Process for preparing cis-4-[4-[4-[(2-(2,4- difluorophenyl)-2- (1h)azolylmethyl-1,3-dioxolan-4-yl]-m

专利摘要:
Novel 4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-azolylmethyl)-1,3-dioxolan-4 -yl] methoxy]phenyl]-1-piperazinyl]phenyl]triazolones of formula <CHEM> wherein Q is N or CH; R is hydrogen, C1-6alkyl or arylC1-6alkyl; and R<1> is hydrogen, C1-6alkyl or arylC1-6alkyl; wherein aryl is phenyl optionally substituted with up to 3 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy and trifluoromethyl, the pharmaceutically acceptable acid addition salts and possible stereochemically isomeric forms thereof, which compounds are anti-microbial agents; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions.
公开号:SU1635900A3
申请号:SU884356110
申请日:1988-03-24
公开日:1991-03-15
发明作者:Хирес Ян；Якобус Жозеф Бакс Лео；Жозеф Элизабет Ван Дер Векен Луи
申请人:Жансен Фармасетика Н.В.(Фирма)；
IPC主号:

专利说明:

This invention relates to a process for the preparation of novel triazolone derivatives that have antifungal and antibacterial properties.
The purpose of the invention is the synthesis of new derivatives of triazalons with improved antifungal activity compared with intraconazole.
A. Preparation of Intermediates
Example 1
a) A mixture of 200 parts of glycerol, 90 parts of 1- (2,4-difluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanol, 600 parts of methanesulfonic acid and 190 hours of benzene is stirred, first at reflux temperature for 3 hours, using a water separator, and still overnight at room temperature. The reaction mixture is added on
dropwise to a sodium bicarbonate solution. The reaction product is extracted with chloroform. The extract is washed with water, dried g, filtered and evaporated. The residue is ground to powder in 4-methyl-2-pentanone. The reaction product is filtered off and dried, yielding 80 parts of (67.27) (cis + trans) -2- (2,4-difluoro-phenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1,3-dioxolane-4-methanol a (compound P-1).
G) A mixture of 69 parts of 3,5-dinitrobenzoyl chloride, 80 parts of (cis + trans) -2- (2,4-dilorophenyl) -2- (1H-1,2,4-triazol-1 -ylmethyl) -1, 3-dioxolane-4-methanol, 400 parts of pyridine and 520 parts of dichloromethane are stirred for 3 hours at room temperature. The reaction mixture is evaporated and the residue is treated with water. The reaction product is extracted with chloroform. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel, using a mixture of chloroform and methanol (99: 1 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 90 parts (70.4%) of (cis) -2- (2,4-difluorophenyl) 2- (1H-
1,2, 4-griazol-1-ylmethyl) -, 3-dioxolane-4-methanol of 3,5-linear nitrobenzoate (ester) as a residue (compound P-2).
c) A mixture of 90 parts of (cis) -2- (2,4-difluoro-phenyl) -2- (111-1, 2,4-triazol-1-yl-metts) -, 3-dioxolan-4-methanol 3,5-dinitrobenzoate (ester), 16 h. A 50% sodium hydroxide solution, 800 parts of 1,4-dioxane and 400 parts of water are stirred overnight at room temperature. The reaction mixture is drunk in water. The reaction product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is ground to powder in 4-metip-2-pentanone. The reaction product is filtered off and dried, yielding 30 parts (56.0%) of cis-2- (2,4-difluorop drank) -. - (1H-1,2,4-three
azol-1-ylmetach) -1, T-t, yoxolan-4-methanol as a residue (compound P-3).
d) A mixture of 1, 1 part of methanesulfonyl chloride, 25 parts of (2,4-difluorophenyl) -2- (1H-1,}., 1 riazol-1-ylmethyl) -1.3-dioxolane- - hm a nola, 300 parts of pyridine and 390 parts of mg; Yurmethane is stirred in flow i at room temperature. -loved mixture of vypa.
5 0 5 Q
five ,
0
five
the residue is treated with a chloro-j form. The organic phase is dried, filtered and evaporated. The residue is triturated in diisopropyl ether. The reaction product is filtered off and dried, yielding 29.4 parts (93.2%) of methanesulfonate (ester) cis-2- (2,4-difluorophenyl) -2- (1H-1,2,4-triazole-1- ylmethyl) -1, 3-dioxolane-4-methanol as a residue (compound P-4).
Analogously, the oxalate salt (1: 1) of methanesulfonate (ester) cis-2- (2,4-difluorophenyl) -2- (1H-imidazol-1-ylmethyl) -1, 3-dioxolane-4-methanol (Compound II -five).
Example 2
a) To a stirred solution of 122.0 parts (cis + trans) -2- (2,4-difluoro-phenyl) -2- (111-1, 2,4-triazol-1-ylmethyl) -1,3- dioxolan-4-methanol and 1.0 part of N, N-di, methyl-4-pyridinamine in 1300 parts of dichloromethane, a solution of 121.2 parts of 2-naphthalenesulfonyl chloride in 100 parts of pyridine was added dropwise over 2 hours. After the addition is complete, stirring is continued overnight at room temperature. The reaction mixture is washed twice with water and evaporated in vacuo. The residue is purified by column chromatography over silica gel using chloroform as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The reaction product is filtered off and dried, yielding 102.3 parts (51.0%) (2,4-difluorophenyl) -2- (1H-1,2, 4-triazol-1-ylmethyl) -1,3-dioxolane 4-yl-methyl-2-naphthalenesulfonate. M.p. 139.5 ° C (compound P-6).
Example 3
a) A mixture of 10 parts of 2,4-dihydro-4-4-4- (4-methoxyphenyl) 1 piperazinyl-phenyl-3H-1, 2, 4-triazole 3-one, 1.5 h. The 50 / dispersion of sodium hydride and 300 parts of dimethyl sulfoxide are stirred at 60 ° C in a nitrogen atmosphere until foaming stops. 5.24 parts of 2-bromopropane are then added and stirring is continued for 1 hour at 60 ° C. After that, another 1.5 parts of the 50% sodium hydride dispersion are added and stirring is continued until foaming stops. Another 5.24 parts of 2-bromopropane are then added and the contents are stirred for 1 hour at.
The reaction mixture is cooled and poured into water. The reaction product is extracted with chloroform. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of chloroform and methanol (99: 1 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 1-butanol to give 5.2 parts (47%) of 2,4-dihydro-4-G4-4- (4-methoxy-phenyl) -1-piperazinylj-phenyl | 2- (1-methyl ethyl ) -ZN-1,2,4-triazole-3-one. M.p. 209.5 (Compound P-9).
b) A mixture of 4.7 parts 2,4-dihydro-4-1.4-4-4 (4-methoxyphenyl) -1-piperazinyl1-phenyl 2- (1-methylethyl) -ZH-1, 2,4-triazole -3-one and 75 parts of a 48% aqueous solution of hydrobromic acid in water are stirred and heated under reflux for 3 hours. The reaction mixture is evaporated and the residue is dissolved in a mixture of methanol and water. The content is neutralized with a solution of bicarbonate and the reaction product is extracted with chloroform. The extract is dried, filtered and evaporated. The residue was triturated in 2-propanol to give 3.9 parts (86%) of 2,5-dihydro - (- 4-G4- (4-hydroxyphenyl) -1-piperazinylZ-phenyl 2- (1-methyl ethyl) - 3N-1, 2,4-triazol-3-one, mp 208.4 ° C (compound L-10).
Similarly receive
2,4-dihydro-4- 4- 4- (4-hydroxyphenyl) -1-piperazinyl-phenyl) -2- (1-methyl propyl) 3N-1,2,4-triazole-3-one. M.p. 187.6 ° C (compound P-11);
2,4-dihydro-4 4- 4- (4-hydroxyphenyl) 1-piperazinyl | -phenyl 2- (3-methylbutyl) -ZCH-1,2,4-t riazole-3-one. M.p. 216, (compound P-12);
2,4-dihydro-4-Ј4-G4- (4-hydroxyphenyl) -1-piperazinyl7-phenyl-5-methyl-2- (1-methylpropyl) -N-1,2,4-triazole-3-one. M.p. 239.9 ° C (compound P-13);
1,2,4-triazole-W-one. M.p. 202.1 ° C (compound GT-16).
B. Obtaining final compounds.
Example 4
a) A mixture of 9.8 parts 2,4-dngydro-4-4-Ј4- (4-hydroxyphenyl) -1-piperazinyl-fe- (1-methylpropyl) -ZN-1,2,4-triazole -3-one, 12 parts methanesulfonate
Yu (ester) cis-2- (2,4-difluorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolane-4-methanol, 4.2 including potassium hydroxide and 135 hours. K, M-dimethyl- Formamide is stirred and heated in
15 for 2 hours at 60 ° C in a nitrogen atmosphere. The reaction mixture is evaporated. The residue is treated with water. The reaction product is filtered and treated with chloroform. The organic layer is dried, filtered and evaporated. The residue is crystallized from acetonitrile. The reaction product is filtered off and dried, yielding 12.8 parts (76.1%) of cis-4-4- (G2- (2,4-difluorophenyl) 25 2- (1H-1,2,4-triazole-1- ylmethyl) -1,3-dioxol n -yl-methoxy -phenyl T-1 -piperazinyl. -phenyl, 4-dihydro-2- (1-methylpropyl) -ZN-1, 2,4-triazole-3-one , Mp 189.58C (compound 1).
30 Similarly receive
cis-4-C4- 4- 4- 2- (2,4-difluorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolane-methoxy-D- phenyl} - 1-piper zinyl-phenyl 1-2,4-dihydro-2, (1-methylethyl) -ZN-1,2,4-triazole-3-one. M.p. 211.1dC (compound 2);
cis-4-Ј4-Ј4-4- Е- (2,4-difluorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl1-methoxy-phenylJ-1-1 pi40 perazinyl D-phenyl -2,4-dihydro-2- (1 - methylethyl) -ZN-1,2,4-triazole-3-one, m.p. 218.8 ° C (compound 3).
b) To the stirred solution
6.8 parts of cis-4- 4- 4- (2,4-difluoro, with phenyl) -2- (1H-1,2,4-triaol-1-ylmethyl) 1,3-dioxolan-4-yl1 - methoxy Phenyl} - 1-piperazinyl.-phenyl 3-2,4-dihydro-2- (1-methylpropyl) -3H-1, 2,4-triazole-3. ...., in 80 hours of acetone, add 3.2 hours.
2,4-dihydro-4- {4-L- (4-hydroxyphenyl) - n methanesulfonic acid. After up-1-piperazinyl3-phenyl -2-propyl-3H-melt, 73 parts of diisopropyl ether 1, 2,4-triazole-3-one as a solid residue (compound P-14);
2-ethyl-2,4-dihydro-4- Ј4-1f4- (4-hydroxyphenyl) -1-piperazinylJ-phenyl J-3H-1,2,4-triazole-3-one. M.p. 217 C (compound P-15);
2,4-dihydro-4- 4- (4-hydroxyphenyl) -piperazinyl-phenyl -2-pentyl-3H55
The crystalline product is filtered and recrystallized from a mixture of acetonitrile and diisopropyl ether. The reaction product is filtered off and dried, yielding 8.4 h, (92.0%) methanesulfonate (2: 5) cis-4-4-H4- | - Rp- (2,4-difluorophenyl) -2- (1H- 1,2,4-three, azol-1-ylmethyl) 71,3-dioxo1, 2,4-triazole-3-one. M.p. 202.1 ° C (compound GT-16).
B. Obtaining final compounds.
Example 4
a) A mixture of 9.8 parts 2,4-dngydro-4-4-Ј4- (4-hydroxyphenyl) -1-piperazinyl-fe- (1-methylpropyl) -ZN-1,2,4-triazole -3-one, 12 parts methanesulfonate
(ester) cis-2- (2,4-difluorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolane-4-methanol, 4.2 h potassium hydroxide and 135 parts. K, M-dimethyl- Formamide is stirred and heated in
5 for 2 hours at 60 ° C in a nitrogen atmosphere. The reaction mixture is evaporated. The residue is treated with water. The reaction product is filtered and treated with chloroform. The organic layer is dried, filtered and evaporated. The residue is crystallized from acetonitrile. The reaction product is filtered off and dried, yielding 12.8 parts (76.1%) of cis-4-4- (G2- (2,4-difluorophenyl) 5 2- (1H-1,2,4-triazole-1- ylmethyl) -1,3-dioxol n -yl-methoxy -phenyl T-1 -piperazinyl. -phenyl, 4-dihydro-2- (1-methylpropyl) -ZN-1, 2,4-triazole-3-one , Mp 189.58C (compound 1).
0 Similarly receive
cis-4-C4- 4- 4- 2- (2,4-difluorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolane-methoxy-D- phenyl} - 1-piper zinyl-phenyl 1-2,4-dihydro-2, (1-methylethyl) -ZN-1,2,4-triazole-3-one. M.p. 211.1dC (compound 2);
cis-4-Ј4-Ј4-4- Е- (2,4-difluorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl1-methoxy-phenylJ-1-1 pi0 perazinylD-phenyl -2,4-dihydro-2- (1 - methylethyl) -ZN-1,2,4-triazole-3-one, m.p. 218.8 ° C (compound 3).
b) To the stirred solution
6.8 parts of cis-4- 4- 4- (2,4-difluoro-c-phenyl) -2- (1H-1,2,4-triaol-1-ylmethyl) -1,3-dioxolane-4- Il1-methoxyZ phenyl} - 1-piperazinyl.-phenylZ-2,4-dihydro-2- (1-methylpropyl) -ZN-1, 2,4-triazole-3
The crystalline product is filtered and recrystallized from a mixture of acetonitrile and diisopropyl ether. The reaction product is filtered off and dried, yielding 8.4 h, (92.0%) methanesulfonate (2: 5) cis-4-4-H4- | - Rp- (2,4-difluorophenyl) -2- (1H- 1,2,4-three, azol-1-ylmethyl) 71,3-dioxate for 8 hours at 70 ° C. under nitrogen atmosphere. After adding 200 parts of water, the precipitated reaction product is filtered, washed with water and 2-propanol and purified by column chromatography over silica gel, first using a mixture of chloroform and methanol (99.5: 0.5
ethyl acetate, hexane, and methanol (45: 30: 20: 5 by volume) as eluents. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from ZON water. The precipitated product was filtered off, washed with water and purified by column chromatography over silica gel, using 4-yl-methoxy-phenyl-1-piperazinyl-phenyl -2,4-dihydro-2- (1-methylpropyl ) -ZN-1,2,4-triazole-3-one. M.p. 151.7PC (compound 4).
Example 5. A mixture of 4 parts. 2,4-di- - hydro-4-4-4- (4-hydroxyphenyl) -1-piperazinyl-phenol-5-methyl-2- (1-methylpropyl) -ZN -1,2,4-triazol-3-one, 5.6 h.
(2,4-difluorophenyl) -2- (1H-1, 2.4) 0 volume), and then a mixture of chloroform, triazol-1-ylmethyl) -, 3-dioxolan-4- -yl | -methyl 2-naphthalene sulfonate , 1 hour of sodium hydroxide granules and 90 hours of N, N-dimethylformamide are stirred for 4 hours at 60 ° C. under a nitrogen atmosphere. Added from 4-methyl-2-pentanone. Product
the reactions are filtered and dried, yielding 10.5 parts (76%) of cis-4-4.2- (2,4-difluorophenyl-2- (1H-imidaeol-1-ylmethyl) -1,3-dioxolane-4- il2 metozu mixture of chloroform and methanol (99: 1 20 si-phenyl 1-1-piperazinyl-phenyl | -2,4-by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol. The reaction product is filtered and dried, yielding 4.7 parts (68.4%) of cis- 25 4-4-4-P4-2- (2, A-dis-fluorophenyl) -2- (1H-1,2,4-triazole-1- ylmethyl) -1,3-dioxol a n-4-yl -me toxin-phenyl J-1 -piperazinyl-phenyl -2, 4-dihydro-5-methyl-2- (1-methylpropyl) -ZH -1,2,4-triazole- 30 3-one. .gsh. 157,2 ° C (compound 5).
Similarly, sex is weakened
cis-4-p- (2,4-difluorophenyl) -2- (1H-1,2,4-1riazol-1-ylmethyl- 1, 3-dioxolan-4-yl-methoxy} -phenyl - 35 1 α-piperazinium β-ε-2, 4-dihydro-2- (3-methylbutl) -ZN-1,2,4-triazole-3-one: mp 181.6 ° C (compound 6);
cis-4- 4- 4-C4- 2- (2,4-difluorophenyl) -2- (1H-1,2,4-griazol-1-ylmethyl) - up to 1, 3-dioxolan-4-and i j-ms goxy 3-feiyl - 1-piperazinyl nyl | -2, 4-dihydro-2-propyl-3N-1,2,4-griazol-3-one. T, pl. 178.2 ° C (compound 7);
Cis-4- 4- 4- 4- 2- (2,4-difluorophen-45nyl) -2- (1H-1,2, -trnazol- -ylmethyl) -1.3-dioxolan-4-c- - methyl-phenyl-1-pi-pyri-nyl -the ui 2-ethyl -2,4-di hydro-3H-1,2,4-tria cho i-3-one, T.p. f
dihydro-2- (3-methylbutyl) -ZN-1,2,4-triazol-3-one. M.p. 205.0 ° C (compound 9).
Similarly receive
cis-4-Ј4-Ј4- A Ј 2- (2,4-difluorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-A-yl-methoxy-phenyl - -gosherazinyl2 -phenyl-2,4-dihydro-2- (1-methylpropyl) -ZN-1,2,4-triazole-3-one. M.p. 180.5 ° C (compound 10);
cis-4-Ј4- L-C4-Ј p- (2,4-difluorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -
1,3-dioxolan-4-ylX-methoxy-phenyl-1-piperazinyl-phenyl -2,4-dihydro-2-peNtil-3N-1,2,4-triazol-3-one, T.pl „172, 8 ° C (compound 11).
Example 7. A mixture of 4.1 parts of 2,4-dihydro-4- (4-hydroxyphenyl) -1-piperazinyl-phenyl} -2- (1,2-dimethylpropyl) - 34-1,2,4- triazol-3-one, 5.6 parts of cis-p- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1 -ylmethyl) -, 3-dioxolan-2-yl - methyl -2-naphthalenesulfonate, 1 part of sodium hydroxide and 90 parts of M, M-dimethylformamide are stirred for 5 hours at 70 ° C under nitrogen atmosphere. After cooling the mixture, water is added to it. The precipitated crystalline product is filtered off, washed with water and subjected to purification by column chromatography using silica gel and a mixture of trichloromethane and methanol (p volume ratio of 99: 1) as eluent. Purified fractions are collected and dissolved therefrom. Dissolve n ,. The residue is twice ground with methanotspm. The product is filtered and persCRI-gaplizuyut from methanol. Reza and i i P get
186, (compound 8).
Example 6. A mixture of 8.1 h. 2,4-dihydro-4- pt- - (| -oxyphenyl) -1-pi-rasinilD-phen1p | - - (3-methylbutyl) -ZN- 1, 2, 4-triazop-5-iin.i, 10 parts of monochlorohydrate Megang 1y1ucag (ester) Pus -.- (2, -difgorfenyl) -2 (1H-imidazol-1-ILMRi g) - 1, 3-dioxolane -4- methanol,} h, IHIIMIUMICH sodium and 90 h, N, N-; niMtj i and 1 rmamida are stirred for 8 hours at 70 ° C. under a nitrogen atmosphere. After adding 200 parts of water, the precipitated reaction product is filtered, washed with water and 2-propanol and purified by column chromatography over silica gel, first using a mixture of chloroform and methanol (99.5: 0.5
 volume), and then a mixture of chloroform, shed from 4-methyl-2-pentanone. Product
ethyl acetate, hexane, and methanol (45: 30: 20: 5 by volume) as eluents. Pure fractions are collected and the eluent is evaporated. The residue crystallizes in volume), and then a mixture of chloroform, from 4-methyl-2-pentanone. Product
0 si-phenyl 1-1-piperazinyl-phenyl | -2,4-5 0
five
about
five
0
five
dihydro-2- (3-methylbutyl) -ZN-1,2,4-triazol-3-one. M.p. 205.0 ° C (compound 9).
Similarly receive
cis-4-Ј4-Ј4- A Ј 2- (2,4-difluorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-A-yl-methoxy-phenyl - -gosherazinyl2 -phenyl-2,4-dihydro-2- (1-methylpropyl) -ZN-1,2,4-triazole-3-one. M.p. 180.5 ° C (compound 10);
cis-4-Ј4- L-C4-Ј p- (2,4-difluorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -
1,3-dioxolan-4-ylX-methoxy-phenyl-1-piperazinyl-phenyl -2,4-dihydro-2-peNtil-3N-1,2,4-triazol-3-one, T.pl „172, 8 ° C (compound 11).
Example 7. A mixture of 4.1 parts of 2,4-dihydro-4- (4-hydroxyphenyl) -1-piperazinyl-phenyl} -2- (1,2-dimethylpropyl) - 34-1,2,4- triazol-3-one, 5.6 parts of cis-p- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1 -ylmethyl) -, 3-dioxolan-2-yl - methyl -2-naphthalenesulfonate, 1 part of sodium hydroxide and 90 parts of M, M-dimethylformamide are stirred for 5 hours at 70 ° C under nitrogen atmosphere. After cooling the mixture, water is added to it. The precipitated crystalline product is filtered off, washed with water and subjected to purification by column chromatography using silica gel and a mixture of trichloromethane and methanol (p volume ratio of 99: 1) as eluent. Purified fractions are collected and dissolved therefrom. Dissolve n ,. The residue is twice ground with methanotspm. The product is filtered and persCRI-gaplizuyut from methanol. Reza and i i P get
3.2 parts of cis-4- 4- 4- 4-g 2- (2,4-difluoro-phenyl) -2- (1P-1,2,4-griazol-1-ylmethyl); 1, 3-dioxolane 4-yl-methoxy-phenyl-1-piperazinyl} -Lenyl -2- (1, 2-dimethyl. 1-propyl) -2,4-dihydro) H-1, 2,4-triazol-3-one. T.nri. 161 ° C.
B. Pharmacological examples.
The excellent antimicrobial activity of the compounds of formula (I) is proved by the data obtained in the following experiments.
Example 8
a) Local treatment of vaginal candidiasis in rats.
Wistar female rats of live weight were subjected to removal of the ovary and uterus, and after three weeks of recovery, they were injected subcutaneously once a week for 3 consecutive weeks with 100 μg of undecytic acid estradiol ester in sesame oil. The pseudoestrus induced in this way was monitored by microscopic examination of vaginal smears. I write and leave water available to choose from and as desired. The rats were infected intravaginally with 8 Ju-cells of Candida albicans, a yeast fungus cultured on Sabouraud broth for 48 hours at 37 ° C and diluted with saline. The date of infection varies from 25 to 32 days after surgery and is dependent on the onset of symptoms of pseudoestrus induction. The study drugs were applied locally twice a day for three consecutive days, starting from the third day after infection. For each experiment, placebo-treated control animals, a placebo-dosage form prepared from an indifferent substance, ml of comparison in the study of the pharmacological activity of new drugs were also used. The results were evaluated by taking vaginal smears with sterile tampons for several days after infection. The swabs were immersed in Saburaud's broth, Petri dishes and incubated for 48 hours at 37 ° C. When animals gave a negative response by the end of the experiment, i.e. if there was no growth of Candida albicans, this was due to medication, since the plaque-treated control belly
five
0
five
0
five
0
they always gave a positive answer.
The first column of the table. Figure 1 shows the lowest local concentration of the study drug, which was found to be active up to 7 days after the last local administration (administration or administration) of the drug.
b) Local treatment of microsporia in guinea pigs.
Adult albino guinea pigs were prepared by trimming their backs and infected on the surface of scarified (disrupting the integrity of the skin by producing small incisions) of the skin by applying 5 cm long transverse cuts using Microsporum canis (strain RV 14314). Animals were placed separately in wire mesh cages, and food and water were available at will and to choose from. The study drugs were administered locally (topically) once a day for 14 consecutive days, starting on the third day after infection. Placebo-treated control animals were also prepared for each experiment.
The animals were evaluated 21 days after infection by microscopic examination of the skin and using cultures on Saburaud agar, including a bacterial antibiotic and an appropriate substance, to eliminate the infection by fungi (see Table 1).
The second column of Table 1 contains the lowest local concentration (%) of the investigational drug, at which no damage is observed and at which no growth of cultures occurs.
45
Table
one
50
55
Example 9
Oral treatment of aspergillosis in mice.
Swiss mice weighing from 23 to g. 27 g were infected with Aspergillus fumigatus fungi. Animals were cured by forced fattening, either with a solvent (polyethylene glycol 200) or with a compound of formula (I) in a polyethylene glycol 200 at an oral dose of 2.5; 1.25 and 0.63 mg / kg for 5 consecutive days, starting on the day of infection. The first treatment (treatment) was performed immediately before the infection. Animals were monitored for 28 days and the efficacy of the drug was evaluated based on the average survival time in days. The solution treated animals infected with A.fumigatus fungus and served as controls had an average survival time of 5.33 days.
In tab. 2 shows the average survival time for some compounds of the invention and for cis-4- | -Ј4-Ј4- 02- (2,4-dichlorophenyl) -2-G1H-1,2,4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl3-methoxy-phenyl -1-piperazinyl - Dheni D-2,4-dihydro-2- (1-methylpropyl) 3N-1,2,4-triazole-3-one, known as intraconool.
I
From tab. 2, it follows that the compounds of the invention are superior to the known compound. table 2
in example 86.
The minimum concentrations (%) of the tested compounds according to the invention and known are given respectively in the table. 3 and 4.
i Table 3 g
V f
CH2 D H ° 4
VUHrOO-NO-O-Kl -R N $ Q
2-CH-SSC
I3
CH30.063
b - (CH2) 2-CH-CH3
CH0, 063
Table 4
131635900

权利要求:
Claims (1)
[1]
Continuation of the Table. A Method for the Preparation of cis-4-J4- (4-J4-15 C 2 - (2,4-difluorophenyl) -2- (1H) -a-oolyl. The Invention
Topical treatment of vaginal candidiasis in rats.
Used the same method as in example 8a ..
The minimum concentrations (%) of test-methyl} -1,3-dioxolan-4-yl-methoxy-nitrite compounds according to the invention and known are given respectively in
tab. 5 and 6.
N20
Table 5
25
phenylJ-1-piperazinylJ-phenylZ-triazolones of general formula I
H
N
(HQ-NGN-O-N N-R
Connection
R
Vaginal
where O is nitrogen or SI:
candidosis
rats, mini-R Cd-C alkyl or hydrogen,
The minimum is con fi ned, characterized in that the percentage,% 3 ° NOL ° General Form. II
h -CH-C2H5,
CH3 0.031
9 - (CH-CH-SgTs
SNO ° 063
Table
r-n
Oh and
U Continued table. 6
- (CH2 2-SN SNA
sn,
0.5
The method of obtaining cis-4-J4- (4-J4-15 C 2 -C (2,4-difluorophenyl) -2- (1H) -aeolyl.
methyl} -1,3-dioxolan-4-yl-methoxyphenylJ-1-piperazinylJ-phenylZ-triazolones of the general formula I
25
35
about HO- QK-NQN
where R has the indicated meanings, is Q-alkylated to proiz-. nm dioxolane of general formula
"
CH
F
h

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法律状态:
2007-09-20| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20040325 |

优先权:

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申请号 | 申请日 | 专利标题

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US3020787A| true| 1987-03-25|1987-03-25|

---