Method of producing derivatives of triazopyrimidine or salts thereof with methanesulfo acid

专利摘要:
The invention relates to triazolopyrimidine (TP) derivatives, in particular the preparation of compounds of the general formula T 1, O Ro where A is pyridinyl, R and R independently, C, -C4-alkyl, or their salts with methanesulfonic acid, which have cardiotonic activity and can be used in medicine. The goal is to create more active substances of the specified class. Synthesis of TP is carried out from 2-hydrazino-4-oxo-6- (3-pyridyl) pyrimidine and the corresponding ethyl ester of R5-acid in butanol medium at boiling, followed by alkylation of R-alkyl halide in dimethylformamide in the presence of sodium hydride at 70 C. If necessary, the target product is converted into salt by treatment with methanesulfonic acid. New TPs exhibit better inotropic activity than amrinone, with good tolerability and low toxicity. 1 tab. SU) from D: 00 O5 SL
公开号:SU1347865A3
申请号:SU843767330
申请日:1984-07-25
公开日:1987-10-23
发明作者:Бартелеми Жерар；Валла Жан-Ноэль；Алло Андре
申请人:Санофи (Фирма)；
IPC主号:

专利说明:

eleven
This invention relates to a process for the preparation of new triazolo pyrimidine derivatives of the general formula
l N
(I)
where A is an unsubstituted pyridine radical,
R,
R, independently of one another, an alkyl residue containing 1-4 carbon atoms with a straight chain,
or their salts with methanesulfonic acid, with cardiotonic activity.
The aim of the invention is to develop a method for producing new triazolopyrimidine derivatives having a higher level of cardiotonic activity as compared with structural aiia. ioroM is 3-amino-5- (A- -pyridinyl) and -pyridine (amrinone).
Example 1. 3-Methyl-5-oxo-7- - (3-pyryl, yl) -triazolo 4, 3-a pyrimidine - 1H SL - 3-pyridyl, R, - H, R 7 CH 3).
23 g (0.113 mol) 2-hydroxide of razino-4-oxo-6- (3-pyridyl) -pyrimidine, 73.6 ethyl acetoacetate and 500 ml of n-butanol are mixed. The reaction mixture is boiled for 4 hours, then filtered and the precipitate is washed with ether. 24 g of crystals are obtained (yield 93%). M.p. 260 С
Example 2, 3-Metich-5-oxo-7- (2-pyridyl) -triazolo 4, 3-aj pyri-M1 Schin-1I (A - 2-pyridig1, R, - H-,
R,
- CH j).
In accordance with the conditions specified in Example 1, this compound is obtained from 2-hydrazino-4-oxo-6- (2-pyridyl) -pyrimidine and ethyl acetoacetate by heating for 4 hours at. White crystals are obtained (yield 91%). Mp. 260 s.
Example 3. 3-Methyl-5-oxo-7- - (4-pyridyl) -triazolo 4, 3-a pyrimidine-111 CA - 4-pyridyl, R - H, RO-CHj).
The compound from 2-hydrazino-4-oxo-6- (4-pyridyl) pyrimidine and ethyl acetoacetate is obtained by boiling for 3 hours, in accordance with the conditions specified in Example 1.
478652
Light yellow crystals are obtained (yield 83%). M.p. 7260 C.
Example 4. 3-Ethyl-5-oxo-7-c- (2-pyridyl) -triazolo 4,3-a pyrimidine-H1H (A - 2-pyridyl, R, - H, RJ - CHj-CHP.
3 according to the conditions specified in example 1, get this
10 a compound from 2-hydrazino-4-oxo-6- (2-pyridyl) pyrimidine (mp) and orthopropionethyl by boiling for 2 hours. White crystals are obtained (yield 85%).
15 T. pl. 260 S.
Example 5. 3-Ethyl-5-oxo-7- - (3-pyridyl) -triazolo C4,3-a pyrimi- (A - 3-pyridyl, R, - H-, Ri -).
20 According to the conditions specified in Example 1, this compound is obtained from 2-hydrazino-4-oxo-6- (3-pyridyl) -pyrimidine and orthopropionate ethyl by boiling
5 2h Light yellow crystals are obtained (yield 63%). M.p. At 260 ° C.
Example 6. 3-ETHYL-5-OXO-7- -7 (4-liridyl) -triazolo 4,3-aJ pyrimidine - Hi J (A - 4-pyridyl, R, - P-,
30 R-, - SNO-SPZ).
In accordance with the conditions specified in Example 1, this compound is obtained from 2-hydrazino-4-oxo-6- (4-pyridyl) -pyrimidine and orthopropyl patethyl by boiling for 2 hours. Beige-colored crystals are obtained. %). M.p. -.
Example 7. 1-Ethyl-3-methyl-5-oxo-7- (3-pyridyl) -triazolo 4,3-a j
40 pyrimidine (A - 3-pyridyl, R - СНз-СПз, К; - С1Ц).
In a flask containing 1.36 g (0.028 mol) of a 50% suspension of patyrid hydride in 50 ml of dimethyl forms 45 and DMF under nitrogen, a solution of 6.4 g (0.028 mol) of 3-methyl 3 is introduced -5-Oxo-7- (3-pyridyl) -triazolo 4, 3-a Zpirimidine-III J in 400 ml of DKP.
50 At the end of hydrogen degassing, the reaction mixture is heated to 70 ° C, after which 2.2 ml (0.028 mol) of ethyl bromide are slowly introduced and the same temperature of the mixture is maintained for 2 hours. DMF is removed, washed with water, then extracted with ethyl acetate. The organic solution is dried over magnesium sulphate, evaporated and crystallized from heptane.
J13
Fluffy white crystals are obtained (yield 69%). T, pl. 144 ° C.
To obtain the methanesulfonate, 5 g (0.0196 mol) of the obtained compound, 20 ml of water and 1.88 g (0.0196 mol) of methanesulfonic acid are mixed. By lyophilization of the solution, a powder is obtained, which, after washing with ether, is dried under vacuum.
6.9 g of a white powder are obtained (yield 98.5%). The resulting salt is crystallized with half of the water molecule, m.p. .
Example 8. 1-Ethyl-3-methyl-5-oxo-7- (4-pyridyl) -triazolo 4,3-aj-pyrimidine (A - 4-pyridyl, R, - CH, - CHj, R 2 - CH).
In accordance with the conditions outlined in Example 7, this compound is prepared using 3-methyl-5-oxo-7- (4-pyridyl) triazolo 4,3-a pyrimidine-PN and ethyl bromide. Whitish crystals are obtained (yield 53%). IT. square 160-162 C.
Example 9. 1-Propyl-3-methyl-5-oxo-7- (2-pyridyl) -triazolo 4,3-a pyrimidine (A is 2-pyridyl, R is CHj — CH. — CH,; Rj is CH ,,).
In accordance with the conditions specified in Example 7, this compound is prepared using 3-methyl-5-oxo-7- (2-pyridyl) -thiazolo f4,3-aJ pyrimidine-1H and propyloid. White crystals are obtained (yield 80%). M.p. 124 C.
Example 10. 1-Methyl-3-methyl-5-OXO-7- (3-pyridyl) -triase, -3-a pyrimidine methanesulfonate (A-3-pyridyl, R, SND, R, -CH, ).
According to the conditions specified in Example 7, this compound is prepared using 3-methyl-5-oxo-7- (3-pyridyl) -triazolo 4,3-a pyrimidine-1H and methyl iodide. Salt is then prepared using methyl sulfonic acid. Whitish crystals are obtained (yield 62%). M.p. bases of 208 ° C.
Example 11. 1-Propyl-3-methyl-5-o-cco-7- (3-pyridyl) -thiazolo-, 3-aJ pyrimidine methanesulfonate (A - 3-pyridyl R - CH., R2 - CH}).
In accordance with the conditions specified in Example 7, this compound is prepared using 3-methyl-5-oxo-7- (3-pyridyl) -triazolo 4,3-a pyri-1-1-Din-1H and propyl bromide. Then by
865
the salt is obtained with megansulfonic acid.
A crystalline, white color is obtained (yield 73%). M.p. 108 C.
-J
Example 12. 1-Methyl-3-ethyl-5-OXO-7- (4-pyridyl) -triazolo 4,3-a pyrimidine methanesulfonate (A - 4-pyridyl, R, - SLC, R; -,). 0 According to the conditions specified in Example 7, this compound is prepared using 3-ethyl-5-oxo-7- (4-pyridyl) -triazolo 4,3-a pyrimidine-1H and methyl iodide. The salt is then prepared using methanesulfoxide-lot.
A crystal is obtained; white (65% yield). M.p. .
The results of toxicological and pharmacological experiments show low toxicity, good tolerability, as well as cardiotonic activity of the derivatives (I).
Toxicological study. 5 During the experiments on acute, chronic, subchronic or delayed toxicity performed on various species of animals (mice, rats and rabbits), the derivatives of formula 0 (I) show excellent porosity, no visible abnormalities or speed a with biochemical and microscopic analyzes performed during and after the experiment.
Pharmacological study.
The cardiotonic activity of a drug derived from compounds (I) is revealed by studying a positive inotropic effect.
In albino guinea pigs (Dun-kin-Harfley), males and females weighing 600-800 g, after rupturing the neck braces, opening the chest and pericardial rupture, the right atrium is quickly removed and placed in a nutritional bath. Compound (1) in the amount of 0.5 ml is poured into a bath with organ 0 with a capacity of 50 ml after dissolving in normal hydrochloric acid. The final pH of the nutrient solution is increased by the end of each experiment.
The following 55 parameters are noted on the polygraph: the developed voltage (isometric myograph), the contractility rate, and the relaxation rate calculated by the derivative of the voltage with respect to time. Curve
513
developed voltage also allows the frequency of contractions to be determined.
The effect of derivatives (I) was obtained at doses ranging from 10 to 10 MOL / L (M / L).
The results are shown in the table.
It has been found that the developed voltage gradually increases to 10 M / l with maximum effect at 2 10-M / l for the derivative of example 7 (-t-197%) and at 10 M / l for the derivative of example 8 (+129 %), according to example 9 (145%), according to example 10 (130%), according to example 11 (110%) and according to example 12 (114%), the frequency of contractions does not vary with different doses of the test compound, the rate of contraction and relaxation proportional to the evolution of developed stress.
The total duration of all effects is 30 min.
Toxicological and pharmaceutical studies have shown low toxicity of the compound (I), their good tolerability, as well as their interesting cardiotonic activity, which allow these compounds to be used in human therapy and in veterinary medicine.
Each single dose of dosage contains mainly 0.050-1.00 g of acousta substance. Doses administered during the day can vary from 0.050 to 3.00 g of the active substance, depending on, the patient and the severity of the disease to be treated.
The drug can have tablets} (administration of its oral HbW, 1, core: g "tablets and iodine, capsules, drops, granules or syrup. It is possible to use means of recalgium (suppositories) and parenteral administration (injection solutions).
Drozh.: "1PO11 tablets: the preparation according to Example 5 0,200 g - excipient - starch, beef medicinal sugar, carbonate; 1 ti, t.pk, magnesium steadrate, gum arabic, carnauba wax.
Tablets: Derivative according to Example 2 0.250 g, excipient — erythrosine, tragacanth, pyenic starch, talc, lactose, hp “powdered sugar.
Gelatin capsule: a derivative of 0.500 g, - the receptor - Telk, stearic acid, magnesium stearate.
five
Suppositories: a derivative of O, 200 g, semi-synthetic triglycerides in an amount sufficient to form a single suppository.
Injection solutions: production-. But 0.250 g, isotonic solvent in an amount sufficient to produce 2 ml.
The compounds of formula (I) show a more significant inotropic activity in the isolated atrial of the guinea pig compared to the cardiotonic preparation amrinone at identical concentrations.
A slight increase in the frequency of contractions was shown by amrinone and preparations of formula (I).
Possess positive inotropic
action, the specified drug also has a significant cardiotonic action.
25

权利要求:
Claims (1)
[1]
Invention Formula
The method of producing triazolopyrimidine derivatives of the general formula
N
A f
T
Oh
RI
1-de A - unsubstituted pyridine radical j
R, and
R. - independently from each other, an alkyl residue containing 1-4 carbon atoms with a straight chain,
or their salts with methanesulfonic acid, characterized by the fact that
, T (1
NH
about
where L has the indicated values, are condensed with the orthoester of the general formula OC HS
OS2N5
1 de RO has the indicated values, and the n-butanyluloid medium at the boiling point of the mixture, is then alkylated with al l with 1l halide of the general formula.
where r | has the indicated values
X is chlorine or bromine,
in dimethylformamide in the presence of sodium hydride at with the pos-J.
Derived according to example 7
Derived according to example 8
Derived according to example 9 402
27 19 33
48 6 73 17 145 19
following, if necessary, the conversion of the target product into a salt by treating with methanesulfonic acid.
4 34
35 70 153
43 48 140
Derivative by

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JP2020504743A|2016-12-22|2020-02-13|カデント セラピューティクス，インコーポレーテッド|NMDA receptor modulator and use thereof|

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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FR8312443A|FR2549834B1|1983-07-25|1983-07-25|TRIAZOLO-PYRIMIDINE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION AS TONICARDIANS|

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