The way to obtain 6,8-dimethyl-2-piperidinomethyl-2,3 - dihydrothiazolo-[2,3-f]xanthine

 

(57) Abstract:

The invention relates to an improved process for the preparation of 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-f] xanthine of the formula I, causing the induction of microsomal liver enzymes. 8-Romeoville subjected to interaction with 2-(N-piperidinomethyl)Tirana in the environment of dimethylformamide in the presence of sodium hydroxide at the boiling temperature of the reaction mixture. Cooled to room temperature and filtered target product with a yield of 65%, TPL238 - 240oC. the Invention allows to increase the output and to simplify the process. The compound obtained in two intragastric administration to mice-males causes a long, pronounced induction of microsomal liver enzymes, exceeding the number of parameters the effect of the reference inducer of microsomal enzymes of benzonal. 3 table.

The invention relates to the field of organic chemistry, namely to a process for the preparation of 6,8-dimethyl-2-piperidinomethyl-2,3 - dihydrothiazolo [2, 3-f] xanthine of the formula I

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which can find application in medicine.

A method of obtaining the compound I (lab code H-68).

1. Processing 8-Romeoville caustic receive the imidazole. L III. Synthesis and pharmacological activity of derivatives of imidazo[1,2-f]xanthine / Chem.-Pharm. journal.- 1971.- N 2.- S. 22 - 26. ]. The interaction of the potassium salt of 8-Romeoville with epimyocardium for 10 h are 8-bromo-1,3-dimethyl-7-(2,3-epithiopropyl)-xanthine with the release of 10% [Khaliullin F. A., Kataev C. A., Strokin Y. C. Interaction of halogenated xanthine and benzimidazole with epimyocardium / Dept. In VINITI 22.1 1.88, n 8223.- C. 88.- 5 C.]. Reaction of 8-bromo-1,3-dimethyl-7-(2,3-epithiopropyl)xanthine with piperidine for 3 h get the connection I with the release of 93%, TPL238 - 240oC [Khaliullin F. A., Mironenkov J. C., Gilmanov A. J. and other Synthesis and study of hypoglycemic activity of derivatives of 2,3-dihydrothiazolo[2,3-f]xanthine / Chem.-Pharm. journal.- 1994.- N 9.- S. 33 - 34]. The overall yield of the target compound I is equal to 92% 0.10 0.93 = 8.6%.

The disadvantages of the method are: low output (8.6%) of compound I; the complexity of the process: getting comes in three stages, the most common duration (13 h).

The purpose of the invention to increase the yield and simplify the process of obtaining 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3 - f]xanthine.

This goal is achieved by obtaining the compounds I by the method lies in the interaction of 8-Romeoville 2-ment of the mixture according to the scheme (see at the end of the description).

The following example illustrates how the described method of obtaining.

Example. A solution of 1.30 g (5 mmol) of 8-Romeoville, 0.79 g (5 mmol) of 2-(N-piperidinomethyl)Tirana and 0.28 g (5 mmol) of sodium hydroxide in 30 ml of dimethylformamide is boiled for 1 hour. Cooled to room temperature, the precipitation is filtered off, washed with water, dried.

Obtain 1.09 g (65%) of compound I with TPL238 - 240oC (isopropanol), which gives no depression of the melting temperature with the sample synthesized by a known method.

Found,%: C 53.92, H 6.39, N 20.75;

Calculated,%: C 53.71, H 6.31, N 20.88.

An NMR spectrum1H (CDCl3, TMS): 3.31 and 3.49 (3H, s, NCH3); 2.65 (J 8.0 Hz) and 2.70 (J 7.5 Hz) (2H,2J 12.7 Hz, 2-CH2N); 4.21 (J 7.1 Hz) and 4.44 (J 7.6 Hz) (2H,2J 11.3 Hz, NCH2); 4.57 - 4.67 (1H, m, SCH); 1.35 - 1.43 (2H, m, CCH2), 1.47 - 1.61 (4H, m, C(CH2)2); 2.37-2.45 (4H, m, N(CH2)2).

An NMR spectrum13With (CDCl3): 27.97 and 29.96 (6 - and 8-CH3); 49.78 (C3), 52.03 (C2), 62.17 (2-CH2); the carbon of the piperidine: 24.16 (CH2); 25.90 (2CH2); 54.86 (N(CH2)2); carbon xanthine 107.11; 151.40; 152.46; 153.72 and 156.91.

An NMR spectrum taken on the instrument Bruker AM-300

Thus, the described method is Holocene, reducing the number of stages to one (in terms of the known method three stages) and reducing the processing time to 1 hour (in terms of the known method 13 hours).

The effect of compound I (X-68) on the microsomal activity of the liver was studied in experiments on weinbrenner Mature mice-males using conventional test "geksenalovy sleep", which allows to indirectly estimate the functional activity of the mixed oxidase [Kasparov A. A., Sanotski I. C., 1986]. To avoid the Central influences on the duration of sleep (psychoactive and gipnosedativnogo effects) investigated the connection test "baritovogo sleep" [hazura centuries, Saratikov A. C., 1977].

As the comparison drug selected benzonal (1-benzoyl-5 - ethyl-5-fenilbarbiturovaya acid), which, along with phenobarbital is the reference inducer of microsomal enzymes, but significantly exceeds its ability to induce microsomal liver enzymes, and has a less pronounced effect gipnosedativny [Mashkovsky M. D., 1997, Navajeevan Etc., 1998].

Compounds were diluted in 2% starch suspension was administered intragastrically twice with an interval of 24 hours, a day after the last injection PR is 2">

Acute toxicity was determined after intragastric administration according to the method of J. Litchfield and F. Wilcoxon modification Prozorovsky C. B., 1962. Survival of animals was observed during the first day. LD50X-68 = 816 (734-892) mg/kg, which corresponds to 3 hazard class (moderately hazardous). Benzonal belongs to the same class of hazardous chemical substances LD50= 192 (162-223) mg/kg

X-68 in a wide range of doses caused a statistically significant reduction in the duration of geksenalovy sleep, a clear effect was observed even at a dose of 0.0005 mg/kg, which is 1/16324000 part from LD50the studied compounds (table. 1). As the table shows, the dependence of the effect of the dose of X-68 was not observed, which is not possible using conventional methods, to calculate the average effective dose and, consequently, therapeutic index of the compound.

Shortening geksenalovy sleep observed after double injection X-68, is not associated with effects on the Central nervous system, because the duration baritovogo sleep (barbitala - trudnootdelyaemoy inert compound, almost entirely, to 95%, output by the kidney in unchanged form) when a similar scheme and the doses did not differ from the values of the control group.

Introduction equitations the project was more pronounced and was superior to any of benzonal. So, in 1/100 of DL50benzonal had no significant effect, whereas X-68 caused shortening the duration geksenalovy sleep 70%; and in 1/20 from DL50the stimulation index of benzonal was 42%, X-68 - 89% (table.2).

We studied the connection, unlike benzonal, has a significantly longer inducing effect (table. 2). Shortening geksenalovy sleep, as the dose of 1/100 DL50(8 mg/kg) and a dose of 1/20 DL50(41 mg/kg) significantly and 8 days after injection, whereas the duration of the effect of benzene (1/20 DL50) no more than 2 days, and the dose of 1/100 DL50without being inducing, at 4-6 days after the last injection causes inhibition of liver microsomal enzymes (table. 3). When using benzonal in the dose that causes a clear induction of microsomal enzymes and, according to literature data, the most frequently used (35 mg/kg) [Navajeevan Etc., 1998], the effect is observed only 4 days (table. 3).

Induction of microsomal enzymes under the influence of X-68 confirmed in experiments directly quantify the level of cytochrome P-450 in rat liver by the method of Omura T. and Sato, R., 1962. The level of cytochrome P 450 after 2-fold intragastric administration X-68 (35 mg/kg) was significantly increased by 32% (X-68 - 657.36 dusiruumis effect, significantly superior benzonal therapeutic breadth, duration of action and more favorably low toxicity.

The way to obtain 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo [2,3-f]xanthine of the formula

< / BR>
including the use of 8-Romeoville, characterized in that the 8-Romeoville subjected to interaction with 2-(N-piperidinomethyl)Tirana in the environment of dimethylformamide in the presence of sodium hydroxide at the boiling temperature of the reaction mixture.

 

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