Method of producing 2-piperazinyl-4-arylquinazoline derivatives or salts with acids thereof

专利摘要:
The invention relates to derivatives of nitrogen-heterocyclic compounds, in particular 2-piperazinyl-4-substituted arylquinazoline of the general formula (I) with -N-CH-CH II) II I CRi CH-C-CRii -N CHj-CH-zN-Rx where RI C1 or nitro, RC H, C-C-alkyl, R o-Rj-CgH, or their salts, which as having antidepressant activity can be used in medicine. To detect the activity of compounds of the indicated class, new ones were obtained (1). The synthesis is carried out by the reaction of the corresponding substituted quinazoline with phosphorus oxychloride followed by separation of chlorine substituted with the corresponding substituted piperazine in absolute ethanol. Isolation is carried out either in free form or in the form of salt. The activity (T) was determined by the time of immobilization with respect to the control samples and it is more pronounced than the activity of imipramine, and although accompanied by toxicity and secondary effects of the cholinergic type, they are lower than that of imipramine. Tab. 2 .. i СО 1C 00 ol cm
公开号:SU1287750A3
申请号:SU833551851
申请日:1983-02-07
公开日:1987-01-30
发明作者:Бизьер Катлин；Алло Андре；Кан Жан-Поль
申请人:Санофи (Фирма)；
IPC主号:

专利说明:

112
The invention relates to novel 2-piperazinyl-4-aryl chinazole derivatives or to their salts, which do not have antidepressant properties, and can be used in medicine. The purpose of the invention is to search in a series of quinazoline derivatives for new 4-piperazinyl-4 arylquinazoline derivatives with antidepressant properties.
Example 1. Preparation of 2- (1-methyl-4-piperazinyl) -4- (2-chlorophenyl) -6-nitroquinazoline (see 40498).
a) 2-Chloro-4- (2-chlorophenyl) -6-nitroquinazoline.
A mixture of 40 g of 4- (2-chlorophenyl) -6-nitro-2-quinazolone and 600 ml of phosphorus oxychloride is heated at reflux for 4 hours. Phosphorus oxychloride is evaporated in vacuum to dryness, then the residue is poured into an ice-water mixture. Alkalinize with a solution of 10% sodium. Dehydrate sludge and wash-. are acetonitrile. The product is purified by chromatography on a silica column. The elution wire with chloroform-methanol (95: 5 v / v) was used to isolate the expected product. Weight 27 gm. (isopropanol).
b) CM 40498,
.
A mixture of 3.2 g of the obtained chloropropane and 3 g of N-methylpiperazine in 120 ml of absolute ethanol is heated under reflux for 3 hours. The solvent is evaporated to dryness in vacuo, then the residue is taken up in ethyl acetate. Wash the solution with an aqueous solution of sodium carbonate, then with water. The solution is dried on sodium sulfate, then evaporated to dryness. The residue is recrystallized from methanol-dichloromethane. Crystals are obtained. Weight 3.1 g, t, pl, 204 ° C,
Examples 2-6, a) Work as in example 1a, but modified: quinazolone, is obtained in the same way:
2-Chloro-4- (2-fluorophenyl) -6-nitroquinazoline, t, mp, higher (isopropanol),
2,6-Dichdor-4- (2-chlorophenyl) -quinazoline t, mp, 175-176 ° C (ethanol),
2,6-Dichloro-4- (2-fluorophenyl) -quinazoline, t, mp, 208-2 ° C (acetonitrile)
b) Of the various chlorine derivatives in position 2 mentioned above, the amine used is changed.
i-1 O: m-Ng
fO
f5
20
25
thirty
40
45
35
50
five .
obtain (as indicated in example 16) various compounds (II) presented in table. one.
The products obtained by the proposed method were subjected to pharmacological tests in order to determine their effect on the central nervous system.
In all cases, the test products were administered by mouth.
Experience PORSOLT.
This experiment was conducted on female mice, GDI (Charles Rivers, France) weighing 18-23 g.
The principle of this experience is as follows. When the mouse is placed in a narrow vessel filled with water, it flounders, then after 2-4 minutes it becomes stationary and floats on the stomach, the back is rounded, the hind legs are tucked under the body. She makes only some of the movements necessary to keep her head above water. This is the so-called despair reaction.
Some psychotropic drugs, especially antidepressants, lengthen the time during which the mouse wallows.
The following method was chosen.
The test products were administered orally to batches of 10 mice. After 1 h, the animals were placed in a narrow vessel (10 X 10 X 10 cm) filled with water at a HEIGHT of 6 cm, the water temperature was 24 ° C. The animals were left in water for 6 minutes and the time was measured when the donor became stationary ( between the second and sixth minutes). The shorter the time, the more active the substance.
The results are expressed in a decrease in the immobilization time with respect to the control samples.
Antagonism of the omission of an organ caused by reserpine.
Most antidepressants counteract ptoa caused by reserpine. This experience, described by Gouret, was implemented on a GDI male-female (Charles Rivers, France), weighing 18–23 g. Reserpine causes ptosis 1 hour after its intravenous administration. Some antidepressants, especially imipramines, counteract this ptosis.
. 312
The following method was chosen.
The test substances were administered through the mouth to batches of 10 mice. At the same time, re-cerpine was administered intravenously at a dose of 2 mg / kg. 1 h after administration of reserpine, the number of animals that do not have ptosis is noted.
Antagonism of hypothermia caused by reserpine.
Most antidepressants counteract hypothermia caused by reserpine. This experiment was carried out according to the method described by HINO on GDI female mice (Charles Rivers, France), weighing 18-23 g.
The following method was chosen.
The test substances were administered orally to the batches, from 10 mice, control samples received one solvent, while reperpine was intraperitoneally administered at a dose of 5 mg / kg. The temperature of each animal was determined immediately before the administration of the test substances and 4 hours after the administration. The temperature difference before and after treatment was calculated for each animal. Results were expressed as percentages of antagonism of hypothermia observed in control samples.
Possibility of toxicity of quebrax
Most antidepressants increase the toxicity of quebracine. The test was carried out according to the method described by MALICK in CDI female mice (Charles Rivers, France).
The test substances were administered through the mouth in batches of 10 mice. Quebec rachin was administered intraperitoneally after 1 hour at a dose of 30 mg / kg. Mortality was noted after 18 h.
Antagonism of tremors from oksotremorina.
The cholinergic effects of imipramine were considered to be responsible for certain secondary effects of the difficult effects of this substance. These actions were due to the tremor antagonism of oxotremorine. This test was performed on CDI female mice (Charles Rivers, France) weighing 18-23 g.
The following method was chosen.
The studied substances were administered in batches of 10 smaller groups. Within 60 minutes, oxotreomorin was administered orally at a dose of 1 mg / kg. Note the number of kids who do not have a third O4
NfopoB K pCT 30 min after administration of okToNfojiHna.
In tab. Figure 2 shows the pharmacological results obtained with various compounds obtained by the proposed method, as well as the results obtained with imipramine (a compound whose antidepressant properties are widely used in therapy) and CM 40331 or 6-chloro-4- (2-chlorophenyl) - 2- (4-hydroxy-1-piperidinyl) quinazoline-chlorohydrate.
The results of Table 2 show that the products obtained by the proposed method have strong antidepressant activity. This activity is in most cases much stronger than the activity of imipramine, and is accompanied by toxicity and secondary effects of the cholinergic type, which are significantly lower than that of imipramine,
11rio prepared 1E hydrochloride CM 40460,
A CM 40460 base is prepared, as described in Example 1, starting from 3.1 g of dichloro-2,6- (chloro-2-phenyl) -4-quinazoline and 3 g of N-methyl-piperazine. Treat in the same way. and after evaporation of the solvent, an oily residue is obtained, and an excess of a solution of hydrogen chloride in ether is added to it. Dry the solid phase and recrystallize the first time from isopropanol, then the second time from absolute ethanol. Get bes-, colored crystals (2.5 g), t, pl.260 ° C,
The results of the elemental content analyzes obtained for each of the products are given below.
CM 40498 (Example 1).
Calculated,%: C 59.45, H 4.72; N 18.24,
C gHjgClN Og (383.85)
Found,%: C 59; 51; H 4.84i N 18.39,
CM 40460 (Example 2)
Calculated,%: C 55.69; H 4.67; N 13.67,
CigHigCl N, HC1 (409.76)
Found,%: C 55.36; H 4.66; N 13.50,
CM 40468 (Example 3)
Calculated,%: C 58.02; H 4.87, N 14.25; C1 18.0,
CigHigFN C1 (393.28),
Found,%: C 57.63, H 4.94; 14.15; C1 18.18,
CM 40508 (Example 4),
51287750
Calculated,%: C 62.12, H 4.94 j 19.06.,
 0 (367.39;
Found,%: C 61.92; H 5.03-, 19.01.5
CM 41125 (example 5).
Calculated,%: C 57.00; H 4.52; 14.77; C1 18.69; F 5.01.
C gHjgOlFN HC1 (379.28).
Found,%: C 57.01, H 4.6 (1, fO 14.65; C1 18.57; F 5.27.
CM 41128 (Example 6).
Calculated; %: C 65.53; H 5.76; 14.65; C1 9.21; F 4.93.
, 2ClFN (384.90). Found,%: C 65.31, H 6.10; 14.37; C1 8.95; F 5.10.
t5

权利要求:
Claims (1)
[1]
Invention Formula
Method for preparing 2-piperazinyl-4-arylquinazoline derivatives of the formula I
Chlorine or fluorine,
or their salts with acids, about tl and h, y y and with the fact that the substituted quinazolone formula
H
N, 0
T
where R, | and Rj have the indicated meanings, are reacted with chloro-CUY phosphorus and the resulting chlorine-substituted quinazoline of the formula
25
where R and R have the indicated meanings, are reacted with an amine of the formula
H-NOS5-R
where R-has the indicated meanings
where R is chlorine or a nitro group,
. Rj is hydrogen or an alkyl group and gives the desired product in free form or as a salt with acids,
with C, -C,
40460
C1 CH C1
40468
C1 SND
40508
N02%
41125
C1 H
41128
C1-CHfEfM F
where R-has the indicated meanings
and provide the desired product in free form or as a salt with an acid.
 Table 1
Hydrochloride,
260 ° C, (methanol)
Base,
146-148 ° C
(methanol)
Base 220-222 ° C (ethanol)
Hydrochloride,
260 ° C (isopropanol)
Base 130-132 ° C, (ethanol)
 p 0.05 p -0.01.
Compiled by T.Yakunina Editor M.Petrova Tehred I.Popovich Proofreader S.Shekmar
Order 7732/1 Circulation 371Subscription
VNIISH State Committee of the USSR
for inventions and discoveries 113035, Moscow, Zh-35, Rag shska nab., 4/5
Production and printing company, Uzhgorod, st. Project, 4
table 2

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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FR8201988A|FR2521144B1|1982-02-08|1982-02-08|

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