Method for producing 4-phenylquinazoline derivatives or salts thereof

专利摘要:
The invention relates to derivatives of 4-phenylquinazoline (PC), in particular compounds of general formula I: where R 1 a) 6) -N-CH2- (R5) - (CH2) v c) -NCH2 CHiN (CH7. CH20HVCH2-CH2 to oR , jr, Rj is halogen or hydrogen, if Ri is NCH2CH2CH (OH) CH2CH2. R H or (CH, j) OH; n 2,3 or 4; R (CH,) OH; Rg (CH) OH; m 0, 1 or 2 and is in the meta- or para-position, which have anti-epileptic and hypnotic action.The goal is to create compounds of the indicated class with better activity. PFs are obtained from olon-2 4-phenyl-6-chlorochinases, while boiling the reaction mixture with the subsequent processing of the resulting product is they are given an amine, taken with a 3-fold molar excess, in sec; with ethanol at boiling. The isolation is carried out in free form or in the form of salt. PF tests show anticonvulsant activity, hypnotic effect and low toxicity (500 mg / kg). 2 Table i CO ND CO e
公开号:SU1299511A3
申请号:SU823502049
申请日:1982-10-20
公开日:1987-03-23
发明作者:Алло Андре；Бизьер Катлин
申请人:Санофи (Фирма)；
IPC主号:

专利说明:


cm
1i
This invention relates to a process for the preparation of novel 4-phenyl-quinh-bach derivatives or their salts, which exhibit anti-epileptic activity and can be used in medicine.
The aim of the invention is to obtain, in a series of 4-phenyl-ninazoline derivatives, new compounds with anxiolytic hypnotic action and anti-epileptic effect.
 Example 1. Preparation of 6-chloro 4- (2 chlorophenyl) -2 - (- hydroxypiperidinyl-) quinazoline hydrochloride (cm 40 331).
A. 2,6-Dichloro-4- (2-chlorophenyl) xin-azo. Iin.
A mixture of 11.8 g of 6-chloro-4- (2-chlorophenyl) -4-quinazolone-2 and 59 ml of phosphorus oxychloride is heated under reflux for 6 hours with stirring. The excess phosphorus oxychloride is evaporated under vacuum to dryness and the residue is taken in a mixture of ice and water. Dry the separated solid, rinse with water, then recrystallize under ethanol. Obtain 11.7 g of the desired product with so pl. 175-6 C.
B. CM 40 331.
A mixture of 13.1 g of the obtained product and 12.8 g of 4-hydroxy piperidinyl in 68 ml of ethanol is heated under reflux for 1 h. Whit-
2 40 332
TO
CH2CH OH
3 40 411
4 40 416
-N (3-OH
5 40 451
one
I2
The solvent is removed and the residue is taken up in water and then extracted with ethyl acetate. The organic solution on sodium sulfate is dried off and the solvent is evaporated to dryness. The residue is dissolved in boiling isopropyl ether and allowed to crystallize upon cooling. Thus, 10.5 g of base are obtained with a mp of 129-131 ° C. : Chlorohydra-g.
Dissolve the resulting base (10.5 g) in 70 ml of absolute ethanol and add hydrochloric acid gas to obtain an acidic pH. Dry the resulting crystals and recrystallize in absolute ethanol., Weight 10.6 g, m.p. 212-4 C,
Examples 2-11.
A. 2,6-Dichloro-4- (K, -2-phenyl) quinazoline.
Conducting the reaction according to Example 1A, but changing the starting quinazolone, 2,6-dichloro-4- (2-fluorophenyl) -quinazoline is obtained in the same way. 208-210 C (acetonitrile), -2,6-dichloro-4-phenylquinazoline with m.p. 159-160 C (ethyl acetate)
B. Starting from the various indicated chlorine derivatives and changing the amine used., As shown in Example 1B, various compounds of the general formula, which are combined in Table 1, are prepared.
Table 1
Hydrochloride, 176-8 (isopropanol)
Base 144-6 (methanol)
Hydrochloride, 194-6 (isopropanol)
Base, 188-190 (methanol)
The base 144-6 (ethyl acetate)
40,621
40,669
-ITH-CHaCHjCHjOH cf С С GSONGON CE
40,744
40 785
40,788
40,854
-CH-CCN2) sCH20N cf ct
)-He N
The products of the proposed method were subjected to pharmacological tests, the purpose of which was to determine their effect on the central nervous system.
The anticonvulsant effects of the proposed products were studied by means of a test for antagonism against convulsions caused by pentetrazole. This test was performed on CFI female mice (Iffa Credo France) weighing 18–23 g.
On the eve of the experiment, the animals were marked, weighed, placed in ten cages from a rabbit (30 cm) and kept in an air-conditioned animal room until the day of the experiment. Animals received food and drink at will. During the experiment, the animals were placed in a laboratory, where the experiment was to be carried out.
The test products were suspended in water mixed with 5% resin and administered orally with a dose of 200 mg / kg (in terms of salt) to groups of ten ml — at a volume of 20 ml / kg. Control animals received only water, sour cream with resin.
One hour after the administration of the test products, pentetrazole dissolved in distilled water was injected intraperitoneally with a dose of 125 mg / kg with a volume of 20 ml / kg. Right after
Continued table. one
Base 124-6 (ether)
Foundation 118-120
(isopropyl
ether)
Base, 126-8 (ethyl acetate)
Hydrochloride, 192-5 (isopropanol)
Chloropvdrat, 210-2 (isopropanol)
Hydrochloride, 260-2 (96% ethanol)
the administration of the substance causing the cramp, the mice were placed in separate vessels (10 10 15 cm). One hour after administration of pentetrazole, mortality was measured. Results are expressed in percentage of surviving animals, t, e, expressed in percentage of the number of animals that were protected from the effects of pentetrazole,
Anesthesia caused by pentobarbital was potentiated on OFI simple infant mice (Iffa Credo, France) weighing 18–23 g. On the eve of the experiment, animals were labeled, weighed, placed ten in cells from macrolon (30 19 12 cm) and kept in a room animals with air conditioning until the day of the experiment. The amount of food and drink arbitrary, on request. On the day of the experiment, the animals were placed in the laboratory where the experiment should take place.
The test products were suspended in water, sour cream with 5% resin, and administered orally with a dose of 120 mg / kg (in terms of salt) to groups of ten mice with a volume of 20 ml / kg. Control animals received simply water mixed with resin.
One hour after the introduction of the test products, pento was introduced.
Barbital (b% sodium pentobarbital) with a dose of 20 mg / kg with a volume of 20 ml / kg. The number of animals that lost the so-called rectification reflex (righ- 5 ting reflex) is noted. The result is expressed as a percentage of sleeping animals. The results obtained during these two tests on the products offered are presented in Table 2. ABOUT
table 2
Where
R
J is hydrogen or a group - (CH) OH and R is a group - (CH OH, where n is V-loe 1 is equal to 2, 3 and A;
b)
)
Kb
20
where R.
- group - (CH,) OH, O
an integer equal to the p-position;
where m is up to 2 in m-
c) -X) c-shdad
25 2 halogen atom, or Rj - hydrogen, if R means
.
thirty
or salts thereof, characterized in that the 4-phenyl-6-chloro-quinazolone-2 derivatives of the general formula
n
35
In addition, the proposed products have low toxicity. All the products tested are completely non-toxic at a dose of 500 mg / kg, and therefore can be used for treating humans as anxiolytic, hypnotic and anti-epileptic drugs.
 the invention
The method of obtaining 4-phenylquinazoline derivatives of the general formula
VNIIPI Order 906/64
Random polygons pr-tie, Uzhgorod, st. Project, 4
where R, j has the indicated meanings, is reacted with phosphorus oxychlog RIDOM at the boiling point of the reaction mixture, and the resulting corresponding 4-phenyl-2,6-dichlorochinazoline derivative is reacted with an amine of the general formula
,
where -R has the indicated values, taken in a ratio of 3 mol per 1 mol of 4-phenyl-2,6-dichloroquinazoline derivative, in ethanol at the boiling point of ethanol and the desired product is isolated in free form or as a salt.
Circulation 372
Subscription

权利要求:
Claims (1)
[1]
* ⁵⁰ Summary of invention
The method of obtaining derivatives of 4-phenylquinazoline of the General formula
D rir ^ ² where R is the group
a) where “hydrogen or a group” (CH) OH and R ₄ is a group - (CH) _h 0H, where η is an integer equal to 2, 3 and 4;
"> -O
Rs where R _g is the group - (CH ^ OH, where m is an integer from 0 to 2 in the m- or p-position;
• c) -X ~) and -CH ₂ CH _g 0H,
R ₂ is a halogen atom, or Rj is hydrogen, if R ₃ means
Νθ-ΟΗ "'or their salts, characterized in that the derivatives of 4-phenyl-6-chloroquinazolone-2 of the general formula n
where R _g has the indicated meanings, 'is reacted with a phosphorus oxychloride at the boiling point of the reaction mixture and the corresponding 4-phenyl-2,6-dichloroquinazoline derivative obtained is reacted with an amine of the general Formula
Ρ _Ί Η, where R has the indicated values, taken in the ratio of 3 mol per 1 mol of the 4-phenyl-2,6-dichloroquinazoline derivative in ethanol at the boiling point of ethanol and the desired product is isolated in free form or in the form of a salt.

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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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FR8119767A|FR2514765B1|1981-10-21|1981-10-21|

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