前苏联专利SU1340589A3 Method of producing 2-(4-substituted piperazino)-4-amino-6,7-dimethoxy quinolines or hydrochlorides

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专利摘要:
Novel derivatives of 4-amino-6,7-dimethoxyquinoline are disclosed as regulators of the cardiovascular system, in particular as antihypertensive agents, which have the formula: …<CHEM>… where R is a dialkylamino, piperidino or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl- group, or a piperazino group optionally substituted in the 4-position by an alkyl, aryl, aromatic heterocyclic, acyl, N-substituted carbamoyl or esterified carboxyl group. Preparation of such compounds by cyclisation of N-(1R-substituted-ethylidene)-2-cyano-4,5-dimethoxy-anilines and by appropriate treatment of the compound in which R is an unsubstituted piperazino group, is described.
公开号:SU1340589A3
申请号:SU843732816
申请日:1984-04-26
公开日:1987-09-23
发明作者:Фрейсер Кемпбелл Симон；Дэвид Хардстоун Джон
申请人:Пфайзер Корпорейшн, (Фирма)；
IPC主号:

专利说明:

This invention relates to the chemistry of heterocyclic compounds, in particular, to a process for the preparation of new 2- (4-substituted piperazino-4-amino-6,7-dimethoxy) quinolines of the general formula vr f-
SNZO
K.-N -Y
Nhr
fj;
where Y is thiazolyl-2; a six-membered heterocycle containing two nitrogen atoms and a monosubstituted C-C4-alkyl, C -C-alkoxyl, chlorine or dialkylamine; triazine disubstituted with C-C4-alkoxyl or kelamine; benzoxazolyl-2 or benzimidazolyl-2, substituted in position 1 with C-Cf-alkyl, or Y is the radical COR, where C is alkyl, cyclopentyl, unsubstituted or 4-halogen-substituted phenyl, furyl-2, cinnamyl, naphthyl- 2, quinolyl-2, piperonyl or chromyl-2, benzodioxanyl-2, or Y is the radical COOR, where R ,, is C-C-alkyl, 2-methylallyl, 4-fluorophenyl or benzyl, or their hydrochlorides which have antihypertensive activity and can be used in medine.
The aim of the invention is to create, on the basis of known methods, a method of obtaining new compounds with pharmacological properties.
Example 1. A solution of 1,4-benzodioxy-2-carbonyl chloride (0.75 g) in chloroform (10 ml) is added dropwise to a solution of 4-amino-6,7-dimethoxy-2- (piperazine -1-yl) quinoline (1.0 g) in chloroform (50 ml) with triethylamine (1.06 g) at 5-10 ° C. The reaction mixture is stirred at 5-10 ° C for one hour, then brought to room temperature. temperature and stirred overnight. The mixture is then evaporated in vacuo, the residue is treated with chloroform (50 ml) and sodium carbonate solution (10%, 50 ml). The chloroform layer is separated, the aqueous phase is extracted with chloroform (2 x 50 ml), the extracts are combined, washed with brine, dried (sodium sulfate) and evaporated in vacuo. The residue is then dissolved in chloroform and chromatographed on silica (Mrpr 9385.60 g), with zylation
a mixture of chloroform and methanol (100: 0 - 97: 8). A solution of the purified product in chloroform is treated with an ethereal solution of hydrogen chloride, evaporated in vacuo, and the residue is recrystallized in isopropanol, and 4-amino-2-4- (1,4-benzodioxane-2-carbonyl) piperazin-1-yl is isolated. -6,7- -dimethoxyquinoline in the form of a hydrochloride hydrate (0.26 g), so pl. 201 ° C. Found 5: C 56.7; H 5.4; N 11.0. C, H 2 N OyHCl HjO
Calculated,%: C 57, 1; H 5.8; N11.1.
Examples 2-11. The following
The compounds are prepared analogously to Example 1, starting from the same quinoline and the corresponding acid chloride. After chromatography the product
crystallized from the solvent shown in each case. The research results are summarized in table 1.
Example 12. 4-amino-6,7-dimethoxy-2- (piperazin-1-yl) quinoline (1.26 g) and 2-chloro-4-dimethylaminopyrimidine (0.76 g) in n-butanol ( 60 ml) is heated under reflux for 16 hours. Mixture
then evaporated in vacuo, the residue is treated with chloroform and sodium carbonate solution (10%), and the aqueous phase is extracted with chloroform. The combined extracts are washed with water,
dried (), evaporated in vacuo, and the residue was chromatographed on silica gel (Merck 9385). Elution with a mixture of chloroform and methanol (100: 0 - 95: 5) with the subsequent treatment of the product with an ethereal solution of hydrogen chloride and recrystallization from methanol gives 4-amino-6,7-dimethoxy- (4-dimethylaminopyrimidin-2- -yl) piperazine-1 -yl quinoline in the form of
dihydrochloride dihydrate (0.19 g), so pl. 260-263 ° C.
Found,%: C 48.4; H 5.8; N 18.9.
., 0, - 2HC1-2H20 Calculated,%: C 48.7; H6.4; N 18.9.
Examples 13-21. The following compounds are prepared analogously to example 12 using the appropriate halo-heterocyclic compound, and the product is crystallized from the solvent shown in each case. In Example 15, chromatography is not necessary. The data are given in table 2.
3
Example 22 A solution of n-butobutyl chloroformate (0.11 g) in chloroform (5 ml) is added dropwise to a stirred solution of 4-amino-6,7-dimethoxy-2- (piperazin-1-yl) quinoline (0.21 g) in chloroform (15 ml) with triethylamine (0.22 g) at. The solution is then stirred for 1 hour at room temperature and sodium carbonate solution (10%, 10 ml) is added. The organic phase is separated, the aqueous solution is extracted with chloroform (2 x 15 ml), and the combined total extracts are dried with sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel (Merck 9385, 25 g), eluting with a mixture of methylene chloride and methanol; (100: 0 93.7), followed by treating the product with an ethereal solution of hydrogen chloride and recrystallization from isopropanol to obtain one-and-a-half hydrate of 4-amino-6 hydrochloride,
Oj (061)
2-Cyano-4,5-dimethoxyaniline (20 g), traces of the corresponding hydrochloride salt (200 mg) and triethyl orthoacetate (40 ml) are stirred at 150 ° C. for 1 h with ethanol being removed by distillation. Mixture
12.2. 12.4
D0589
-dimethoxy-2- (4-) isobutoxycarbonyl (piperazin-1-yl) quinoline, b.p. 254-256 C (0.065 g).
Found,%: C 52.8; H 6.9; N Crc Hj N404- HC1 -1.5 HjO
Calculated,%: C 53.2; H 7, 1; N Examples 23-26. The following compounds are prepared analogously to example 1Q of py 22 using the corresponding chloroformate of formula C1COOR, the product is crystallized from the solvent shown in each case. The compound of Example 38 is obtained as the 15th byproduct of Example 37, with ethyl chloroformate being formed due to the presence of traces of ethanol and a chloroform solvent for the reaction. Data for compounds of total 2Q formulas are given in table 3.
The following preparation methods illustrate the preparation of starting materials of formula (IA) 25 Preparation 1
snz. IT
OH - CN SPZUN
then evaporated in vacuo, and the crude ethyl-K- (2-cyano-4,5-dimethoxyphenyl) acetimidate (27.95 g) is used directly.
35
Cooking 2
OS, N:
about
-1-NK i CH CeHSPT T O e 5
Crude product (26.7 g) from the previous preparation N-benzyl piperazine (21 g) and p-toluenesulfonic acid (100 mg) are stirred together for 2 hours with a slight decrease in pressure. After cooling, the residue is treated with methylene chloride and extracted with dilute hydrochloric acid (2 norms. 2x200 ml). The acidic layer was adjusted to pH 4 (5 Nm. NaOH), extracted with methylene chloride (2x200 ml) and the combined extracts discarded. The aqueous phase is then basified to pH 9, extracted with methylene chloride (3 x 200 ml), the combined extracts are washed with brine, dried sodium sulfate and evaporated.
five
0
five
vacuum. The residue was purified by column chromatography (Merck 9385, silica, 400 g), eluted with methylene chloride / methanol (100: 0- 98: 2), a sample of the product (11.68 g) was dissolved in ethyl acetate-methanol and planted with an ethereal solution of hydrogen chloride. The solid is washed with ether and dried to give (4-benzylpiperzazin-1-yl) ethyl idene-2-cyano-4,5-di-methoxyaniline as dihydrochloride hydrate, m.p. 181-182 C.
Found,%: C 56.6; H 6.7; N 11.9. Cj, 2HC1 H, 0
Calculated,%: C 56.1; H 6.4; N 11.9. Cooking 3
N-C1 (4 benzylpiperazin-1-yl) these 2-cyano-4,5-dimethoxyanaline lidide (13.5 g) and zinc chloride (4.86 g) in dimethylacetamide (90 ml) are stirred under heating to reflux. Over 2.5 hours, zinc chloride (0.5; 0.2 g) is additionally added after 0.5 hours and 1.5 hours. The mixture is cooled, treated with simple ether (700 ml 2x100 ml), the surface layer is discarded each time. The residual tar is then treated with sodium hydroxide solution (2 nos., 100 ml) and methylene chloride (100 ml), and the mixture is stirred at room temperature for 5 minutes. The organic layer is separated, the aqueous phase is extracted with methylene chloride, the total organic extracts are washed with water.

sns0.

CH-iCe
The sodium sulfate-dried extracts are evaporated in vacuo, and the brown residue (about 13 g) is purified by chromatography on silica gel (Merck 9385, 250 g), eluting with a mixture of chloroform and methanol (100: 0 - 88:12). A sample of pure product (6.95 g) was dissolved in ethanol, treated with ethereal hydrogen chloride solution and evaporated in vacuo. The residue is recrystallized from methanol to give 4-amino-6,7-dimethoxy-2- - (4-benzyl-piperazin-1-yl) -quinoline dihydrochloride sesquihydrate, m.p. 260-263 S.
Found,%: C 54.9; H 5.9; N 11.5.
11.7.
(2C1 1.5 Calculated,%: C 55.2; H 6.5; Preparation 4
N
si oh
n,
,
Pd / C SNSO
4-Amino-b, 7-dimethoxy-2- (4-benzylpiperazin-1-yl) quinoline (6.2 g) in ethanol (300 ml) with palladium-carbon catalyst (Pd / C) is stirred at atmospheric hydrogen (50 pounds per square inch, 3.515 kg / / sq.cm) for 20 hours. The mixture is cooled, chloroform is added (100 ml solution is filtered through Solkaflok, the solid is washed with a mixture of chloroform and methanol (1: 1, 4x100 ml), and the combined filtrates are evaporated in vacuo. The residue is distributed between a chloroform-sodium carbonate solution (10%), the organic layer is removed, the aqueous phase is saturated with salt, and then the extract ruyut chloroform. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give 4-amino-but-6,7-dimethoxy-2- (piperazin-1-yl) quinoline (2.42 g). I
Trials for antihypertensive activity were conducted on groups of five Okamoto male rats with spon
this hypertension, with systolic smooth pressure of more than 200 mm Hg. Art. (compared to 130 mmHg in normal rats). Blood pressure is measured by means of an inflation cuff worn on the animal's tail and a variable capacitance transducer to determine the systolic pressure pulse. Animals are placed in a heated box at 33 ° C for 20-30 minutes before measuring blood pressure in order to facilitate accurate pulse determination. After controlling the recording of blood pressure and heart rate, the animals are given orally the tested compounds at doses of 3 mg / kg and the blood pressure is determined 1.5 and 4 hours after administration of the test compound.
Results are expressed as the maximum recorded drop in blood pressure in% of the average blood pressure in five rats before taking the test compound and are summarized in Table 4.
The compounds of general formula (I) and their salts may be administered by themselves, but usually they are administered in admixture with a pharmaceutical carrier selected depending on the intended mode of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing excipients such as starch or lactose, either in capsules either alone or in a mixture with excipients, or in the form of elixirs or suspensions containing flavoring or flavoring or coloring agents. They may be injected parenterally, for example, intramuscularly, intravenously or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution that may contain other solutes, such as an adequate amount of salt or glucose, to make the solution isotonic.
The compounds of formula (I) and their salts can be administered to people for the treatment of hypertension, either orally or parenterally, they are usually administered orally in doses ranging from 1-50 mg / day to an average adult patient (70 kg by weight), and are given in as a single dose up to three divided doses. Intravenous dosage levels are 1 / 5-1 / 10 of the daily oral dose. For an average adult patient, individual oral doses in the form of tablets or capsules are approximately in the range of 1 to 25 mg of active compound. However, deviations or variations necessarily occur depending on the weight and condition of the subject being treated, as well as on the particular method of administration chosen.
Thus, the proposed method allows to obtain compounds of about 3405898
formula I, possessing valuable pharmacological properties.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining 2- (4-substituted piperazino-4-amino-6,7-dimethoxy J quinolines of the general formula
g-
-N / -Y
NZS-0
/
NH.
where Y -, - thiazolyl-2; six-membered
a heterocycle containing two nitrogen atoms and monosubstituted by C -C-alkyl, C-, -alkoxy, chloro or dialkylamino triazine disubstituted by C4-alkoxy or C-alkylamine, benzoxazolyl-2 or benzimidazolyl -2, substituted in position 1 by C -C4-alkyl, or Y is the radical COR, where R is C -C-alkyl, cyclopentyl, unsubstituted or 4-halogen-substituted phenyl, furyl-2, cinnamyl, naphthyl-2, quinolyl-2, piperonyl or chromo-2, benzodioxanil-2, or Y is a COOR radical, where C is C-alkyl, 2-methyl-allyl, 4-fluorophenyl or benzyl,
or hydrochlorides thereof, characterized in that the compound of the formula
N
45
; NH (b)
with a compound of the general formula
Y-C1, (II) where Y have the indicated meanings,
with the release of the target product in free form or in. hydrochloride.
Table 1
Carried out in ethanol at room temperature in the presence of triethylamine.
T bl c 2
.BUT,
at, (cHjOtable 3
.BUT,
(J

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公开号 | 公开日

EP0100200B1|1987-05-06|

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JPH0219112B2|1990-04-27|

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SU1251801A3|1986-08-15|

DD211555A5|1984-07-18|

DK337383D0|1983-07-22|

ES524320A0|1985-04-16|

PL243131A1|1984-12-17|

YU157283A|1986-02-28|

DK166821B1|1993-07-19|

PT77082B|1986-04-11|

US4758568A|1988-07-19|

FI78296B|1989-03-31|

US4656174A|1987-04-07|

US4686228A|1987-08-11|

NO171594C|1993-04-07|

EP0100200A1|1984-02-08|

FI78296C|1989-07-10|

IL69311D0|1983-11-30|

DK337383A|1984-01-25|

GR79603B|1984-10-31|

SG6489G|1989-06-09|

CS247073B2|1986-11-13|

JPS5933264A|1984-02-23|

KR840005428A|1984-11-12|

PH19424A|1986-04-15|

IE831730L|1984-01-24|

KR880001315B1|1988-07-23|

YU42628B|1988-10-31|

PT77082A|1983-08-01|

NZ204996A|1986-05-09|

NO171594B|1992-12-28|

FI832658A|1984-01-25|

HK32289A|1989-04-28|

IE55798B1|1991-01-16|

AU548036B2|1985-11-21|

PL139498B1|1987-01-31|

DE3371336D1|1987-06-11|

HU190907B|1986-12-28|

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法律状态:

优先权:

申请号 | 申请日 | 专利标题

GB8221457|1982-07-24|

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