前苏联专利SU1356962A3 Method of producing derivatives of carbostyrene

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专利摘要:
The invention relates to the production of carbostyril (CS), in particular compounds of the general formula K where (O) -A-NCH CH non-or substituted CH, CN, N02, HH2, mono-yl, di- or trimethoxy methylenedioxy; cinnamoyl, non-or substituted with mono- or trimexyl; A-methylene, ethylene- /; ethylidene, a carbon-carbon bond in the 3-yi position of 4-carbostyril and is a single or double bond, and K may be in the 5-, 6-or 8-carbostyryl-1 positions, which be used in medicine. The purpose of the invention is to obtain new CS with valuable properties. Preparation of CS is carried out from the corresponding halogen-substituted carbostyril and piperazine in the medium of solvent at 20–200 ° C for 1-24 hours. Tests of CS show that they have high cardiotonic activity. 5 tab. g CO with sd ss: o 05 tsD CM
公开号:SU1356962A3
申请号:SU823485500
申请日:1982-08-13
公开日:1987-11-30
发明作者:Томинага Митиаки；Янг Юнг-Хсиунг；Огава Хиденори；Накагава Казуюки
申请人:Оцука Фармасьютикал Ко, Лтд (Фирма)；
IPC主号:

专利说明:

This invention relates to a process for the preparation of novel chemical compounds of the carostyryl series, namely carbostyril derivatives of the general formula
NR
ABOUT
de R - lower alkanoyl, ethoxycarbo-. NIL, 2-furoyl, phenoxyistil, mesyl, tosyl, benzoyl, unsubstituted or substituted by methyl, cyano, nitro, amino, mono- or dichloro, MONO-, di- or trimethoxyl, methylenedioxy; cinnamoyl, unsubstituted or substituted by mono- or trimethoxyl, methylene, ethylene or ethylen, the carbon-carbon bond in position 3 and 4 of the carbostyril skeleton is a simple epi double bond,
L group on gd-d / / may
located in the 5.6 or 8 position of the carbostyril skeleton, which have a cardiotonic effect and can be used in medicine.
The purpose of the invention is to develop, on the basis of a well-known method, a method for the preparation of new compounds of a carostyrene series with valuable pharmacological properties.
Example 1. To a solution of 6.7 g of b- (c / -chloroacetyl.} - 3, 4-dig1 Scrocarbosteril in 60 ml of anhydrous dimethylformamide, 14.3 g of 4- (3,4,5-three - methoxybenzoyl) pyrazine and 5 ml of triethylamine, after which the reaction mixture is stirred for 1 hour at 50-60 ° C. Then the reaction mixture is poured into a large amount of water, the organic layer is extracted with chloroform, the chloroform layer is washed with water, dried, chloroform is removed distillation, the residue obtained is recrystallized from ethanol, the crystals are filtered off, suspended in a mixture of chloroform and methanol, after it was converted to the hydrochloride by addition of hydrochloric acid
five
five
0
five
0
five
0
five
in methanol, the crystal is recrystallized from ethanol. 6.3 g of 6-G4- (3,4,5-trimethoxybbnzoyl) -1-piperazinylacetyl-3,4-dihydrocarbostyril 3,5-hydroxyhydrochloride pentahydrate were obtained in the form of needles of colorless crystals with a melting point of 2213–17 s (decomposed ).
Analogously to Example 1, using the corresponding starting materials, the compounds of Examples 2-24 were obtained (see Table 1 j.
EXAMPLE 25 To a solution of 6.6 g of b-Sog-chloroacetyl) carbylity: dril in 60 ml of anhydrous dimethylformamide, 14.3 g of 4- (3,4,5-trimethoxybenzoyl) piperazine and 5 ml of triethylamine, after which the mixture is stirred for 1 h at 50-60 C. Then the reaction mixture is poured into a large amount of water, the organic layer is extracted with chloroform, the chloroform layer is rinsed with water and dried. The chloroform is distilled off, the obtained residue is recrystallized from ethanol, the crystals are filtered off, and the suspension is suspended from the comfort of the mixture. methanol with chloroform to the addition of a solution of hydrochloric acid in ethanol, the product is converted into chloridide. After recrystallization from methanol, 6 g of monochlorine were obtained; a solution of sesquihydrate (3,4,5-trimethoxybenzoyl) -1-piperazinyl acetric carbostyryl in the form of colorless powdery crystals with m.p. 201-204 ° С (decomposed) „
Example 26. Analogously to Example 25, using the appropriate starting materials, the compound (3-chlorobenzoyl) -1-piperazinyl acetyl carbostyryl Mons padrochloride hydrate was obtained as colorless: powdery crystals with mp of 212-215 ° С ( )
PRI me R 27. Using the procedure of Example 25, using the appropriate starting materials, 4.7 g of (3,4,5-trimethoxybenzoyl) -1-pig monohydrochloride monohydrochloride, 4-dihydrocarbostyril were obtained. colorless crystals with t, pl. 158-162 S.
Calculated,%: C 64.09; H 6.45; N 8.97.
, NjO (,. HCl
Found,%: C 64.26; H 6.34; N 9.09.
. PRI me R 28. According to the procedure of Example 25, 4., 3 g of monochlorohydrate (3,4,5-trimethoxybvzoyl) - 1-piperazinylacetyl-3,4-dihydrocarbostyril in the form of colorless crystals with m.p. .157-162 p.
Calculated,%: C 64.09; H 6.45; N 8.97.
C25H, .HGl
Found,%: C 64.26; H 8.34; N 9.09.
Example 29. To a solution of 6.7 g of 6- ((U-chloroacetyl) -3,4-dihydrocarbostyryl in 60 yl of anhydrous dimethyl-formamide, 4.8 g of 4- (3.5v 4-trimethoxybenzene) piperazine was added and 14.3 g of potassium carbonate, after which the reaction mixture is stirred for 1 hour at 50-60 s. Then the reaction mixture is drunk in a large amount of water, the organic layer is extracted with chloroform, the chloroform layer is rinsed with water, dried chloroform is removed by distillation, the resulting residue: recrystallized from ethanol, the crystals are filtered off, suspended in a mixture of chloroform and methanol, after This is transferred to the hydrochloride by adding a solution of hydrochloric acid in methanol, and the crystals are recrystallized from ethanol to obtain 6.5 g of monohydrochloride of sesquihydrate 6-4- (3,4,3-trimethoxybenzoyl) -1-piperazinylacetyl J 3,4-dig. 1 durocarbyl in the form of colorless needle crystals with mp 213-217 ° C (decomposed).
Example 30-37. According to the procedure of Example 25, the following were obtained: the compounds which are summarized in Table 2.
PRI me R 38. To a solution containing g (0.03 mol) of 6- (o) -chloroacetyl) -3,4-dihydrocarbosterine 1 and 60 ml of anhydrous xylene, 8.4 g (0, 03 mol) 4- (3,4,5-trimethoxibenzoyl) piperidine and 5 ml of triethyl amine, the reaction mixture was stirred at the boiling point of xylene for 10 hours. Then the reaction mixture was drunk into more water, and the organic layer was extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by evaporation. the residue thus crystallized was ethanol and the crystals were;
collected by filtration, suspended in chloroform-methanol, and then converted to hydrochloride by addition of hydrochloric acid; / / methanol and recrystallized from ethanol to form 5.4 g of 6-f4- (3, -4,5-trimethoxybenzo® 1) - G-piperazine acetyl-3,4-dihydrocarbostyryl
10 3/2 hydrate monohydrochloride in the form of colorless needle-like crystals. M.p. 213-217 ° С (with decomposition).
Example39. In a solution of 0.67 g. (0.003 mol) of 8- (c-chloro-acetosh1) -3.415 dihydrocarbostyril in 60 ml of anhydrous diethyl ether, 4.2 g (0.015 mol) of 4- (3,4,5-trimethoxybenzoyl) piperazine and 5 ml of triethylamine were added, then the mixture was stirred 20 at room temperature for 24 hours. The reaction mixture was then poured into a large amount of water, and the organic layer was extracted with chloroform. Chloroform layer
25 with water, dried, after which chloroform was removed by evaporation. The resulting residue was crystallized with ethanol and the crystals collected were collected by filtration. Crystals
30 were weighed in methanol-chloroform and converted to hydrochloride by adding hydrochloric acid / methanol to obtain 0.4 g of 8- {4- (3,4,5-tri-methoxybenzoyl} - piperazinyl25 acetyl-3,4-dihydrocarboxyryl - nogidrochloride in the form of colorless crystals. So pl.158-162 ° C. Elemental, composition. Calculated,%: C 64.09; H 6.45;
40 N 8.97.
CjjHjjNjOj-HCl
Found,%: C 64.23; H 6.35; N 8.91.
PRI am ep 40. A mixture of 6.7 g
45 (0.03 mol) 6- (sU-chloroacetyl) -3,4-di-gvdrocarbostyril, 16.8 g (O, Omol) 4- (3,4,5-trimethoxybenzene 1) piperazine, 4.8 g of potassium carbonate and 60 ml of anhydrous ethanol is stirred for 1 hour at 50-60 s. The mixture was then poured into a large amount of water, and the organic layer was extracted with chloroform. The chloroform layer was washed with water, dried and then the chloroform of the forms was removed by evaporation. The residue was crystallized from ethanol, and the crystals were collected by filtration, then the crystals were suspended in chloroform-methanol and converted to hydrochloride by addition of hydrochloric acid / methanol and recrystallized from ethanol to obtain 6.1 g of 6-G4- ( 3,4,5-trimethoxybenzoyl) - 1-ni-terazinylacetyl-3,4-dihydrocarbostyryl myohydrochloride 3/2 hydrate in the form of colorless needle-like crystals. M.p. 213-217 s (with decomposition),
: P and ° meper 41, 0.67 g (0.003 mol) 6- (c / -chloroacetyl) -3, 4-dihydrocarboxyryl, 8.4 g (0.03 mol) 4- (3, 4,5-trimethoxybenzoyl) piperazine and 5 ml: triethylamine was stirred for 3 hours. Then, the reaction of iCMecB was poured into a large amount of water, and the organic layer was extracted with chloroform. Chloroform; the layer was washed with water, dried, and chloroform was removed by evaporation. The residue thus obtained was crystallized with ethanol and the crystals were suspended in chloroform-methanol, then converted to hydrochloride by adding hydrochloric acid / methanol and recrystallized from ethanol to give 4.9 g (3, 4,5-trpmethoxybenzoyl) -1 α-piperazinyl acetyl-3,4-dihydrocarbostyryl monoglycrochloride 3/2 hydrate in the form of colorless needle-like crystals. So pl.213-217 with (with decomposition).
EXAMPLE 42. To a solution containing 6.7 g (0.03 mol) of 6- ("-chloro-acetyl) -3,4-dihydroc. Rbostiryl and 60 ml of hexamethylphosphorotriam1-scha was added 8.4 g (0.03 mol) of 4- (3,4,5-trimethoxybenzoyl) piperazine and 5 ml of triethylamine, the reaction mixture was stirred at 200 ° C for 10 hours. Then the reaction mixture was poured into a large amount of water, and the organic layer was extracted with chloroform. Wash the chloroform layer with water, dry it, and chloroform is removed by evaporation. The residue thus obtained was crystallized with ethanol and. the crystals were collected by filtration, suspended in chloroform-methanol, then converted to hydrochloride by the addition of hydrochloric acid / methanol, and recrystallized from ethanol to form 5.2 g of 6-4- (3,4,5- trimethoxybenzoyl) -1-piperazine acetyl-3,4-dihydrocarboxyl-3/2-hydrate monohydrochloride in the form of colorless needle-like crystals. M.p. 2 3-21 (with decomposition),
,
five
ten
15
20
25
569626
PRI me R 43. O., 67 g (0.003 mol) 6- (o / chloroacetyl) -3,4-di1 idrocarbosteryl, 8.4 g (0.03 mol) 4- (3, 4,5-trimethoxybenzoyl) piperazine and 5 ml of triethylamine were stirred at .3 h. Then the reaction mixture was poured into a large amount of water, and the organic layer was extracted with chloroform. The chloroform layer was washed with water, dried, and chloroform was removed by evaporation. The residue thus obtained was crystallized with ethanol and the crystals were suspended in chloroform-methanol and then converted to the hydrochloride by addition of hydrochloric acid / methanol and recrystallized from ethanol to give 4.1 g of 6-f4- (3, 4, 5-trimethoxybenzoi) -; - piperazinyl acetylZ-3, 4-dihydrocarbostyryl 3/2-hydrate monohydrochloride in the form of colorless needle-like crystals Tpl.213-217 0 (with decomposition).
Table 3 presents the compounds used in the tests.
Study of pharmacological action.
Adult yard dogs of both sexes weighing 8-13 kg are anaesthetized with sodium pentobarbital at the rate of 30 mg / kg intravenously, after subsequent intravenous administration of sodium heparin at the rate of 1000 units / kg, the dogs are killed due to blood loss. The dog's heart is cut out and immediately placed in Locke's solution, then the right coronary artery is connected with the tubule to the atrium, followed by the right atrium. carefully isolated.
Next, adult domestic workers from both sexes weighing 18–27 kg are anaesthetized with sodium pentobarbital at the rate of 30 mg / kg intravenously, after which they are administered sodium vapor at the rate of 1000 units / kg.
Blood from the carotid artery of donor dogs is poured into the right atrium E using a peristaltic pump, while the infusion pressure is constantly maintained. level of 100 mm Hg Movement E; the heart can be measured with a force change sensor with a constant load of 2 g. The amount of blood entering the coronary arteries is measured by electromagnetic flow measurement.
thirty
35
40
50
55
7
The test compound solution was injected into the artery through a rubber tube attached close to the inlet, in an amount of 10-30 µl.
The positive inotropic effect of the test compound is expressed as a percentage of the change in load before and after the injection of the compound. The effect of the compound on the blood flow in the coronary artery is expressed in absolute terms ml / min from the value measured before the injection of the compound. The results are shown in Table 4.
Adult yard dogs of both sexes weighing 8–13 kg are anesthetized with sodium tabarbital at the rate of 30 mg / kg intravenously. After additional administration of intravenous heparin sodium at the rate of 1000 units / kg, the test dogs are killed due to blood loss. The dog's heart is cut out and preparations are subjected to the anterior nipple muscle and the septum, the ventricle. The preparations were infused with blood through the anterior artery of the ventricle associated with the blood flow of donor dogs at a constant pressure of 100 mm Hg. The dogs used as donors weighed 18–27 kg and were anesthetized with sodium penta-barbital at the rate of 30 mg / kg intravenously, and then heparin was administered intravenously at a rate of 1000 units / kg. The papillary muscle was driven by a rectangular pulse, 1.5 times the threshold voltage of 0.5–3 V and a Zoya duration with a constant speed of 120 beats / min through bipolar flat electrodes. Voltage variation is measured by a voltage sensor. Muscle is loaded with a weight of approximately 1.5 g. Blood flow through the anterior artery of the ventricle is measured using an electromagnetic flow meter.
The test compound was administered as an intraarterial injection in the amount of 10-30 ml for 4 s.
The inotropic effect of the compound is expressed as a percentage of the voltage change before and after the injection of the compound.
The effect of the compound on the bloodstream is expressed as the difference in ml / min in numerical terms before and after injection.
eight
compounds. The results are shown in table.5.
Thus, the carbostyril derivatives of the general formula C 1} possess high cardiotonic activity.

权利要求:
Claims (1)
[1]
Invention Formula
The method of producing carbostyril derivatives of the general formula
0 C-A-L / -K
15
ABOUT
where R is nipgy alkanoyl, ztoxycarbonyl, 2-furoyl, phenoxyethyl, mesyl, tosyl, benzoyl, unsubstituted or substituted by methyl, cyano, nitro, amino, mono- or di-chloro, MONO-, di-di-trime- toxyl, methylenedioxy; cinnamoyl, unsubstituted or substituted with mono- or tri-methoxy;
A is methylene, ethylene or spi ethyl, the carbon-carbon bond in position 3 and 4 of the carbstilic skeleton is a single or double bond;
O (- A -N N-R
walk in position 5 j 6 or
8 of a carbostyril skeleton, characterized in that the compound of the formula.
0-c-a-cr
Group
maybe 45
1 de A — the carbon-carbon bond in position 3 and 4 of the carostyril skeleton and the position of the side chain substitution in the carbostyril skeleton have the indicated values
subjected to interaction with piperazine General formula
H / V. / V-i
1356962
value of 1J dissolution
by prize
in le
in le
6 6
6
23
24
OSH5
™ -so-guosnz
SI.
2
ten
01.09,81 - carbon-carbon bond in position 3 and A; the booster skeleton is a simple Eu;
25.1 2 .81 - the carbon-carbon bond in position 3 and 4 of the carboxyl carbon skeleton is a double bond.
t aolp in 1
225-228
251-258
2 2-244
207-210
1/2-H, 0
I-IICI-I-II
227.5-229
t-HCl 1/2-H, 0 ras.

242-2 5 {with Rael.)
252-253 (with rael.)
167.5-169
235-237 (with razp;)
249-252 (with rael.)
226-228 (with rael.)
191-194 (with diff.)
254-256 with rael.
207-210
231-234 186-188
232-242 (with diff.)
262-264 (with rael.)
270-272 (with diff.)
250-253.5 (with diff.)
I-hci
I-hci
I-IIC1-1-H, 0 1-IS1 1/2-H, 0 1-HC1
l / 4-HjO
240-242
(with different)
t-HCl-2-H, 0
I-HCI-l-HjO 1-HC1-1 / 2-H, 0
I-HCl-1-HjO. 2-HCl
Colorless acicular 214-216 crystals (with diff.)
1-HC1
Colorless powder-O-229-233 different crystals (with Rael.)
I-HC1
carbostyril
Table2
: i
2 106- 4- (3,4-Dimethoxybenzosh1) -1-piperazinyl acetyl-3,4-dihydrocarbostyryl
116-4- (3-Chlorobenzoyl) -1-piperazinyl acetyl-3,4-dihydrocarbostyryl hemihydrate
126- 4- (3,4-Methylenedioxybenzoyl) -1-piperazinylacetyl - carbostyryl hemihydrate
136-4- (3, A-Dichlorobenzoyl) -1-piperazinyl acetyl-3,4-dihydrocarbostyryl hemihydrochloride monohydrochloride
146- (4-Furoyl-1-piperazinyl acetyl) -3,4-dihydrocarboxystyryl monochlorohydrate
156- (4-Benzoyl-1-piperazinyl acetyl) -3, 4-dihydroxy-1-boxy-styryl 1/4 hydrate
166-4- (3-Chlorobenzoyl) -1-piperazinsh1-acetyl} carbostyryl monohydrochloride monohydrate
with
176- 4- (3,4-Dimethoxybenzoyl) -1-piperazinyl acetate-j carbostyrst monochlorohydrate sesquihydrate
186-4- (4-Methoxybenzoyl) -1-piperazinylacetyl car-, bostyril monochlorohydrate sesquihydrate
196-4- (4-Methylbenzoyl) -1-piperazinyl acetyl1 j carbostyryl monochlorohydrate sesquihydrate
206- (4-Benzoyl-1-piperazinsh1acetyl) carbostyryl monochlorohydrate and a half hydrate
216-4- (4-Cyanobenzoyl) -1-piperavinylacetyl carbostyryl monohydrochloride sesquihydrate
226-4- (3,4,5-Trimethoxybenzoyl) -1-piperazinylacetyl J-carbostyryl monohydrochloride one and a half-hydrate
236-4- (4-Nitrdbenzoyl) -1-pip8razinilatsvtil carbostyryl monochlorohydrate hemihydrate
24 (4-Methoxycinnamoyl) -1-piperazinyl acetyl 3, 4-dihydrocarbostyryl monohydrochloride monohydrate
256- (4-Tsinnamoil-1-piperazinyl acetyl) 3,4-dihydrocarbostyryl monohydrochloride hemihydrate
266-4- (4-Aminobenzoyl) -1-piperazinylacetyl carbostyrnl dihydrochloride monohydrate
27, (2-Phenoxyethyl) -1-piperazinyl acetylJ-3,4-dihydrocarbostyryl dihydrochloride hemihydrate
28Amrinone (3-amino-5- (4-pyridinyl) -2 (H) -pyridinone)
296-4- (3-Chlorophenyl) -1-piperazinyl / acetyl-3,4-di-hydrocarbostiril. ,
one
100 100 300
one
one
one
one
one
one
one
one
one
one
2.5
one
five
8.5 3.5
3
2
1.0
3
2.5
Table 5
100
100 100
100 100
100 1
one
1,100
eleven
18,8
23.1 16.1
17.4 18
28.8 17
12.9 18.7
12
, 31.6 22
Compiled by I. Bocharova Editor A...Dolynich Tehred L.Serdyukova Proofreader I.Musk
Order 5817/58 Circulation 372Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
Production and printing company, Uzhgorod, st. Project, 4
0.5
one
1.5
3

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同族专利:

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FI822803L|1983-03-02|

DE3230209C2|1985-08-22|

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KR860000135B1|1986-02-26|

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AU8698082A|1983-04-14|

KR840001157A|1984-03-28|

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引用文献:

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法律状态:

优先权:

申请号 | 申请日 | 专利标题

JP56137984A|JPS643194B2|1981-09-01|1981-09-01|

JP56210368A|JPH0310620B2|1981-12-25|1981-12-25|

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