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WO1993009106A1 - Derives de 5-phenoxymethyle-1,2,4-oxadiazole, leur sels, procede d'obtention et preparation pharmaceutique a base de ceux-ci presentant des proprietes antihypertensives, antiangineuses, antiarrhythmiques et antiglaucomatomeuses - Google Patents

Derives de 5-phenoxymethyle-1,2,4-oxadiazole, leur sels, procede d'obtention et preparation pharmaceutique a base de ceux-ci presentant des proprietes antihypertensives, antiangineuses, antiarrhythmiques et antiglaucomatomeuses Download PDF

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Publication number
WO1993009106A1
WO1993009106A1 PCT/SU1991/000215 SU9100215W WO9309106A1 WO 1993009106 A1 WO1993009106 A1 WO 1993009106A1 SU 9100215 W SU9100215 W SU 9100215W WO 9309106 A1 WO9309106 A1 WO 9309106A1
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WO
WIPO (PCT)
Prior art keywords
phenoxymethyl
compound
oxadiazole
methyl
effect
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.)
Ceased
Application number
PCT/SU1991/000215
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English (en)
Russian (ru)
Inventor
Sergei Dmitrievich Sokolov
Svetlana Mikhailovna Vinogradova
Olga Gennadievna Azarevich
Marina Valentinovna Berg
Mikhail Davydovich Mashkovsky
Sergei Danilovich Juzhakov
Alexandr Vladimirovich Morozov
Leonid Valentinovich Rozenshtraukh
Oleg Stefanovich Medvedev
Evgeny Pavlovich Anjukhovsky
Elena Vladimirovna Dorodnikova
Olga Viktorovna Dolgun
Aron Yankelevich Bunin
Valentina Nikolaevna Ermakova
Vladimir Isakovich Metelitsa
Vladimir Konstantinovich Piotrovsky
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.)
MOSKOVSKY NAUCHNO-ISSLEDOVATELSKY INSTITUT GLAZNYKH BOLEZNEI IMENI GELMGOLTSA
TSENTR PO KHIMII LEKARSTVENNYKH SREDSTV
Vsesojuzny Kardiologichesky Tsentr Akademii Meditsinskikh Nauk Sssr
Original Assignee
MOSKOVSKY NAUCHNO-ISSLEDOVATELSKY INSTITUT GLAZNYKH BOLEZNEI IMENI GELMGOLTSA
TSENTR PO KHIMII LEKARSTVENNYKH SREDSTV
Vsesojuzny Kardiologichesky Tsentr Akademii Meditsinskikh Nauk Sssr
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 MOSKOVSKY NAUCHNO-ISSLEDOVATELSKY INSTITUT GLAZNYKH BOLEZNEI IMENI GELMGOLTSA, TSENTR PO KHIMII LEKARSTVENNYKH SREDSTV, Vsesojuzny Kardiologichesky Tsentr Akademii Meditsinskikh Nauk Sssr filed Critical MOSKOVSKY NAUCHNO-ISSLEDOVATELSKY INSTITUT GLAZNYKH BOLEZNEI IMENI GELMGOLTSA
Priority to PCT/SU1991/000215 priority Critical patent/WO1993009106A1/fr
Publication of WO1993009106A1 publication Critical patent/WO1993009106A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

Definitions

  • the ⁇ -adrenergic drug is known to have been treated, used for the treatment of and
  • the drug is also known to have been chemically affected by the presence of cx and ⁇ -adrenergic properties.
  • the drug eliminates the need to use only an antihypertensive medication, but 20 does not result in ischemic or mild illness.
  • the inventive preparation in the form of a tablet contains a predominantly active substance in the amount of 0.01-0.04 g 5 per one tablet; in the form of injectable substances in the active substance in the amount of 0.1 or 1.0 wt.%; in the form of eye droplets of an active substance in the amount of 1, 0-2.0 wt.%.
  • the claimed compounds are 5-derivative derivatives.
  • 1, 2,4-oxadiazole (bases) are either white or with off-the-shelf crystalline substances, not disposable in the environment.
  • Salts of the claimed compounds are either white 15 or with short-circuited materials, irreversible, or are moderate to moderate
  • the structure of the claimed compounds is supported by the data of elemental analysis, UF-, I ⁇ -, Sh ⁇ -sect. 20
  • the inventive compounds possessing the expressed ⁇ - and os-adrenergic activity were studied experimentally on animals.
  • beta-adrenergic blocking activity was judged by a decrease in the reaction of arterial pressure and sinus - b - rhythm for the administration of isadrine.
  • a decrease in the reaction of the sinus rhythm of the testosterone is * - adrenal reactive activity, and a decrease in the reaction of the arterial pressure is beneficial.
  • the studied substances were added to the growing doses - 0.001; 0.0025; 0.01 0.025 and 0.1 mg / kg in small groups of animals (6-10 in each).
  • the claimed compound is 3-methyl-5- [2- (3-isopropylpilamine-2-hydroxypropyl-alkoxyphenyl) phenoxymethyl] -I, 2,4-oxo-hydroxydehydroxyl 0.003 0.03
  • the claimed compound is 3-methyl-5- [2- (3-triethylbutylamine-2-hydroxypropyl-phenoxymethyl) phenoxymethyl] -I, 2,4-oxo-hydroxydehydride, 0.00B 0.03
  • the claimed compound is 3-phenyl-5- [2- (3-isopropylpilamine-2-idroxi- ⁇ xy) -phenoxymethyl] -1,2,4- ⁇ -sadiazole hydr ⁇ lloid 0.380 0.65
  • the claimed compound is 3-isopropyl-5- [2- (3-isopropylpropylamino-2-guide-phenyl) phenoxymethyl] -1,2,4-oxadiazid hydrochloride 0,500 1,75
  • the claimed compound is -3-benzyl- 5- [2-isopropylpylamine-2-hydroxy- ⁇ xy) phenoxymethyl] -I, 2,4-oxo-diazidyl hydride 0.1 0.1
  • the claimed compound is 3-methyl-5- [2- (3- triethylbutylamine-2-hydropoxyxypropoxy) phenoxymeth] - 1,2, 4-oxadiazole hydropoxide-hydrochloride 10 76 72.5 - 9 - Offer of table I
  • the claimed compound is 3-phenyl-5- [2- (3-hydroxypylamine-2-hydroxyxypropoxy) -phenoxymethyl] - 1, 2,4-oxydiazid hydroxy- 10 x 23, 0
  • the claimed compound is 3-methyl- 5- [2- (3-vol. Butylamine-2-hydroxypropyl) phenoxymethyl] - 1, 2,4-oxydiazid hydrochloride 10 48 37,0
  • the claimed compound is 3-methyl-5- [2- (3-2-isobutiramide-ethylamino-2-hydroxyxypropoxy) phenoxymethyl] - 1, 2,4-oxydiazid hydroxy * 10 35 35.0
  • the claimed compound is 3-benzyl-5- [2-and ⁇ ⁇ yl amine ⁇ -2-hydroxypropyl) phenoxymethyl] - -1, 2,4-oxybenzyl hydride 10 37 45,0
  • a known compound is 3-methyl-4-chloro-5- [2- (3-isopropylpilamin ⁇ - 2-hydroxyxypropyl oxi) phenoxymethyl] -exsid hydrous (8 ⁇ , ⁇ , 97934 - 10 - ⁇ a ⁇ vidn ⁇ of ⁇ ezul ⁇ a ⁇ v, ⁇ eds ⁇ avlenny ⁇ in ⁇ ablitse I, the inventive s ⁇ edineniya ⁇ bladayu ⁇ - i ⁇ s-ad ⁇ en ⁇ bl ⁇ i ⁇ u- guide a ⁇ ivn ⁇ s ⁇ yu, ⁇ ichem ⁇ s-ad ⁇ en ⁇ bl ⁇ i ⁇ uschemu e ⁇ e ⁇ - ⁇ u all e ⁇ edineniya ⁇ ev ⁇ s ⁇ dya ⁇ ⁇ si ⁇ en ⁇ l ⁇ l and ne ⁇ ye 5 ⁇ ev ⁇ s ⁇ dya ⁇ or bliz ⁇ i ⁇ izves ⁇ n ⁇ mu
  • Beta and alpha-adrenergic activating activity of the territory - 20 years of rooting, as well as salt of the claimed compounds were carried out on the specific ⁇ -blocking activity of adipate, maleate, and the hydrochloride of Z-methyl-5- [2- (3-compound, butylamine-2-azyl-azide). 25 experiments were carried out on 15 male rats weighing 250-300 g, injected with etaminal sodium (40-50 mg / kg internal dose). Beta-adrenergic activity of the tested compounds of the claimed compounds was evaluated at the degree of the vehicle’s connection to a healthy and negative (30-year-old)
  • the unit of the claimed compound is 0.4 + 0.005 0.01 + 0.001
  • the unit of the claimed compound is 0.057 + 0.005 0.009 + 0.0007
  • the hydraulic unit of the claimed compound is 0.03 + 0.001 .0.008 + 0.0007
  • the beta-adrenergic activity of adipate, the malaite of the claimed compounds do not differ significantly between themselves.
  • the beta adrenoceptive activity of the claimed compounds has been studied. ⁇ liyanie zayavlyaem ⁇ g ⁇ s ⁇ edineniya ⁇ i vnu ⁇ ivenn ⁇ m administered at ⁇ l ⁇ zhi ⁇ elny ⁇ n ⁇ ny and de ⁇ - 10 ⁇ ess ⁇ ny e ⁇ e ⁇ y izad ⁇ ina at na ⁇ izi ⁇ vanny ⁇ ⁇ ys ⁇ - v ⁇ dilis anal ⁇ gichn ⁇ vyshe ⁇ isann ⁇ mu in s ⁇ avnenii with izves ⁇ - GOVERNMENTAL ⁇ e ⁇ a ⁇ a ⁇ ami ⁇ an ⁇ l ⁇ l ⁇ m, ⁇ e ⁇ en ⁇ l ⁇ l ⁇ m, ⁇ ind ⁇ l ⁇ - l ⁇ m and labe ⁇ al ⁇ l ⁇ m.
  • the investigated substances were added to the public dose of 0.001; 0.0025; 0.01; 0.025 and 0.1 mg / kg for
  • the claimed compound caused a decrease in the heart rate (from 271 + 7 at the end to 249 +11 238 +16; 204 + 14 and 181 + 14 beats / min at a cost of 0.0025; 01; 0.025 and 0.1 mg / kg) and 20 doses of 0.1 mg / kg lowering the arterial pressure (from 159 + 9 at the end for ⁇ 4 ⁇ + ⁇ 127 + 10 and 123 + 11 mm rt.st. at doses of 0) , 01; 0.025 and 0.1 mg / ⁇ g).
  • the claimed compound caused a dependent dose of a load (by ⁇ 263; 82 and 90% 25 at a dose of 0.0025; 0.01; 0.025 and 0.1 mg / kg) doses of 0.01 mg / kg are positive (25 46 and 78 in doses of 0.01 0.025 and 0.1 mg / kg) of isadrine effects.
  • ⁇ ezul ⁇ a ⁇ y is ⁇ y ⁇ any ⁇ azali, ch ⁇ ⁇ be ⁇ a ⁇ -ad ⁇ en ⁇ - bl ⁇ i ⁇ uschey a ⁇ ivn ⁇ s ⁇ i ⁇ i ⁇ e ⁇ aln ⁇ m administered zayavlya- em ⁇ e s ⁇ edinenie ⁇ ev ⁇ s ⁇ di ⁇ ⁇ an ⁇ l ⁇ l, ⁇ s ⁇ en ⁇ l ⁇ l and 15 labe ⁇ al ⁇ l (s ⁇ ve ⁇ s ⁇ venn ⁇ 14.8 and 35 ⁇ az) n ⁇ us ⁇ u ⁇ ae ⁇ ⁇ ind ⁇ l ⁇ lu.
  • the device In general, in case of plugged-in batteries, as well as in the case of beta-adrenergic active components, the device is connected to the
  • connection is made of a small port. 15 P ⁇ i issled ⁇ vanii s ⁇ etsi ⁇ ichn ⁇ s ⁇ i be ⁇ a-ad ⁇ en ⁇ bl ⁇ i ⁇ uyu- scheg ⁇ deys ⁇ viya us ⁇ an ⁇ vlen ⁇ , ch ⁇ zayavlyaem ⁇ e s ⁇ edinenie not ⁇ ' ⁇ l ⁇ not umeny ⁇ ae ⁇ , even n ⁇ nes ⁇ l ⁇ usilivae ⁇ ⁇ l ⁇ zhi- ⁇ elny in ⁇ ny e ⁇ e ⁇ s ⁇ an ⁇ ina, ⁇ altsiya ⁇ l ⁇ ida and ⁇ e ⁇ illina, ⁇ ya ⁇ ln ⁇ s ⁇ yu us ⁇ anyae ⁇ anal ⁇ gichny e ⁇ e ⁇ 20 izad ⁇ ina.
  • the claimed connection is subject to beta-adrenergic devices of a specific
  • ⁇ ⁇ ezul ⁇ a ⁇ e is ⁇ y ⁇ any byl ⁇ us ⁇ an ⁇ vlen ⁇ , ch ⁇ zayavlya- 5 em ⁇ e s ⁇ edinenie ⁇ d ⁇ bn ⁇ ⁇ an ⁇ l ⁇ lu not ⁇ bladae ⁇ chas ⁇ ich- n ⁇ y an ⁇ ag ⁇ nis ⁇ iches ⁇ y a ⁇ ivn ⁇ s ⁇ yu and ⁇ d ⁇ bn ⁇ ⁇ an ⁇ l ⁇ lu and ⁇ lichie ⁇ labe ⁇ al ⁇ la and ⁇ s ⁇ en ⁇ l ⁇ la ⁇ bladae ⁇ nes ⁇ e- tsi ⁇ iches ⁇ im memb ⁇ an ⁇ s ⁇ abilizi ⁇ uschim deys ⁇ viem.
  • Partial dose causing a decrease in a-s: ( ⁇ - amount of pressure by 20%, live) internally - 16 -
  • the claimed 15 compounds (10 mg / kg once a day) increased the effect of the antihypertensive effect.
  • the arterial pressure was 110 + 8.6 mm or more. ⁇ Similar conditions ⁇ an ⁇ lol is not very effective.
  • the claimed drug has a beneficial effect on the condition of the extenders. Distinctive environment
  • the claimed connection with the internal introduction is less toxic (2–4 times) than pranolol, and is indispensable and not inconsistent with 5.
  • the claimed connection is less toxic (by a factor of 2–3) compared with a direct analogue and is non-existent.
  • the claimed compound is Z-methyl-5 [-2- (3-carbethyl-2-hydroxyxypropoxy) phenoxymethyl] -1,2,4-
  • 25 Hydroxide Hydrochloride is a highly effective beta-adrenergic blocker, which is equipped with a modern alpha-blocking and vessel-expanding agent.
  • the claimed compound exhibits antihypertensive, anti-ischemic - 25 - and anti-rhythmic action. Due to the basic pharmaceutical properties, the claimed compound is the closest to the label. It also has the effect of operating with standard beta-adrenergic blocking devices, an ox-5 analog, and an integrator. In comparison with the known beta-adrenergic devices, the claimed connection has a number of good features:
  • the claimed compound causes under conditions of experiment
  • the inventive drug was studied in the clinic.
  • 35 activity of the drug was studied in 38 patients at the age of 37 to 70 years with arterial hypertension of various degrees of severity, the antianginal effect is 12 - 26 - at the age of 40-59 years, suffering from ischemic disease of the heart, with a voltage range of the S-Sh functional zone. Due to the presence of irregularities of the disease, the anti-rheumatic activity of the claimed medication was divided. 5 ⁇ the study did not include patients with a deficiency of circulatory system, cerebral palsy (heart rate less than 50 per min.), Disturbances of arterial syndrome,
  • Yu ⁇ lz ⁇ valis following me ⁇ dy issled ⁇ vaniya izme ⁇ enie a ⁇ - ⁇ e ⁇ ialn ⁇ g ⁇ ⁇ ⁇ vu pressure (lying in ⁇ l ⁇ zhenii, ⁇ e ⁇ - ⁇ a ⁇ n ⁇ with in ⁇ e ⁇ val ⁇ m in I min.), 12 ele ⁇ a ⁇ di ⁇ g ⁇ a ⁇ iya ⁇ bsche ⁇ inya ⁇ y ⁇ ⁇ vedeniya ⁇ , ele ⁇ a ⁇ di ⁇ g ⁇ a ⁇ iches ⁇ e m ⁇ ni ⁇ - ⁇ i ⁇ vanie, ⁇ a ⁇ nye vel ⁇ e ⁇ me ⁇ iches ⁇ ie ⁇ by with ele ⁇ a ⁇ -
  • a decrease in arterial pressure was noted immediately after the introduction of the drug, with a maximum of 0-15 and a decrease of 60 minutes, the pressure was only a little less than 8 minutes. up to 170.17, which is 18.5, diastolic arterial pressure from 109.17 to 95.9 - that is 13.5, average dynamic arterial pressure from 142.37 to 121.51 5 mm.p. ct. - by 14.7.
  • the heart rate decreased from 80 to 65 strokes per minute. That is 18.8.
  • the benefits of a hypnotic effect in the majority - 27 - the patient was 3-4 hours. In two patients (16.7), the effect was not achieved.
  • the claimed preparation was administered at a dose of 10-40 mg, depending on the values of the arterial pressure and the speed of the heart and sensitivities.
  • the treatment of the claimed disease was observed in 14 large groups and in 12 large groups.
  • the drug was administered in doses of 30-120 mg per day, divided by 3
  • Dyza was divided by the initial indicators of hemodynamics and the results obtained in the course of a simple medicine. - 28 - On the 3rd-4th week of the Kursk international diet, eating indicators were obtained: in the 3rd group, the average dynamic arctic pressure decreased by 16.8 times, the pressure is reduced to 13 5, the arterial pressure of 15.6%. The frequency of heart sections decreased by 15.7. In this case, the minute volume of the heart decreased by 21.7, and the overall operational system was 9.5% less. The second group of average dynamic arterial pressure decreased by 10-17, the diastolic arterial pressure decreased by 14.1, and the average dynamic arterial pressure by 15.4.
  • ⁇ d ⁇ ug ⁇ m ⁇ latseb ⁇ - ⁇ n ⁇ li ⁇ uem ⁇ m issled ⁇ vanii gi ⁇ - ⁇ enzivn ⁇ g ⁇ and an ⁇ ianginaln ⁇ g ⁇ deys ⁇ viya zayavlyaem ⁇ ⁇ ⁇ e ⁇ a- 35 ⁇ a ⁇ a ⁇ veden ⁇ in 18 b ⁇ lny ⁇ - ⁇ luzhchin in v ⁇ z ⁇ as ⁇ e 47-58 le ⁇ with ishemiches ⁇ y b ⁇ leznyu se ⁇ dtsa and s ⁇ abiln ⁇ y s ⁇ en ⁇ a ⁇ diey na ⁇ yazheniya II and III ⁇ un ⁇ tsi ⁇ nalny ⁇ ⁇ lass ⁇ v and 18 with b ⁇ lny ⁇ - 29 - with a medical illness of I and P stages at the age of 34-63 years.
  • the 30 throat effective effect of the registers was controlled after 2 and 3 hours after the preparation (in average 15 beats / min). After 5 hours after receiving an alternate dose, a negative effect remained sufficiently pronounced (a decrease in the heart rate by 10 times was less than 5%).
  • vy ⁇ azhenn ⁇ s ⁇ ⁇ itsa ⁇ eln ⁇ g ⁇ ⁇ n ⁇ - n ⁇ ⁇ ⁇ deys ⁇ viya zayavlyaem ⁇ ⁇ e ⁇ a ⁇ a ⁇ a in ⁇ e in b ⁇ lshey s ⁇ e- 5 ⁇ eni ⁇ edelyalas is ⁇ dnym value chas ⁇ y se ⁇ dechny ⁇ s ⁇ ascheny and individualn ⁇ s ⁇ yu b ⁇ ln ⁇ g ⁇ instead is ⁇ lz ⁇ van- n ⁇ y ⁇ az ⁇ v ⁇ y d ⁇ z ⁇ y ⁇ e ⁇ a ⁇ a ⁇ a.
  • Average and individual data on the effect of the declared product on the load on the device is 15 on the basis of the increase
  • the intangible action of the claimed product starts after 0.5 hours after the receipt and lasts at least 6 hours in the average.
  • the claimed appliance exerted a more pronounced effect
  • Acute cure for 2 weeks in a permanent condition was given in 5 patients with arterial hypertension.
  • Dose of the drug at the end of the autoimmune intercepta-th week was - 33 - from 80 to 240 mg per day (average 144.0 + 22.1 mg), at the end of the 2nd week also from 80 to 240 mg per day (average 152.0 + 26.5 mg).
  • the inventive preparation was tested in a clinic in the quality of 35 anti-glaucoma medications.
  • the first case of the claimed drug did not cause painful sensations in the eyes of large patients.
  • the inventive preparation was studied in 108 patients with 20 different forms of glaucoma, resistant to traditional antiglaucoma therapy.
  • the decrease in intraocular pressure is greater than 2 mm ⁇ .sg. (average from 28.1 to 21.2 mm Hg) is achieved in 94 over 25 of them and its normalization (less than 22 mm Hg) in 50 patients.
  • Long-term, over I month, normalization of the physical condition was achieved in 76 patients.
  • the negative effect was absent or turned out to be unacceptable, which made them unable to install the second part of the claimed 30-phase.
  • 4 out of 7 large ophthalmologists were normalized (decrease in intraocular pressure from 24.2 to 21.3 mm Hg).
  • the claimed drug is an antihypertensive, anti-anginal, anti-rhythmic and anti-glaucoma medication, it is used in patients with various
  • the inventive product is used in tablets of 0.01 and 0.04 g, in ampoules of only 5 ml of 0.1-new or 1% of the active substance. Eye drops use in the form of I or 2-nd part of the active substance.
  • the claimed medication is prescribed in tablets, starting with a dose of 0.01 g (10 mg) 2-3 times a day. In case of good tolerance, the dose increases gradually (by necessity) by 10-20 mg in a dose of 80-120 mg.
  • the claimed drug is prescribed in tablets, starting with a dose of 0.01 g (10 mg) 2-3 times a day. With - 36 - Usually, increase the dose gradually (by and if necessary) by. 10-20 mg in a day before a daily dose of 80-120 mg.
  • the claimed preparation is used in the form of eye drops (I or 2% of the active substance used). Eye 5 drops are used by instillation into the conjunctival sac (only 2 drops 2 times a day).
  • the inventive preparation is usually normally transferred. In some cases, it is possible to slow down the heart rate and lower the systemic arterial pressure (Responsive Activity).
  • ⁇ , 4-benzodioxin-2 ( ⁇ ) -0 ⁇ is the interaction of 15 with where ⁇ is
  • I I (0.003 mole) was found to have been found to be 3-methyl-5- [2- (3-chain butylamine-2-hydroxyxypropyl) phenyl] - 1,2,4-oxydiazed, in 10 ml of ethanol, add I ml of concentrated sulfuric acid when cooled. The sprinkled plant is removed. 0.9 g (82% by weight) of 3-methyl-5- [2- (3-compound, butylamine-2-hydroxyxypropoxy) phenol] -1, 2,4-oxide of the sulfate are obtained. 30 ⁇ . ⁇ . ⁇ 49.5- ⁇ 50.5 ° C.
  • Example I out of 4.5 g (0.03 mol) of 20 ⁇ , 4-benzodioxin-2 (3 ⁇ ) -one, 4.5 g (0.03 mol) of phenylacetate in 60 ml of oxygen For 4 hours, 5.4 g (64% by weight) of 3-benzyl-5- [2-oxo-phenoxymethyl] - 1, 2,4-oxadiazal, ⁇ . pl. 8 ⁇ -82 ⁇ C, analogous to imeters are obtained. In addition, there is an interaction with 0.8 g (0.02 mole) of an extra 25 natra and 3.7 g (0.04 mole) of hydrated hydrate.
  • the process is carried out in a similar way to Example I.
  • the epoxy process is the same as for example I out of 4.7 g (0.02 mol) 3-yl-2-yl-2, 2-hydroxy, (0.04 moles) of ethyl hydride in the presence of 0.8 g (0.02 moles) of sodium hydroxide, processes about 6 ml (4.35 g, 0.075 moles) of 10 ml of the unit.
  • the resulting amine derivative processes a synthetic product, and 30 g is obtained and irradiates 3.6 g (47 wt.%) Of 2-ispyl-2- , 4-oxadazole hydrochloride, mp 74.5-75, 5 ° C.
  • the resulting processed product is 8 ml (5.6 g, ⁇ 0.1 mole) of 10 mg of methylpropyl amine, and the chemical is absorbed, 3.9 g (40 wt.%) Of 3-phenyl-5- [2- (3-iso-propylamino-2-hydroxypropylpropyl) phenoxy-15 methyl]-2,4, 2,4-hydroxyadiazide hydride, ⁇ .pl. 52 are obtained. 52 -153 ° C.
  • the claimed 5-phenoxymethyl derivatives, 2,4-oxadiazole and their salts possess a pronounced ⁇ - and ⁇ . -adrenolytic activity and find use in medicine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dérives de 5-phénoxyméthyle-1,2,4-oxadiazole et leurs sels de la formule générale (I) dans lequel R représente -CH3, -C2H5, -CH(CH3)2, -CH2C6H5, -C6H5; R1 représente -CH(CH¿3?)2, -C(CH3), -CH(CH3)-CH2CH3, -CH2CH2NHCOCH(CH3)2; X représente un acide non-organique ou organique ou est absent. Un procédé d'obtention des composés de l'invention consiste à faire réagir 1,4-benzodioxine-2(3H)-OH avec amidoxime de la formule générale (II) dans lequel R représente -CH3, -C2H5, -CH(CH3)2, -CH2C6H5, -C6H5, à une température comprise entre 90 et 140 °C dans le milieu d'un solvant organique aprotique, à faire réagir le dérivé obtenu de 5-(2-oxyphénoxyméthyle)-1,2,4-oxadiazole avec l'épichlorohydrine, et à faire réagir le dérivé époxy ainsi obtenu avec l'alkylamine de la formule générale: R?1NH¿2, dans lequel R représente -CH(CH3)2, -C(CH3)3, -CH(CH3)CH2CH3, -CH2CH2NHCOCH(CH3)2, permettant l'extraction ultérieure du produit voulu. Le plus actif des composés de l'invention -3-méthyle-5-[2-(3-tert.butylamino-2-hydroxypropoxy)phénoxyméthyle]-1,2,4 oxidiazole hydrochlorure est le constituant actif d'une préparation pharmaceutique ayant une action antihypertensive, antiangineuse, antiarrhythmique et antiglaucomatomeuse.
PCT/SU1991/000215 1991-10-28 1991-10-28 Derives de 5-phenoxymethyle-1,2,4-oxadiazole, leur sels, procede d'obtention et preparation pharmaceutique a base de ceux-ci presentant des proprietes antihypertensives, antiangineuses, antiarrhythmiques et antiglaucomatomeuses Ceased WO1993009106A1 (fr)

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PCT/SU1991/000215 WO1993009106A1 (fr) 1991-10-28 1991-10-28 Derives de 5-phenoxymethyle-1,2,4-oxadiazole, leur sels, procede d'obtention et preparation pharmaceutique a base de ceux-ci presentant des proprietes antihypertensives, antiangineuses, antiarrhythmiques et antiglaucomatomeuses

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PCT/SU1991/000215 WO1993009106A1 (fr) 1991-10-28 1991-10-28 Derives de 5-phenoxymethyle-1,2,4-oxadiazole, leur sels, procede d'obtention et preparation pharmaceutique a base de ceux-ci presentant des proprietes antihypertensives, antiangineuses, antiarrhythmiques et antiglaucomatomeuses

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2135487C1 (ru) * 1993-04-30 1999-08-27 Яманоути Фармасьютикал Ко., Лтд. Производное бисоксадиазолидиндиона, фармацевтическая композиция

Citations (6)

* Cited by examiner, † Cited by third party
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SU615070A1 (ru) * 1976-09-20 1978-07-15 Пермский государственный фармацевтический институт Способ получени фенацил (3-фенил1,2,4-оксадиазолил-5)-кетонов
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SU615070A1 (ru) * 1976-09-20 1978-07-15 Пермский государственный фармацевтический институт Способ получени фенацил (3-фенил1,2,4-оксадиазолил-5)-кетонов
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