前苏联专利SU1232144A3 Method of producing carbostyrene derivatives

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专利摘要:
Carbostyril derivatives having antihistamic action and central nervous controlling action are useful as antihistamic agents or central nervous controlling agents. The derivatives are represented by the general formula, <IMAGE> (1) wherein R1 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms or a phenylalkyl group having an alkylene group containing 1 to 4 carbon atoms; R2 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a phenyl group; R3 is a hydrogen atom, a hydroxy group, an alkyl group having 1 to 4 carbon atoms, an alkanolyoxy group having 1 to 4 carbon atoms or a 3,4,5-trimethoxybenzoyloxy group; R4 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R5 is a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group (which may have 1 to 3 substituted groups selected from the group consisting of halogen atoms, alkyl groups having 1 to 4 carbon atoms and alkoxy groups having 1 to 4 carbon atoms), an alkyl group having 1 to 4 carbon atoms (having one substituted group such as a hydroxy group, a phenyl group or an alkanoyloxy group having 1 to 4 carbon atoms), an alkanoyl group having 1 to 4 carbon atoms or benzoyl group; X is a halogen atom; n is 0, or an integer of 1 or 2; Q is an integer of 2 or 3, l and m are respectively an integer of 0 or 1-6, but the sum of l and m should not exceed 6; the carbon-carbon bond at the 3- and 4-positions in the carbostyril skeleton is a single or double bond; and the substituted position of the side chain of <IMAGE> is any one of the 4-, 5-, 6-, 7- or 8-positions.
公开号:SU1232144A3
申请号:SU813328599
申请日:1981-09-08
公开日:1986-05-15
发明作者:Банно Казуо；Фудзиока Такафуми；Осиро Ясуо；Накагава Казуюки
申请人:Оцука Фармасьютикал Ко.,Лтд (Фирма)；
IPC主号:

专利说明:

where R |., Rj, X and n have the indicated meanings,
subjected to interaction with the compound of General formula (III)
fibto) Q
X- (CH2.) R CH4CH2) m-N (jN - R i,
Jaz
where R, R, R ,, B, m and Q have the indicated meanings,
X is a halogen atom,
and isolating the desired product or, if necessary, the resulting carbostyril derivative of formula (1)
J
The invention relates to a method for the preparation of new carbostyryl derivatives having pharmacological activity, in particular anesthetic activity.
The aim of the invention is a method for producing new carbostyril derivatives having enhanced analgesic activity.
The invention is illustrated by the following examples.
Example 1. 2 g of 5- 2-hydroxy-3- (4-phenyl-pilerazinyl) pro-j-3,4-dihydrocarbostyril are mixed with 30 MP of acetone and then 12 ml of acetyl chloride are added, after which the mixture is heated for 10 hours at reflux temperature. After cooling the reaidion mixture, the precipitated product is collected by filtration and washed with acetone. The resulting crude crystals were dissolved in 80 ml of water and the mixture was basified with ammonia water, then extracted with chloroform, dried and distilled off chloroform. The residue is purified by chromatography on silica gel to give 0.5 g of 5-2-acetyl-hydroxy-3-C4-fensch1 piperazinyl) njpopoxy 3 - 3,4-dihydrocarbostyril as colorless crystals with a melting point of 159-161 ° C .
Example 2. Analogously to example 1, 7- 2-acetoxy-3- (4-phenyl-piperazinyl) propoxy-3,4-dihydro is obtained.
where Ry is a hydroxy group, is reacted with a compound of general formula (IV)
R, - X or (RpjO
where Ry is a C-C alkanoyl group or a 3,4,5-trimethoxybenzoyl group
X is a halogen atom, to form an ester of the carbostyryl derivative of formula (1), provided that when R is a phenyl group, R 4 should not mean C (-C-alkyl group substituted by a phenyl group.
rocarbostiril in the form of colorless crystals with a melting point of 130-132 ° C. Example .3. 1.9 g of 3- 2-hydroxy-3- (4-phenyl-piperazinyl) propoxy-3,4 dihydrocarbostyril and 0.24 g of sodium hydride are dispersed in 40 mp of xylene and heated at a temperature of defpeg (for 1 h. Then the bath temperature is lowered up to 130 ° C and 1.40 g of 3,4,5-trimethoxybenzoyl chloride are gradually added and the mixture is heated at reflux for 8Co Xylene is distilled off from the reaction mixture, then the residue is drunk
ml of water and extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was distilled off. The residue was recrystallized from ethanol CZ, to obtain 1.5 g (3.4,
5-trimethoxybenzoyloxy) -3- (4-fensh1-piperazinyl) propoxy-3,4-dihydroburostyryl in the form of colorless crystals with a melting point of 125-127 C. Example 4. 2.5 g of 1-benzyl-5oxy-3, 4-dihydrocarbostyryl. And 0.48 g of 500% NaOH oily solution are mixed with 30 ml of dimethylformamide and stirred, then 4 g of 1-chloro-3- (4-phenylpiperazinyl) propane is added thereto and the mixture is heated at 50-60 ° C for 2.5 hours. The reaction mixture is concentrated under reduced pressure and the resulting residue is extracted with chloroform. After chloroform dichloride, the resulting residue is recrystallized from ligroin to give 2.1 g of 1-benzyl-5- 3- (4-phenylpiperazinyl) -propoxy-3,4-dihydrocarbestryl in the form of pale yellowish needle crystals with a melt point. - laziness 113 C.
The following compounds are prepared analogously:
6-chloro-7- 3- 4- (2,3-dimethylphenyl) -1-piperazinyl propoic -3,4-dihydrobrostyryl, 1/2 hydrate; m.p. 155-156 C; colorless needle-like crystals (from methanol-ethanol),
1-nor-hexyl-6-chloro-7- (2, 3-dimethylphenyl) -1-piperazinylJ propoxy C |-3, A-dihydrocarbostyryl monoxal; Trplo 78 ° C; colorless needle-like crystals (of isopropanol) 1-allyl-6-chloro-7- 3- 4- (2,3-dimethylphenyl) -1-piperazinyl propo 3,4-dihydrocarbostyryl monooxalate; m.p. 171-172 ° C, colorless needle-like crystals (from isopropanol);
. 1- (3-phenylpropyl) -6-chloro-7- 3- 4- (2,3-dimethylphenyl) -1-piperazinyl propoxy-3,4-dihydrocarbostyryl monooxalate / t.shts. 218-219 0, colorless needle-like crystals ( from methanol-water)
8-bromo-5- {6- 4- (2,5-dichlorophenyl) -1-piperaenoyl-hexyloxy carboxy; m.p. 125-126 ° C, colorless needle-like crystals (from ethanol);
(2-chloro-6-methylphenyl) -1-piperazinyl prog.oxy-3,4-dihydrocar bostyril / m.p. 206-209 С; colorless plate-like crystals of a flat form (from ethanol),
7- (2-chloro-6-methylphenyl) -1-piperazinyl propoxy} -3,4-dihydrobrostyryl; m.p. 162-164 ° C; colorless prismatic crystals (from ethanol);
5- (2 „3-dimethylphenyl) -1-piperazinyl propoxy 1 3,4-dihydrocarbostyryl, m.p. 197-198 s, colorless plate-like crystals (of ethyl acetate);
7-z- 4- (2,3-dimethylphenyl) -1-pipa razinst propoxy j-3,4-dihydrocarbostyryl; m.p. 153-154 C, colorless needle-shaped crystals (of ethanol),
7- {3- 4- (3,5-dichlorophenyl) -1-piperazinyl} propoxy-3,4-dihydrocarbostyryl} so pl. 225-22b C, light-yellow, needle-shaped crystals;
five
ABOUT
5 20
25 30
,,
40
five
5o
55
2321444
7- (2,3-dimethylphenyl) -1-piperazinyl propoxy-carbostyryl monohydr Lorida monohydrate; m.p. 262-263 ° C, colorless needle-shaped crystals (from methanol);
5- (2,5-dichlorophenyl) -1-piperazinylpropoxy-3,4-dihydrocarboxyryl; m.p. 170-172 ° C, colorless prismatic crystals (from ethanol-chloroform mixture);
(2,5-dichlorophenyl) -1-piperizinyl propoxy} -3,4-dihydrocarboxyryl; m.p. 153-155 ° C, colorless flocculent crystals (from ethanol / chloroform mixture);
(2,3-dichlorophenyl) -1-piperra 3 and copolyol nyl; and 3,4-dihydrocarboxyryl; m.p. 206-207 C, colorless prismatic crystals (from ethanol-chloroform mixture);
7-Gz- 4- (2,3-dichlorophenyl) -1-piperazinyl propoxy-3,4-dihydrocarbostyryl, m.p. 170-172 s, colorless prismatic crystals (and mixtures of ethanol - chloroform);
5-fz-4- (3,4-dichlorophenyl) -1-piIse-rasinyl Jproproxy J-3, 4-dihydrocarbostyryl; m.p. 188-190 C, colorless needle-shaped crystals (from ethanol-chloroform mixture),
7- (3,4-dichlorophenyl) -1-piperidopropyl propoxy-3,4-dihydrocarbostyryl} so pl. 180-182 C, colorless crystals. Prismatic form (from a mixture of ethanol - chloroform),
5- {h-4- (3,5-dichlorophenyl) -1-piperazinyl propoxy-3,4-dihydrocarbostyryl; mp 224-225 C, colorless prismatic crystals (from a mixture of ethg.nol — chloroform);
(3,4-dimethylphenyl) -1-piperazinyl propoxy-3.4-dihydrocarboxyryl; m.p. 200-201 С, colorless needle-shaped crystals (from methanol) -,
7- 3- 4- (3,4-dimethylphenyl) -1-piperazinyl propoxy-3,4-dihydrocarbostyryl, m.p. 170-171 ° C, prismatic yellowish crystals (of ethanol),
5-Gz- 4- (3-chloro-4-methylphenyl) -1-piperazinyl propoxy-3,4-dihydrobrostyryl, m.p. 192-193 C; needle-shaped crystals, slightly yellowish color (from a mixture. and methanol - chloroform);
(chloro-4-metilfenshI) -1-piperazinyl-propoxy} -3,4-dihydrocarobenzir; m.p. 158-157 ° C, slightly yellowish needle-like crystals (of ethanol);
(2-methyl-3-chlorophenyl) -1-piperazinyl propoxy-3, A-dihydrobyrostyryl, T.GO1, 202-203 C, colorless lamellar crystals (from ethanol-chloroform mixture);
(2-methyl-5-chlorophenyl) -1-piperazinyl propoxy-3, 4-dihydroburostyryl; m.p. 172-176 ° C, colorless prismatic crystals (from ethanol: chloroform mixture) j 7- (2-methyl-3-chlorophenyl) -1 piperazinyl propoxy-3,4-dihydrocarstyryl; m.p. 162-163 C, colorless prismatic crystals (from a mixture of ethanol - chloroform),
(2-methyl-5-chlorophenyl) -1-piperazinyl-l propopoxy) -3,4-dihydroburostyryl; m.p. 138-139 ° C, colorless prismatic crystals (from ethanol);
(3,5-dimethylphenyl) -1-piperazinyl propoxy-3,4-dihydrocarbostyryl; T..SH1. 208-209 s; colorless needle crystals (from ethanol),
(2,5-dimethylphenyl) 1-piperazinyl propoxy-3,4-dihydrocarbostyryl; m.p. 166-167 ° C; colorless prismatic crystals (from ethanol),
(3,5-dimethylphenyl) -1-piperazpooropoxy-3,4-dihydrocarbo styryl; m.p. 167-168 s, - colorless crystals of a prismatic form (from methanol) -,
7- {3- 4- (2,5-dimethylphenyl) -1-piperazinyl 1popoxy-3,4-dihydrocarbostyryl, m.p. 148-150 C, colorless prismatic crystals (from ethanol),
7- (3-chlorophenyl) -1-Ishpazinil | propoxy-hydroxychloride, t “sh1. 236-237 C, colorless needle-shaped crystals (from a mixture of ethanol - water);
.5-z-4- (3-chlorophenyl) -1-piperazi-propoxy-3,4-dihydrocarbosteryl; m.p. 265-268 ° С, colorless needle-shaped crystals (from ethanol – water mixture);
(2-ethoxyphenyl) -1-piperazinyl prop-xy -carbostyryl dihydrochloride monohydrate; m.p. 128-131 ° C colorless amorphous crystals (from ethanol – water mixture);
5- {3- 4- (4-fluorophenyl) -1-piperazinyl-propoxy-3,4-dihydrocarbostyryl; m.p. 187-188 s, colorless needle-shaped crystals (from ethanol),
(4-fluorophenyl) -1-piperazinyl proproxy-J-3,4-dihydrocarboxytil; m.p. 168-169 s, colorless needle-like crystals (from ethanol);
4- (2,5-dimethylphenyl) -1-pi-perazinyl propoxy-3,4-dihydrocarbostyryl; m.p. 148-150 C, colorless prismatic crystals (from ethanol);
(3-chlorophenyl) -1-piperazinyl propoxy carbostyryl hydrochloride; m.p. 236-237 s, colorless needle-shaped crystals (from mixtures, si ethanol - water);
(3-Chlorophenyl) -1-piperazinyl-propoxy-3,4-dihydrocarbostyril, m.p. 265-268 C, colorless needle-shaped crystals (from a mixture of ethanol - water) -,
7- (2-ethoxyphenyl) -1-gshperazinyl propoxy-carbostyryl dihydrochloride monohydrate; m.p. 128-131 ° С colorless amorphous crystals (from ethanol – water mixture),
5- {3- 4- (2-methylphenyl) -1-piperazinyl propoxy-3,4-dihydrocarbostyryl, m.p. 177-179 ° C, colorless flocculent crystals (from ethanol);
5- (3-methylphenyl) -1-piperai and nyl propoxy-3,4-dihydrocarbostyryl; t.sh. 171-172 s, colorless needle-shaped crystals (from ethanol);
(4-methylphenyl) -1-piperazinyl propoxy - 3,4-dihydrocarbostyryl; m.p. 195-196 ° C, colorless flocculent crystals (ethanol);
7- (2-methylphenyl) -1-piperazinyl propoxy-3,4-dihydrocarboxyryl, m.p. 151-153 0, colorless prismatic crystals (from ethanol);
(3-methylphenyl) -1-piperazinyl propoxy-3,4-dihydrocarboxyryl, m.p. 169-171 C, colorless prismatic crystals (from ethanol);
5- (2-chlorophenyl) -1-piperaenoyl propoxy-3,4-dihydrocarboxyryl; m.p. 1b -169 ° C; colorless
7
flocculent crystals (from ethanol),
(3-bromophenyl) -1-piperazyl nyl propoxy-3,4-dihydrocarboxyryl; m.p. 190-192 with, colorless
plate-shaped crystals (s sms chloroform-ethanol);
(3-bromophenyl) -1-piperazn nilZpropoxy-3, A-dihydrocarboxyryl; m.p. 159-160 C, colorless
needle-shaped crystals (from ethanol):
5- {3- 4- (4-nor-butylphenyl) -1-piperazinyl} propoxy-3,4-dihydrobrostyryl; m.p. 184-185 ° C; colorless crystals
(4-nor-butylphenyl) -1-pi-perazinyl propoxy-3, 4-dihydrocarbostyryl / t.p. 134-135 ° C, colorless crystals of a lamellar form (from isopropanol);
6,8-dichloro-5- {2-methyl-3- 4- (3-fluorophenyl) -1-piperazinyl} propoxy-3,4-dihydrocarbostyryl mp; 133-135 ° C, colorless prismatic crystals (from ethanol);
1-benzyl-6-chloro-5- 3- (4-benzyl-1-homopiperazinyl) -propoxy-3,4-di hydrocarbostyril, oily substance, PD 1.5738,
6-chloro-5- 3- (4-benzyl-1-homopiperazinyl) -propoxy-3,4-dihydrocar bostyril m.p. 121-124 C, colorless prismatic crystals (from ethanol-water mixture),
7- 5- (4-pheny 1 -1 -piperazinyl) pentyloxy) -3,4-dihydrocarbostyryl, m.p. 156-158 ° C, yellow needle-shaped crystals (from ethanol),
1-ethyl-7- 3- 4- (4-bromophenyl) -1-piperazinyl propoxy | -3,4-dihydroburostyryl monohydbromide; t. pcs. 144, colorless needle crystals,
(4-bromophenyl) -. 1-piperazinyl-propoxy-3,4-dihydrocarboxyryl; m.p. 22C-222 C, colorless needle-shaped crystals;
8-chloro-5- 3- 4- (3-chlorophenyl) -1-piperazinyl propoxy-3,4-digtodrobrostiryl; m.p. 133-134 ° C, colorless flocculent crystals (from ethanol);
1-methyl-7- (3-chlorophenyl) -1-piperazinyl-J propoxy} -3,4-dihydrobrostyryl; m.p. 78-79 s, colorless needle-shaped crystals (from isopropanol – water mixture);
1448
8-chloro-5- 3- (4-phenyl-1-piperazinyl) propoxy-3,4-dihydrocarbosyl, so pl. 133-134 ° C, colorless prismatic crystals (from ethanol);
6-bromo-5- 3- (4-phenyl-1-piperazinyl) propoxy-3,4-dihydrocarbostyryl; m.p. 160-161 s, colorless needle-shaped crystals (from isopropanol);
4-phenyl-6-Z- (9-phenyl-1-piperazinyl) propoxy-3,4-dihydrocarbosyryl; t.pcs 163-165 ° C, colorless needle-shaped crystals (from ethanol);
6- (2-methoxyphenyl) -Piperzinyl propoxy-3,4-dihydrocarbyl reel; m.p. 147-149 ° C, colorless needles crystals {forms (from isopropanol – water mixture);
(4-methylphenyl) -1-pip (erasinyl propoxy-3,4-dihydrocarboxyryl; mp 193-194 ° C; light yellow crystals with a mathematical form (from methanol);
1-ethyl-6-EZ- (4-fe NIL-1-piperaz1-nyl) propoxy-3,4-dihydrocarboxyryl, t. TTL. 100 ° C; colorless prismatic crystals (ligroin
1-benzyl-6- 3- (4-phenyl-1-piperazinyl) propoxy-3,4-dihydrocarbostyryl, t.s. 95 s, colorless crystals of the needle Form (from a mixture of naphtha - ether);
1-benzyl-5-W- (4-benzyl-1-piperazinyl) propoxy-3,4-dihydrocarboxyryl, m.p. 108-1 10 ° С, colorless needle-shaped crystals (from isopropanol),
4-methyl-6- 3- (4-fe NIL-1-piperazinyl) propoxy-carbostyryl; t / 4-hydrate, so pl. 201-202 ° C, colorless flocculent crystals (from methanol);
6- 4- (4-phenyl-1-piperazinyl) butox, 4-dihydrocarboxyryl, tgr 142-144 ° C; colorless crystals of acicular forms (from ethanol),
8-3-G4- (4-fluorophenyl-1-piperazinyl) propoxy-3,4-dihydrocarbostyril, pcs. 157-159 С; colorless prismatic crystals (from ethanol)
5- (2-toxiphenyl) -1-piperazin1tZpentiloxy-3,4-dihydrocarbo-anil, so pl. 134-15 ° C, colorless needle-shaped crystals (from ethanol);
912
4-phenyl-7- 3- (4-phenyl-1-piperazinyl) propoxy-3, A-dihydrocarbostyryl, m.p. 138-140 Ci-colorless needle-shaped crystals (from ether-hexane mixture)}
4-phenyl-7-Gz-4- (2-methoxyphenyl) -1-piperazinyl 2 propoxy-carbostyryl; t.ll. 161-162 Ci colorless needle-shaped crystals (from isopropanol-water mixture) /
Examples 5-35 are shown in table.1.
Example 36 1.8 g of 1-methyl-5-hydroxy-3,4-dihydrocarbostyril and 1 g of NaOH (50% in oil) are mixed with 30 ml of dimethylformamide. Then 2.6 g of 1-chloro-2-hydroxy-3- (4-phenyl-piperazinip) propane are added thereto at room temperature and the mixture is stirred at 70-80 ° C for 3 hours. The reaction mixture is poured into water and the organic layer extracted with chloroform. After distilling off the chloroform, the resulting residue is dissolved in acetone and the pH of the solution is measured by adding an acetone solution of oxalic acid. The precipitated crystals are collected by liter and recrystallized from methanol-acetone to obtain 2.8 g of 1-methyl-5-2-hydroxy-3- (4-phenyl-piperazinyl) propoxy-3,4-dihydrocarboxyrylate) in the form colorless crystals with a melting point of 220-221 ° C (decomposition).
The following compounds were obtained:
7- 2-hydroxy-3- 4- (3-chlorophenyl) -1-piperazinyl propoxy-3,4-dihydrocarbostyryl, m.p. 172-174 C, colorless prismatic crystals (from a mixture of chloroform - ethanol),
1-benzyl-5-2-hydroxy-3- (4-phenyl-1-piperazinyl) propoxy 3 -3,4-dihydrocarbostil; m.p. . 152-153 ° C, colorless needle-shaped crystals (from a mixture of ligroin - benzene),
1-ethyl-5- 2-hydroxy-3- (4-phenyl-1-piperazinyl) propoxy-3,4-dihydrocar410
bostyril, t.pp. llVc; colorless needle-shaped crystals (from ligroin-benzene mixture) i
6- 2-hydroxy-3- (A-phenyl-1-piperazinyl) pro-coxy tkarbostyril; T.rai.221- 224 С, colorless prismatic crystals (from a mixture of zanol and chloroform);
Examples s 37-46. Analogously to Example 36, the following compounds were obtained (see Table 2).
Study of analgesic activity.
We used male strain: ddy with a live weight of about 20 g. The study group consisted of 10 mice. An aqueous gum arabic suspension of the test compound (80 mg of the test compound and 1 g of gum arabic) per 100 ml of physiological KaCl solution is administered orally to each g & t at a dose of 8 mg of the test compound per kilogram of live weight. One hour after the injection, the mouse was placed in a gas chamber (TK O 124 cm). Gaseous oxygen containing 4% halogen 2-bromo-2-chloro-1,1,1-trifluorozane is passed through the chamber at a rate of 2 liters / min for 3 minutes. The sleepy animal is taken out of the chamber and the time between the occurrence of anesthesia and the awakening of the installation refpee is measured as a sign. In mice of the control group, 1% aqueous physiological solution of gum arabic was orally administered at a dose of 0.1 ml / 10 g of live weight.
The compounds investigated.
The proposed compounds 1-39 are given in Table 3.
Tests for an increase in activity in the anaesthesia (see Table 4).
The test results are shown in Table. 5 and 6.
5- 3- (4-Phenylpiperazinyl) prbpoxy-3,4-dihydrocarboxystyryl; monohydrochloride
(D-Phenylpiperazinyl) ethoxy3-3, A-dihydrocarboxyryl; monohydrochloride monohydrate
(4-Phenylpiperazinyl) progloxy-3,4-dihydrocarbamoyl, dihydrochloride; 3/4 hydrate
(4-Phenylpiperazinyl) propoxy-3,4-dihydrocarboxyryl
(4-Phenyliperazinyl) propoxy-carbostyryl
7- 3-C4- (4-Methylphenyl) piperazinyl propoxy-3,4 dihydrocarbostyryl
6-Bromo-7- 3- (4-phenyl-piperidinyl) propoxy-3,4-di-hydrocarboustyryl; dihydrochloride
(3-Chlorophenyl) 1-spazinyl 3-propoxy j-3,4-dihydrocarbostyryl
(2-Methoxyphenyl) piperazinyl propoxy-3,4-di-hydrocarbostyryl
14 (4-Phenylpiperazinyl) butoxy-3,4-dihydrocarboxyryl
Table 1
Colorless needles (isopropanol)
12313
:: g:
15 1-Methyl-7- 3- (4-phenylpip6-Colorless
Razinyl) propoxy-3,4-di-crystals
hydrocarbyl styryl; dihydro- (ethanol)
chloride
16 1-Benzyl-7- 3- (4-phenyl-pi-perazinyl) propoxy-3,4-di-hydrocarbostyryl
1-Allyl-7-EZ- (4-0enylpiperaz and NILE) pro coxyj-3,4-dihydrocarbostyryl; dihydrochloride
1-propargyl-7-Cs- (4-phenyl-piperisinyl) propoxy} -3,4-dihydrocarbostyryl; dihydrochloride
4-Methyl-7- {3- (4-phenyl-P1-terazinyl) propoxy} -3,4-di-hydrocarboustryl; dihydro-yjiopujit di hydrate
7-C-C4- (3,4,5-Trimethoxyphenyl) piperazinyl-J propoxy 3,4-dihydrocarbosty 1 1;
. dihydrochloride
(3,4-Dimethoxyphenyl) piperazinyl} propoxy - 3,4-dihydrocarbostyryl
22 7- 2-Metsh-3- (4-phenyl-pi-rasinyl) propoxy-J-3,4-di-hydrocarbylstyryl
8-Bromo-6-chloro-7- 3- (4-phenylpiperazinyl) propoxy - 3,4-dihydrocarbosteryl, digidrat,
(4-Phenyl-homopiperazinyl) -propoxy} -3,4-dihydrocarbostyryl
123214414
Continued table. one
one
204-207

t25-127
189-192
- 215-216 l)
260-265
225-227 - (decomposition)
146-147
e
229-232
122-125
6,8-Dichloro-5-2-hydroxy-3-Colorless
(4-phenylpiperazinyl) propok-crystals
, 4-dihydrocarbostyril, (water) MO noHydrochloride
b-Chloro-7- 2-hydroxy-3-4- (2-methoxyphenyl) piperazinylyl propoxy-3,4-dihydrocarbostyryl
1-Benzyl-5- 2-hydroxy-3- (4-phenylpiperazinyl) propoxy - 3,4-dihydrocarbostyryl
5- 2-Oxy-3- (4-phenylpiperazinyl) propoxy-3,4-dihydrocarbostyryl; monohydrochloride
6- 2-Oxy-3- (4-phenylpiper-Colorless zinyl) propoxy-3,4-dihydrogen-needle carbostyryl, monohydrochlo-crystals read; hemihydrate (water)
7- 2-Oxy-3-4- (4-chlorophenyl) piperazinylJ propoxy} - 3,4-dihydrcarboxyryl; monohydrochloride, monohydrate
8- 2-Oxy-3- (4-phenylpiperazinyl) propoxy-3,4-dihydrocarbostyryl, monohydrochloride
1-Allyl-5- 2-hydroxy-3- 4- (4-methylphenyl) piperazinyl proxy-3,4-dihydrocarbosteryl
6- 2-Oxy-3- (4-phenylpipera zinyl) propoxy carbostyryl, hemihydrate
4-Methyl-7-f2-hydroxy-3- (4-fe - Colorless nilpiperazinyl) propoxy) cartiry bostyril; monohydrochloride (ethanol ether)
1232144
T a
18 persons 2
251-253
Colorless crystals
183-184
-

148-150
239-241
223-224

66-70
263
123-124
218-219
190-191
191232144
Table 3
5- 2-Oxy-3- (4-phenylpiperidinyl) propoxy-3,4-dihydro-ap-botiri; 7-2-hydroxy-3- (4-phenylpiperazinyl) propoxy-3,4-dihydrocarbostyril monohydrochloride; monohydrochloride
8-Chloro-5-2-hydroxy-3- 4- (4-chlorophenyl) -piperaoinyl propoxy-3 4-dihydrocarbostyryl; mono-hydrochloride
6,8-Dichloro-5-2-hydroxy-3- (4-phenyl-piperaenoyl) propoxy-3, 4-dihydrocarbostyril, monohydrochloride
5- 3- (4-Phenylpiperazinyl) propoxy-3,4-dihydrocarbosyryl; (4-Phenylpiperazinyl) proxy-3,4-dihydrocarbostyril dihydrochloride; 1-Methyl-5-2-hydroxy-3- (4-phenyl-piperazinyl) propoxy dihydrochloride. -3,4-dihydrocarbostyril, monohydrochloride
1-Benzyl-5-2-hydroxy-Z- (4-phenyl piperazinyl) propoxy) -3,4-dihydrocarbostyril monohydrochloride
1-Methyl-5-З- (4-phenylpipprazinyl) propoxyZ-3,4-dihydrocar-, bostyryl, monohydrochloride
(4-Methylphenyl) piperazinyl butoxy-3,4-dihydrocarbostyryljg
1-Allyl-5-G2-hydroxy-3- (4-methylphenip) piperazinyl propoxy - 3,4-dihydrocarbostyryl
12
1-Benzyl-7-GZ- (4-phenylpiperidin) propoxy-3,4-dihydrobrostyryl
20 Continued table. 3
25
ten
15
20
thirty
five
0
,
g
five
157- 3- 4- (4-Methylphenyl) piperazynyl propoxy-3,4-dihydrobrostyryl
167- 3- 4- (4-Chlorophenyl) piperazinyl propoxy-3,4-dihydrocarbostyryl
177-d-t4- (2-methoxyphenyl) piperazinyl propoxy-3,4-dihydrocarbostyryl
187- | 3- 3-Ketil-4- (4-chlorophenyl) piperazinyl pro po, 4-dihydrocarbostyril dihydrochloride
198- 3- (4-Phenylpiperazinyl) propoxy-3,4-dihydrocarbostyryl
205-2-Acetyloxy-3- (4-phenylpiperazinyl) propoxy-3,4-dihydro carbostyryl
215- 2- (3,4,5-TropimethoxibenzshI-oxy) -3- (4-phenylpiperidinyl) propoxy-3,4-dihydrocarbostyryl
227- 3- 4- (2-Cetg.xyphenyl) piperazinyl propoxy -carbostyril
dihydrochloride
231- (2-Propyl) -7-Gx- (4-phenyl-piperazinyl) schyupoxy-3,4-dihydro-icarbostyril; Dig; Drochloride
247- 3- 4- (3-Fluorophenyl) piperazinyl-Propoxy-3,4-dihydrocarbostyryl
257-2-Methyl-3- (4-phenylpiperazinyl) propoxy-3,4-dihydrocarbostyryl
264- 3- (4-phenipiperazinyl) propoxy -carbostyryl
211232144
Continuation of table.3
2
27/4-Phenyl-7- 3- (4-phenyl-piperaz-5-dinine) propoxy-carbostyryl
6-Chloro-8-bromo-7- 3- (4-phenylg-perazinyl) propoxy-3,4-dihydro-JQ rocarbostyril, dihydrochloride
(3,4,5-Trimethoxyphenyl) piperazinyl propoxy-3,4-dihydrocarbostyril, dihydrochloxy
Reed
5-1z- (4-Cyclohexylpyrazine) propoxy-3,4-dihydrocarbostyryl
5-h- (4-Phenyl-homopiperazinyl) propoxy-3,4-dihydrocarboxyryl
7- (h- 4- (2-Acetyloxyethyl) piperazinyl propoxy) -3,4-dihydrobrostyryl
(2-Hydroxyethyl) piperazinyl-3-propoxy-3,4-dihydrocarbacyl;
7- 3- (4-Acetylpiperazinyl) proxy-3,4-dihydrocarbostyryl
7- 3- (4-Benzoylpiperazinyl) propoxy} -3,4-dihydrocarbostyR 40
6- 3- (4-Phenylpiperazinyl) propoxy carbostyryl
(4-Fensch1piperazinyl) - 45 coxy carbosti5 "l
47
1-Hexyl-7-z- (4-phenylpiperazinyl) propoxy-3,4-dihydro-50 carbostyryl dihydrochlo 1 1D
7- | 3- 4- (3-Chporpenyl) piperazinyl propoxy} -3,4-dihydrocarbo styryl55
22
Table 4
6- 2-Hydroxy-3- (4-phenyl-pi-rasinyl) propoxy-3,4-dihydrobrostyryl; monohydrochloride; 1/2 hydrate
7 - ((3-Bromophenyl) piperazinyl propoxy-3,4-dihydrocarbostyryl
20 42 6,8-Dichloro-5- 2-hydroxy-3- 4- (4-chlorophenyl) piperazinyl D-Propoxy 3-3,4-dihydrocarbostyryl, mono hydrochloride; 1/2 hydrate
437-C2- (4-Phenylpiperazinyl) ethoc-, 4-dihydrocarbostyryl
448-Bromo-5-3- 4- (4-methylphenyl) piperazinyl pro poxy-3, 4-dihydrocarbostyryl
455-p- 4- (2-Methoxyphenyl) piperazinyl pentoxy-3,4-dihydrocarbostyryl
468-Z- A- (2-Methoxyphenyl) piperazinyl propoxy carbostyryl dihydrochloride
478-Bromo-5- {3- (4-phenylpiperazinyl) propoxy-carbostyryl diprochloride; monohydrate
5 (3-C4- (2-Ethoxyfensh1) piperazinyl propoxy-3,4-dihydrocarbostyryl
497- 3- (2-Ethoxyphenyl) piperazinyl propoxy-3,4-dihydrocarbostyryl
506-Chloro-7- 3- (4-phenylpiperazinyl) propoxy} -3,4-dihydrocarbstyryl; dihydrochloride; monohydrate
23
I
Continuation of table 4
, c I TT .- I t g-TZH | I TGTG G-TC-t
2
6-Bromo-7-GZ- (4-phenylpiperazinyl) propoxy} -3,4-dihydrocarbostyryl; dihydrochloride
(2-Chorophenyl) piperaz-10nyl propoxy-3,4-dihydrocarboxystyryl
(4-Methoxyphenyl) piperazinyl propoxy-3,4-dihydro-15 carbostyryl
7- 4- (4-Phenyl tshperazinil) buto-, 4-dihydrocarbostyryl
ten
25
68
69
1-Ketil-7- 3- (4-phenylpiperazinyl) propoxy 3-3,4-dihydrocarbostyryl dihydrochloride
4-Methyl-7- 3- (4-phenylpiperazinyl) propoxy-3,4 dihydrocarbostyryl; dihydrochloride; dihydrate
5- 3- 4- (2-Fluorophenyl) piperazinyl-propoxy-3,4-dihydrocarbostyryl
58
7- (2-Fluorophenyl) piperazine-Zpropoxy) -3,4-dihydrocarbostyryl
59
5- (3-Fluorophenyl) piperazinyl-propoxy-3,4-dihydrocarbostyryl
, 4-dimethoxyphenyl (perazinyl) propoxy-3,4-dihydrocarbostyryl45
7- 3-G4-3,4-Dimethoxyphenyl (piperazinyl) pro cox-3,4-dihydrocarbostyryl
50
5- 2-Methyl-3- (4-phenylpiperazinyl) nponoKcaJ-3,4-dihydrocarbostyryl
5- 2-hydroxy-3- (4-phenyl-pipera-) propoxy J-3,4-dihydrocarbostyryl; my hydrochloride
24
Continue lying tabl 4 2
6- 2-Hydroxy-3- (4-phenylpiperazinyl) propoxy-3,4-dihydrocarbostyryl, monohydrochloride
1/2 hydrate
8-ChLOR-5 2-hydroxy-3 4- (4-chlorophenyl) -piperazinyl propo-, 4-dihydrocarbosyryl; monohydrochloride
6,8-Dichloro-5- 2-hydroxy-3- (4-phenylpipprazinyl) propoxy - 3,4-dihydrocarbostyryl, mono-hydrochloride
67 8-Bromo-5-G2-hydroxy-3 (4-fe-10nylpiperazinyl) propoxy-3,4. Dihydrocarbostyryl
68
69
6- 2-Hydroxy-3- (4-phenylpiperazinyl) -propoxy-3, 4-dihydrocarbostyryl; 1/2 hydrate of 8-Bromo-5- 2-hydroxy-3- (4-phenylpiperazinyl) propoxy-carboxyryl
1-Ethyl-7- (3-phenylpiperazinyl) - propoxy-3,4-dihydrocarbostyryl J dihydrochloride
715- {h-4- (4-fluorophenyl) piperidinol propoxy-3, 4-dihydrocarbostyryl
727- 3- (4-Fluorofensch1) piperazinyl / propoxy-3,4-diI adrocap-batir
737- 3- (3-Methylfeiyl) pipera-zinil propoxyZ-3,4-dihydrost. reel
745- 3- (2-Chloropent) Piperisynyl-J Proxy j3,4-dihydrodroster
755-3- 4- (3-Bromophenip) piperidazinyl propoxy-3,4-dihydrocarbostyryl
765- (2-Hydroxy-3-tert-butylam- (isopropoxy) -3,4-dihydrocarboxystyrene oxalate
some)

权利要求:
Claims (6)
[1]
METHOD FOR PRODUCING CARBOS 1IRIPANIC DERIVATIVES of general formula (I)
C ₍ -C ₄ alkoxy groups, C ^ -C ^ -alkyl group having one substituted group selected from the group consisting of a phenyl group and C ₍ -C ₄ -alkanoyloxy groups, C _f -C ₄ -alkanoyl group or benzoyl group ,
R ₅ is a hydrogen atom, an oxy group or a C _d -C ₄ -alkyl group, a C _f -C ₄ alkanoyloxy group or a 3,4,5-trim ^ toxibenzoyl group;
X is halogen;
η is 0 or an integer 1 or
[2]
2;
Q is an integer of 2 or
[3]
3;
A sieve is respectively 0 or an integer from 1 to 6, but the sum of I and m should not exceed 6;
carbon-carbon bond between 3 and
[4]
4 positions in the carbostyril skeleton - single or double bond; ' the substituted position of the side chain of the general formula where R ₍ is a hydrogen atom, a C, —C _{g is an} alkyl group, a C ₂ ~ C ₄ alkenyl group, a C ₂ -C ₄ alkynyl group or a C (—C ₄ phenylalkyl group,
Rj, is a hydrogen atom, C, -C ₄ -alkyl group or phenyl group,
R4 is a hydrogen atom or a C, -C ₄ alkyl group,
R ₄ is a Cj-Cp cycloalkyl group, a phenyl group which may have 1-3 substituents selected from a halogen, C, —C ₄ alkyl group or
V ^s Hsn ₂ Sh
G have the following values, Rj, R ₄ , R, I, m and Q, is one of 4,
[5]
5, Provisions of the Formula (II) Compound General
[6]
6, 7 or 8 so that
SU ·. " 1232144 AZ where R |., Rj, X and n have the indicated meanings, are reacted with a compound of the general formula (III) x- (cn _g ) _g
R ₃ where Rj, R ₄ , R ,, β, m and Q have the indicated meanings,
X * -halogen atom, and the target product is isolated or, if necessary, the obtained carbostyril derivative of the formula (1), where R - oxy group, is subjected to interaction with the compound of General formula (IV)
R - X ”or (Rj) ₂ 0 where Ry is a C ₅ -C ₄ alkanoyl group or a 3,4,5-trimethoxybenzoyl group j
X ^m is a halogen atom, with the formation of an ester of a carbo · styryl derivative of the formula (1) provided that when R ^ is a phenyl group, R ₄ should not mean a C | -C ₄ -alkyl group substituted with a phenyl group.
¹

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同族专利:

公开号 | 公开日

ES486990A1|1980-10-01|

SU1140687A3|1985-02-15|

ZA791516B|1980-04-30|

NL7902514A|1979-10-02|

SE7902794L|1979-10-01|

DK158225C|1990-09-17|

AU4548079A|1979-10-04|

FI70704C|1986-10-06|

AU515531B2|1981-04-09|

SE434945B|1984-08-27|

FR2421174A1|1979-10-26|

CH641350A5|1984-02-29|

NO151321B|1984-12-10|

IT7967674D0|1979-03-30|

BE875174A|1979-10-01|

ATA235179A|1984-04-15|

US4734416A|1988-03-29|

CA1117110A|1982-01-26|

JPS6223750B2|1987-05-25|

ES479134A1|1980-06-16|

US4824840A|1989-04-25|

DE2912105C2|1985-08-29|

DE2912105A1|1979-10-11|

FI70704B|1986-06-26|

PT69422A|1979-04-01|

NL183189C|1988-08-16|

GB2017701A|1979-10-10|

IT1119284B|1986-03-10|

NO151321C|1985-03-20|

AT376432B|1984-11-26|

CH641455A5|1984-02-29|

GB2017701B|1983-03-16|

DK158225B|1990-04-16|

ES486992A1|1980-10-01|

ES486991A1|1980-10-01|

JPS54130587A|1979-10-09|

DK128679A|1979-10-26|

MX5862E|1984-08-13|

FR2421174B1|1982-11-19|

DE2953723C2|1989-01-12|

NO791049L|1979-10-02|

FI791034A|1979-10-01|

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法律状态:

优先权:

申请号 | 申请日 | 专利标题

JP53037783A|JPS6223750B2|1978-03-30|1978-03-30|

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