前苏联专利SU1322978A3 Method of producing 1-(2-aryl-2-halo-1-ethinyl)-1h-azoles

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专利摘要:
Novel 1-(2-aryl-2-halo-1-ethenyl)-1H-azoles of the formula …<CHEM>… the pharmaceutically acceptable acid-addition salts and possible stereochemically isomeric forms thereof, which compounds are anticonvulsant agents; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions.
公开号:SU1322978A3
申请号:SU843805474
申请日:1984-11-02
公开日:1987-07-07
发明作者:Херес Ян
申请人:Жансен Фармасетика Н.В. (Фирма)；
IPC主号:

专利说明:

This invention relates to new 1 - (2-aryl-2-halo-1-ethynyl) -1H-azoles having anticonvulsant properties.
The purpose of the invention is a method for producing new azoles with new properties for a given range of compounds.
Example I. A mixture of 10 h 1 - (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) -ethanone monohydrochloride and 10 h of pentachlorophosphorane is stirred and heated in a vessel under reflux for I h. The reaction mixture is cooled and treated with ice water. The whole is neutralized with potassium carbonate and the product is extracted twice with 2, 2-oxibispropane. The combined sumat extracts are filtered and evaporated. The residue is converted to the nitrate salt in 4-methyl-2-pent none. The salt is filtered and crystallized from ethanol, which gives 5.1 h (40%) of mononitrate (Z) -l-2-chloro-2- (2,4-dichlorophenyl) ethenyl -1H-imidazole; mp.161.4 (compound T).
Take p2. To a stirred mixture of 20.2 hours of (Z) -1-2-chloro-2- (2,4-dichlorophenyl) ethenyl-INH-imidachon mononitrate, 100 hours of water and 70 hours of 2,2-hydroxy-bispropane are added 5 hours amd day hydroxide. Mix everything for 5 minutes. The layers are separated. The liquid phase is extracted for 35 hours with 2,2-oxy-bis-prop a. Q7: The combined organic layers are washed with water, dried, filtered, and evaporated to give 15.9 h (g) -1-2-chloro-2- (2,4-dichloro-phenesO -thenyl 3 -H-imidazole; m.p. 59.1 C (compound 2).
Example 3. To a stirred mixture of 12.76 hours of mononitrate (Z) chloro-2- (2,4-dichlorophenyl) ethenyl -1H-imidazole, 120 hours of water and 70 hours of 2,2-oxybispropane, was added 3.5 hours of hydroxide am {they . All are shifted to a uniform state. The layers are separated. Liquid Laeau is extracted for 35 hours with 2,2 - oxybispropane. The combined organic layers are washed with water, dried, filtered off and dried in a vacuum. The residue is converted to chloro-hydroxy salt in 64 hours of 2-propanol. (olu from) ylutpor are extracted, washed with 2-iiponanoHOM and dried in an E1 vacuum, which gives 8.5 h of monohydrochloride (Z) -1 - 2-chloro-2- (2, 4-dichloro (1enyl) ethe-
322978 2
Nile -1H-imidazole; mp.178.8 C (connect} 1, 3)
PRI me R 4. A mixture of 10 h of monohydrochloride 1 - (2,6-dichlorophenyl) -2-5 (1H-imidazol-1-sh) ethanone and 20 hours of pentachlorophosphorane is stirred and heated in a refluxed vessel. for 3 hours. The solution is diluted with dichloromethane and 300 hours of water to pH 0 is added dropwise in 1 hour. The whole is neutralized with potassium carbonate. The product is extracted twice with dichloromethane. The extract is sutaat, filtered and evaporated. The residue was purified by capillary chromatography over silica gel using dichloromethane as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted to the nitrate salt in 4-methyl-2-pentanone and 2,220 oxybispropane. The salt is filtered off and crystallized from 4-methyl-2-pentanone, which gives 4.6 hours (40%) of mononitrate (E + 7.) - 1 - 2-chloro-2- (2,6-dichlorophenyl) ethenyl -1H-imidazole;
5 mp.122.3 s (compound 4).
In the same way, the compounds shown in Table 1 are obtained.
five
Example To mixed
a mixture of 1.9 h of mononitrate (E) chloro-2- (2,4-dichlorophenyl) ethenyl -1H-imidazole, 50 h of water and 75 h of trichloromethane was added I, 0 h of potassium carbonate. All is stirred until a clear solution is obtained (pH 8-9). The organic layer is separated, dried, filtered and evaporated. The residue is converted to the hydrochloride salt in 4-methyl-2-pentanone and 2.2 oxybispropane and 2-propanol. The salt is filtered and dried, which gives 1.5 hours (86%) of monohydrochloride (E) -1-2-chloro-2 - (2,4-dichlorophenyl) ethenyl-IN-imidazole; mp 203.2 ° C
(compound 24).
PRI me R 6. A mixture of 30 h of hydrochloric 1 - (2-methoxyphenyl) -2- (1H-imidazol-1-yl) ethanone and 60 parts of pentachlorophosphorane is stirred and
The mixture is heated in a reflux flask for 3 hours. The reaction mixture is diluted with 600 parts of dichloromethane and added to 100 parts of potassium carbonate. Then water is added dropwise to
for 2 hours. The product is extracted three times with dichloromethane. The combined extracts are filtered and evaporated. The residue is purified by capillary chromatography over silica gel using trichloromethane and as eluent. Pure Lraktsich sobfayut and eluent evaporated. The residue is crystallized from 2,2-oxy-bis-propane, which gives 7 parts (22%) of 1 - 1, 2-dichloro-2- (2-methoxynphenyl) ethylene-1H-imidaeol; mp.101.4 C (compound 25).
In the same way, the compounds listed in Table 2 are obtained.
Example 7. A mixture of 23 parts of 1- (2-bromo-4-chlorophenyl) -2-P P -im1 -vdaeol-1-yl) -ethanone, 23 hours, pentachlorophosphorane and 17 parts of phosphoryl chloride are mixed and heated in a vessel with reflux for 4 h. The reaction mixture is cooled and diluted with 260 h, dichloromethane. This solution is added dropwise over 2 hours to a solution of 300 parts of potassium carbonate in 500 hours of water. All is stirred overnight at room temperature. The product is extracted twice. 2,2-oxibispropane. The combined extracts are dried, filtered and evaporated. The residue is converted to the nitrate salt in ethyl acetate and 2,2-oxy-bispropane. The salt is filtered and purified by reverse phase chromatography over ifi Chroper RP 18 using a mixture of methanol containing 0.1% N- (1-methyl-ethyl) -2-propanamine and thieves containing 0.5% ammonium acetate, {65: 35 by volume) as eluent
The first fraction is removed and the eluent is added. The residue is converted to a nitrate salt in a mixture of ethyl acetate and 2,2-oxybispropane. The salt is filtered off and crystallized from 4-methyl-2-pentanone, which gives 2.9 h- (10%) of mononitrate (E) -1-2- (2-bromo-4-chlorophenyl) -2-chloroethenyl -1 H-imidazole; m.p. 1 62 j9 C (compound 36).
The second fraction is removed and the eluent is evaporated. The residue is converted to a nitrate salt in a mixture of ethyl acetate and 2,2-oxybispropane. The salt is filtered off and crystallized from 4-methyl-2 pentanone, which gives 3.3 parts (11%) of (Z) (2-bromo-4-chlorophenyl) -2-chloroethenyl -1H-imidazole mononitrate; m.p. 1 67, 8 with connection 37 /.
In the same way receive;
(Z) -1 -2-chloro-2- (2,4-dibromoenyl) ethenyl -1H-imidazole moionitrate; mp.1b2.4 C (compound 38);
229784
mononitrate (E) -1-2-chloro-2- (2,4-dibromophenyl) reading; - 1 | -imi; azola; m.p. 17p, 4 ° C (compound 39);
mononitrate (Z) - 1 - 2- f (1, l-beef-NILE) -4-np -2-chloretenyl -1H-imidazole; m.p. 186.5 - 187.2 ° С (compound 40);
mononitat (E) (1, 1 -biphenyl-4-yl) -2-J chloretenyl -1H-imidazole; fO m.p.I55.7-156.0 ° C (compounds 4l);
(Z) -1 -2-chloro-2- (2-chloro-4-methylphenyl) ztenyl-IN-imidazole mononitrate; mp.153.6 C (compound 42); mononitrate (E) -1-2-chloro-2- (2-15 chloro-4-methylphenyl) ztenyl -1H-imidazole; m.p. 144.4 C (compound 43). I
EXAMPLE 8 A mixture of 20 parts of 1- (4-bromo-2-chlorophenyl) -2- (1H-1,2,4-triazol-1-yl) ztanone, 40 parts of pentzchlorophos phoran and 300 hours. 1,2-dichloroethane is displaced and heated under reflux overnight. Add 300 parts potassium carbonate and
f. 650 parts of dichloromethane and water are carefully added dropwise to a volume of approximately 1500 hours. The aqueous phase is extracted with dichloromethane. The combined organic layers are washed with water, dried, filtered and embedded. The residue is purified by reverse phase chromatography (high pressure liquid chromatography — HPLC) over Sfi Chroper RP IB using a mixture of 75% methanol containing 0.1% N- (1-methylethyl) -2-propanamine and 25% water, containing 0.5% ammonium acetate as eluent.
The first fraction (E-isomer) is collected and the eluent is evaporated. The residue is crystallized from hexane at 0 ° C. The product is filtered and dried under vacuum at 60 ° C, yielding 7.9 parts (37%) (E) (4-bromo-2-chlorophenyl)., 2-chloretenyl -1H-1 , 2, 4-triazole; m.p. 84.0 C (compound 44).
The second fraction (Z-isomer) is also taken up. The residue is crystallized from hexane at O C.
rn Product is filtered off and vyfLr r
sewn under vacuum at S.P., which gives 0.36 parts of (Z) -1 -2 2-f4-bromo-2-chlorophenyl) -2-x: yurttenyl -1H-1, 2, 4-triazole; m.p. 96.0 C (compound 45).
Similarly, using the equivalent amounts of suitable starting materials, the compounds listed in Table 2 are prepared. 3
thirty
513229786
In the same way, 350 parts of potassium carbonate are prepared in 500 hours.
served while stirring overnight. The product is extracted with dichloromethane. The extract is dried, filtered and you (Z) -l-2-chloro-1- (2,4-dichlorophenyl) -2- (4-fluoroLenyl) ethenyl -1H-imidazole; ggsh.104.4 C (compound 5A);
(E) -1 - 2-chloro-1 - (2, 4-dichlorophenyl) -2- (4-fluorophenyl) ethenyl -1H-imidazole; mp.146.2 C (compound 55),
PRI me R 9. A mixture of 18.7 parts of 2- (1H-imidazol-1 -yl I -1 -phenylethanone, 37.4 parts of phosphorus pentachloride and 240 parts of 1,2-dichloroethane is stirred and heated in a reflux vessel. The mixture is diluted with dichloromethane. This solution is added dropwise over 2 hours to a solution of 350 hours of potassium carbonate in 500 parts of water. Stirring is continued overnight. The organic layer is separated. extracted with dichloromethane. Ammonium volume. The pure fraction is collected and
The washed opraHi-layers are washed with water, dried, filtered and evaporated. The residue is converted to the nitrate salt in 4-methyl-2-pentanone. The salt is filtered off, triturated in 2-propanone, the mixture is filtered and the mixture is crystallized from 2-propanol. The product is filtered off, the base is released with potassium carbonate solution and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue was purified by capillary chromatography over silica gel using a mixture of methylbene} {ash and eta- {ol (98.5: 1.5 according to about 1) for it) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is converted to the nitrate salt in 2,2-hydroxy-propane. After mixing
overnight, the salt is filtered off and crystallized from ethanol. Everything is allowed to stand overnight. Product
filtered and dried in vacuum at 60 ° C, which gives 4 hours (14%) of mono san. The precipitated product is stirred all night. It is filtered off and dried in a pistol dryer at room temperature, which gives 4.4 hours (9%) of mononitrate (Z), 2-nitrate (Z) -l- (2-chloro-2-Lenilstenyl) - 45 dichloro-2 - (2,4-dibromophenyl) ethenyl - 1H-imidazole, mp.144.0 ° C (compound- 1H-1, 2, 4-triazole. Mp.98.1 s (56) .dinification 62).
In the same way, the compounds shown in Table 4 are obtained.
The second fraction (the E-isomer is collected, the CQ is boiled and the elute is isolated. The residue
Example 10. A mixture of 55 parts of I- (22, 4-dibromolenyl) -2- (1 Fi-1, 2, 4-tribo fraction (E-isomer is collected CQ lyute and elute is boiled down. Residue
treat with activated charcoal. Last filter out
azol-1-yl) ethanone, 70 parts of pentachlorophosphate and the filtrate is added. The residue of foran and 180 parts of 1,2-dichloroethane are converted into a nitrate salt in a large amount of 2,2-oxybispropane and hexa. (The precipitated product is stirred overnight. It is filtered off (the filtrate is taken aside) and dried in a pistol dryer.
stir and heat under reflux for 4 h. After cooling the mixture, add methyl chlorine. The geyclay mixture is added dropwise over 2 hours to the solution until it is dry. The residue is converted to the nitrate salt in 2,2-oxybispropane. The salt is filtered off (and scooped aside) and the filtrate is concentrated. A small amount of nitric acid is added to the concentrate. The precipitated product is filtered off (the filtrate is retracted to the side) and otschtsayut together with the salt, which was separated to the side, by reversed-Baseline chromatography (HPLC) over (H1) Cflg RP 18, using a mixture of 70% methanol containing 0.1% N - (1-methyl-ethyl) -2-propanamine and 30% water containing 0.5% acetate
add eluent. Residue crystallisation: lot of 2,2-oxybispropane. The product is filtered and the filtrate, together with the filtrate, which was
set aside, neutralized with potassium carbonate. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The oily residue is purified (by capillary chromatography over silica gel using a mixture of methyl benzene and ethanol (99: 1 by volume) as eluant.
The first fraction (Z-isomer) is collected and the eluent selected. The residue is treated with activated charcoal. The latter is filtered and evaporated. The residue is converted into a nitrate salt in a small amount of 2,2-oxybispropane and hexa
The second fraction (the E-isomer is collected, the CQ is boiled and the elute is isolated. The residue
they process with activated wood-carbon. The latter is filtered out in large quantities of 2,2-oxy-bis-propane and hexaia. (The precipitated product is stirred overnight. It is filtered (the filtrate is taken aside) and dried in a pistol dryer.
at room temperature, which gives the first fraction of 3.7 parts (7%) of the mono constituent of (E) -1-1, 2-lichloro-2- (2,4-dynbromophenyl) ethenyl -1 H -1, 2 , 4-triazole, so pl. 126, (compound 63).
Example II A mixture of 29.0 parts of monohydrochloride 1- (2-bromo-4-methoxy-phenyl) -2- (| H-imidazol-1-yl) ethanol, 58.0 parts of phosphorus pentachloride and 360 parts 1.2 -dichloroethane is stirred and heated in a vessel under reflux for 4 hours. The reaction mixture is cooled and diluted with dichloromethane. The resulting solution is added dropwise over 2 hours to a mixed solution of 300 parts of potassium carbonate in 500 parts of water. FlepeMedJH- continued overnight at room temperature. The product is extracted twice with dichloromethane. The combined extracts are rinsed with water, dried, filtered and evaporated. The oily residue is purified by capillary chromatography over silica gel using a mixture of methipbenzene and trichloromethane (75:25 by volume) as eluent. The first fraction is collected and the eluent is evaporated. The residue is converted to the nitrate salt in ethyl acetate, and 2,2-oxyibispropane. The salt is filtered and crystallized from ethyl acetate, which gives, after drying at 80 ° C under vacuum overnight, 0.7 h (1%) of mononitrate 1 - 2- (2-Bromo-4-methoxyphenyl) -1,2-dichloroethenylJ-1H-imidazole, mp. 124.9 ° C (compound 64).
EXAMPLE 12 A mixture of 30.0 parts of 2- (1H-imidazol-1-yl) -1- (2-naphthalenyl) ethanone, 60.00 parts of pentachlorophosphine and 40 hours. I, 1,2,2-tetrachloroethane is stirred and heated under reflux for 4 hours. After cooling, the reaction mixture is diluted with 260 parts of dichloromethane and 300 parts of potassium carbonate is added. Then 250 parts of water are added dropwise over 2 hours and more water is added sequentially. Stirring is continued overnight at room temperature. The product is extracted twice with dichloromethane. The combined extracts are rinsed with water, dried, filtered and evaporated in vacuo. The residue is converted to the nitrate salt in 2-propanol and 2,2-oxy-bis-propane. The salt is filtered off and crystallized from ethanol.
229788
(act (tweened charcoal), which gives 7.9 parts of (20) mononitrate of (Z) -I-2-chloro-2- (2-naphthalenyl) ethenyl-I F-imidazole, so pl. 150, lc (compound 65).
Example 13. A mixture of 30 parts of 2- (1H-imidazol-1-yl) -1- (2-naphthalene 1) - ethanone, BO, 0 parts of phosphorus pentachloride
JO and 40 hours. 1,1,2,2-tetrachloroethane is stirred and heated in a vessel under reflux for 4 hours. After cooling, the reaction mixture is diluted with dichloromethane. Add
f5 potassium carbonate and water dropwise over 2 hours. To completion, another 500 hours of water is added and stirring is continued overnight. The product is extracted with methyl benzene. The organic layer was dried, filtered and evaporated in vacuo. The residue is purified by capillary chromatography over silica gel using a mixture of methyl benzene and trichloromethane (75:25 by volume) in
25 as eluent. Pure fractions
collected and the eluent is evaporated. The residue is converted to the nitrate salt in 4-methyl-2-pentanone and 2,2-oxybispropane. The salt is filtered off and triturated in 2-propanol. The product is filtered off and crystallized from 2-propanone, which gives 1.3 parts of mononitrate (E) -1 - 2-chloro-2- (2-naphthalenyl) ethenyl -1 H-imidazole, so pl.
35 131.0 ° C (compound 66).
Example 14. A mixture of 10.0 parts of monohydrochloride 1 - (2,4-dichlorophenyl) -2- (IH-imidazol-1-yl) ethanone, and 20.0 hours
The Q pentabromo phosphorane is stirred and heated in a reflux vessel} P {com for 3 hours. After cooling, the reaction mixture is diluted with dichloromethane. 30.0 parts of potassium carbonate are added, followed by adding dropwise to water for 2 hours. More water is added and the whole is neutralized with potassium carbonate. The product is extracted twice with dichloromethane. The combined extracts were dried, filtered and evaporated. The remainder is formed by capillary chromatography over Si: Ij-gel using dichloromethane as eluent. The pure fractions are collected and
, 5 evaporate the eluent. The residue is converted to nitrate with SOL1, n 4-motil-2-pentanone and 2,2-oxybispropane. The salt is filtered and crystallized from 4-methyl-2-psn; 1Noia, which gives
3.5 parts (27%) of mononitrate (E + Z) -1-2-bromo-2- (2,4-dichlorophenyl) ztenyl-1H-imidazole, m.p. 137.9 ° C (compound 67.
Example 15. A mixture of 15.6 h of hydrochloric 1- (2,4-dichlorophenyl) (1H-imidazol-1-yl) ethanol and 31.2 parts of phosphorus pentabromide is stirred and heated in a vessel under reflux for 4 hours. the mixture is cooled and diluted with dichloromethane. This solution is added to a solution of 100 parts of potassium carbonate in water for 2 hours. Stirring is continued overnight at room temperature. The product is extracted with dichloromethane. The extract is dried, filtered and ground. The residue was purified by capillary chromatography over silica gel using a mixture of dichloromethane and methylbenzene (50:50 by volume) as eluent. the fraction is collected and evaporated elgoent. The residue is converted to the salt of the ethanedioate in 4-methyl-2-pentanone and 2,2-oxybispropane. The salt is filtered off and crystallized with 4-methyl-2-pentanone, yielding 1.9 parts (8%) of (Z) -l-2-brom-2- (2,4-dichlorophenyl) ethynyl-IN-imidazole ethanoate (1: 1), t. Pl. 183.4 C (compound 68).
PRI me R 16. A mixture of 35.0 h. 1 - (2, 4-dichlorophenyl) -2- (1} 1-imidazol-1-yl) -ethanon-4-methylbenzenesulfonate (1: 1) and 70 , 0 parts of phosphorus pentabromide is stirred and heated in a reflux vessel B for 4 hours. The reaction mixture is allowed to cool and diluted with trichloromethane. This solution is added dropwise over 2 hours to a solution of 400 parts of potassium carbonate in 1500 parts of water. All is stirred overnight at room temperature. The product is extracted with dichloromethane. The extract is washed twice with water, dried, filtered and evaporated. The residue was purified by capillary chromatography over silica gel, using methylbenzene as eluant. Pure fractions are collected and the eluent is evaporated. The residue is converted to a nitrate salt in 4-methyl-2-pentanone and 2.2 oxybispropane. The salt is filtered off and purified by reverse-phase chromatography pap jf Chroper RP 18, using a mixture of methanol and water | 35: 6 to
2297810
volume) as eluent. Chigate fractions are collected and charged into the eluent. From the residue, the free base is released and the nitrate salt is again converted to 5 in a mixture of ethyl acetate and 2,2-oxybispropane. The salt is filtered off and crystallized with 4-methyl-2-pentanone, which gives 2.5 parts of mononitrate (E) -1-2-bromo-2- (2, 4-dichlorophenyl) ethenyl -1H-imidazole, t. square 1 44.4 ° C (compound 69).
EXAMPLE 17 A mixture of 35.0 parts of 1- (2, 4-dichlorophenyl) -2- (1H-imidazol-1 5 yl) -ethanone-4-methylbenzene sulfonate (1: 1) and 70.0 The phosphorus pentabromide is stirred and heated in a vessel under reflux for 2 hours. After cooling, the reaction mixture is diluted with g) chloromethane. A solution of 400 parts of potassium carbonate from 500 parts of water is added dropwise over 2 hours with stirring. Stirring is continued for
nights The product is extracted with dichloromethane (pH 9-10). The organic layer is washed with water, dried, filtered and evaporated in vacuo. The residue is purified by capillary chromatography over
30 silica gel using methylbenzene as eluent. The third fraction is collected and the eluent is evaporated in vacuo. The residue is converted to a nitrate salt in a mixture of 4-methyl-2-pentanone.
35 and 2,2-oxybispropane. The salt is filtered and purified by reverse phase chromatography (HPLC) over 1 Chloride RP 18, using a mixture of 70% methanol containing 0.1% H- (1-methyl40-methyl) -2-propanamine and 30% water containing 0.5% ammonium acetate, as eluent. Pure fractions are collected and charged into the eluent. The residue is crystallized from 2-propanol, which
45 gives 2.5 parts of mononitrate (E) bromo-2- (2,4-dichlorophenyl) ethenyl - H-imide, azole, so pl. 148.3 C (compound 70).
Q The beneficial anticonvulsant properties of the compounds of formula (l), acid adducts and stereochemically, the isomeric forms of these compounds are illustrated in the test for maximum
metrazol seizure.
Protection against various seizures caused by petrazole (penteletrazole) is a good method for quantifying the anticonvulsant potential of the tested compounds.
Maximum metrazole test (by them.
Female Wistar rats weighing 1 g are starved overnight, having water ad libitum. Each rat is injected intraperitoneally with iodine mixture containing the test compound.
Che
1 h after drug treatment, the maximum metrazal MMP seizures are effected by rapid injection of 80 mg / kg of live weight of pentylenetetrazole in a volume of 0.4 ml / 100 g of body weight into the tail veiou. The lowest effective area of the test compound, which is capable of antagonizing CLO (common cloning seizures), TPL (tonic inverse extension of the front paws), TPL (tonic - extrusion of the hind paws) is given in Table 5, respectively in the first, second and third columns.
The compounds listed in Table 5 are given as examples of the beneficial pharmaceutical action of all compounds encompassed by formula (I).
In terms of anticonvulsant properties, the compounds of formula (I), their acid adducts and stereochemically isomeric forms are very useful in the treatment of convulsions and, more specifically, in the treatment of common forms of epilepsy. In addition to the anti-convulsive effect of the compound of formula (I), they have a useful antihypoxic effect.
The results of testing the known compounds are given in Table. 6
The five compounds subjected to the maximum metrazol test did not show any activity in it, while the proposed compounds in this test showed such activity.
The proposed compounds have anticonvulsant activity in contrast to known compounds that do not exhibit such activity.
All the compounds listed in gabl.5 have been tested at a maximum dose of 40 mg / kg of live weight on at least three rats. All twelve uk
297812
Those who were abducted from the compound did not experience a fatal outcome at the indicated dose on any rat.

权利要求:
Claims (1)
[1]
5 claims
The method of obtaining 1- (2-apyl-halo-l-ethynyl) -1 And-azoles of the General formula
ten
20
Tya
C
R
X
AH Halo
0
five
0
where q r
AG CH or N;
hydrogen, lower alkyl, aryl-NOWSE 1 alkyl or halogen; aryl in which aryl is phenyl, substituted phenyl, naphthalenyl, thienyl, substituted by halogen, and said phenyl is phenyl having from 1 to 3 substituents, each independently selected from the group consisting of phenyl halide, lower alkyl, lower al - coxy, trifluoromethyl, nitro group, lower alkyl, substituted by phenyl, different
by that.
azole of general formula
Q-
B O I II
R-CH-C-Ar
where the radicals have the indicated meanings, or its acid adduct is subjected to halogenation, if necessary, in a suitable solvent, with the desired product being isolated as a therapeutically active non-toxic acidic adduct. or a free base, mixture of isomers or individual isomers.
Priority on the grounds: 07/12/84 - with Q - CH or N; R is hydrogen, lower alkyl, aryl-lower alkyl or halo, and L is aryl, in which aryl is rfiemui,: 1 m is phenyl, naphthalenes, THPHII: I,; lchr1chennt halogen and yiioMHuyTivii (n l gnil et131322978 with phenyl imeyuschi from 1 to 3 aryl batch-set - phenyl, substituted phenyl, Titel, vybrannyynaftalenil each independently, thienyl, substituted galoi- from the group consisting of phenyl, halo, and the said phenyl is f, d, alkyp, lower alkoxy, having from 1 to 3 substituents, trifluoromethyl, nitro, amino, or 5 each is non-selected from lower alkyl, substituted by phenyl, the group consisting of halogen, low 07.11.83 with Q - CH or N; R - hydrogen, lower alkyl, aryl lower alkyl or halo and Ar - Ar l, koto
CH
CH
CH
N
CH
CH
CH
CH
CH
CH
H 2-C1-C H4 E + Z CH, 2 ,, E + Z
2, 4-Cl-C H
C, H, CH
H
H
H
CH,
H
H
H
2,4-С1, -С, Н, - 4-F-0, H, 4-С1-СБН4
-Wr-С Н Е
5-C1-2-TienilD
2-Cl, i; -F-C, H, O E
4-F-C, H
your alkyl, lower alkoxy, nitro, amino, or lower alkyl substituted by Lenil.
Table 1
the
)
, 4 112.0 161.3 145.7 102.2 102.6 125.6 148.6 140.1 156.4
Table 3
1322978
pn
I II Q N
I / Ar
Cl
N2,
N2 ,,
CH3-CF, -CgH
HNO - salt l (COOH) salt HCl - salt
Table 4
E e
Foundation 92, I
HNO 125.9
Table 5
nineteen
1322978
20 Table 6
4-C1 4-Vg
2,6-С1, С, Н, - CHj-0-4-С
4-C1-C, 4-C1
sn.
2-Cl-CjH, - СН -0Compiler G.Zhukova Editor I.Nikolaychuk Tehred L.Serdyukova Corrector l.Pnlnpenko
Order 2882/58, Circulation 371Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., d./5
Production and printing company, Uzhgorod, st. Design, D
118.6 111.6
127.2
HNO, 129.7
4-C1
HNO,
117

类似技术:

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同族专利:

公开号 | 公开日

FI844349L|1985-05-08|

CS382091A3|1992-04-15|

DK528284A|1985-05-08|

EP0142190A2|1985-05-22|

HK52591A|1991-07-19|

FI85854C|1992-06-10|

NO161800C|1989-09-27|

CY1606A|1992-04-03|

EP0142190B1|1989-06-21|

AU566022B2|1987-10-08|

IE842852L|1985-05-07|

NZ210014A|1987-03-06|

IL73425A|1987-09-16|

JPS60166666A|1985-08-29|

FI85854B|1992-02-28|

IE57826B1|1993-04-21|

NO161800B|1989-06-19|

DK162984C|1992-06-01|

SG46991G|1991-07-26|

IL73425D0|1985-02-28|

DK528284D0|1984-11-06|

JPH0613480B2|1994-02-23|

US4539325A|1985-09-03|

EP0142190A3|1986-12-03|

DK162984B|1992-01-06|

CA1241657A|1988-09-06|

AU3513784A|1985-05-16|

DE3478743D1|1989-07-27|

FI844349A0|1984-11-06|

NO844420L|1985-05-08|

引用文献:

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US3679697A|1970-10-08|1972-07-25|Searle & Co|1-imidazoles|

GB1533705A|1975-03-10|1978-11-29|Ici Ltd|Method of combating fungal infections in plants using imidazoles and 1,2,4-triazoles|

DE2839388A1|1978-09-11|1980-03-27|Siegfried Ag|IMIDAZOLYLVINYLAETHER AND THEIR USE|

NL8005204A|1980-09-17|1982-04-16|Gist Brocades Nv|ETHENYL-IMIDAZOLE DERIVATIVES WITH ANTIMYCOTIC EFFICACY.|

GR78234B|1981-03-10|1984-09-26|Ciba Geigy Ag|

CA1189857A|1981-03-27|1985-07-02|Janssen Pharmaceutica Naamloze Vennootschap|Antimicrobial triazole derivatives|

CA1206970A|1981-10-01|1986-07-02|Hak-Foon Chan|Substituted ethylenic imidazoles and triazoles|AT33982T|1983-12-20|1988-05-15|Ciba Geigy Ag|MICROBICIDES.|

JP2792694B2|1989-12-12|1998-09-03|エスケ−化研株式会社|Coating device|

US5418245A|1990-04-16|1995-05-23|Rhone-Poulenc Rorer InternationalInc.|Styryl-substituted monocyclic and bicyclic heteroaryl compounds which inhibit EGF receptor tyrosine kinase|

US5196446A|1990-04-16|1993-03-23|Yissum Research Development Company Of The Hebrew University Of Jerusalem|Certain indole compounds which inhibit EGF receptor tyrosine kinase|

US5302606A|1990-04-16|1994-04-12|Rhone-Poulenc Rorer Pharmaceuticals Inc.|Styryl-substituted pyridyl compounds which inhibit EGF receptor tyrosine kinase|

AU2122202A|2000-12-04|2002-06-18|Biovitrum Ab|Novel method and use|

SE0004462D0|2000-12-04|2000-12-04|Pharmacia Ab|Novel method and use|

RU2632682C1|2016-09-30|2017-10-09|Федеральное государственное автономное образовательное учреждение высшего образования Первый Московский государственный медицинский университет им. И.М. Сеченова Министерства здравоохранения Российской Федерации |Complex of zinc acetate with 1-propargylimidazol with anti-hypoxic activity|

法律状态:

优先权:

申请号 | 申请日 | 专利标题

US54912783A| true| 1983-11-07|1983-11-07|

US06/630,158|US4539325A|1983-11-07|1984-07-12|1--1H-azoles, and anticonvulsant use thereof|

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