EP0000452A1 - 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
EP0000452A1
EP0000452A1 EP78400026A EP78400026A EP0000452A1 EP 0000452 A1 EP0000452 A1 EP 0000452A1 EP 78400026 A EP78400026 A EP 78400026A EP 78400026 A EP78400026 A EP 78400026A EP 0000452 A1 EP0000452 A1 EP 0000452A1
Authority
EP
European Patent Office
Prior art keywords
radical
alkyl
radicals
atom
compounds
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
EP78400026A
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English (en)
French (fr)
Other versions
EP0000452B1 (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
Original Assignee
Synthelabo SA
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
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
Publication of EP0000452B1 publication Critical patent/EP0000452B1/de
Expired legal-status Critical Current

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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

  • Certain compounds of the invention form pharmaceutically acceptable acid addition salts; these salts are part of the invention.
  • R 1 and R 5 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'R "(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.
  • Example 1 (4-methyl-piperazinyl-1) -3 (2,6-dichloro benzyl) -5 oxadiazole-1,2,4 and its methanesulfonate.
  • This compound is dissolved in 300 ml of carbon disulfide and a current of chlorine is passed through the solution under UV irradiation.
  • the solvent is removed and the residual oil is distilled under vacuum.
  • the product a pale yellow oil, boils at 122-4 ° C / 0.15mmHg.
  • the free base is obtained from this salt by addition of 2N sodium hydroxide followed by extraction with methylene chloride. Mp 121.5-122.5 ° C.
  • the methanesulfonate melts at 193.7 ° C.
  • the solid obtained is crystallized from iso ether p ropylique / isopropanol 70/30. Mp 108.8 ° C.
  • 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 wrung 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 following table I shows the compounds of the invention which have been prepared by way of examples according to one of the methods described above.
  • 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 CD1 rat (Charles River) weighing 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 principle, 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.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (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)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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 true EP0000452A1 (de) 1979-01-24
EP0000452B1 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)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4242352A (en) * 1977-07-12 1980-12-30 Synthelabo 3-Amino-5-benzyl-1,2,4-oxadiazoles and anti-hypertensive compositions thereof

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5625877B2 (de) * 1973-06-19 1981-06-15
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
ES2184858T3 (es) * 1995-05-09 2003-04-16 Bayer Cropscience Ag Cetoenoles alquil-dihalogenofenil substituidos como pesticidas y herbicidas.

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2100914A1 (de) * 1970-07-15 1972-03-24 Squibb & Sons Inc
DE2461882A1 (de) * 1973-12-29 1975-07-03 Chinoin Gyogyszer Es Vegyeszet Verfahren zur herstellung von 3-amino-1,2,4-oxadiazolen

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL302339A (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
FR1559629A (de) * 1966-09-23 1969-03-14
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
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
DE2860691D1 (en) * 1977-07-12 1981-08-13 Synthelabo 1,2,4-oxadiazol derivatives, their preparation and application in pharmaceutical compositions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2100914A1 (de) * 1970-07-15 1972-03-24 Squibb & Sons Inc
DE2461882A1 (de) * 1973-12-29 1975-07-03 Chinoin Gyogyszer Es Vegyeszet Verfahren zur herstellung von 3-amino-1,2,4-oxadiazolen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZEITSCHRIFT FUER CHEMIE 1974, 14(3) pages 94-95. G. WESTPHAL et R.SCHMIDT: "Reaktionen an 3-Amino-1,2,4-oxadiazolen" *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4242352A (en) * 1977-07-12 1980-12-30 Synthelabo 3-Amino-5-benzyl-1,2,4-oxadiazoles and anti-hypertensive compositions thereof

Also Published As

Publication number Publication date
NZ187825A (en) 1980-03-05
ES478527A1 (es) 1979-05-16
US4242352A (en) 1980-12-30
AU515506B2 (en) 1981-04-09
DE2860691D1 (en) 1981-08-13
AR222310A1 (es) 1981-05-15
GR64924B (en) 1980-06-09
EP0000452B1 (de) 1981-05-06
IL55104A0 (en) 1978-09-29
AU3790978A (en) 1980-01-17
CA1130806A (en) 1982-08-31
DK307378A (da) 1979-01-13
FI782220A (fi) 1979-01-13
PT68267A (fr) 1978-08-01
US4261994A (en) 1981-04-14
IT7825497A0 (it) 1978-07-10
IL55104A (en) 1982-07-30
NO782404L (no) 1979-01-15
AT362367B (de) 1981-05-11
IT1096906B (it) 1985-08-26
JPS5834473B2 (ja) 1983-07-27
ES471609A1 (es) 1979-09-16
ATA505378A (de) 1980-10-15
JPS5419978A (en) 1979-02-15

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