EP0000452B1 - 1,2,4-Oxadiazolderivate, ihre Herstellung und Verwendung als Arzneimittel - Google Patents

1,2,4-Oxadiazolderivate, ihre Herstellung und Verwendung als Arzneimittel 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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EP
European Patent Office
Prior art keywords
formula
radical
compound
compounds
reacting
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
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EP78400026A
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English (en)
French (fr)
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EP0000452A1 (de
Inventor
Michael John Dimsdale
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.)
Synthelabo SA
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Synthelabo SA
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Publication date
Priority claimed from FR7721447A external-priority patent/FR2397408A1/fr
Priority claimed from FR7817114A external-priority patent/FR2428034A2/fr
Application filed by Synthelabo SA filed Critical Synthelabo SA
Publication of EP0000452A1 publication Critical patent/EP0000452A1/de
Application granted granted Critical
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Classifications

    • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Claims (7)

1. Oxadiazolderivate der allgemeinen Formel (I)
Figure imgb0026
in der
R1 und R2 unabhängig voneinander Halogen-atome oder Alkylgruppen bedeuten, und
R entweder eine Gruppe der Formel NR3R4, in der
R3 und R4 unabhängig voneinander für Wasserstoffatome oder Alkylgruppen stehen,
oder eine Gruppe der Formel -N = CH-NR5R6, in der R5 und Ra unabhängig voneinander für Alkyl-oder Hydroxyalkylgruppen stehen, oder N, R5 und R6 gemeinsam für eine Gruppe
Figure imgb0027
stehen, bedeutet wobei die Alkylgruppen 1 bis 4 Kohlenstoffatome aufweisen.
2. Additionssalze, die bestimmte Verbindungen der allgemeinen Formel (I) mit pharmazeutisch annehmbaren Säuren bilden.
3. Derivate nach Anspruch 1, dadurch gekennzeichnet, daß R1 und R2 unabhängig voneinander Chloratome, Fluoratome oder Methylgruppen bedeuten.
4. Derivate nach Anspruch 1, dadurch gekennzeichnet, daß die Alkylgruppen der Gruppen R Methylgruppen sind.
5. Verfahren zur Herstellung der Verbindungen nach Anspruch 1, dadurch gekennzeichnet, daß man eine Verbindung der allgemeinen Formel (II)
Figure imgb0028
mit Ammoniak oder einem Amin der allgemeinen Formel HNR3R4 (III) umsetzt, dann das erhaltene Zwischenprodukt mit Hydroxylamin umsetzt und
zur Bildung der Verbindungen der allgemeinen Formel I, in der R eine Gruppe der Formel -N = CH-NR5R6 darstellt, eine Verbindung der Formel I, in der R für eine NH2-Gruppe steht,
entweder mit einer Verbindung der allgemeinen Formel (alkO)3CH und dann das erhaltene Zwischenprodukt mit einem Amin der allgemeinen Formel HNR5R6 umsetzt
oder mit einer Verbindung der allgemeinen Formel
Figure imgb0029
umsetzt, wobei die Substituenten die in Anspruch 1 angegebenen Bedeutungen besitzen.
6. Verfahren zur Herstellung der Verbindungen der allgemeinen Formel (I), in der R für eine NH2- gruppe steht, dadurch gekennzeichnet, daß man eine Verbindung der Formel (V)
Figure imgb0030
mit Cyanamid umsetzt und dann das erhaltene Zwischenprodukt mit Hydroxylamin umsetzt.
7. Pharmazeutische Zubereitung, dadurch gekennzeichnet, daß sie eine Verbindung gemäß den Ansprüchen 1 bis 6 enthält.
EP78400026A 1977-07-12 1978-06-20 1,2,4-Oxadiazolderivate, ihre Herstellung und Verwendung als Arzneimittel Expired EP0000452B1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
FR7721447A FR2397408A1 (fr) 1977-07-12 1977-07-12 Derives d'oxadiazole, leur preparation et leur application en therapeutique
FR7721447 1977-07-12
FR7817114 1978-06-08
FR7817114A FR2428034A2 (fr) 1978-06-08 1978-06-08 Derives d'oxadiazole-1,2,4, leur preparation et leur application en therapeutique

Publications (2)

Publication Number Publication Date
EP0000452A1 EP0000452A1 (de) 1979-01-24
EP0000452B1 true EP0000452B1 (de) 1981-05-06

Family

ID=26220123

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78400026A Expired EP0000452B1 (de) 1977-07-12 1978-06-20 1,2,4-Oxadiazolderivate, ihre Herstellung und Verwendung als Arzneimittel

Country Status (17)

Country Link
US (2) US4261994A (de)
EP (1) EP0000452B1 (de)
JP (1) JPS5834473B2 (de)
AR (1) AR222310A1 (de)
AT (1) AT362367B (de)
AU (1) AU515506B2 (de)
CA (1) CA1130806A (de)
DE (1) DE2860691D1 (de)
DK (1) DK307378A (de)
ES (2) ES471609A1 (de)
FI (1) FI782220A (de)
GR (1) GR64924B (de)
IL (1) IL55104A (de)
IT (1) IT1096906B (de)
NO (1) NO782404L (de)
NZ (1) NZ187825A (de)
PT (1) PT68267A (de)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5625877B2 (de) * 1973-06-19 1981-06-15
DE2860691D1 (en) * 1977-07-12 1981-08-13 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 (de) * 1991-01-31 1993-03-25 Chem Pharm Forsch Gmbh Neue imidazolderivate, verfahren zu ihrer herstellung und ihre verwendung
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
CN1131209C (zh) * 1995-05-09 2003-12-17 拜尔公司 可用作杀虫剂和除草剂的烷基－二卤代苯基取代的酮烯醇

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL132134C (de) * 1963-03-22
US3564607A (en) * 1965-07-30 1971-02-16 Olin Corp Halogenated aryloxyacetyl cyanamides
DE1670338A1 (de) * 1966-03-14 1972-08-10 Heyden Chem Fab Verfahren zur Herstellung von antimikrobiell wirksamen Nitrofuranderivaten
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 (de) * 1970-11-05 1972-05-10 Farbenfabriken Bayer Ag, 5090 Leverkusen Neue 1,2,4-Oxdiazole
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 (de) * 1973-12-29 1977-02-28
DE2860691D1 (en) * 1977-07-12 1981-08-13 Synthelabo 1,2,4-oxadiazol derivatives, their preparation and application in pharmaceutical compositions

Also Published As

Publication number Publication date
FI782220A (fi) 1979-01-13
IL55104A (en) 1982-07-30
PT68267A (fr) 1978-08-01
ES478527A1 (es) 1979-05-16
EP0000452A1 (de) 1979-01-24
ES471609A1 (es) 1979-09-16
JPS5419978A (en) 1979-02-15
GR64924B (en) 1980-06-09
JPS5834473B2 (ja) 1983-07-27
US4261994A (en) 1981-04-14
IT7825497A0 (it) 1978-07-10
ATA505378A (de) 1980-10-15
AT362367B (de) 1981-05-11
AU515506B2 (en) 1981-04-09
CA1130806A (en) 1982-08-31
AR222310A1 (es) 1981-05-15
NZ187825A (en) 1980-03-05
NO782404L (no) 1979-01-15
DK307378A (da) 1979-01-13
US4242352A (en) 1980-12-30
DE2860691D1 (en) 1981-08-13
AU3790978A (en) 1980-01-17
IT1096906B (it) 1985-08-26
IL55104A0 (en) 1978-09-29

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