RU2750867C1 - Guanine derivatives - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to the field of chemistry, specifically to new guanine derivatives of the formula indicated below, which can be used as antiviral agents. In the formula, R is C1-C6 alkyl.

EFFECT: producing guanine derivatives that can be used as antiviral agents.

1 cl, 1 dwg, 4 tbl, 4 ex

Description

The invention relates to the field of chemistry and relates to the production of new derivatives of guanine.

Valacyclovir is acyclovir L-valine ester. In the human body, valacyclovir is rapidly and completely converted to acyclovir, under the influence of the enzyme valacyclovyl hydrolase. Acyclovir is widely used for the treatment and prevention of viral infections (Goodman and Gilman's, The Pharmacological Basis of Therapeutics, pp. 1193-1198, 9th ed., 1996). Structural formula of valacyclovir ([1-valine, 2 - [(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl ester], CAS No. 124832-26-4) :

From the USSR patent SU 1634138 A3, a method for producing valacyclovir, which has antiviral properties, is known.

Taking into account the need to develop new antiviral agents and the presence of antiviral properties in valacyclovir (which is also a guanine derivative, like the claimed compounds), there is a need for the synthesis of new guanine derivatives that could be effective antiviral agents.

The objective of the present invention is to expand the arsenal of chemical derivatives of guanine.

The following patents and applications are known which constitute the prior art of the claimed invention:

- from US application US 20080281099 A1 and international application WO 2005/073233 A1 - a method for purifying valacyclovir hydrochloride is known;

- from the international application WO 2005/085247 A1 - crystalline forms of valacciclovir hydrochloride are known;

- from the international application WO 2018/122626 A1 - derivatives of palmitic acid are known;

- from the application US US 4957924 B1 - known compound valacyclovir and its derivatives;

- from the application US US 5686611 B1 - known derivatives of valacyclovir (see example 6,7,8,14,18,37);

- from US applications US 6,825,348 B2 and US 7,553,812 B2 - valaciclovir derivatives are known.

The closest technical solution to the claimed invention is the compound N-formyl-valacyclovir, described in US patent US 7629461 B2.

To solve this problem, compounds with the following structural formula are proposed:

As R, C1-C6 alkyl can be used. "Alkyl" means an aliphatic hydrocarbon linear group with 1-6 carbon atoms in the chain.

The invention can be illustrated by examples of its implementation, confirming industrial applicability and contributing to a more accurate and complete understanding of its essence. The person skilled in the art will recognize possible modifications and substitutions that do not go beyond the scope of the claims indicated in the claims. These examples confirm but do not limit the claimed invention.

Example 1. A method of obtaining N ^α- palmitoyl-valacyclovir.

In a three-necked flat-bottomed flask with a capacity of 200 ml, equipped with a magnetic stirring element in a Teflon sheath, an immersion thermometer, a dropping funnel and a calcium chloride tube, 7.40 g (0.020 mol) of valacyclovir hydrochloride were placed and 25 ml of N-methylpyrrolidone was added. In this case, the taken valacyclovir hydrochloride is almost completely dissolved. After that, the flask with the contents was immersed in a cooling ice bath and the reaction mixture was cooled to ~ 5 ° C. Next, 4.20 g (0.0415 mol) of triethylamine was added to the reaction mixture with vigorous stirring, while observing the precipitation of a white precipitate of triethylamine hydrochloride, after which 5.61 g (0.020 mol) of palmitoyl chloride was slowly added dropwise from the dropping funnel, making sure that the temperature of the reaction mixture does not rise above 7 ° C. The addition of palmitic acid chloride continued for 20 minutes. After the addition of palmitoyl chloride was complete, the reaction mixture was stirred at 5-7 ° C for another half hour, and then the cooling bath was removed, the reaction mixture was brought to room temperature, and the mixture was stirred under these conditions for another 2 hours. Next, the contents of the reaction flask were quantitatively transferred with stirring into a beaker containing 250 ml of deionized water. After that, an abundant white curd precipitate fell out, which was filtered onto a filter with a glass porous plate. The filter cake was thoroughly washed with water (3 × 15 ml) and dried to constant weight in a vacuum desiccator (at a residual pressure of 1 mm Hg) over phosphorus pentoxide. As a result, 11.27 g of white fine-crystalline substance was obtained (the calculated theoretical yield of the target palmitoyl-valacyclovir was 11.25 g), which, according to elemental analysis, NMR and IR spectroscopy, was the desired N ^α- palmitoyl-valacyclovir with a small (~ 5% ) impurity of N ^α- palmitoyl-valine (which could be expected given that the starting valacyclovir hydrochloride contained, according to NMR spectroscopy data, an impurity of valine hydrochloride).

For purification, the reaction product was recrystallized from a mixture of tetrahydrofuran-dimethylformamide. After recrystallization, 5.65 g of a finely crystalline white substance was obtained, which, according to the results of: elemental analysis (see Table 1), NMR and IR spectroscopy, was identified as N ^α- palmitoyl-valacyclovir.

The IR spectrum of N ^α- palmitoyl-valacyclovir (for a KBr tablet) is shown in Fig. 1: a small smoothed peak in the region of 3465 cm ^-1 (overtone of stretching vibrations of the ester carbonyl); an absorption band of medium intensity with a maximum of 3315 cm ^-1 (stretching vibrations of the NH guanidine group of acyclovir); an absorption band of average intensity 3191 cm ^-1 (stretching vibrations NH of the amide group of palmitoyl-valacyclovir); a narrow unresolved peak of average intensity at 2958 cm ^-1 and a narrow intense peak at 2921 cm ^-1 (stretching vibrations of the CH metal group); very narrow intense peak 2852 cm ^-1 (stretching vibrations of CH methylene groups); a small smoothed peak at 2731 cm ^-1 (overtone of OH bending vibrations); narrow intense peak 1730 cm ^-1 (stretching vibrations of the ester carbonyl group: C = O valacyclovir); narrow unresolved peak of average intensity at 1687 cm ^-1 and rather intense absorption bands at 1647 cm ^-1 and 1632 cm ^-1 (stretching vibrations of carbonyl groups of amide groups of palmitoyl-valacyclovir - Amide I band); narrow unresolved peak of low intensity 1575 cm ^-1 and narrow peak of average intensity 1540 cm ^-1 (bending vibrations: NH amide groups of palmitoyl-valacyclovir - Amide II band); palisade of narrow absorption bands in the region of 1488, 1468, 1390, 1348 and 1311 cm ^-1 (deformation vibrations CH); palisade of absorption bands of low and medium intensity 1186, 1155, 1132 and 1107 cm ^-1 (stretching vibrations of C-O bonds).

Structural formula of N ^α- palmitoyl-valacyclovir:

The NMR spectrum of H ¹ N ^α- palmitoyl-valacyclovir was recorded on a Bruker AVANCE 400 instrument with a maximum operating frequency of 400 MHz and a magnetic field of 9.37 T in a de-DMSO solution with an approximate concentration of 40 mg per 0.9 ml.

Refined numerical values of chemical shifts were obtained by correcting the observed signals with a DMSO signal in the spectrum and are presented in ppw; phase correction was not performed. δ _H (400MHz, d ₆ -DMSO): 10.66 (s, 1H, H ₇ ); 8.03 (d, J 7.6Hz, 1H, H ₂₀ ); 7.81 (s, 1H, H ₂ ), 6.54 (s, 2H, H ₂₁ ); 5.35 (s, 2H, H ₁₀ ); 4.22 (d, J 11.6Hz, 1H, H _13a ); 4.12 (dd, J ₁ 6.8Hz, J ₂ 6.8Hz, 2H, H _13b , H ₁₃ ); 3.66 (s, 2H, H ₁₂ ); 2.14 (dd, J ₁ 6.8Hz, J ₂ 7.6 Hz, J ₃ 7.6 Hz, 2H, H ₃₆ ); 1.94 (dd, J ₁ 6.4 Hz, J ₂ 6.4 Hz, J ₃ 6.4 Hz, 1H, H ₁₇ ); 1.58-1.38 (br s, 2H, H ₂₃ ); 1.38-1.06 (br s, 24H, H ₂₄ -H ₃₅ ); 0.82 (dist t, J ₁ 7.6 Hz, J ₂ 3.6 Hz, 9H, H ₁₈ , H ₁₉ , H ₃₇ ).

δ _C (100MHz, d ₆ -DMSO): 172.59 C ₂₂ ; 171.60 C ₁₅ ; 156.69 C ₈ ; 153.83 C ₆ ; 151.33 C ₄ ; 137.55 C ₂ ; 116.43 C ₉ ; 71.67 C ₁₀ ; 66.41 C ₁₃ ; 62.93 C ₁₂ ; 57.11 C ₁₆ ; 34.73 C ₂₃ ; 31.22 C ₃₅ ; 29.66 C ₁₇ ; 28.98 C ₂₈ -C ₃₃ ; 28.89 C ₂₇ ; 28.68 C ₃₄ ; 28.64 C ₂₆ ; 28.50 C ₂₅ ; 25.21 C ₂₄ ; 22.02 C ₃₆ ; 18.77 C ₁₈ ; 18.01 C ₁₉ ; 13.86 C ₃₇ .

Example 2. A method of obtaining N ^α -lauroyl-valacyclovir.

In accordance with the method of obtaining N ^α -lauroyl-valacyclovir, given in example 1, to obtain N ^α- lauroyl-valacyclovir, the following actions were performed: to a cooled solution of 7.40 g (0.020 mol) of valaciclovir hydrochloride hemihydrate in 25 ml of N-methylpyrrolidone added with stirring, first 4.20 g (0.0415 mol) of triethylamine, while observing the precipitation of a white precipitate of triethylamine hydrochloride, and then 4.38 g (0.020 mol) of lauroyl chloride was slowly added from the dropping funnel, making sure that the reaction temperature the mixture was in the range of 5-7 ° C. After completion of the addition of lauroyl chloride and subsequent stirring of the reaction mixture, first with cooling and then at room temperature, the reaction suspension was quantitatively transferred with stirring into 250 ml of water. The resulting white curdled precipitate was filtered onto a filter with a glass porous plate, the precipitate on the filter was thoroughly washed with water and dried in a vacuum desiccator over phosphorus pentoxide to constant weight. As a result, 10.14 g of white fine-crystalline product was obtained (calculated theoretical yield of N ^α -lauroyl-valacyclovir - 10.12 g), which was purified by recrystallization from a mixture of tetrahydrofuran-dimethylformamide. As a result of recrystallization, 6.02 g of a white powdery product was obtained, which, according to elemental analysis and NMR spectroscopy, was identified as the target N ^α -lauroyl-valacyclovir.

Structural formula of N ^α -lauroyl-valacyclovir:

The NMR spectrum of H ¹ N ^α -lauroyl-valacyclovir was recorded on a Bruker AVANCE 400 instrument with a maximum operating frequency of 400 MHz and a magnetic field of 9.37 T. in a de-DMSO solution with an approximate concentration of 40 mg per 0.9 ml.

Refined numerical values of chemical shifts were obtained by correcting the observed signals with the DMSO signal in the spectrum and are given in ppm; phase correction was not performed. δ _H (400MHz, d ₆ -DMSO): 10.66 (br. s, 1H, H ₆ ); 8.02 (d, J 7.6Hz, 1H, H ₂₀ ); 7.81 (s, 1H, H ₂ ), 6.54 (s, 2H, H ₂₁ ); 5.35 (s, 2H, H ₁₀ ); 4.21 (dist d, J 11.6 Hz, 1H, H _13a ); 4.12 (dist dd, J _H16 6.0Hz, J _H13 11.8Hz, 2H, H _13b , H ₁₆ ); 3.66 (s, 2H, H ₁₂ ); 2.13 (quart, J ₁ 7.3Hz, J ₂ 15.0 Hz, 2H, H ₂₃ ); 1.94 (m, J ₁ 6.32 Hz, J ₂ 12.61 Hz, 1H, H ₁₇ ); 1.58-1.38 (br. S, 2H, H ₂₄ ); 1.38-1.06 (br. S, 16H, H ₂₅ -H ₃₂ ); 0.82 (dist t, J ~ 3.6 Hz, 9H, H ₁₈ , H ₁₉ , H ₃₃ ).

δ _C (100MHz, d ₆ -DMSO): 172.59 C ₂₂ ; 171.60 C ₁₅ ; 156.69 C ₅ ; 153.83 C ₇ ; 151.33 C ₉ ; 137.55 C ₂ ; 116.43 C ₄ ; 71.67 C ₁₀ ; 66.41 C ₁₃ ; 62.93 C ₁₂ ; 57.11 C ₁₆ ; 33.56 C ₂₃ ; 31.34 C ₃₁ ; 29.66 C ₁₇ ; 29.03 C ₂₈ -C ₂₉ ; 28.87 C ₂₇ ; 28.77 C ₃₀ ; 28.69 C ₂₆ ; 28.50 C ₂₅ ; 24.10 C ₂₄ ; 22.11 C ₃₂ ; 18.77, 18.01 C ₁₈ , C ₁₉ ; 13.48 C ₃₃ .

Example 3. A method of obtaining N ^α -myristoyl-valacyclovir.

In accordance with the methods of preparation given in examples 1 and 2: when using 4.94 g (0.020 mol) of myristic acid chloride (myristoyl chloride) as an acylating agent, 10.72 g of a white powdery product was obtained (calculated theoretical yield of N ^α -myristoyl derivative valacyclovir = 10.68 g), the recrystallization of which from a mixture of tetrahydrofuran-dimethylformamide gave 5.84 g of a finely crystalline white substance, which, according to elemental analysis and NMR spectroscopy, was identified as the target product - N ^α -myristoyl-valacyclovir.

Structural formula of N ^α -myristoyl-valacyclovir:

The NMR spectrum of H ¹ N ^α -myristoyl-valacyclovir was recorded on a Bruker AVANCE 400 instrument with a maximum operating frequency of 400 MHz and a magnetic field of 9.37 T. in a de-DMSO solution with an approximate concentration of 40 mg per 0.9 ml.

Refined numerical values of chemical shifts were obtained by correcting the observed signals with the DMSO signal in the spectrum and are given in ppm; phase correction was not performed.

δ _H (400MHz, (d ₆ -DMSO): 10.66 (br. s, 1H, H ₆ ); 8.02 (d, J 7.6 Hz, 1H, H ₂₀ ); 7.81 (s, 1H, H ₂ ), 6.54 ( s, 2H, H ₂₁ ); 5.35 (s, 2H, Н ₁₀ ); 4.21 (dist d, J 11.6 Hz, 1H, H ₁₃ ); 4.12 (dist dd, J _H13 6.0 Hz, J _H13 11.8 Hz, 2H, H _13b , H ₁₆ ); 3.66 (s, 2H, H ₁₂ ); 2.13 (quart, J ₁ 7.3Hz, J ₂ 15.0 Hz, 2H, H ₂₃ ); 1.94 (m, J ₁ 6.32 Hz, J ₂ 12.61 Hz , 1H, H ₁₇ ); 1.58-1.38 (br. S, 2H, H ₂₄ ); 1.38-1.06 (br. S, 20H, H ₂₅ -H ₃₄ ); 0.82 (dist t, J ~ 3.6 Hz, 9H, H ₁₈ , H ₁₉ , H ₃₅ ).

δ _C (100MHz, d ₆ -DMSO): 172.59 C ₂₂ ; 171.60 C ₁₅ ; 156.69 C ₅ ; 153.83 C ₇ ; 151.33 C ₉ ; 137.55 C ₂ ; 116.43 C ₄ ; 71.67 C ₁₀ ; 66.41 C ₁₃ ; 62.93 C ₁₂ ; 57.11. C ₁₆ ; 33.55 C ₂₃ ; 31.34 C ₃₃ ; 29.66 C ₁₇ ; 29.07 C ₂₅ -C ₂₈ ; 28.84 C ₂₉ 28.77 C ₃₀ ; 28.66 C ₃₁ ; 28.48 C ₃₂ ; 24.09 C ₂₄ ; 22.09 C ₃₄ ; 18.77, 18.01 C ₁₈ , C ₁₉ ; 13.47 C ₃₅ .

Example 4. A method of obtaining N ^α -stearoyl-valacyclovir.

In accordance with the methods of preparation given in examples 1 and 2: when using 6.06 g (0.020 mol) of stearic acid chloride (stearoyl chloride) as an acylating agent, 11.84 g of a white lumpy product was obtained (calculated theoretical yield of N ^α -stearoyl derivative valacyclovir - 11.80 g), the recrystallization of which from a mixture of tetrahydrofuran-dimethylformamide gave 6.5 g of a fine-crystalline powdery product of white color, which, according to elemental analysis and NMR spectroscopy, was identified as the target product - N ^α -stearoyl-valacyclovir.

Structural formula of N ^α -stearoyl-valacyclovir:

The NMR spectrum of H ¹ N ^α -stearoyl-valacyclovir was recorded on a Bruker AVANCE 400 instrument with a maximum operating frequency of 400 MHz and a magnetic field of 9.37 T. in a de-DMSO solution with an approximate concentration of 40 mg per 0.9 ml.

Refined numerical values of chemical shifts were obtained by correcting the observed signals with a DMSO signal in the spectrum and are given in ppm; phase correction was not performed.

δ _H (400MHz, d ₆ -DMSO): 10.66 (br. s, 1H, H ₆ ); 8.02 (d, J 7.6Hz, 1H, H ₂₀ ); 7.81 (s, 1H, H ₂ ), 6.54 (s, 2H, H ₂₁ ); 5.35 (s, 2H, H ₁₀ ); 4.21 (dist d, J 11.6 Hz, 1H, H _13a ); 4.12 (dist dd, J _H16 6.0Hz, J _H13 11.8Hz, 2H, H _13b , H ₁₆ ); 3.66 (s, 2H, H ₁₂ ); 2.13 (quart, J ₁ 7.3Hz, J ₂ 15.0 Hz, 2H, H ₂₃ ); 1.94 (m, J ₁ 6.32 Hz, J ₂ 12.61 Hz, 1H, H ₁₇ ); 1.58-1.38 (br. S, 2H, H ₂₄ ); 138-1.06 (br. S, 28H, H ₂₅ -H ₃₈ ); 0.82 (dist t, J ~ 3.6 Hz, 9H, H ₁₈ , H ₁₉ , H ₃₉ ).

δ _C (100MHz, d ₆ -DMSO): 172.59 C ₂₂ ; 171.60 C ₁₅ ; 156.69 C ₅ ; 153.83 C ₇ ; 151.33 C ₉ ; 137.55 C ₂ ; 116.43 C ₄ ; 71.67 C ₁₀ ; 66.41 C ₁₃ ; 62.93 C ₁₂ ; 57.11 C ₁₆ ; 33.57 C ₂₃ ; 31.39 C ₃₇ ; 29.66 C ₁₇ ; 29.13 C ₂₈ -C ₃₅ ; 28.89 C ₂₇ ; 28.83 C ₃₆ ; 28.69 C ₂₆ ; 28.53 C ₂₅ ; 24.12 C ₂₄ ; 22.12 C ₃₈ 18-77, 18.01 C ₁₈ , C ₁₉ ; 13.47 C ₃₉ .

Claims (3)

Guanine derivatives, which are compounds of the formula

, where R represents C1-C6 alkyl.

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