RU2393174C1 - Method of producing polymeric water-soluble betulonic acid derivatives - Google Patents

Abstract

FIELD: chemistry. ^ SUBSTANCE: invention relates to methods of producing biologically active substances and specifically to a method of producing a polymeric water-soluble form of betulonic acid. The method involves reacting betulonic acid chloride with polyvinyl alcohol in a water-acetone solution in the presence of potassium hydroxide or sodium hydroxide. The ratio of betulonic acid chloride to the polyvinyl alcohol link is equal to 2-10, while concentration of polyvinyl alcohol equals 1-3 wt % and concentration of potassium or sodium hydroxide equals 0.5-2.0 wt %. ^ EFFECT: invention simplifies the method of producing a polymeric betulonic acid derivative and enables addition of a defined quantity of betulonic acid residues into the polymer. ^ 1 cl, 2 ex

Description

The invention relates to a method for producing a polymer of a water-soluble form of a biologically active compound - betulonic acid, which may find application in the food, pharmaceutical industry and in agriculture.

It is known that betulonic acid and its derivatives have a wide spectrum of biological activity, in particular, a number of betulonic acid derivatives have high anti-HIV activity [Tolstikov A.G. and other Chemistry in the interests of sustainable development, 2005, No. 13, S.22-26].

The main disadvantage of betulonic acid and its derivatives in terms of their use as drugs is the practical insolubility in water, which makes it difficult to introduce into the body.

An important factor that largely determines the effectiveness of water-insoluble medicinal substances is the possibility of obtaining their water-soluble forms. Several approaches can be applied to solve this problem: the use of mixtures of solvents (most often dimethyl sulfoxide or alcohol) with water; obtaining water-soluble derivatives, including salts; preparation of inclusion compounds with cyclodextrins and their derivatives; the formation of complexes with amphiphilic polymers and the inclusion of the studied substances in the composition of nanoparticles - liposomes and fat emulsions [Bioorganic chemistry, 1998. V.24, No. 10, S.787-793].

Also known are polymer systems containing biologically active substances bound to the polymer chain by a hydrolytically labile covalent bond, which gradually breaks down under the conditions of the functioning of the system. They are used in medicine to create water-soluble forms transported to the affected organ, which helps to reduce the administered dose of the drug, increase the time of its circulation in the body and reduce the possibility of manifestation of a general side effect. Preparations based on these polymers are intended for injection into the bloodstream [Shtilman M.I. Polymers of biomedical use. M .: Academic book, 2006. P.36].

The closest in technical essence and the achieved result is a method for producing polymer water-soluble forms of triterpenoids, including the interaction of the ternary copolymer III, where k = 65-95 mol.%; 1 = 0.1-34 mol. %; x = 1.0-34.9 mol%: R ₁ , —H, CH ₃ ; R ₂ -H, CH ₃ ; R _{3 is} CH ₃ ; C ₂ H ₅ ; R ₄ -C ₆ H ₁₃ -C ₁₆ H ₃₃ ; Hal = J, Br, Cl; MM (7100) 10 ³ D, with triterpenoid, including betulonic acid, to obtain the target product II

where A is the residue of triterpenoid, including betulonic acid, in an organic solvent at a concentration of a ternary copolymer of 1-30 wt.%, a concentration of betulonic acid of 0.05-3.4 wt.%; the molar ratio of a unit containing quaternary nitrogen to betulonic acid is from 1 to 10 [RU 2253657, publ. 06/10/2005].

The disadvantage of this method is the need for preliminary preparation of a complex polymer carrier, synthesized by copolymerization of the three starting monomers. In addition, the disadvantages of this method include the impossibility of introducing a certain, reproducible amount of betulonic acid in the form of a betulonate anion, since when receiving a carrier polymer by copolymerization of three different monomers, it is impossible to introduce a certain, reproducible number of quaternary alkyl ammonium groups into the polymer - m, which follows from formula III, where m varies in a very wide range (0.1-33.9 mol.%).

The objective of the invention is to develop a simple method for producing a water-soluble form of betulonic acid, where polyvinyl alcohol produced by the industry is used as a carrier polymer (GOST 10779-78).

It is known that a water-soluble polymer - polyvinyl alcohol - is a medical material that is used as a carrier of drugs and blood substitute components [RU 2328313, publ. 07/10/2008].

The problem is solved by the proposed method, which consists in the interaction of betulonic acid chloride with polyvinyl alcohol in an aqueous acetone solution in the presence of potassium hydroxide or sodium hydroxide with a ratio of betulonic acid chloride - polyvinyl alcohol unit of 2-10; the concentration of polyvinyl alcohol is 1-3 wt.% .; the concentration of potassium or sodium hydroxide is 0.5-2.0 wt.%.

The proposed method allows to obtain a polymer derivative of betulonic acid of the General formula (I)

where polyvinyl alcohol is used as the carrier polymer, with Ac being the acyl residue of betulonic acid

k = 24.5-35.2 mol%, medium viscosity molecular weight (M) = (15.5-77.5) 10 ³ .

The method is as follows.

In an aqueous solution of polyvinyl alcohol (GOST 10779-78) with a concentration of 1-3 wt.%, In the presence of potassium or sodium hydroxide (0.5-2.0 wt%), cooled to 0 ° C, a solution of betulonic acid chloride is introduced with stirring acid in acetone with a ratio of betulonic acid chloride - a link of polyvinyl alcohol 2-10. The desired product is isolated from the reaction mixture by filtration. Further purification of the acylated polyvinyl alcohol is carried out by reprecipitation of it from an aqueous solution into ethanol. The yield of the target product is 79.4-83.5%. Samples are analyzed by IR spectroscopy for the presence of an ester bond. IR spectrum of compound (I), ν, cm ^-1 : 3392.5; 3070; 2944.8; 2869.5; 1750; 1,705.7; 1643; 1,456.9; 1378.7; 1244.8; 1,137.3; 1022.4; 985.4; 941; 916.6; 871.2; 852.5; 764.9; 611.7.

The invention is supported by specific examples:

Example 1. 0.18 g (4 mmol) of polyvinyl alcohol in 5.6 ml of water and 0.11 g (2.8 mmol) of NaOH in 5 ml of H ₂ O are introduced into a 50 ml round-bottomed two-necked flask equipped with a stirrer. The solution is cooled to 0 ° C. Then, a solution of 0.21 g (0.4 mmol) of betulonic acid chloride in 10 ml of acetone is added to this solution with stirring. The reaction mixture was stirred for one hour. The precipitate formed is filtered off, washed with alcohol and dried at room temperature. Purification of the acylated polyvinyl alcohol is carried out by reprecipitation of it from an aqueous solution into ethanol. The yield of the target product is 83.5%.

Example 2. The experiment is carried out similarly to the experiment described in example 1, but using a solution of 0.27 g (6.0 mmol) of polyvinyl alcohol in 12.5 ml of water, a solution of 0.38 g (9 mmol) of NaOH in 13 ml of water is introduced and 1.57 g (3.0 mmol) of betulonic acid chloride in 30 ml of acetone are introduced. The yield of the target product 79.4%.

Thus, a simple one-step method has been developed for producing a water-soluble form of betulonic acid, where polyvinyl alcohol produced by the industry is used as a carrier polymer. An advantage of the proposed method is also the possibility of introducing into the polymer a certain amount of betulonic acid residues associated with it by a covalent hydrolytically labile bond.

Claims (1)

A method of producing a polymer of a water-soluble betulonic acid derivative, which consists in the interaction of betulonic acid chloride with polyvinyl alcohol in an aqueous acetone solution in the presence of potassium hydroxide or sodium hydroxide, with a ratio of betulonic acid chloride - polyvinyl alcohol unit of 2-10, wherein the concentration of polyvinyl alcohol is 2-10, 3 wt.%, The concentration of potassium or sodium hydroxide is 0.5-2.0 wt.%.