d'acétone, de façon à ce que la température interne du mélange reste inférieure à 5°: On maintient le pH de la solution entre 10 et 11 à l'aide de quelques gouttes de soude concentrée.4.2 g (0.1 mole) of cyanamide are dissolved in 96 ml of water and 9.6 ml of concentrated sodium hydroxide. Cool to 0-5 ° C in an ice and salt bath and slowly add a solution of 23.5 g (0.1 mole) of chloride (2,6-dichloro phenyl) -2 acetic acid in 50 ml of acetone, so that the internal temperature of the mixture remains below 5 °: The pH of the solution is kept between 10 and 11 using a few drops of concentrated sodium hydroxide.

Quand tout le chlorure d'acide a été ajouté, on agite pendant 1 heure le mélange réactionnel en vérifiant que le pH et la température ne se modifient plus.When all the acid chloride has been added, the reaction mixture is stirred for 1 hour, checking that the pH and the temperature no longer change.

On acidifie alors avec de l'acide chlorhydrique 6N à 0° ; l'intermédiaire précipite ; on l'essore ou on le dissout dans du chloroforme. Dans ce cas, on lave la solution avec de l'eau, on la sèche sur sulfate de magnésium et on la concentre à siccité.Then acidified with 6N hydrochloric acid at 0 °; the intermediary precipitates; it is wrung out or dissolved in chloroform. In this case, the solution is washed with water, dried over magnesium sulfate and concentrated to dryness.

L'intermédiaire brut est dissous dans 60 ml d'éthanol et on ajoute la solution obtenue à une suspension de 10,75 g (0,15 mole) de chlorhydrate d'hydroxylamine dans 25 ml de pyridine.The crude intermediate is dissolved in 60 ml of ethanol and the solution obtained is added to a suspension of 10.75 g (0.15 mole) of hydroxylamine hydrochloride in 25 ml of pyridine.

La réaction est lente et très légèrement exothermique. On laisse la réaction se faire pendant une nuit. La température se stabilise en général aux environs de 40°. On essore le produit précipité, puis on le lave avec de l'éthanol et de l'éther.The reaction is slow and very slightly exothermic. The reaction is allowed to take place overnight. The temperature generally stabilizes around 40 °. The precipitated product is filtered off, then washed with ethanol and ether.

Le filtrat est concentré à siccité, puis repris dans l'eau et alcalinisé avec de la soude 2N. Un deuxième jet d'oxadiazole précipite ; on l'essore et le lave avec de l'éthanol et de l'éther. On recristallise dans de l'éthanol l'amino-3 (dichloro-2,6 benzyl)-5 oxadiazole-1, 2, 4 qui fond à 185 °C..The filtrate is concentrated to dryness, then taken up in water and made alkaline with 2N sodium hydroxide. A second jet of oxadiazole precipitates; it is drained and washed with ethanol and ether. The 3-amino (2,6-dichloro-benzyl) -5 oxadiazole-1, 2, 4 is recrystallized from ethanol, which melts at 185 ° C.

Dans le tableau I suivant sont représentés les composés de l'invention qui ont été préparés à titre d'exemples selon l'une des méthodes décrites ci-dessus.

Figure imgb0013
Figure imgb0014
 In the following table I are represented the compounds of the invention which have been prepared by way of examples according to one of the methods described above.
Figure imgb0013
Figure imgb0014

Les composés de l'invention ont été soumis à des essais pharmacologiques qui ont montré leur activité comme antihypertenseurs.The compounds of the invention have been subjected to pharmacological tests which have shown their activity as antihypertensive agents.

La toxicité des composés (I) a été déterminée par voie i.p., chez le rat mâle CDI (Charles River) de 100 à 120 g, tenu à jeun 18 heures.The toxicity of the compounds (I) was determined i.p., in the male CDI rat (Charles River) of 100 to 120 g, kept fasting for 18 hours.

La dose létale 50 % (DL 50) est indiquée dans le tableau Il.The lethal dose 50% (LD 50) is shown in Table II.

L'activité antihypertensive est évaluée chez des rats mâles spontanément hypertendus selon la méthode de Gerold et Tschirky (Arzneim. Forsch. 1968, 18, 1285). La pression systolique est mesurée par captage du pouls au niveau de l'artère caudale.Antihypertensive activity is evaluated in spontaneously hypertensive male rats according to the method of Gerold and Tschirky (Arzneim. Forsch. 1968, 18, 1285). Systolic pressure is measured by sensing the pulse at the caudal artery.

A la dose de 10 mg/kg, (5 mg/jour administrés 2 jours de suite par voie orale) on observe les diminutions de la pression sanguine et on les déterminé au bout de 4 et 24 heures.At a dose of 10 mg / kg (5 mg / day administered 2 days orally in a row), the decreases in blood pressure are observed and are determined after 4 and 24 hours.

Les résultats obtenus pour certains composés représentatifs de l'invention sont indiqués dans le tableau II.

Figure imgb0015
The results obtained for certain representative compounds of the invention are shown in Table II.
Figure imgb0015

On doit noter que, dans l'épreuve d'actimétrie chez la souris, l'action sédative des composés de l'invention s'est révélée négligeable.It should be noted that, in the actimetry test in mice, the sedative action of the compounds of the invention was found to be negligible.

Les résultats des essais pharmacologiques montrent que les composés de l'invention sont utilisables comme médicaments, en thérapeutique humaine et vétérinaire, dans le domaine cardiovasculaire, comme antihypertenseurs.The results of the pharmacological tests show that the compounds of the invention can be used as medicaments, in human and veterinary therapy, in the cardiovascular field, as antihypertensives.

Ils sont particulièrement utilisés dans le traitement de toutes les formes d'hypertension essentielle ou secondaire.They are particularly used in the treatment of all forms of essential or secondary hypertension.

L'invention comprend, par conséquent, toutes compositions pharmaceutiques renfermant au moins l'un des composés (I) comme principe actif, en association avec tous excipients appropriés à leur administration, principalement par voie orale, mais aussi par voie endorectale ou parentérale.The invention therefore includes all pharmaceutical compositions containing at least one of the compounds (I) as active ingredient, in combination with any excipients suitable for their administration, mainly by the oral route, but also by the endorectal or parenteral route.

La posologie quotidienne par voie orale peut varier de 4 à 100 mg.The daily oral dosage can vary from 4 to 100 mg.

Claims (7)

1. Oxadiazole derivatives of the formula (I)
Figure imgb0021
in which
each of R1 and R2 independently represents a halogen atom or an alkyl radical, R represents
either a NR3R4 radical in which each of R3 and R4 independently represents a hydrogen atom or an alkyl radical,
or a -N = CH-NR5R6 radical in which each of R5 and R6 independently represents an alkyl radical,
a hydroxyalkyl radical or N, R5 and R6 together form a
Figure imgb0022
radical, each of the above-specified alkyl radicals having 1 to 4 carbon atoms.
2. Pharmaceutically acceptable acid addition salts of certain compounds of formula (I).
3. Derivatives according to claim 1, in which each of R1 and R2 independently represents a chlorine atom, a fluorine atom or a methyl radical.
4. Derivatives according to claim 1, wherein the alkyl radicals represented by R are methyl radicals.
5. A process for the preparation of compounds according to claim 1, which process comprises reacting a compound of the formula
Figure imgb0023
with ammonia or an amine HNR3R4 (III) to produce an intermediate and reacting said intermediate with hydroxylamine, and for obtaining compounds of the formula (I) in which R represents -N = CH-NR5R6, reacting the compound of formula (I), in which R represents NH2,
- either with a compound of formula (alkO)3CH to produce an intermediate and reacting said intermediate with an amide of formula HNR5R6,
- or with a compound of formula
Figure imgb0024
the radicals having the meanings given in claim 1.
6. A process for the preparation of compounds of formula (I) in which R is NH2, which process comprises reacting a compound of formula (V)
Figure imgb0025
with cyanamide to produce an intermediate and reacting said intermediate with hydroxylamine.
7. A pharmaceutical composition comprising a compound according to anyone of claims 1 to 4.
EP78400026A 1977-07-12 1978-06-20 1,2,4-oxadiazol derivatives, their preparation and application in pharmaceutical compositions Expired EP0000452B1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
FR7721447 1977-07-12
FR7721447A FR2397408A1 (en) 1977-07-12 1977-07-12 Antihypertensive 5-benzyl-1,2,4-oxadiazole derivs. - with negligible sedative activity, for treatment of essential or secondary hypertension
FR7817114 1978-06-08
FR7817114A FR2428034A2 (en) 1978-06-08 1978-06-08 Antihypertensive 5-benzyl-1,2,4-oxadiazole derivs. - with negligible sedative activity, for treatment of essential or secondary hypertension

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EP0000452A1 EP0000452A1 (en) 1979-01-24
EP0000452B1 true EP0000452B1 (en) 1981-05-06

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EP0000452B1 (en) * 1977-07-12 1981-05-06 Synthelabo 1,2,4-oxadiazol derivatives, their preparation and application in pharmaceutical compositions
US5180731A (en) * 1986-06-03 1993-01-19 Sumitomo Pharmaceuticals Company, Limited Aminoazole derivatives and their production and use
US4914112A (en) * 1986-06-03 1990-04-03 Sumitomo Pharmaceuticals Company, Limited Aminoazole derivatives and their production and use
AT395853B (en) * 1991-01-31 1993-03-25 Chem Pharm Forsch Gmbh NEW IMIDAZOLE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND THEIR USE
WO1993009106A1 (en) * 1991-10-28 1993-05-13 Tsentr Po Khimii Lekarstvennykh Sredstv Derivatives of 5-phenoxymethyl-1,2,4-oxadiazol, their salts, method of obtaining them and a pharmaceutical preparation with antihypertensive, antianginal, antiarrhythmic and antiglaucomatomic properties based on them
MX9708597A (en) * 1995-05-09 1998-02-28 Bayer Ag Alkyl dihalogenated phenyl-substituted ketoenols useful as pesticides and herbicides.

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1053825A (en) * 1963-03-22
US3564608A (en) * 1965-07-30 1971-02-16 Olin Corp Selected n-acylsubstituted-n'-hydroxyguanidines
DE1670338A1 (en) * 1966-03-14 1972-08-10 Heyden Chem Fab Process for the production of antimicrobially active nitrofuran derivatives
US3538087A (en) * 1966-09-23 1970-11-03 Sandoz Ag Oxadiazole derivatives
US3452035A (en) * 1966-12-23 1969-06-24 American Cyanamid Co 2 - amino - 5 - (5 - nitro - 1 - substituted-2 - imidazolyl) - 1,3,4 - thiadiazoles and oxadiazoles
US3720685A (en) * 1970-07-15 1973-03-13 Squibb & Sons Inc 3-amino-5-benzyl-1,2,4-oxadiazoles
GB1314427A (en) * 1970-07-17 1973-04-26 Beecham Group Ltd Amino acid esters of 2,2-dialkyl-4-4-pyridyl-2h-7-substituted- chromen-5-ols
DE2054342A1 (en) * 1970-11-05 1972-05-10 Farbenfabriken Bayer Ag, 5090 Leverkusen New 1,2,4-oxdiazoles
US3879407A (en) * 1973-02-09 1975-04-22 Johnson & Son Inc S C 1,2,4-Oxadiazole and thiadiazole esters and compositions containing same
HU169666B (en) * 1973-12-29 1977-02-28
EP0000452B1 (en) * 1977-07-12 1981-05-06 Synthelabo 1,2,4-oxadiazol derivatives, their preparation and application in pharmaceutical compositions

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AU515506B2 (en) 1981-04-09
ES471609A1 (en) 1979-09-16
US4261994A (en) 1981-04-14
DE2860691D1 (en) 1981-08-13
IL55104A (en) 1982-07-30
NO782404L (en) 1979-01-15
FI782220A (en) 1979-01-13
GR64924B (en) 1980-06-09
IT1096906B (en) 1985-08-26
US4242352A (en) 1980-12-30
AU3790978A (en) 1980-01-17
NZ187825A (en) 1980-03-05
DK307378A (en) 1979-01-13
JPS5834473B2 (en) 1983-07-27
AT362367B (en) 1981-05-11
EP0000452A1 (en) 1979-01-24
ATA505378A (en) 1980-10-15
CA1130806A (en) 1982-08-31
PT68267A (en) 1978-08-01
JPS5419978A (en) 1979-02-15
AR222310A1 (en) 1981-05-15
IT7825497A0 (en) 1978-07-10
ES478527A1 (en) 1979-05-16
IL55104A0 (en) 1978-09-29

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