Method of producing imidazo(1,2-a)pyrimidines

专利摘要:
The invention relates to heterocyclic compounds, in particular to the preparation of imidazo (1,2-a) pyrimidines of the formula NN FV-X R xhm where R {is 1,2,4-oxadiazolyl-3, substituted C-C - alkyl, which may - be substituted by one or more fluorine atoms; RЈ and the same or different H, C-C-alkyl or R2- and R-tetramethylene; X - 0 or S; R-Cj-Cj-alkyl, which have anxiolytic properties. The goal is to develop a method for producing more active compounds. The preparation is carried out by the reaction of imidazo (1,2-a) pyrimidine with hydroxylamine hydrochloride with the subsequent treatment of dimethylacetamide di-methyl acetal in the form of (CHgO) C (D) N (CH9) 2, where D is C-C-alkyl, which can be substituted by one or more fluorine atoms. New compounds in l / 6 times more active than known compounds Table 2. s /)
公开号:SU1650013A3
申请号:SU854005003
申请日:1985-12-18
公开日:1991-05-15
发明作者:Джон Гиллеспи Роджер；Роджер Тулли Уилфред
申请人:Руссель-Юклаф (Фирма)；
IPC主号:

专利说明:

The invention relates to methods for the preparation of new imidazo- (1,2-a) pyrimidine derivatives having valuable anxiolytic properties that can be used in medicine.
The purpose of the invention is to develop a method for the preparation of new imidazo (1,2-a) pyrimidines with a higher anxiolytic activity.
The method is carried out as follows.
Example 1. 6-Ethyl-7-methoxy-5-methyl-2- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo (1,2-a) pyrimidine.
Stage A: 6-ethyl-M-hydroxy-7-methoxy-5-methylimidazo (1,2-a) pyrimidine-2-carboxamide
A suspension of 6-ethyl-7-methoxy-5-methylimidazo (1,2-a) pyrimidine-2-carbonitrile (8.0 g), hydroxylamine hydrochloride (2.82 g) and potassium hydroxide ( 2.28 g) in ethanol (100 ml) is boiled under reflux with stirring for 2 hours. The mixture is cooled and the precipitated product is filtered, suspended in water with stirring for 15 minutes, filtered, then washed with water and ether and dried in a vacuum. Get
OS SP
Od
s
6-methyl-M-hydroxy-7-methoxy-5-methyl-g imidazo () pyrimidine-2-carboxamidine (7.96 g; 86%) so pl. 249-250 ° C.
Stage B: 6-ethyl-7-methoxy-5-methyl-2- (5-methyl-1,2,4-oxadiazol-3-yl) - imidazo (1,2-a) pyrimidine „
A mixture of 6-ethyl-M-hydroxy-7-methoxy-5-methylimidazo (1,2-a) pyrimidine-2-carboxamidine (1.70) and dimethyl acetamide dimethyl acetal (3.5 ml) is heated to | Yut at 100 ° C for 15 minutes, then the resulting mixture is evaporated to dryness and purified by chromatography. The solid obtained is recrystallized from aqueous methanol and 6-ethyl-7-methoxy-5-methyl-2- (5-methyl-1,2,4-oxadiazol-3 yl) imidazo (1,2-a) pyrimidine (1 , 76 rj 95%) as a white solid, T.roio 176-.
EXAMPLE 2: 6 Ethyl-7-methoxy-5-methyl-2- (5-trifluoromethyl-1,2,4-oxadiazole 3-yl) imidazo (1,2-a) pyrimidine.
Under stirring at room temperature, 1.7 ml of trifluoroacetic anhydride is added to a solution of 1.2 g of 6-ethyl-N-hydroxy-7-methoxy-5-methyl-imidazo (15 2-a) pyrimidine-2-carboxamine- Dine and 0.8 ml of triethylamine in 30 ml of dichloromethane. The mixture is heated to 45 ° C in 30 minutes, cooled, washed with water, dried and concentrated to dryness. The compound was recrystallized from ethyl acetate to afford the title compound in a yield of 95%, mp 197–200 ° C.
Similar to that described in Example 2, starting from the corresponding carbonitrile, the compounds are prepared according to Examples 3-5.
Note 3. 3. 7-Methoxy-5-methyl-2 (5-methyl-152, D-oxadiazol-3-yl) -6-propyl imidazo (1,2-a) pyrimidine (yield 87%), mp 185-185 , 50С „
Example A 6-Ethyl-5-methyl-2- (5-methyl-1,2,4-oxadiazol-3-yl -) - 7-methylthioimidazoO, 2-a) pyrimidine (89% yield), t „pl„ 209 -210 ° C.
PRI me R 5. 6,7,8,9-Tetrahydro-5-methoxy-2- (5-methyl-1,2,4-oxadiazol-3-yl) imidazo (1,2-a a) quinazoline (yield 75%), so pl. 218-222 ° C.
Compounds obtained by the proposed method have high anxiolytic activity, which was determined by a modification of the Geller and Seyfter method.
Data on the minimum effective doses (the minimum doses at which the effect appears compared to the control) are given in Table 1.
The compound of Example 2 was associated with the activity of a known compound.
N N
CH About IN; F
c2H5XT JTc
Q 5 0
five
,
five
five
by tests:
1. Suppression of ultrasound stress (A).
2. Suppression of leptazole convulsions (B).
3. Potentiating effect of phenobarbital (C).
4o Hold time on rotating drum (D).
In Test A, the compounds were administered intraperitoneally 30 minutes before the start of the experiment. In tests B, C and D, the compounds were administered orally 1 hour before the start of the experiment.
Table 2 shows the doses that provide a 50% effect.
As follows from the above data, the compounds obtained by the proposed method show anxiolytic activity exceeding the activity of the known compound (6 times).
The compounds of the invention belong to the group of low-toxic substances.

权利要求:
Claims (1)
[1]
Invention Formula
The method of producing imidazo (1,2-a) pyrimidines of the general formula
CL-X
N N
de Ry - 1,2,4-oxadiazolyl-3, substituted with C -C-alkyl, which, in turn, may be substituted with a few fluorine atoms, R2
and R-- is the same or different and is hydrogen, C ,, is C-alkyl or R, and R together is tetramal;
1650013
X - oxygen or cepaj
R. - C-C-alkyl, characterized in that the imidazo (1,2-a) pyrimidine of the general formula
FU-X
R xJVV0
R, W NH2
5R2
where X have the indicated meanings,
treated with dimethylacetamidodimethyl Yu acetal of the General formula
(CH30) 2CN (CH3) 2
where im610 11 indicated zn-D
h eni 15
interact with the salt where D is a C -C3-alkyl, which can
acidic hydroxylamine, the resulting be substituted by one or non-connection of the general formula with several fluorine atoms
Table 1
ExampleMinimum effective dose, mg / kg
15
210-50
35
410
510
Table 2
Dose, mg / kg Test
Connection- Known by compound Example 2
A0,63,5
B7,421
C10,549
D17200
Compiled by V. Volkov /
Editor A0 Ogar Tehred M. Morgancorrector T. Paliy
Order 1527 Circulation 247Subscription
VNIIPI State Committee for Inventions and Discoveries under the State Committee on Science and Technology of the USSR 113035, Moscow, Zh-35, 4/5 Raushsk nab.
Production and publishing plant Patent, Uzhgorod, st. Gagarin, 101
1650013

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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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GB848432073A|GB8432073D0|1984-12-19|1984-12-19|Chemical compounds|

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