Flavanone conjugates

Abstract

The invention relates to organic chemistry, and more particularly to flavanone derivatives, and even more particularly to derivatives of flavanones modified by a guanidine group. The given compounds can be used in the field of medicine as medicinal preparations. Claimed are compounds having the specified general formula in which R1, R2, R4 is Н or OH, and R3 is OH or ОСН3. The compounds of this general formula, namely flavanone hydrazones, exhibit elevated solubility in water and, therefore, greater bioavailability than the parent flavanones.

Description

[0001] Flavanone conjugates

[0002] Field of technology

[0003] The claimed invention relates to organic chemistry, namely to flavanone derivatives and, in particular, to flavanone derivatives with increased solubility in water. The said compounds can find application in medicine as medicinal preparations.

[0004] Prior art

[0005] Flavanones (2-phenylchroman-4-one derivatives) of the general formula where Ri is H; OH or carbohydrate residue; R2- H or OCH3are natural polyphenolic compounds that can be obtained from plant materials. Due to their high and versatile activity, combined with low toxicity, flavanones are of great interest in the development of new drugs.

[0006] It is known [Heim K.E., Tagliaferro AR, Bobliya DJJ Nutr. Biochem. 13:572-5841, 2002; Cushnie TP, Lamb AJ Int. J. Antimicrob.

[0007] SUBSTITUTE SHEET (RULE 26) Agents. 26: 343-356, 2005; Zandi K, Teoh BT, Sam SS, et al. Vir. Jour. 8:560, 2011; Salehi B., Tsouh Fokou P.V., Sharifi-Rad M., et.al.

[0008] Pharmaceuticals (Basel). 12: 11, 2019, doi:10.3390 / phl2010011; Das A., Baidya R., Chakraborty T., et.al. Biomedicine & Pharmacotherapy. 142, 112004, 2021, doi: 10.1016 / j.biopha.2021.112004] that many compounds belonging to this class have pronounced antioxidant, angioprotective, hepatoprotective, diuretic, antitumor, antiviral and neurotropic activities

[0009] Below are the structural formulas of some flavanones that have pronounced biological activity, namely: Where

[0010] SUBSTITUTE SHEET (RULE 26) (1) hesperidium, consisting of an aglycone (hesperetin) and a carbohydrate part (rutinoside), namely 5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-7-(2R,3S,4R,5R,6R)-3,4,5-TpHTHflpoKCH-6-(2S,3R,4S,5S)-3,4,5-trihydroxy-6-methyl-tetrahydropyran-2-yl]oxymethyl]tetrahydropyran-2-yl]-oxy-chroman-4-one,

[0011] (2) hesperetin - (28)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-2,3-dihydro-4H- 1 -benzopyran-4-one;

[0012] (3) naringenin - 5,7-dihydroxy-2-(4-hydroxyphenyl)-chroman-4-one and

[0013] (4) dihydroquercetin - 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-chroman-4-one.

[0014] Hesperidium is used as a venoprotective and antioxidant agent. Data have been published on the possibility of using hesperidin in rheumatoid arthritis, its ability to reduce diastolic pressure and suppress the proliferation and growth of cancer cells [Umar S., Kumar A., ​​Sajad M., et al. Rheumatol. Int. 33: 657-663, 2013; Homayouni F., Haidari F., Hedayati M. et al. Phytother. Res., 32: 1073-1079, 2018; Devi KP, Rajavel T., Nabavi SF Ind. Crop. Prod., 76: 582-589, 2015].

[0015] Hesperetin, like hesperidium, has antioxidant and anti-inflammatory effects [Parhiz H., Roohbakhsh A., Soltani F., Rezaee R., Iranshahi M. Phytother. Res. 29, 323, 2015]; it induces apoptosis of tumor cells as a result of influencing the formation of reactive oxygen species [Zhang J., Wu D., et.al. Dig. Dis. Sci. 60, 2985, 2015].

[0016] Naringenin has pronounced anti-inflammatory and antioxidant activity in combination with antibacterial

[0017] SUBSTITUTE SHEET (RULE 26) action. The possibility of its use in the treatment of various types of liver and lung damage, as well as neurodegenerative diseases has been shown [Zhao Y., Liu S. Pharmazie. 76, 359, 2021]. A number of studies have established the presence of antitumor activity in naringenin [Bao L., Liu F., Guo H.B., et.al. Tumor Biol. 37, 11365, 2016].

[0018] Dihydroquercetin (taxifolin) is a highly active antioxidant, which also has anti-inflammatory, antimicrobial and antitumor effects. The possibility of using taxifolin in the treatment of cardiovascular and liver diseases has been shown [Das A., Baidya R., Chakraborty T., et.al. Biomedicine & Pharmacotherapy. 142, 112004, 2021, doi: 10.1016 / j .biopha.2021.112004].

[0019] A significant disadvantage of the listed flavanones, which limits the possibilities of pharmacological application, is their low solubility in water. Thus, 1 g of hesperidin dissolves in 50 l of water. The solubility of hesperetin is approximately 48 mg / l; naringenin - 4.38 mg / l; dihydroquercetin - 700 mg / l, which is completely insufficient to obtain a solution of such a concentration that is acceptable for the manufacture of a drug. Therefore, a number of attempts have been made to increase the solubility of flavanones in aqueous media and, accordingly, their bioavailability.

[0020] The solubility of hesperidin increases approximately 100-fold with the addition of 20% 2-hydroxypropyl-0-cyclic dextrin, resulting in the formation of a non-covalent complex [Majumdar S., Srirangam R. Pharm. Res. 26: 1217–1225, 2009; Tommasini S., Calabro ML 39: 572–580, 2005].

[0021] SUBSTITUTE SHEET (RULE 26) Another option for increasing the bioavailability and effectiveness of flavanone is the use of micronization (grinding particles to a micron size, for example, using ultrasound) [Hnatek L. Vnitr. Lek. 61(9): 807-814, 2015]. However, in both cases, the possibilities for practical use of the drugs remain limited, and the cost of the dosage form increases significantly.

[0022] Disclosure of invention

[0023] The result that the claimed invention is aimed at achieving is the production of flavanones with increased solubility in water.

[0024] The stated objective is achieved by obtaining modified compounds containing a hydrophilic guanidine group of the general formula: where Ri, R2, R4 - H or OH; R3-OH or OCH3;

[0025] SUBSTITUTE SHEET (RULE 26) Individual compounds corresponding to the declared general formula are hydrazones of hesperetin (5), naringenin (6) and dihydroquercetin (7):

[0026] Hesperetin hydrazone (5) corresponds to the general formula presented above, in which R b R4= H; R2= OH; R3= OCH3; naringenin hydrazone (6) also corresponds to the general formula presented above if Ri, R2, R4 = H; R3= OH; dihydroquercetin hydrazone (7) corresponds to the general formula when R b R3, R4 = OH, and R2= H.

[0027] The claimed flavanone derivatives can be obtained by reacting the starting compounds (hesperitin, naringenin and dihydroquercetin) with aminoguanidine hydrochloride in an organic solvent in the presence of hydrochloric acid.

[0028] SUBSTITUTE SHEET (RULE 26) The production of a highly water-soluble hesperidin derivative was described by us earlier [RU 2742030, IPC C07H17 / 06, 2021]. According to RU2742030, a hesperidin conjugate modified with a guanidine group is obtained by reacting hesperidin with aminoguanidine in a dimethylformamide or dimethyl sulfoxide solvent in the presence of hydrochloric acid.

[0029] Aminoguanidine (2-aminoguanidine), which has the structural formula: was investigated as a potential drug that interferes with protein glycosylation, the drug passed two stages of clinical trials, but further testing was interrupted due to potential side effects. Nevertheless, aminoguanidine derivatives are still considered as promising compounds in the screening of new drugs [Aldini G., Vistoli G., Stefek M., et al. Free Radic. Res., 47 (Suppl. 1): 93-137, 2013].

[0030] The inclusion of a hydrophilic guanidine group in the structure of flavanones allows for an increase in the solubility of drugs in water and, at the same time, does not have a significant effect on their antioxidant activity and ability to capture reactive keto derivatives, as we have shown previously using hesperidin as an example [RU2742030]. Moreover, the presence of similar activity in aminoguanidine allows us to expect the manifestation of a synergistic

[0031] SUBSTITUTE SHEET (RULE 26) of action [Courderot-Masuyer C., Dalloz F., Maupoil V., Rochette L. Fundam. Clin. Pharmacol. 13: 535-540, 1999].

[0032] The synthesis of hydrazones of the claimed general formula is carried out in an organic solvent, preferably in methanol or isopropyl alcohol, predominantly in methanol.

[0033] The use of other aminoguanidine salts soluble in the indicated organic solvents, such as, for example, p-toluenesulfonate or tetraphenylborate, leads to a significant decrease in the yield of the target product.

[0034] Variants for obtaining water-soluble flavanone conjugates are given in Examples 1-3.

[0035] Example 1. Synthesis of hesperetin conjugate with 2-aminoguanidine

[0036] To a mixture of 300 mg (1 mmol) of hesperetin and 160 mg (1.45 mmol) of aminoguanidine hydrochloride in 15 ml of isopropanol is added 0.1 ml of hydrochloric acid and heated at boiling for 5 hours. The reaction mixture is cooled, the resulting precipitate is filtered off, washed with water, isopropyl alcohol and dried in air. 300 mg (0.83 mmol, 83%) of the product are obtained as a hydrochloride.

[0037] The obtained product, like other compounds of this class, is a mixture of geometric isomers (syn- and antiforms), which is confirmed by analytical high-performance reversed-phase chromatography data. The structure of the obtained compound is confirmed by ^-NMR spectroscopy and mass spectrometry data:

[0038] NMR *H, δ, ppm: 2.89-3.27 m (2H, CH2), 3.78 s (3H, CH3), 5.1 dd (1H, J = 3 Hz, J2 = 12 Hz, CH3), 5.94 d (III, J = 2 Hz), 5.97 d (1H, J = 2 Hz), 6.94 m (3H),

[0039] SUBSTITUTE SHEET (RULE 26) 7.74 br (4H, 3NH+HC1), 9.14 s (1H, OH), 10.24 s (SH, OH), 10.78 s (1H,

[0040] OH), 11.16 br (1H, NH).

[0041] Molecular weight: calculated for CI7HI8N4O5358.13; found [M+H] + 359.13.

[0042] Example 2. Synthesis of naringenin conjugate with 2-aminoguanidine

[0043] 270 mg (1 mmol) of naringenin and 160 mg (1.45 mmol) of aminoguanidine hydrochloride are dissolved in 10 ml of methanol. One drop of hydrochloric acid is added to the solution and the mixture is heated at boiling for 5 hours. The reaction mixture is cooled and left for 10 hours at +4°C. The formed precipitate is filtered off and dried in air. 200 mg (0.62 mmol, 62%) of naringenin hydrazone hydrochloride and aminoguanidine are obtained.

[0044] NMR spectrum 'H, 8, ppm: 2.95-3.26 m (2H, CH2), 5.1 dd (1H, =3Hz, J2=13Hz, CH), 5.92 d (1H, V=2Hz), 5.96 d (1H, V=2Hz), 6.81 d (2H, V=8Hz), 7.32 d (2H, 7 =8Hz), 7.7 br (4H, 3NH+HC1), 9.63 s (1H, OH), 10.22 s (1H, OH), 10.80 s (lH, OH), 11.09 br (1H, NH).

[0045] Molecular weight: calculated for CI6HI6N4O4328.12; found [M+H] + 328.99.

[0046] Example 3. Synthesis of dihydroquercetin conjugate with 2-aminoguanidine

[0047] To a mixture of 300 mg (1 mmol) of dihydroquercetin and 160 mg (1.45 mmol) of aminoguanidine hydrochloride in 15 ml of methanol is added 0.1 ml of hydrochloric acid. The reaction mixture is stirred for 20 hours. The methanol is distilled off on a rotary evaporator and the precipitate is crystallized from a methanol-ethyl acetate mixture. The resulting precipitate is filtered off and dried in air. 200 mg (0.58

[0048] SUBSTITUTE SHEET (RULE 26) mmol, 58%) dihydroquercetin hydrazone hydrochloride and aminoguanidine.

[0049] NMR spectrum 'H, δ, ppm: 5.04 br (1H, CH), 5.21 d (1H, / =4 Hz, CH), 5.94 d (1H, / =2 Hz), 5.97 d (1H, / =2 Hz), 6.46-6.7 m (4H), 7.8 br (4H, 3NH+HC1), 9.01 s (1H, OH), 9.06 s (1H, OH), 10.24 s (1H, OH), 10.42 s (1H, OH), 11.35 br (lH, NH).

[0050] Molecular weight: calculated for C16H16N4O6 360.11; found [M+H] + 361.1.

[0051] Example 4. Study of the solubility of the obtained conjugates in water

[0052] The results of the study of the solubility of flavanone conjugates with aminoguanidine in distilled water at room temperature are presented in Table 1.

[0053] Table 1.

[0054] Thus, conjugation with aminoguanidine allows increasing the solubility of the studied compounds in the range from 20 to 900 times.

[0055] SUBSTITUTE SHEET (RULE 26) Industrial applicability

[0056] The method for obtaining conjugates of flavonones with aminoguanidine is simple and is accompanied by a sufficiently high yield of the target product, which makes it possible to organize industrial production of the claimed products.

[0057] SUBSTITUTE SHEET (RULE 26)

Claims

CLAUSES OF THE INVENTION 1. Conjugates of flavanones of the general formula: where Ri, R2, R4 - H or OH; R3-OH or OCH3.

2. A flavanone conjugate according to claim 1, characterized in that R b R4 = H; R2= OH; R3= OCH3.

3. A flavanone conjugate according to claim 1, characterized in that R b R2, R4 = H; R3= OH.

4. The flavanone conjugate according to claim 1, characterized in that R b R3, R4 = OH, and R2 = H. SUBSTITUTE SHEET (RULE 26)

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