RU2161160C2 - Method of preparing 6,8-dimethyl-2-piepridino methyl-2,3-dihydrothiazolo [2,3-f] xanthine - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: described is improved method of preparing 6,8-dimethyl-2-piperidinomethy-2,3-dihydrothiazolo [2,3-f] xanthine of formula I which induces induction of microsomal liver enzymes. Bromotheophylline is reacted with 2-N-piperidinomethyl)chiiran in dimethyl formamide in the presence of potassium hydroxide at boiling temperature of reaction mixture. The whole is cooled to room temperature and the product with yield of 65% and melting temperature of 238-240 C is filtered off. Two-fold intragastric administration of the resulting compound into male mice causes lengthy, explicit induction of microsomal liver enzymes which is superior in some parameters over effect of standard inductor of microsomal benzonal enzymes. EFFECT: more efficient preparation method. 3 tbl

Description

которое может найти применение в медицине.The invention relates to the field of organic chemistry, and in particular to a method for producing 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo [2, 3-f] xanthine of the formula I

which may find application in medicine.

 A known method for producing compound I (laboratory code X-68).

1. Treatment of 8-bromteophylline with potassium hydroxide produces the potassium salt of 8-bromteophylline with a yield of 92% [Kochergin P. M., Linenko V. I., Tkachenko A. A. et al. Studies in the imidazole series. L III. Synthesis and pharmacological action of imidazo [1,2-f] xanthine derivatives / Chem. Zh. - 1971.- N 2.- S. 22-26.]. The interaction of the potassium salt of 8-bromotheophylline with epithiochlorohydrin for 10 h gives 8-bromo-1,3-dimethyl-7- (2,3-epithiopropyl) -xanthine with a yield of 10% [Haliullin F.A., Kataev V.A. , Strokin Yu.V. The interaction of halogenated xanthine and benzimidazole with epithiochlorhydrin / Dep. In VINITI 22.1 1.88, n 8223.- V. 88.- 5 p.]. The reaction of 8-bromo-1,3-dimethyl-7- (2,3-epithiopropyl) xanthine with piperidine for 3 hours to obtain compound I with a yield of 93%, _mp 238-240 ^o C [Haliullin F.A., Mironenkova Zh.V., Gilmanov A. Zh. Et al. Synthesis and study of the hypoglycemic activity of 2,3-dihydrothiazolo [2,3-f] xanthine derivatives / Chem. J.- 1994.- N 9.- S. 33-34]. The total yield of target compound I is 92% • 0.10 • 0.93 = 8.6%.

 The disadvantages of the method are: low yield (8.6%) of compound I; the complexity of the process: the production proceeds in three stages, a large total duration (13 hours).

 The purpose of the invention is 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 compound I by the method consisting in the interaction of 8-bromotheophylline with 2- (N-piperidinomethyl) thiran in dimethylformamide medium in the presence of caustic potassium at the boiling point of the reaction mixture according to the scheme (see the end of the description).

 The following example illustrates the described production method.

 Example. A solution of 1.30 g (5 mmol) of 8-bromotheophylline, 0.79 g (5 mmol) of 2- (N-piperidinomethyl) thiran and 0.28 g (5 mmol) of potassium hydroxide in 30 ml of dimethylformamide is boiled for 1 hour. It is cooled to room temperature, the precipitate formed is filtered off, washed with water, and dried.

Obtain 1.09 g (65%) of compound I with T _PL 238-240 ^o C (isopropanol), which does not give depression of the melting temperature with the sample synthesized by the known method.

Found,%: C 53.92, H 6.39, N 20.75;
Calculated,%: C 53.71, H 6.31, N 20.88.

¹ H NMR Spectrum (CDCl ₃ , TMS): 3.31 and 3.49 (3H, s, NCH ₃ each); 2.65 (J 8.0 Hz) and 2.70 (J 7.5 Hz) (2H, ² J 12.7 Hz, 2-CH ₂ N); 4.21 (J 7.1 Hz) and 4.44 (J 7.6 Hz) (2H, ² J 11.3 Hz, NCH ₂ ); 4.57- 4.67 (1H, m, SCH); 1.35-1.33 (2H, m, CCH ₂ ); 1.47-1.61 (4H, m, C (CH ₂ ) ₂ ); 2.37-2.45 (4H, m, N (CH ₂ ) ₂ ).

¹³ C NMR Spectrum (CDCl ₃ ): 27.97 and 29.96 (6- and 8-CH ₃ ); 49.78 (C ₃ ), 52.03 (C ₂ ), 62.17 (2-CH ₂ ); piperidine carbons: 24.16 (CH ₂ ); 25.90 (2CH ₂ ); 54.86 (N (CH ₂ ) ₂ ); xanthine carbons 107.11; 151.40; 152.46; 153.72 and 156.91.

NMR spectrum recorded on a Bruker AM-300 instrument
Thus, the described production method allows you to: increase the yield of compound 1 to 65% (in the conditions of the known method 8.6%); to simplify the production process by reducing the number of stages to one (in the conditions of the known method, three stages) and reducing the duration of the process to 1 hour (in the conditions 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 non-inbred mature male mice using the generally accepted hexenal sleep test, which allows indirectly judging the functional activity of mixed oxidases [Kasparov A.A., Sanotsky I.V. , 1986]. In order to exclude central influences on the duration of sleep (psychostimulating and hypnotic effects), the compound was studied in the test of "barbital sleep" [Gatsura VV, Saratikov AS, 1977].

 Benzonal (1-benzoyl-5-ethyl-5-phenylbarbituric acid), which, along with phenobarbital, is a reference inducer of microsomal enzymes, but significantly surpasses it in its ability to induce microsomal enzymes of the liver and has a less pronounced hypnosative effect, was chosen as the comparison drug [ Mashkovsky M.D., 1997, Novozheeva T.P., 1998].

 Compounds were diluted in 2% starch suspension, injected twice intragastrically with an interval of 24 hours, a day after the last injection, testing was performed. Control animals received 2% starch suspension in equivolume amounts.

Acute toxicity was determined by intragastric administration according to the method of Litchfield J. and Wilcoxon F. as modified by Prozorovsky VB, 1962. Survival of animals was observed during the first day. LD ₅₀ X-68 = 816 (734-892) mg / kg, which corresponds to hazard class 3 (moderately hazardous). Benzonal belongs to the same class of chemically hazardous substances LD ₅₀ = 192 (162-223) mg / kg.

X-68 in a wide range of doses caused a statistically significant decrease in the duration of hexenal sleep, a clear effect was observed even at a dose of 0.0005 mg / kg, which is 1/16324000 part of the LD _{50 of the} studied compound (Table 1). As can be seen from the table, the dependence of the effect on the dose of X-68 was not observed, which did not allow, using conventional methods, to calculate the average effective dose and, accordingly, the therapeutic index of the compound.

 The shortening of hexenal sleep observed after twice administration of X-68 is not associated with an effect on the central nervous system, since the duration of barbital sleep (barbital is a difficult metabolizable inert compound, almost completely, up to 95%, excreted by the kidneys unchanged) with a similar scheme and doses of administration is not differed from the values of the control group.

The introduction of equitoxic doses of benzonal and X-68 revealed significant advantages of the described compound: the observed inducing effect was more pronounced and exceeded that of benzonal. So, in 1/100 of DL _50, benzonal did not have a noticeable effect, while X-68 caused a shortening of the duration of hexenal sleep by 70%; and in 1/20 of DL _50, the benzonal stimulation index was 42%, X-68 - 89% (Table 2).

The studied compound, in contrast to benzonal, has a significantly longer inducing effect (Table 2). Shortening of hexenal sleep, both at a dose of 1/100 DL ₅₀ (8 mg / kg) and at a dose of 1/20 DL ₅₀ (41 mg / kg), is also reliable on the 8th day after administration, while the duration of the effect of benzene (1/20 DL ₅₀ ) no more than 2 days, and a dose of 1/100 DL ₅₀ , not being inducing, 4-6 days after the last injection causes inhibition of microsomal liver enzymes (Table 3). When using benzonal in a dose that induces a clear induction of microsomal enzymes and, according to the literature, the most frequently used (35 mg / kg) [Novozheeva TP, 1998], the effect is registered only 4 days (Table 3).

 Induction of microsomal enzymes under the influence of X-68 was confirmed in experiments of direct quantitative determination of 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 of X-68 (35 mg / kg) significantly increased by 32% (X-68 - 657.36 ± 38.22 mM / g of tissue; control - 499.17 ± 39.99 mM / g of tissue; P <0.05).

 Thus, X-68 has a pronounced long-lasting inducing effect, significantly exceeds benzonal in therapeutic breadth, duration of action and compares favorably with lower toxicity.

Claims (1)

The method of obtaining 6,8-dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo [2,3-f] xanthine of the formula

including the use of 8-bromteophylline, characterized in that 8-bromteophylline is reacted with 2- (N-piperidinomethyl) thiran in dimethylformamide medium in the presence of caustic potassium at the boiling point of the reaction mixture.

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