RU2436775C1 - Novel optically active 4-hydroxy-2-aza-9,10-anthraquinones, having antiinflammatory activity, and synthesis method thereof - Google Patents

Abstract

FIELD: chemistry. ^ SUBSTANCE: invention relates to novel optically active 3-alkyl-4-hydroxy-2-aza-9,10-anthraquinones of formula (Ia-f): R=H, R1=Me (la); R=H, R1=Et (1b); R=H, R1=i-Pr (Ic); R=R1=Me (Id); R=Me, R1=Et (1e); R=Me, R1=i-Pr (If). The invention also relates to the method of obtaining compounds of formula (Ia-f). ^ EFFECT: novel low-toxicity optically active derivatives of 3-alkyl-4-hydroxy-2-aza-9,10-anthraquinone, having anti-inflammatory activity, are obtained. ^ 2 cl, 3 tbl 8 ex

Description

The invention relates to organic chemistry, namely to new optically active derivatives of 4-hydroxy-2-aza-9,10-anthraquinone of the formula (Ia-e)

R = H, R ¹ = Me (Ia); R = H, R ¹ = Et (Ib); R = H, R ¹ = i-Pr (Ic); R = R ¹ = Me (Ig); R = Me, R ¹ = Et (Id); R = Me, R ¹ = i-Pr (Ie),

possessing anti-inflammatory activity.

The specified property suggests the possibility of using these compounds in medicine as pharmaceuticals.

The group of substituted 1-, 2-, 3- or 4-aza-9,10-anthraquinones is promising for the creation of new drugs due to the fact that many of them have pronounced antitumor activity, a wide range of antibiotic properties [R.H. Thomson. Naturally Occurring Quinones. IV. Recent Advances. // London: Chapman & Hall, 1997. P.583-648]. The claimed compounds are structural analogues of natural 2-azaanthraquinones, for example, bostricoidin (II), which is highly active in vitro against Mycobacterium tuberculosis [2. Cameron D.W., Dentscher K.R., Feutrill G.I., Tetrahedron Lett., 1980, 21, 5089-5090; D. Parisot, M. Deoys, M. Barbier, J. Antibiotics, 1989, 42, 1189-1190].

The objective of the invention is the creation of new agents with anti-inflammatory activity with improved properties.

The task is achieved by new chemical compounds of the specified formula (Ia-e), with pronounced anti-inflammatory activity.

It should be emphasized that natural 2-aza-9,10-anthraquinones are rare inaccessible compounds, and the development of methods for the synthesis of their analogues is of significant interest. The value of the proposed method for the preparation of optically active 2-azaanthraquinones is that based on such available products as pine gum, 1,4-benzoquinone and α-amino acids (used to obtain the necessary 2-methyl-4-alkyl-5-methoxyoxazoles [ Kondratyev G.Ya., Zhi-Heng L. Journal of General Chemistry, 1962, 32, 2348-2356; Doctorova ND, Somova LV, Karpeisky M.Ya., Padyukova N.Sh., Turchin KF, Florentiev VL Tetrahedron, 1969, 25, 3527-3553]) using simple technological operations, optically active compounds of a unique structure are obtained. The method is carried out according to the sequence of transformations from levopimaric acid (III) shown in Scheme 1. Levopimaric acid is the main component of the sum of acids of the turpentine pine ordinary Pinus silvestris L. and is highly reactive [Pentegova VA, Dubovenko Zh.V., Raldugin VA, Shmidt E.N. Terpenoids of coniferous plants // Novosibirsk: Nauka, 1987].

At the first stage, the reaction of 1,4-benzoquinone with levopimaric acid (III), which is present in pine resin and does not require isolation, is carried out. The yield of diketone (IVa), released in the form of crystals, not less than 80%. This is followed by dissolution in a 5% solution of sodium hydroxide and treatment with acid, which gives hydroquinone (Va) (87% yield). Oxidation of the latter with cerium ammonium nitrate or potassium bromate gives acid (VIa) in 84% or 96% yield, respectively. Thermolysis takes place in up to 97% naphthoquinone (VIIa). The diene synthesis between quinone (VIa) and 4-alkyl-2-methyl-5-methoxyoxazoles (VIIIa-b) is carried out by catalysis with boron trifluoride etherate in methylene chloride, giving tricyclic epoxy adducts (IXa-b) (yield 62-68%). The final stage of the synthesis is the thermolysis of epoxy compounds (IXa-c) in a solution of 1,4-dioxane in the presence of trifluoroacetic acid, which leads to 3-substituted-4-hydroxy-2-aza-9,10-anthraquinones (Ia-c) (yield 72-81%).

Methylation of the adduct (IVa) with dimethyl sulfate gives methyl ester (IVb) (yield 83%), for which a similar sequence of conversions was carried out. Treatment of compound (IVb) with sodium hydroxide leads to hydroquinone (Vb) (90% yield). Oxidation of hydroquinone (Vb) yields chrysenquinone methyl ester (VIb) (89% yield). By thermolysis of polycyclic quinone (VIb), substituted 1,4-naphthoquinone (VIIb) is obtained (98% yield). The interaction of quinone (VIIb) with oxazoles (VIIIa-c) during catalysis of boron trifluoride etherate in methylene chloride leads to a mixture of regioisomeric cycloducts, from which the main regioisomers - epoxy adducts (IXx-e) are isolated (yield 62-64%). Thermolysis of compounds (IXh-e) in a solution of dioxane in the presence of trifluoroacetic acid leads to 3-substituted-4-hydroxy-2-aza-9,10-anthraquinones (Ige) (yield 76-85%). The reaction of cycloaddition of quinones (VIIa, b) with oxazoles during catalysis with boron trifluoride etherate differs in regioselectivity and ultimately [after acid treatment of oxadducts (IXa-c)] (Scheme 1) leads to the formation of 4-hydroxy-2-azaanthraquinones ( Ia-c) with a total yield of 28-34% based on the levopimaric acid (III) introduced into the reaction. The total yield of compounds (Ie) according to Scheme 1, calculated on levopimaric acid (III), is 26-28%. Physico-chemical constants of the new, first-obtained compounds are shown in examples 1-6.

An advantage of the invention is a method for producing compounds (Ia-e) by chemical modification of the available plant metabolite of Scots pine - levopimaric acid (III) and 1,4-benzoquinone. Due to the high activity of both components in the diene synthesis reaction, it is not necessary to isolate levopimaric acid from the resin, and 1,4-benzoquinone is directly added to the resin, as described in [Tolstikov GA, Schulz E.E., Mukhametzyanova T. Sh., Baykova I.P., Spirikhin L.V. ZhORKh, 1993, 29, 698-716]. A distinctive feature of the invention is the preparation of optically active substituted 1,4-naphthoquinones (VIIa, VIIb) (total yield 53-62% based on levopimaric acid contained in pine resin) and their introduction into the diene synthesis reaction with oxazoles (VIIIa, b). The regioselectivity of the diene synthesis reaction is ensured by the use of a catalyst, which is available and convenient to use Lewis acid - boron trifluoride etherate.

In the work [Tolstikov G.A., Shults E.E., Mukhametzyanova T.Sh., Sultanova BC, Spirikhin L.V. ZhORKh, 1992, 28, 1310-1313] describes a method for producing isomeric 1-hydroxy-2-aza-9,10-anthraquinone (X) based on the thermal reaction of cycloaddition of polycyclic quinone (VIa) to 5-methoxyoxazole (VIIIb) (boiling in acetonitrile) and subsequent retro-diene cleavage of the polycyclic adduct (XI) (Scheme 2). As can be seen from Scheme 2, as a result of the diene synthesis reaction, a mixture of regioisomers is formed — the primary reaction products (XI, XII) [the yield of compound (XI) is 58%]. Thermal cleavage (XI) by heating in DMF and subsequent column chromatography afforded compound (X) (yield 66%). Compound (XII) (minor product) was not isolated individually; its formation was fixed according to the ¹ H NMR spectrum of a mixture of compounds (XI, XII).

Thus, the method for producing 4-hydroxy-2-azaanthraquinones (Ia-e) consists in reacting the optically active 1,4-naphthoquinones (VIIa, b) with 4-alkyl-5-methoxyoxazoles (VIIIa-c), catalyzed by Lewis acid, and subsequent acid-catalyzed thermal cleavage of the regioselectively formed epoxy adducts (IXa-e). Optically active naphthoquinones (VIIa, b) are synthesized from levopimaric acid (III) contained in pine resin, and 1,4-benzoquinone.

The widespread prevalence of inflammatory diseases, as well as the imperfection of known anti-inflammatory drugs, consisting not so much of insufficient effectiveness as the existence of side effects of almost all existing groups of compounds of this type, have become an incentive for the search for new non-steroidal anti-inflammatory drugs (NSAIDs).

It is known to use orthophene (voltaren, diclofenac sodium) as the anti-inflammatory agent, having the formula (XIII)

The compound has a pronounced ulcerogenic effect [M.D. Mashkovsky. Medicines, Torsing, Kharkov, 1998, v.1, p.198].

Analysis of literature data shows that the synthesis and pharmacological testing of new chemical compounds that differ from existing NSAIDs in their ability and selectivity of action, prolonged effect and the absence of side effects is an urgent task.

Effective directions of anti-inflammatory therapy is the search for agents that stabilize lysosomal membranes [H.G. Vogel, V. Vogel, Drug Discovery and Evaluation, Springer Verlag, Heidelberg, 1996, 236 p.], The use of antioxidants [A.S. Saratikov, T.P. Clothespin. Modern concepts of aniflogistic action of NSAIDs. // Farmakol. and toxicol., 1982, v.45, No. 2, p.133-138], as well as substances that inhibit the production of antibodies by lymphoid and plasma cells [A.M. Chernukh. Inflammation, Medicine, M., 1999, 448 pp.].

The biological activity of the claimed compounds (Ia-e) was studied by determining the toxicity and anti-inflammatory activity in a model of carrageenin and formalin inflammation.

The acute toxicity of 4-hydroxy-2-azaanthraquinones (Ia-e) was determined on outbred white mice of both sexes with a single injection into the stomach. The toxicity parameters were calculated by Litchfield and Wilcoxon by probit analysis.

LD ₅₀ new compounds are shown in table 1. As can be seen from the data in table 1, widely used in medicine, anti-inflammatory substances are more toxic than the studied compounds. All compounds belong to the III class of moderately hazardous substances.

Table 1 Comparison of acute toxicity of compounds of formula (I) and anti-inflammatory drugs widely used in medical practice No. Compound LD ₅₀ mg / kg one. Brufen 320 2. Butadion 250 3. Hydrocortisone 200 four. Ortofen (XIII) 150 5. Prednisone 160 6. (Ia) 2500 7. (Ib) 2000 8. (Ic) 1800 9. (Ig) 1850 eleven. (Id) 1300 12. (Ie) 1260

The anti-inflammatory effect of the least toxic 4-hydroxy-2-azaanthraquinones (Ia, b) was studied in two models of inflammation caused by a 1% carrageenin solution and 3% formalin solution under the aponeurosis of one of the hind legs of the mouse at a dose of 0.05 ml. The anti-inflammatory effect of the compound was judged by the percentage increase in the mass of the inflamed paw compared to a healthy one. The comparison drug was orthophene taken at a dose of ED ₅₀ .

On a model of carrageenin-induced inflammation in mice and rats, the ED ₅₀ compounds (Ia, b) were calculated, which amounted to:

for compound (Ia) - 30 (24-38) mg / kg;

for compound (IB) - 33 (25-49.4) mg / kg.

The results of the study of the anti-inflammatory activity of compounds (Ia, b) at a dose of ED ₅₀ are shown in tables 2, 3.

In the model of inflammation caused by the introduction of formalin, compounds (Ia, b) statistically significantly delay the development of inflammatory edema (P <0.001) (table 2). The anti-inflammatory effect of the compounds at doses of 30 mg / kg (1/83 of LD ₅₀ ) for (Ia) and 33 mg / kg (1/60 of LD ₅₀ ) for (Ib) is similar to the effect of orthophene.

Both tested compounds in effective doses reliably delay the development of inflammatory edema caused by carrageenan (table 3). Both compounds 1.7-1.8 times reduce swelling of the legs of animals compared with the control group.

table 2 The effect of the claimed compounds (I) on formalin edema of the legs of animals Compound Dose mg / kg Number of animals % paw weight increase to healthy R (Ia) thirty 8 44.2 ± 1.7 <0.001 (Ib) 33 8 41.6 ± 2.04 <0.001 Ortofen (XIII) 8 8 42.16 ± 4.2 <0.001 The control 8 70.3 ± 2.04

Table 3 The effect of the claimed compounds (I) on carrageenan edema of the paws of mice Connections Dose mg / kg Number of animals % increase in weight of the legs to healthy. R (Ia) thirty 8 43.3 ± 3.06 <0.001 (Ib) 33 8 48.16 ± 3.23 <0.01 Ortofen (XIII) 8 8 47.5 ± 1.53 <0.001 The control 8 73.8 ± 3.23

The distinctive features of the method include:

- obtaining optically active 4-hydroxy-2-azaanthraquinones from available domestic raw materials - pine resin and 1,4-benzoquinone;

- preparation of 4-hydroxy-2-azaanthraquinones using, at a key stage, a Lewis acid catalyzed reaction of diene synthesis of optically active polyfunctional 1,4-naphthoquinones with 4-alkyl-2-methyl-5-methoxyoxazoles;

- obtaining new low-toxic 4-hydroxy-2-azaanthraquinones with anti-inflammatory activity.

The invention is illustrated by examples.

Example 1. Synthesis of (2R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-hydroxy-7-isopropyl-1,3-dimethyl-2 α-azanthraquinone (Ia).

- 168° (с 10.1, хлф) (т.пл. 212-214°С [Herz W., Blackstone R.C., Nair M.G. J.Org. Chem. 1967, 32, 2992]; 192°С [Ruzicka L., Kaufmann S.Helv. Chim. Acta. 1941, 24, 1425]).1. Preparation of 7,10a-dimethyl-13-isopropyl-7-carboxy-4,4a, 5,6,6a, 7,8,9,10,10a, 10b, 11, 1212a-tetradecahydro-4b, 12- ( etheno) -1H-chrysene-1,4-dione (IVa). To a solution of 110 g of pine resin in 100 ml of acetonitrile, a solution of 5.9 g of benzoquinone in 50 ml of acetonitrile is poured and left at room temperature in a dark place for 7 days. The solvent is distilled off, 50 ml of ethanol are added to the residue, 30 ml of diethyl ether are added to the resulting solution. The precipitate formed is filtered off, washed with cold ether, and 13.6 g of adduct (IVa) are obtained [yield 82.4% based on levopimaric acid (III)] as a yellow crystalline precipitate. T. pl. 208-210 ° C,

- 168 ° (s 10.1, hlf) (mp 212-214 ° С [Herz W., Blackstone RC, Nair MGJOrg. Chem. 1967, 32, 2992]; 192 ° С [Ruzicka L., Kaufmann S. Helv. Chim. Acta. 1941, 24, 1425]).

2. Preparation of 7,10a-dimethyl-1,4-dihydroxy-13-isopropyl-7-carboxy-4b, 5,6,6a, 7,8, 9,10,10a, 10b, 11,12-dodecahydro-4b , 12-etheno-chrysene (Va). To 5 ml of a 5% solution of NaOH, previously purged with argon, 8.52 g (20.4 mmol) of endeione (IVa) are added with stirring and incubated for 30 minutes, then the reaction mixture is acidified with 3% hydrochloric acid solution (30 ml, pH 6). The precipitate formed is filtered off, the residue is washed thoroughly with water and dried in air, and then 2 hours at 90 ° C. Get 8.0 g (87%) of hydroquinone (Va), so pl. 208-210 ° C.

3. Preparation of 7,10a-Dimethyl-7-carboxy-13-isopropyl-4b, 5,6,6a, 7,8,9,10,10a, 10b, 11,12-dodecahydro-4b, 12- (etheno) chrysene-1,4-dione (VIa).

but). To a stirred solution of 16.76 g (40.9 mmol) of hydroquinone (Va) in 70 ml of dioxane is added a solution of 3.41 g (20.4 mmol) of KBrO ₃ heated to 60 ° C in 34 ml of water and 3.4 ml of 1 N. H ₂ SO ₄ . After 10 minutes, 100 ml of water was added to the mixture, the product was removed with chloroform. The chloroform layer was washed with water, evaporated in vacuo, the residue was dissolved in 100 ml of ether and 100 ml of hexane was added. 6.44 g (39%) of chrysenquinone (VIa) is filtered off, while cooling, 9.57 g (57%) (overall yield 96%) of compound (VIa) is filtered off.

- 13.2° (с 5.2, EtOH). Найдено, %: С 76.65; Н 7.80. С₂₆Н₃₂O₄. Вычислено, %: С 76.44; Н 7.90. Спектральные данные аналогичны приведенным в работе [Шульц Э.Э., Олейников Д.С., Нечепуренко И.В., Шакиров М.М., Толстиков Г.А. Журнал органической химии, 2009, 45, 108].b) To a solution of 0.94 g (2.3 mmol) of hydroquinone (Va) in 40 ml of anhydrous acetonitrile, 2.3 mmol of (NH ₄ ) ₂ Ce (NO ₃ ) ₆ is added with stirring. Stirring is continued for 5-6 hours (TLC control). The reaction mixture was poured into 70 ml of water, the product was extracted with chloroform (3 × 20 ml). The extract was washed with water, brine (2 × 20 ml), dried with MgSO ₄ , and evaporated in vacuo. After purification by column chromatography (silica gel, eluent-chloroform), 0.78 g (84% yield) of polycyclic quinone (VIa) are obtained. T. pl. 140-145 ° C (from ether-hexane)

- 13.2 ° (c 5.2, EtOH). Found,%: C 76.65; H, 7.80. C ₂₆ H ₃₂ O ₄ . Calculated,%: C 76.44; H, 7.90. The spectral data are similar to those given in [Schulz E.E., Oleinikov D.S., Nechepurenko I.V., Shakirov M.M., Tolstikov G.A. Journal of Organic Chemistry, 2009, 45, 108].

4. Preparation of 5- [2- (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] 7-isopropyl-1,4-naphthoquinone (VIIa). A solution of 0.94 g (2.3 mmol) of quinone (VIa) in 15 ml of dioxane is heated in a sealed ampoule in an argon atmosphere for 10 hours at 150 ° C. After cooling, the ampoule is opened, chloroform is added to the residue, mechanical impurities are filtered off, the solution is evaporated in vacuo, the residue is chromatographed on silica gel (eluent-chloroform). 0.91 g (yield 97%) of substituted 1,4-naphthoquinone (VIIa) is obtained. T. pl. 86-100 ° C. [α] ₅₈₀ - 22.9 ° (c 1.8, EtOH). Mass spectrum, m / z (I _Rel ,%): 408 (33), 362 (100), 214 (38), 43 (36). Found: [M] ⁺ 408.23001. C ₂₆ H ₃₂ O ₄ . Calculated: M 408.23004. The data of ¹ H and ¹³ C NMR spectra are similar to those given in [Schulz E.E., Oleinikov D.S., Nechepurenko I.V., Shakirov M.M., Tolstikov G.A. Journal of Organic Chemistry, 2009, 45, 108].

5. Preparation of (2R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-methoxy-7-isopropyl-1,3-dimethyl-1, 4-epoxy-2-azaanthracene-9,10-dione (IXa).

A solution of 1.04 g (2.55 mmol) of compound (VIIa) in 20 ml of methylene chloride was loaded into a glass ampoule, 0.032 ml (0.26 mmol) of BF ₃ · Et ₂ O was added, then 0.42 g (3.31 mmol) of oxazole (VIIIa). The ampoule is flushed with argon, cooled and sealed. The reaction mixture was kept at 20 ° C for 48 hours. After the specified time, the ampoule was opened, the reaction mass was poured into 100 ml of water, the product was extracted with methylene chloride (20 × 3 ml), the organic layers were combined, washed with water, then dried over calcined magnesium sulfate. The desiccant is filtered off, the mother liquor is evaporated, the residue is separated by silica gel column chromatography (eluents: chloroform, chloroform - ethanol, in a 10: 1 ratio). Collect 3 fractions. The last fraction (1.26 g) was further purified by silica gel column chromatography (eluent: benzene-ethyl acetate). Get 2 fractions. Subsequent chromatography of fraction 2 gave 0.90 g (68% yield) of the adduct (IXa) as a mixture of stereoisomers (endo- and exo-location of the epoxymic). Oily substance. ¹ H NMR spectrum (CDCl ₃ ), δ, ppm, J, Hz: 1.00 s, 1.03 s (3H, CH ₃ at C ^{6 '} ), 1.18 s, 1.20 s (3H, CH ₃ at C ¹ ) , 1.26 d, 1.28 d [6H, CH (C H ₃ ) ₂ at C ⁷ , J = 6.9], 1.28 s (3H, CH ₃ at C ^{2 '} ), 1.30-1.52 m (5H, H ^{4', 4 ', 5', 12 ', 12'} ), 1.65 s, 1.70 s (3H, CH ₃ at C ³ ), 1.80-2.02 m (3H, H ^{1 ', 3', 5 '} ), 2.22 m [2H, 1Н, С Н (СН ₃ ) ₂ and 1Н, Н ^{3 '} ], 2.46-2.60 m (2Н, Н ^{13', 13 '} ), 3.59 s, 3.65 s (3Н, СН ₃ ), 3.85 m (1Н, Н ^9a ), 4.12 m (1H, H ^4a ), 4.82-4.91 m (2H, H ^{8 '} ), 5.60-5.68 m (1H, H ^7' ), 7.27 d (1H, H ⁶ , J = 1.8), 7.84 d (1H, H ⁸ , J = 1.8), 10.01 s (1H, OH). ¹³ C NMR spectrum (CDCl ₃ ), δ, ppm: 16.2 k, 16.6 k (CH ₃ at C ^{6 '} ), 17.68 t (C ^4' ), 18.01 k (CH ₃ at C ¹ ), 18.43 k , 18.63 k (CH ( C H ₃ ) ₂ ), 19.4 k, 19.7 k (CH ₃ at C ^{2 '} ), 22.79 k (CH ₃ at C ³ ), 28.76 t (C ^12' ), 33.37 d ( C H -i-Pr), 35.01 t (C ^{3 '} ), 36.46 t (C ^5' ), 38.05 t (C ^{13 '} ), 41.43 s (C ^6' ), 44.25 d (C ^{1 '} ), 45.97 s (C ^{2 '} ), 46.05 d (C ^4a ), 50.32 d (C ^9a ), 52.42 k (OCH ₃ ), 73.01 s (C ¹ ), 88.54 s (C ⁴ ), 110.46 t (C ^8' ), 123.73 d (C ⁸ ), 130.68 s (C ^10a ), 134.17 s (C ^8a ), 135.16 d (C ⁶ ), 140.08 s (C ⁵ ), 149.35 s (C ⁷ ), 150.24 d (C ^{7 '} ), 160.35 s (C ³ ), 187.21 s (C ⁹ ), 189.81 s (C ¹⁰ ), 184.61 s (C = O). Found,%: C 71.55; H 7.45; N, 2.44. C ₃₂ H ₄₁ BUT ₆ . Calculated,%: C 71.75; H, 7.71; N, 2.61.

+31.8° (с 1.2, хлф.). Спектр ЯМР ¹Н (CDCl₃), δ, м.д., J, Гц: 1.04 с (3Н, СН₃ при С^2'), 1.18 д, 1.24 д (6Н, СН(СН ₃)₂ при С⁷), 1.32 с (3Н, СН₃ при С^6'), 1.40-1.79 м (8Н, H^{1',3',4',4',5',5',12',12'}), 1.88 с (3Н, СН₃), 2.08 м (2Н, 1Н, CH-i-Pr и 1Н, Н^3'), 2.42-2.56 м (2Н, Н^13',13'), 2.18 с (3Н, СН₃), 4.91 д, 4.98 д (2Н, Н^8', J_гем 2.2, J_виц 10.8 и 15.0). 5.74 м (1Н, Н^7', J 10.8 и 15.0), 7.08 д (1Н, Н⁶, J 1.8), 7.82 д (1Н, Н⁸, J 1.8 Гц), 8.05 с (1Н, ОН), 9.90 с (1Н, ОН) Спектр ЯМР ¹³С (СDСl₃), δ, м.д.: 17.46 к (СН₃ при С^6'), 17.8 т (С^4'), 18.66 к (2xСН₃-i-Рr), 21.88 к, 22.92 к (СН ₃ при С¹ и С³), 25.61 к (СН₃ при С^2'), 29.30 т (С^12'), 32.10 д (CH-i-Pr), 35.10 т (С^13'), 36.90 т (С^5'), 38.00 т (С^3'), 39.80 с (С^6'), 43.10 с (С^2'), 46.10 д (С^1'), 110.50 т (С^8'), 123.90 д (С⁸), 125.80 с (С^8a), 126.10 с (С^10a), 129.05 с (С^9a), 130.80 д (С⁶), 133.18 с (С^4a), 140.67 с (С⁵), 146.91 с (С⁴), 151.10 д (С^7'), 156.10 с (С¹), 158.20 с (С³), 161.10 с (С⁷), 179.86 с (С¹⁰), 183.02 с (С⁹), 184.62 с (СООН). Найдено, %: С 73.61; Н 7.22; N 2.59. С₃₁Н₃₇NO₅. Вычислено, %: С 73.93; Н 7.41; N 2.78. Общий выход соединения (Iа) в расчете на исходную левопимаровую кислоту (III) составляет 31%.6. Preparation of (2R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-hydroxy-7-isopropyl-1,3-dimethyl-2- azaanthraquinone (Ia). 2.14 g (4 mmol) of the epoxy compound (IXa) in 10 ml of dioxane, 0.08 ml of trifluoroacetic acid, 3A molecular sieves are loaded into a glass ampoule in a stream of argon, cooled to 0 ° C and sealed. The ampoule is carefully heated and incubated for 15 hours at 125 ° C (bath). After cooling, the ampoule is opened, chloroform is added to the residue, mechanical impurities are filtered off, the solution is evaporated in vacuo. Column chromatography (silica gel, chloroform, chloroform alcohol, 10: 1) gave 1.77 g of (2R, 6R) -5- [2 (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-hydroxy- 7-isopropyl-1,3-dimethyl-2-aza-9,10-anthraquinone (Ia) as a yellow oily substance. Recrystallization from petroleum ether gave 1.48 g (74% yield) (2R, 6R) -5- [2 (6-vinyl-2-carboxy-2,6-dimethylcyclohexyl) ethyl] -4-hydroxy-7-isopropyl-1 , 3-dimethyl-2-aza-9,10-anthraquinone (Ia). T. pl. 102-104 ° C.

+ 31.8 ° (c 1.2, hlf.). ¹ H NMR (CDCl _3), δ, ppm, J, Hz: 1.04 s (3H, _CH3 at C ^{2 '),} 1.18 d, 1.24 d (6H, CH (C H _{3) 2,} with C ⁷ ), 1.32 s (3H, CH ₃ at C ^{6 '} ), 1.40-1.79 m (8H, H ^{1', 3 ', 4', 4 ', 5', 5 ', 12', 12 '} ), 1.88 s (3H, CH ₃ ), 2.08 m (2H, 1H, C H -i-Pr and 1H, H ^{3 '} ), 2.42-2.56 m (2H, H ^{13', 13 '} ), 2.18 s (3H, CH ₃ ), 4.91 d, 4.98 d (2H, H ^{8 '} , J _heme 2.2, J _vice 10.8 and 15.0). 5.74 m (1H, H ^{7 '} , J 10.8 and 15.0), 7.08 d (1H, H ⁶ , J 1.8), 7.82 d (1H, H ⁸ , J 1.8 Hz), 8.05 s (1H, OH), 9.90 s (1H, OH) ¹³ C NMR Spectrum (CDCl ₃ ), δ, ppm: 17.46 k (CH ₃ at C ^{6 '} ), 17.8 t (C ^4' ), 18.66 k (2x C H ₃ -i- Pr), 21.88 k, 22.92 k (C H ₃ at C ¹ and C ³ ), 25.61 k (CH ₃ at C ^{2 '} ), 29.30 t (C ^12' ), 32.10 d (CH-i-Pr), 35.10 t (C ^{13 '} ), 36.90 t (C ^5' ), 38.00 t (C ^{3 '} ), 39.80 s (C ^6' ), 43.10 s (C ^{2 '} ), 46.10 d (C ^1' ), 110.50 t ( C ^{8 '} ), 123.90 d (C ⁸ ), 125.80 s (C ^8a ), 126.10 s (C ^10a ), 129.05 s (C ^9a ), 130.80 d (C ⁶ ), 133.18 s (C ^4a ), 140.67 s ( C ⁵ ), 146.91 s (C ⁴ ), 151.10 d (C ^{7 '} ), 156.10 s (C ¹ ), 158.20 s (C ³ ), 161.10 s (C ⁷ ), 179.86 s (C ¹⁰ ), 183.02 s ( C ⁹ ), 184.62 s (COOH). Found,%: C 73.61; H 7.22; N, 2.59. C ₃₁ H ₃₇ NO ₅ . Calculated,%: C 73.93; H 7.41; N, 2.78. The total yield of compound (Ia) based on the initial levopimaric acid (III) is 31%.

Example 2. Synthesis of (2R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-hydroxy-7-isopropyl-1-methyl-3-ethyl -2-azaanthraquinonone (1b).

Stage 1-4 are performed according to the methods described in the description of example 1.

5. Preparation of (2R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-methoxy-7-isopropyl-1-methyl-3-ethyl- 1,4-epoxy-2-azaanthracene-9,10-dione (IXb).

A solution of 1.04 g (2.55 mmol) of compound (VIIa) in 20 ml of methylene chloride was loaded into a glass ampoule, 0.032 ml (0.26 mmol) of BF ₃ ^· Et ₂ O was added, then 0.46 g (3.26 mmol) of oxazole (VIIIb). The ampoule is flushed with argon, cooled and sealed. The reaction mixture was kept at 20 ° C for 52 hours. After the specified time, the ampoule was opened, the reaction mass was poured into 100 ml of water, the product was extracted with methylene chloride (20 × 3 ml), the organic layers were combined, washed with water, then dried over calcined magnesium sulfate. The desiccant is filtered off, the mother liquor is evaporated, the residue is separated by silica gel column chromatography (eluents: chloroform, chloroform - ethanol, in a 10: 1 ratio). Collect 3 fractions. The final fraction (1.18 g) was further purified by silica gel column chromatography (eluent: benzene-ethyl acetate). Get 2 fractions. Subsequent chromatography of fraction 2 isolates 0.95 g (67% yield) of the adduct (IXb) as a mixture of stereoisomers (endo- and exo-location of the epoxymic). Oily substance. ¹ H NMR spectrum (CDCl ₃ ), δ, ppm, J, Hz: 1.06 s, 1.08 s (3H, CH ₃ at C ^{2 '} ), 1.18 s, 1.20 s (3H, CH ₃ at C ¹ ) , 1.20 t (3H, CH ₃ , J = 7), 1.29 d [6H, CH (C H ₃ ) ₂ at C ⁷ , J = 6.9], 1.32 s (3H, CH ₃ at C ^{6 '} ), 1.38- 1.81 m (8H, H ^{1 ', 3', 4 ', 4', 5 ', 5', 12 ', 12'} ), 2.02-2.12 m [2H, 1H, C H -i-Pr and 1H, H ^{3 '} ], 2.46-2.65 m (2H, H ^{13', 13 '} ), 3.58 s, 3.61 s (3H, CH ₃ ), 3.72 m (1H, H ^9a ), 4.02 k (2H, CH ₂ , J = 7), 4.14 m (1Н, Н ^4a ), 4.85-4.94 m (2Н, Н ^{8 '} ), 5.60-5.66 m (1Н, Н ^7' ), 7.26 d (1Н, Н ⁶ , J = 1.8), 7.82 d (1H, H ⁸ , J = 1.8), 10.11 s (1H, OH). ¹³ C NMR spectrum (CDCl ₃ ), δ, ppm: 13.24 k (CH ₃ ), 16.4 k, 16.6 k (CH ₃ at C ^{2 '} ), 18.01 t (C ^4' ), 18.12 k (CH ₃ at C ¹ ), 18.68 k, 18.73 k (CH ( C H ₃ ) ₂ ), 22.41 k, 22.61 k (CH ₃ at C ^{6 '} ), 28.85 t (C ^12' ), 33.37 d ( C H-i- Pr), 36.12 t (C ^{3 '} ), 37.05 t (C ^5' ), 37.96 t (C ^{5 '} ), 41.02 s (C ^6' ), 43.97 s (C ^{2 '} ), 45.05 d (C ^1' ) , 45.85 d (C ^4a ), 49.83 d (C ^9a ), 52.42 k (OCH ₃ ), 57.46 t (CH ₂ ), 74.11 s (C ¹ ), 89.08 s (C ⁴ ), 111.26 t (C ^{8 '} ) , 122.96 d (C ⁸ ), 131.01 s (C ^10a ), 134.21 s (C ^8a ), 133.01 d (C ⁶ ), 139.35 s (C ⁵ ), 150.08 s (C ⁷ ), 150.41 d (C ^{7 '} ) , 161.17 s (C ³ ), 188.04 s (C ⁹ ), 189.75 s (C ¹⁰ ), 184.80 s (C = O). Found,%: C 71.92; H, 7.68; N, 2.41. C ₃₃ H ₄₃ NO ₆ . Calculated,%: C 72.10; H 7.88; N, 2.55.

+45.1° (с 3.1, СНСl₃). Спектр ЯМР ¹Н (СDСl₃), δ, м.д., J, Гц: 0.99 с (3Н, CH₃ пpи C^2'), 1.18 д, 1.21 д (6H, CH(CH ₃)₂ при C⁷, J=6.8), 1.23 к (3H, CH₃, J=7.0),1.32 с (3Н, СН₃ при С^6'), 1.35-1.78 м (8Н,Н^{1',3',4',4',5',5',12',12'}), 2.15 м(2Н, 1Н, CH-i-Рr и 1Н, Н^3'), 2.06 с (3Н, СН₃), 2.41-2.59 м (2Н, Н^13',13'), 4.18 к (2Н, СН₂, J=7.0), 4.88-4.98 м (2Н, Н^8'), 5.75 м (1Н, Н^7', J 10.8 и 15.0), 7.20 д (1Н, Н⁶, J=1.8), 7.85 д (1Н, Н⁸, J=1.8), 8.09 с (1Н, ОН), 10.0 с (1Н, ОН). Спектр ЯМР ¹³С (СDСl₃), δ, м.д.: 12.42 к (СН₃), 17.46 т (С^4'), 17.88 к (СН₃ при С^6'), 18.66 к, 18.83 к (2 х СН₃-i-Рr), 21.88 к (СН ₃ при С¹), 25.46 к (СН₃ при С^2'), 29.30 т (С^12'), 32.10 д (CH-i-Pr), 34.58 т (С^3'), 36.02 т (С^13'), 37.90 т (С^5'), 39.80 с (С^6'), 40.26 т (СН₂), 42.12 с (С^2'), 46.73 д (С^1'), 110.50 т (С^8'), 124.08 д (С⁸), 125.88 с (С^8a), 126.65 с (С^10a), 129.45 с (С^9a), 130.14 д (С⁶), 133.18 с (С^4a), 139.68 с (С⁵), 147.18 с (С⁴), 151.18 д (С^7'), 156.18 (С¹), 158.27 с (С³), 161.34 с (С⁷), 179.80 с (С¹⁰), 183.34 с (С⁹). 184.46 с (СООН). Найдено, %: С 74.43; Н 7.01; N 2.46. С₃₂Н₃₉NO₅. Вычислено, %: С 74.25; Н 7.59; N 2.71. Общий выход соединения (Iб) в расчете на исходную левопимаровую кислоту (III) составляет 34%.6. Preparation of (2R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-hydroxy-7-isopropyl-1-methyl-3-ethyl- 2-azaanthraquinonone (IB). 1.85 g (1.7 mmol) of epoxy compounds (IXb) in 10 ml of dioxane, 0.08 ml of trifluoroacetic acid, 3A molecular sieves are loaded into a glass ampoule in a stream of argon, cooled to 0 ° С and sealed. The ampoule is carefully heated and incubated for 15 hours at 125 ° C. After cooling, the ampoule is opened, chloroform is added to the residue, mechanical impurities are filtered off, the solution is evaporated in vacuo. Column chromatography of the residue (1.93 g) (silica gel, chloroform, chloroform-alcohol, 10: 1) gave 1.44 g (81% yield) (2R, 6R) -5- [2 (6-vinyl-2,6-dimethyl-2 -carboxycyclohexyl) ethyl] -4-hydroxy-7-isopropyl-1,3-dimethyl-2-aza-9,10-anthraquinone (IB) as a yellow oily substance, which crystallizes upon standing. T. pl. 116-122 ° C (from ether).

+ 45.1 ° (c 3.1, CHCl ₃ ). ¹ H NMR spectrum (CDCl ₃ ), δ, ppm, J, Hz: 0.99 s (3H, CH _{3 for} C ^{2 '} ), 1.18 d, 1.21 d (6H, CH (C H ₃ ) ₂ at C ⁷ , J = 6.8), 1.23 q (3H, CH ₃ , J = 7.0), 1.32 s (3H, CH ₃ at C ^{6 '} ), 1.35-1.78 m (8H, H ^{1', 3 ', 4', 4 ', 5', 5 ', 12', 12 '} ), 2.15 m (2H, 1H, C H -i-Pr and 1H, H ^3' ), 2.06 s (3H, CH ₃ ), 2.41-2.59 m (2H, H ^{13 ', 13'} ), 4.18 q (2H, CH ₂ , J = 7.0), 4.88-4.98 m (2H, H ^{8 '} ), 5.75 m (1H, H ^7' , J 10.8 and 15.0) 7.20 d (1H, H ⁶ , J = 1.8), 7.85 d (1H, H ⁸ , J = 1.8), 8.09 s (1H, OH), 10.0 s (1H, OH). ¹³ C NMR spectrum (CDCl ₃ ), δ, ppm: 12.42 k (CH ₃ ), 17.46 t (C ^{4 '} ), 17.88 k (CH ₃ at C ^6' ), 18.66 k, 18.83 k (2 x C H ₃ -i-Pr), 21.88 k (C H ₃ at C ¹ ), 25.46 k (CH ₃ at C ^{2 '} ), 29.30 t (C ^12' ), 32.10 d ( C Hi-Pr), 34.58 t (C ^{3 '} ), 36.02 t (C ^13' ), 37.90 t (C ^{5 '} ), 39.80 s (C ^6' ), 40.26 t (CH ₂ ), 42.12 s (C ^{2 '} ), 46.73 d (C ^{1 '} ), 110.50 t (C ^8' ), 124.08 d (C ⁸ ), 125.88 s (C ^8a ), 126.65 s (C ^10a ), 129.45 s (C ^9a ), 130.14 d (C ⁶ ), 133.18 s (C ^4a ), 139.68 s (C ⁵ ), 147.18 s (C ⁴ ), 151.18 d (C ^{7 '} ), 156.18 (C ¹ ), 158.27 s (C ³ ), 161.34 s (C ⁷ ), 179.80 s (C ¹⁰ ), 183.34 s (C ⁹ ). 184.46 s (COOH). Found,%: C 74.43; H 7.01; N, 2.46. C ₃₂ H ₃₉ NO ₅ . Calculated,%: C 74.25; H 7.59; N, 2.71. The total yield of compound (IB) calculated on the basis of the initial levopimaric acid (III) is 34%.

Example 3. Synthesis of (2R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-hydroxy-3,7-diisopropyl-1-methyl-2 -azanthracene-9,10-dione (Ic).

Stage 1-4 are similar to those described in the description of example 1.

5. Preparation of (2R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-methoxy-3,7-diisopropyl-1-methyl-1,4- epoxy-2-azaanthracene-9,10-dione (IXb).

A solution of 1.58 g (3.87 mmol) of compound (VIIa) in 20 ml of methylene chloride was loaded into a glass ampoule, 0.05 ml (0.4 mmol) of BF ₃ · Et ₂ O was added, then 0.67 g (4.32 mmol) of oxazole (VIIIa). The ampoule is flushed with argon, cooled and sealed. The reaction mixture was kept at 20 ° C for 48 hours. After the specified time, the ampoule was opened, the reaction mass was poured into 100 ml of water, the product was extracted with methylene chloride (25 × 3 ml), the organic layers were combined, washed with water, then dried over calcined magnesium sulfate. The desiccant is filtered off, the mother liquor is evaporated, the residue is separated by silica gel column chromatography (eluents: chloroform, chloroform - ethanol, in a 10: 1 ratio). Collect 3 fractions. The last fraction (1.66 g) was further purified by silica gel column chromatography (eluent: benzene-ethyl acetate).

Get 2 fractions. Subsequent chromatography of fraction 2 isolated 1.31 g (60% yield) of the adduct (IXb) as a mixture of stereoisomers (endo- and exo-location of the epoxymic). Oily substance. ¹ H NMR (CDCl _3), δ, ppm, J, Hz: 1.05 s, 1.08 s (3H, _CH3 at C ^{6 '),} 1.18 d, 1.20 d, 1.26 d, 1.28 d (12H, CH (C H ₃ ) ₂ at C ³ and CH (C H ₃ ) ₂ at C ⁶ ), 1.30 s, 1.33 s (3H, CH ₃ at C ^{2 '} ), 1.38-1.79 m (8H, H ^{1', 3 ', 4', 4 ', 5', 5 ', 12', 12 '} ), 2.09 m (2H, 1H, C H -i-Pr and 1H, H ^3' ), 2.22 m (1H, C H -i-Pr), 2.42-2.60 m (2Н, Н ^{13 ', 13'} ), 2.62 s, 2.67 s (3Н, СН ₃ ), 3.59 s, 3.64 s (3Н, СН ₃ ), 3.78 m (1Н, H ^4a ), 4.06 m (1H, H ^4a ), 4.81-4.91 m (2H, H ^{8 '} ), 5.60-5.68 m (1H, H ⁷ ), 7.28 d (1H, H ⁶ , J 1.8 Hz), 7.81 d (1H, H ⁸ , J 1.8 Hz), 10.01 s (OH). ¹³ C NMR spectrum (CDCl ₃ ), δ, ppm: 16.2 k, 16.8 k (CH ₃ at C ^{2 '} ), 17.71 t (C ^4' ), 18.61 k (CH ₃ at C ¹ ), 18.91 k , 19.03 k (CH ( C H ₃ ) ₂ ), 21.55 k, 21.78 k (CH ( C H ₃ ) ₂ ), 23.22 k (CH ₃ at C ^{6 '} ), 28.74 t (C ^12' ), 32.18 d. 32.66 d ( C H-i-Pr), 35.12 t (C 3 ^' ), 36.19 t (C ^3' ), 38.08 t (C ^{5 '} ), 40.66 s (C ^6' ), 43.73 s (C ^{2 '} ), 45.38 d (C ^{1 '} ), 45.32 d (C ^4a ), 49.51 d (C ^9a ), 52.46 s (OCH ₃ ), 75.01 s (C ⁴ ), 89.54 s (C ¹ ), 110.46 t (C ^8' ), 123.03 d (C ⁸ ), 131.21 s (C ^10a ), 134.17 s (C ^8a ), 132.16 d (C ⁶ ), 140.08 s (C ⁵ ), 149.65 s (C ⁷ ), 150.24 d (C ^{7 '} ), 160.35 s (C ³ ), 184.53 s (C = O), 188.01 s (C ⁹ ), 189.95 s (C ¹⁰ ). Found,%: C 72.18; H 7.77; N, 2.04. C ₃₄ H ₄₅ NO ₆ . Calculated,%: C 72.44; H 8.05; N, 2.48.

+28.5° (с 2.3, СНСl₃). Спектр ЯМР ¹H (СDСl₃), δ, м.д., J, Гц: 1.12 с (3Н, СН₃ при С^6'), 1.18 д, 1.21 д (6Н, СН(СН ₃)₂ при С⁷, J=6.8), 1.25 с (3Н, СН ₃ при С^2'), 1.28 д, 1.32 д (6Н, СН(СН ₃)₂ при C³, J=7.0), 1.40-1.79 м (8Н, H^{1',3',4',4',5',5',12',12'}), 2.08-2.22 м (2Н, 1Н, CH-i-Pr и 1Н, Н^3'), 2.28 м (1Н, CH-i-Pr), 2.38 с (3Н, СН ₃ при С¹), 2.48-2.58 м (2Н, Н^13',13'), 4.91 д, 4.96 д (2Н, Н^8', J_гем 2.2, J_виц 10.8 и 15.0), 5.70 м (1Н, Н^7', J 10.8 и 15.0), 7.18 д (1Н, H⁶, J=1.8), 7.81 д (1Н, H⁸, J=1.8), 8.05 с (1Н, ОН), 9.90 с (1Н, ОН). Спектр ЯМР ¹³С (СDСl₃), δ, м.д.: 17.21 к (СН₃ при С^6'), 17.68 т (С^4'), 18.66 к, 18.73 к (СН₃-i-Рr), 20.08 к, 20.39 к (СН₃-i-Рr), 21.92 к (СН ₃ при С¹), 25.81 д (CH-i-Pr), 26.08 к (СН₃ при С^2'), 29.68 т (С^12'), 32.19 д (CH-i-Pr), 35.88 т (С^3'). 36.10 т (С^13'), 37.67 т (С^5'), 39.43 с (С^6'), 42.31 с (С^2'), 46.10 д (C^1'), 111.65 т (С^8'), 123.90 д (С⁸), 125.80 с (С^8a), 126.10 с (С^10a), 130.05 с (С^9a), 130.80 д (С⁶), 132.18 с (С^4a), 140.07 с (С⁵), 148.16 с (С⁴), 151.10 д (С^7'), 155.42 (С¹), 158.04 с (С³), 161.10 с (С⁷), 179.86 с (С¹⁰), 183.02 с (С⁹), 184.62 с (СООН). Найдено, %: С 74.32; Н 7.43; N 2.51. С₃₃Н₄₁NO₅. Вычислено, %: С 74.55; Н 7.77; N 2.63. Общий выход соединения (Iв) в расчете на исходную левопимаровую кислоту (III) составляет 28%.6. Preparation of (2R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-hydroxy-3,7-diisopropyl-1-methyl-2- azaanthracene-9,10-dione (Ic). 1.07 g (2 mmol) of epoxy compounds (IXB) in 15 ml of dioxane, 0.1 ml of trifluoroacetic acid, 3A molecular sieves are loaded into a glass ampoule in a stream of argon, cooled to 0 ° C and sealed. The ampoule is carefully heated and incubated for 15 hours at 105 ° C. After cooling, the ampoule is opened, chloroform is added to the residue, mechanical impurities are filtered off, the solution is evaporated in vacuo. Column chromatography (silica gel, chloroform, chloroform alcohol, 10: 1) isolated (2R, 6R) -5- [2 (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-hydroxy-7- isopropyl-1,3-dimethyl-2-aza-9,10-anthraquinone (Ic) as a yellow oily substance (0.88 g). Recrystallization from petroleum ether gives 0.77 g (72% yield) of crystalline product (Ic). T. pl. 133-136 ° C.

+ 28.5 ° (c 2.3, CHCl ₃ ). ¹ H NMR spectrum (CDCl ₃ ), δ, ppm, J, Hz: 1.12 s (3H, CH ₃ at C ^{6 '} ), 1.18 d, 1.21 d (6H, CH (C H ₃ ) ₂ at C ⁷ , J = 6.8), 1.25 s (3H, C H ₃ at C ^{2 '} ), 1.28 d, 1.32 d (6H, CH (C H ₃ ) ₂ at C ³ , J = 7.0), 1.40-1.79 m ( 8H, H ^{1 ', 3', 4 ', 4', 5 ', 5', 12 ', 12'} ), 2.08-2.22 m (2H, 1H, C H -i-Pr and 1H, H ^{3 '} ) , 2.28 m (1H, C H -i-Pr), 2.38 s (3H, C H ₃ at C ¹ ), 2.48-2.58 m (2H, H ^{13 ', 13'} ), 4.91 d, 4.96 d (2H, H ^{8 '} , J _heme 2.2, J _vice 10.8 and 15.0), 5.70 m (1H, H ^7' , J 10.8 and 15.0), 7.18 d (1H, H ⁶ , J = 1.8), 7.81 d (1H, H ⁸ , J = 1.8), 8.05 s (1H, OH), 9.90 s (1H, OH). ¹³ C NMR spectrum (CDCl ₃ ), δ, ppm: 17.21 k (CH ₃ at C ^{6 '} ), 17.68 t (C ^4' ), 18.66 k, 18.73 k ( C H ₃ -i-Pr), 20.08 k, 20.39 k ( C H ₃ -i-Pr), 21.92 k (C H ₃ at C ¹ ), 25.81 d ( C H-i-Pr), 26.08 k (CH ₃ at C ^{2 '} ), 29.68 t (C ^{12 '} ), 32.19 d ( C H-i-Pr), 35.88 t (C ^3' ). 36.10 t (C ^{13 '} ), 37.67 t (C ^5' ), 39.43 s (C ^{6 '} ), 42.31 s (C ^2' ), 46.10 d (C ^{1 '} ), 111.65 t (C ^8' ), 123.90 d (C ⁸ ), 125.80 s (C ^8a ), 126.10 s (C ^10a ), 130.05 s (C ^9a ), 130.80 d (C ⁶ ), 132.18 s (C ^4a ), 140.07 s (C ⁵ ), 148.16 s ( C ⁴ ), 151.10 d (C ^{7 '} ), 155.42 (C ¹ ), 158.04 s (C ³ ), 161.10 s (C ⁷ ), 179.86 s (C ¹⁰ ), 183.02 s (C ⁹ ), 184.62 s (COOH ) Found,%: C 74.32; H 7.43; N, 2.51. C ₃₃ H ₄₁ NO ₅ . Calculated,%: C 74.55; H 7.77; N, 2.63. The total yield of compound (Ic) based on the initial levopimaric acid (III) is 28%.

Example 4. Synthesis of (2R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-methoxycarbonylcyclohexyl) ethyl] -4-hydroxy-7-isopropyl-1,3-dimethyl-2 -azanthracene-9,10-dione (Id).

- 118° (с 4.5, СНСl₃) (литературные данные 163°С [Herz W., Blackstone R.C., Nair M.G. J. Org. Chem. 1967, 32, 2992]).1. Preparation of 7,10a-dimethyl-13-isopropyl-7-methoxycarbonyl-4,4a, 5,6,6a, 7,8,9,10,10a, 10b, 11,12,12a-tetradecahydro-4b, 12 etheno-1H-chrysene-1,4-dione (IVb). 4.14 g (30 mmol) of K ₂ CO ₃ and 2.84 ml (30 mmol) of dimethyl sulfate are added to a solution of 10.25 g (25 mmol) of endion (IVa) in 150 ml of acetone. The reaction mixture is boiled for 20 hours, after cooling, the precipitate is filtered off, washed with chloroform, and the organic layers are evaporated. 50 ml of water was added to the residue, the product was extracted with chloroform, the extract was washed with water, dried over MgSO ₄ and evaporated. The residue (9.62 g) was dissolved in 120 ml of ethanol, add 1.5 g of activated carbon and boiled for 20 minutes, the carbon was filtered off, the clarified ethanol solution was evaporated. The residue was recrystallized from ethanol-petroleum ether (1: 3) to give 8.82 g (83%) of quinopimaric acid methyl ester (IVb), mp. 167-168 ° C,

- 118 ° (c 4.5, CHCl ₃ ) (published data 163 ° C [Herz W., Blackstone RC, Nair MGJ Org. Chem. 1967, 32, 2992]).

- 106° (с 1.5, СНСl₃). Спектр ЯМР ¹Н (CDCl₃), δ, м.д.: 0.67 с (3Н, СН₃ при С^10a), 0.76-0.86 м (3Н, Н^11a,e,10b), 0.97 д, 1.0 д (6Н, СН(СН ₃)₂, J 6.9 Гц), 1.15 с (3Н, СН₃ при С⁷), 1.18-1.32 м (4Н, H^6a,e,9a,10a), 1.62.1.83 м (6Н, Н^{8a,e,5a,9e,6а,10е}), 2.30 м (1Н, СН(СН₃)₂, J 6.9 Гц), 2.80 м (1Н, Н^5e), 3.66 с (3Н, ОСН₃), 4.08 с (1Н, Н¹²) 5.62 с (1Н, Н¹⁴), 6.30 д (1Н, H², J 8.0 Гц), 6.38 д (1Н, Н³, J 8.0 Гц), 8.0 с (2Н, ОН).2. Preparation of 7,10a-dimethyl-1,4-dihydroxy-13-isopropyl-7-methoxycarbonyl-5b, 6a, 8,9,10,10b, 11,12-dodecahydro-4b, 12-ethenochrysene (Vb). To a solution of 4.21 g (10 mmol) of methylquinopyrimarate (IVb) in 30 ml of EtOH, 25 ml of a 5% NaOH solution are added with stirring, the mixture is kept for 40 minutes, then acidified with a 3% HC1 solution to pH 5 (≈ 24 ml). The precipitate formed is filtered off, washed with water, dried and recrystallized from ethyl acetate. 3.84 g (90%) of hydroquinone (Vb), t. 185-187 ° C,

- 106 ° (c 1.5, CHCl ₃ ). ¹ H NMR spectrum, CDCl ₃ , δ, ppm: 0.67 s (3Н, СН ₃ at С ^10a ), 0.76-0.86 m (3Н, Н ^{11a, e, 10b} ), 0.97 d, 1.0 d (6Н , СН (С Н ₃ ) ₂ , J 6.9 Hz), 1.15 s (3Н, СН ₃ at С ⁷ ), 1.18-1.32 m (4Н, H ^{6a, e, 9a, 10a} ), 1.62.1.83 m (6Н, H ^{8a, e, 5a, 9e, 6a, 10e} ), 2.30 m (1H, C H (CH ₃ ) ₂ , J 6.9 Hz), 2.80 m (1H, H ^5e ), 3.66 s (3H, OCH ₃ ), 4.08 s (1H, H ¹² ) 5.62 s (1H, H ¹⁴ ), 6.30 d (1H, H ² , J 8.0 Hz), 6.38 d (1H, H ³ , J 8.0 Hz), 8.0 s (2H, OH) .

3. Preparation of 7,10a-dimethyl-13-isopropyl-7-methoxycarbonyl-4,4a, 5,6,7,8,9,10,10a, 10b, 11,12-dodecahydro-4b, 12-etheno-1H -chrysene-1,4-dione (VIb). To a solution of 3.85 g (8.2 mmol) of hydroquinone (Vb) in 40 ml of anhydrous acetonitrile, 4.55 g (8.3 mmol) (NH ₄ ) ₂ Ce (NO ₃ ) _{6 are} gradually added portionwise with stirring. Stirring is continued for 6 hours (TLC control). The reaction mixture was poured into 150 ml of water, the product was extracted with chloroform (3 × 60 ml). The extract was washed with water, brine (2 × 20 ml), dried with MgSO ₄ , and evaporated in vacuo. After purification by column chromatography (silica gel, eluent-chloroform), 3.43 g (89% yield) of polycyclic quinone (VIb) are obtained. The spectral data of compound (VIb) are similar to those given in [Schulz E.E., Oleinikov D.S., Nechepurenko I.V., Shakirov M.M., Tolstikov G.A. Journal of Organic Chemistry, 2009, 45, 108].

4. Preparation of 5- [2- (6-vinyl-2,6-dimethyl-2-methoxycarbonylcyclohexyl) ethyl] -7-isopropyl-1,4-naphthoquinone (VIIb). A solution of 0.96 g (2.3 mmol) of quinone (VIb) in 15 ml of dioxane is heated in a sealed ampoule in an argon atmosphere for 10 hours at 150 ° C. After cooling, the ampoule is opened, chloroform is added to the residue, mechanical impurities are filtered off, the solution is evaporated in vacuo, the residue is chromatographed on silica gel (eluent-chloroform). Obtain 0.91 g (yield 98%) of substituted 1,4-naphthoquinone (VIIb). T. pl. 116-118 ° C. [α] _D - 8.6 ° (c 4.0, CHCl ₃ ). Found,%: C 76.3; H 8.2. C ₂₇ H ₃₄ O ₄ . Calculated,%: C 76.74; H 8.11. The data of ¹ H and ¹³ C NMR spectra are similar to those given in [Schulz E.E., Oleinikov D.S., Nechepurenko I.V., Shakirov M.M., Tolstikov G.A. Journal of Organic Chemistry, 2009, 45, 108]. Found,%: C 76.3; H 8.2. C ₂₇ H ₃₄ O ₄ . Calculated,%: C 76.74; H 8.11.

5. Preparation of (2R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-methoxy-7-isopropyl-1,3-dimethyl-1, 4-epoxy-2-azaanthracene-9,10-dione (IXx).

A solution of 2.16 g (5.12 mmol) of compound (VIIb) in 20 ml of methylene chloride was loaded into a glass ampoule, 0.066 ml (0.52 mmol) of BF ₃ · Et ₂ O was added, then 0.70 g (5.51 mmol) of oxazole (VIIIa). The ampoule is flushed with argon, cooled and sealed. The reaction mixture was kept at 20 ° C for 48 hours. After the specified time, the ampoule was opened, the reaction mass was poured into 100 ml of water, the product was extracted with methylene chloride (20 × 3 ml), the organic layers were combined, washed with water, then dried over calcined magnesium sulfate. The desiccant is filtered off, the mother liquor is evaporated, the residue is separated by silica gel column chromatography (eluents: chloroform, chloroform - ethanol, in a 10: 1 ratio). Collect 3 fractions. The last fraction (2.11 g) was further purified by silica gel column chromatography (eluent: benzene-ethyl acetate). Get 2 fractions. Subsequent chromatography of fraction 2 gave 1.77 g (63% yield) of the adduct (IXx) as a mixture of stereoisomers (endo- and exo-location of the epoxymic). Oily substance. ¹ H NMR spectrum (CDCl ₃ ), δ, ppm, J, Hz: 1.16 s, 1.18 s (3H, CH ₃ at C ¹ ), 1.22 s (3H, CH ₃ at C ^{6 '} ), 1.26 d , 1.28 d [6Н, СН (С Н ₃ ) ₂ at С ⁷ , J = 6.9], 1.30 s, 1.33 s (3Н, СН ₃ at С ^{2 '} ), 1.35-1.56 m (5Н, H ^{4', 4 ', 5', 12 ', 12'} ), 1.65 s, 1.67 s (3H, CH ₃ at C ³ ), 1.77-2.04 m (3H, H ^{1 ', 3', 5 '} ), 2.22 m [2H, 1H, C H (CH ₃ ) ₂ and 1H, H ^{3 '} ], 2.48-2.60 m (2H, H ^{13', 13 '} ), 3.59 s (3H, OCH ₃ ), 3.65 s (3H, OCH ₃ ), 3.82 m (1H, H ^9a ), 4.12 m (1H, H ^4a ), 4.86-4.91 m (2H, H ^{8 '} ), 5.62-5.71 m (1H, H ^7' ), 7.22 d (1H, H ⁶ , J = 1.8), 7.80 d (1H, H ⁸ , J = 1.8). ¹³ C NMR spectrum (CDCl ₃ ), δ, ppm: 16.8 k, 17.0 k (CH ₃ at C ^{6 '} ), 17.88 t (C ^4' ), 18.01 k (CH ₃ at C ¹ ), 18.43 k , 18.63 k (CH ( C H ₃ ) ₂ ), 20.4 k, 20.7 k (CH ₃ at C ^{2 '} ), 22.79 k (CH ₃ at C ³ ), 29.17 t (C ^12' ), 32.45 d ( C H -i-Pr). 34.97 t (C ¹³ ), 36.12 t (C ^{3 '} ), 38.66 t (C ^5' ), 42.08 s (C ^{2 '} ), 41.48 s (C ^6' ), 44.89 d (C ^{1 '} ), 44.31 d ( C ^4a ), 50.65 d (C ^9a ), 52.89 k (OCH ₃ ), 56.11 k (OCH ₃ ), 74.12 s (C ¹ ), 91.41 s (C ⁴ ), 110.46 t (C ^{8 '} ), 123.41 d (C ⁸ ), 131.11 s (C ^10a ), 133.51 s (C ^8a ), 134.09 d (C ⁶ ), 139.25 s (C ⁵ ), 150.08 s (C ⁷ ), 150.55 d (C ^{7 '} ), 161.17 s (C ³ ), 177.61 s (C = O), 187.21 s (C ⁹ ), 189.81 s (C ¹⁰ ). Found,%: C 71.86; H 7.75; N, 2.32. C ₃₃ H ₄₃ NO ₆ . Calculated,%: C 72.10; H 7.88; N, 2.55.

6. Preparation of (1R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-hydroxy-7-isopropyl-1,3-dimethyl-2- azaanthraquinone (Ig). 1.55 g (2.82 mmol) of the epoxy compound (IXX) in 10 ml of dioxane, 0.03 ml of trifluoroacetic acid, molecular sieves 3A, are cooled to 0 ° C and sealed in a glass ampoule in a stream of argon. The ampoule is carefully heated and incubated for 15 hours at 130 ° C. After cooling, the ampoule is opened, chloroform is added to the residue, mechanical impurities are filtered off, the solution is evaporated in vacuo. The residue (1.65 g) is chromatographed on a column (silica gel, chloroform, chloroform-alcohol, 10: 1) to obtain 1.39 g (2R, 6R) -5- [2 (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl ] -4-hydroxy-7-isopropyl-1,3-dimethyl-2-aza-9,10-anthraquinone (Id) as a yellow oily substance, which crystallizes upon trituration with petroleum ether. 1.19 g (yield 82%) is filtered off (2R, 6R) -5- [2 (6-vinyl-2-carboxy-2,6-dimethylcyclohexyl) ethyl] -4-hydroxy-7-isopropyl-1,3-dimethyl- 2-aza-9,10-anthraquinone (Ig), mp 142-144 ° C. [α] _D + 18.2 ° (c 4.5, CHCl ₃ ). ¹ H NMR (CDCl _3), δ, ppm, J, Hz: 1.12 s (3H, _CH3 at C ^{2 '),} 1.18 d, 1.24 d (6H, CH (C H _{3) 2,} with C ⁷ ), 1.32 s (3H, CH ₃ at C ^{6 '} ), 1.45-1.77 m (8H, H ^{1', 3 ', 4', 4 ', 5', 5 ', 12', 12 '} ), 1.86 s (3H, CH ₃ ), 1.99-2.18 m (2H. 1H, C H -i-Pr and 1H, H ^{3 '} ), 2.44-2.61 m (2H, H ^{13', 13 '} ), 2.18 s (3H , CH ₃ ), 3.68 (3H, OCH ₃ ), 4.92 d, 4.98 d (2H, H ^{8 '} , J _heme 2.2, J _vice 10.8 and 15.0), 5.74 m (1H, H ^7' , J 10.8 and 15.0) 7.08 d (1H, H ⁶ , J 1.8), 7.82 d (1H, H ⁸ , J 1.8 Hz), 9.90 s (1H, OH). ¹³ C NMR spectrum (CDCl ₃ ), δ, ppm: 17.66 k (CH ₃ at C ^{6 '} ), 17.45 t (C ^4' ), 18.66 k, 19.03 k (2 x C H ₃ -i-Pr ), 22.54 k, 23.08 k (CH ₃ at C ¹ and C ³ ), 25.88 k (CH ₃ at C ^{2 '} ), 29.30 t (C ^12' ), 32.10 d ( C H-i-Pr), 35.10 t (C ^{13 '} ), 37.08 t (C ^5' ), 38.65 s (C ^{3 '} ), 40.05 s (C ^6' ), 43.29 t (C ^{2 '} ), 46.28 d (C ^1' ), 55.09 k (OCH ₃ ) , 111.06 t (C ^{8 '} ), 123.90 d (C ⁸ ), 125.38 s (C ^10a ), 126.12 s (C ^8a ), 129.45 s (C ^9a ), 131.11 d (C ⁶ ), 133.15 s (C ^4a ) , 132.67 s (C ⁵ ), 139.98 s (C ³ ), 146.18 s (C ⁴ ), 151.68 d (C ^{7 '} ), 155.11 s (C ⁷ ), 156.48 (C ¹ ), 177.68 s (C = O) , 179.86 s (C ¹⁰ ), 183.02 s (C ⁹ ). Found,%: C 74.14; H 7.28; N, 2.81. C ₃₂ H ₃₉ NO ₅ . Calculated,%: C 74.25; H 7.59; N, 2.71. The total yield of compound (Ig) based on the initial levopimaric acid (III) is 27.6%.

Example 5. Synthesis of (2R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-methoxycarbonylcyclohexyl) ethyl] -4-hydroxy-7-isopropyl-1-methyl-3-ethyl -2-azaanthracene-9,10-dione (Id).

Stage 1-4 are similar to those described in the description of example 4.

5. Preparation of (2R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-methoxy-7-isopropyl-1-methyl-3-ethyl- 1,4-epoxy-2-azaanthracene-9,10-dione (IXd).

A solution of 1.52 g (3.6 mmol) of compound (VIIb) in 20 ml of methylene chloride was loaded into a glass ampoule, 0.045 ml (0.36 mmol) of BF ₃ · Et ₂ O was added, then 0.62 g (4.4 mmol) of oxazole (VIIIb). The ampoule is flushed with argon, cooled and sealed. The reaction mixture was kept at 20 ° C for 52 hours. After the specified time, the ampoule was opened, the reaction mass was poured into 100 ml of water, the product was extracted with methylene chloride (30 × 3 ml), the organic layers were combined, washed with water, then dried over calcined magnesium sulfate. The desiccant is filtered off, the mother liquor is evaporated, the residue is separated by silica gel column chromatography (eluents: chloroform, chloroform - ethanol, in a 10: 1 ratio). Collect 3 fractions. The last fraction (1.58 g) was further purified by silica gel column chromatography (eluent: benzene-ethyl acetate). Get 2 fractions. Subsequent chromatography of fraction 2 isolated 1.29 g (64% yield) of the adduct (IXd) in the form of a mixture of stereoisomers (endo- and exo-location of the epoxymic). Oily substance. ¹ H NMR spectrum (CDCl ₃ ), δ, ppm, J, Hz: 1.06 s, 1.08 s (3H, CH ₃ at C ^{2 '} ), 1.18 s, 1.20 s (3H, CH ₃ at C ¹ ) , 1.20 t (3H, CH ₃ , J = 7), 1.29 d [6H, CH (C H ₃ ) ₂ at C ⁷ , J = 6.9], 1.32 s (3H, CH ₃ at C ^{6 '} ), 1.38- 1.81 m (8H, H ^{1 ', 3', 4 ', 4', 5 ', 5', 12 ', 12'} ), 2.02-2.12 m [2H, 1H, C H -i-Pr and 1H, H ^{3 '} ], 2.46-2.65 m (2H, H ^{13', 13 '} ), 3.58 s (3H, OCH ₃ ), 3.61 s (3H, OCH ₃ ), 3.72 m (1H, H ^9a ), 4.02 to (2H , CH ₂ , J = 7), 4.14 m (1Н, Н ^4a ), 4.85-4.94 m (2Н, Н ^{8 '} ), 5.60-5.66 m (1Н, Н ^7' ), 7.26 d (1Н, Н ⁶ , J = 1.8), 7.82 d (1H, H ⁸ , J = 1.8). ¹³ C NMR spectrum (CDCl ₃ ), δ, ppm: 16.2 k, 16.6 k (CH ₃ at C ^{2 '} ), 17.4 k, 17.7 k (CH ₃ at C ^6' ), 17.68 t (C ^{4 '} ), 18.01 k (CH ₃ at C ¹ ), 18.43 k, 18.63 k (CH ( C H ₃ ) ₂ ), 22.79 k (CH ₃ at C ¹ ), 28.76 t (C ^{12 '} ), 33.37 d ( C H -i-Pr), 35.01 t (C ^{3 '} ), 36.46 t (C ^5' ), 38.05 s (C ^{2 '} ), 40.25 d (C ^1' ), 41.43 s (C ^{6 '} ), 45.97 t (C ^{13 '} ), 46.05 d (C ^9a ), 52.32 d (C ^4a ), 52.42 k (OCH ₃ ), 54.88 k (OCH ₃ ), 70.01 s (C ¹ ), 83.54 s (C ⁴ ), 110.46 t (C ^{8 '),} 123.73 d (C ^8), 127.21 s (C ^8a), 134.17 s (C ^3), 135.16 d (C ^6), 142.08 s (C ^7), 145.35 s (C ^12'), 150.24 d (C ^{7 '} ). 160.35 s (C ⁵ ), 177.78 s (C = O), 187.21 s (C ⁹ ), 189.81 s (C ¹⁰ ). Found,%: C 71.92; H, 7.68; N, 2.41. C ₃₃ H ₄₃ NO ₆ . Calculated,%: C 72.10; H 7.88; N.55.

6. Preparation of (2R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-hydroxy-7-isopropyl-1-methyl-3-ethyl- 2-azaanthraquinonone (Ie). 1.15 g (1.7 mmol) of epoxy compounds (IXd) in 8 ml of dioxane, 0.02 ml of trifluoroacetic acid, 3A molecular sieves are loaded into a glass ampoule in a stream of argon, cooled to 0 ° С and sealed. The ampoule is carefully heated and incubated for 15 hours at 130 ° C. After cooling, the ampoule is opened, chloroform is added to the residue, mechanical impurities are filtered off, the solution is evaporated in vacuo. Column chromatography (silica gel, chloroform, chloroform alcohol, 10: 1) gave 0.83 g (76% yield) (2R, 6R) -5- [2 (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-hydroxy-7-isopropyl-1,3-dimethyl-2-aza-9,10-anthraquinone (Ie) as a yellow oily substance that crystallizes upon standing. T. pl. 148-152 ° C (from ether). [α] _D + 25.5 ° (c 3.6, CHCl ₃ ). ¹ H NMR spectrum (CDCl ₃ ), δ, ppm, J, Hz: 1.09 s (3H, CH ₃ at C ^{6 '} ), 1.21 d, 1.25 d (6H, CH (C H ₃ ) ₂ at C ⁷ , J = 6.8), 1.25 k (3H, CH ₃ , J = 7.0), 1.30 s (3H, CH ₃ at C ^{2 '} ), 1.38-1.78 m (8H, H ^{1', 3 ', 4', 4 ', 5', 5 ', 12', 12 '} ), 2.10 s (3H, CH ₃ ). 2.16 m (2H, 1H, C H -i-Pr and 1H, H ^{3 '} ), 2.40-2.61 m (2H, H ^{13', 13 '} ), 3.55 s (3H, OCH ₃ ), 4.18 q (2H, CH ₂ , J = 7.0), 4.86-4.94 m (2H, H ^{8 '} ), 5.75 m (1H, H ^7' , J 10.8 and 15.0), 7.21 d (1H, H ⁶ , J = 1.8), 7.85 d (1H, H ⁸ , J = 1.8), 10.08 s (1H, OH). ¹³ C NMR spectrum (CDCl ₃ ), δ, ppm: 12.48 k (CH ₃ ), 17.69 t (C ^{4 '} ), 18.66 k, 18.75 k (2 x C H ₃ -i-Pr), 19.05 k (CH ₃ at C ^{6 '} ), 22.84 k (C H ₃ at C ¹ ), 25.81 k (CH ₃ at C ^2' ), 29.30 t (C ^{12 '} ), 32.16 d ( C Hi-Pr), 34.72 t (C ^{13 '} ), 36.10 t (C ^3' ), 38.18 t (C ^{5 '} ), 40.02 s (C ^6' ), 41.85 s (C ^{2 '} ), 48.26 t (CH ₂ ), 46.81 d (C ^{1 '} ), 55.19 k (OCH ₃ ), 110.50 t (C ^8' ), 124.61 d (C ⁸ ), 126.05 s (C ^10a ), 125.75 s (C ^8a ), 129.33 s (C ^9a ), 130.91 d (C ⁶ ), 133.29 s (C ^4a ), 140.06 s (C ⁵ ), 147.76 s (C ⁴ ), 151.04 d (C ^{7 '} ), 153.84 s (C ⁷ ), 155.65 (C ¹ ), 160.02 s (C ³ ), 177.86 s (C = O), 179.80 s (C ¹⁰ ), 183.34 s (C ⁹ ). Found,%: C 74.31; H 7.43; N, 2.41. C ₃₃ H ₄₁ NO ₅ . Calculated,%: C 74.55; H 7.77; N, 2.63. The total yield of compound (Id) based on the initial levopimaric acid (III) is 26%.

Example 6. Synthesis of (2R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-methoxycarbonylcyclohexyl) ethyl] -4-hydroxy-3,7-diisopropyl-1-methyl-2 -azanthracene-9,10-dione (Ie).

Stage 1-4 was performed as described in example 4.

5. Preparation of (2R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-methoxy-3,7-diisopropyl-1-methyl-1,4- epoxy-2-azaanthracene-9,10-dione (IXe).

A solution of 2.07 g (4.90 mmol) of compound (VIIb) in 20 ml of methylene chloride is loaded into a glass ampoule, 0.062 ml (0.49 mmol) of BF ₃ · Ee ₂ O is added, then 0.84 g (5.42 mmol) of oxazole (VIIIc). The ampoule is flushed with argon, cooled and sealed. The reaction mixture was kept at 20 ° C for 48 hours. After the specified time, the ampoule was opened, the reaction mass was poured into 100 ml of water, the product was extracted with methylene chloride (40 × 3 ml), the organic layers were combined, washed with water, then dried over calcined magnesium sulfate. The desiccant is filtered off, the mother liquor is evaporated, the residue is separated by silica gel column chromatography (eluents: chloroform, chloroform - ethanol, in a 10: 1 ratio). Collect 3 fractions. The last fraction (2.02 g) was further purified by silica gel column chromatography (eluent: benzene-ethyl acetate). Get 2 fractions. Subsequent chromatography of fraction 2 isolated 1.76 g (yield 62%) of the adduct (IXe) as a mixture of stereoisomers (endo- and exo-location of the epoxymic). Oily substance. ¹ H NMR (CDCd _3), δ, ppm, J, Hz: 1.08 d, 1.10 d [6H, CH (C H _{3) 2} at C ^3, J 6.8], 1.18 d, 1.23 d (6H , and СН (С Н ₃ ) ₂ at С ⁶ , J 6.8), 1.25 s, 1.27 s (3Н, СН ₃ at С ¹ ), 1.25 s, 1.28 s (3Н, СН ₃ at С ^{6 '} ), 1.30 s , 1.33 s (3H, CH ₃ at C ^{2 '} ), 1.38-1.79 m (8H, H ^{1', 3 ', 4', 4 ', 5', 5 ', 12', 12 '} ), 1.80-2.08 m (2H, 1H, C H -i-Pr and 1Н, Н ^{3 '} ), 2.22 m (1Н, С H -i-Pr), 2.42-2.60 m (2Н, Н ^{13', 13 '} ), 3.59 s (3H, OCH ₃ ), 3.64 s (3H, OCH ₃ ), 3.85 d (1H, H ^4a , J 6.0), 4.26 d (1H, H ^4a , J 6.0), 4.82-4.90 m (2H, H ^{8 '} ), 5.60-5.68 m (1Н, Н ⁷ ), 7.28 d (1Н, Н ⁶ , J 1.8), 7.81 d (1Н, Н ⁸ , J 1.8). ¹³ C NMR spectrum (CDCl ₃ ), δ, ppm: 17.71 k, 17.86 k (CH ₃ at C ^{6 '} ), 18.01 k (CH ₃ at C ¹ ), 17.71 t (C ^4' ), 18.61 k , 18.63 k [CH ( C H ₃ ) ₂ ], 22.79 k, 22.80 k [CH ( C H ₃ ) ₂ ], 23.22 k, 24.21 k, (CH ₃ at C ^{2 ′} ). 30.04 t (C ^{12 '} ), 32.12 d ( C H-i-Pr), 32.48 d ( C H-i-Pr), 34.32 t (C ^13' ), 35.15 t (C ^{3 '} ), 37.98 t (C ^5' ), 40.73 s (C ^{6 '} ), 43.28 s (C ^2' ), 46.65 d (C ^{1 '} ), 44.51 d (C ^4a ), 50.38 d (C ^9a ), 52.42 k (OCH ₃ ), 55.42 k (OCH ₃ ), 76.13 s (C ¹ ), 90.09 s (C ⁴ ), 110.88 t (C ^{3 '} ), 123.35 d (C ⁸ ), 130.68 d (C ⁶ ), 132.35 s (C ^10a ), 133.87 s (C ^8a ), 140.73 s (C ⁵ ), 149.87 d (C ^{7 '} ), 151.66 s (C ⁷ ), 163.17 s (C ³ ), 177.83 s (C = O), 188.01 s (C ⁹ ), 189.95 s (C ¹⁰ ). Found,%: C 72.33; H 7.93; N, 2.41. C ₃₅ H ₄₇ NO ₆ . Calculated,%: C 72.76; H, 8.20; N, 2.42.

6. Preparation of (2R, 6R) -5- [2- (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-hydroxy-3,7-diisopropyl-1-methyl-2- azaanthracene-9,10-dione (Ie). 1.62 g (2 mmol) of epoxy compounds (IXe) in 10 ml of dioxane, 0.01 ml of trifluoroacetic acid, 3A molecular sieves are loaded into a glass ampoule in a stream of argon, cooled to 0 ° C and sealed. The ampoule is carefully heated and incubated for 12 hours at 133 ° C. After cooling, the ampoule is opened, chloroform is added to the residue, mechanical impurities are filtered off, the solution is evaporated in vacuo. Column chromatography (silica gel, chloroform, chloroform alcohol, 10: 1) gave 1.30 g (85% yield) (2R, 6R) -5- [2 (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) ethyl] -4-hydroxy-7-isopropyl-1,3-dimethyl-2-aza-9,10-anthraquinone (Ie) as a yellow oily substance. When standing, the substance crystallizes, so pl. 157-160 ° C (from petroleum ether). [α] _D + 26.4 ° (c 4.1, CHCl ₃ ). ¹ H NMR spectrum (CDCl ₃ ), δ, ppm, J, Hz: Found,%: C 73.61; H 7.22; N, 2.59. C ₃₁ H ₃₇ NO ₅ . Calculated,%: C 73.93; H 7.41; N, 2.78. ¹ H NMR spectrum (CDCl ₃ ), δ, ppm, J, Hz: 0.98 d, 1.08 d [6H, CH (C H ₃ ) ₂ at C ³ , J = 6.8], 1.18 d, 1.20 d [ 6H, CH (C H ₃ ) ₂ at C ⁷ , J = 7.0], 1.22 s (3H, C H ₃ at C ^{6 '} ), 1.28 s (3H, CH ₃ at C ^2' ), 1.42-1.80 m ( 8H, H ^{1 ', 3', 4 ', 4', 5 ', 5', 12 ', 12'} ), 2.00-2.20 m (2H, 1H, C H -i-Pr and 1H, H ^{3 '} ) , 2.35 m (1H, C H -i-Pr), 2.40 s (3H, C H ₃ at C ¹ ), 2.48-2.58 m (2H, H ^{13 ', 13'} ), 3.61 s (3H, OCH ₃ ) , 4.91 d, 4.98 d (2H, H ^{8 '} , J _heme 2.2, J _vice 10.8 and 15.0), 5.62-5.68 m (1H, H ^7' , J 10.8 and 15.0), 7.20 d (1H, H ⁶ , J = 1.8), 7.81 d (1H, H ⁸ , J = 1.8), 10.15 s (OH). ¹³ C NMR spectrum (CDCl ₃ ), δ, ppm: 17.36 k (CH ₃ at C ^{6 '} ), 17.88 t (C ^4' ), 18.58 k, 18.70 k ( C H ₃ -i-Pr), 20.18 k, 20.41 k ( C H ₃ -i-Pr), 22.92 k (C H ₃ at C ¹ ), 25.18 k (CH ₃ at C ^{2 '} ), 26.48 d ( C H-i-Pr), 29.30 t (C ^{12 '} ), 32.19 d ( C H-i-Pr), 35.49 t (C ^13' ), 36.34 t (C ^{5 '} ), 37.87 t (C ^3' ), 39.80 s (C ^{6 '} ), 42.00 s (C ^{2 '} ), 46.66 d (C ^1' ), 55.11 k (OCH ₃ ), 110.92 t (C ^{8 '} ), 124.08 d (C ⁸ ), 126.12 s (C ^8a ), 126.47 s (C ^10a ), 129.68 s ( C ^9a ), 131.19 d (C ⁶ ), 132.42 s (C ^4a ), 140.22 s (C ⁵ ), 147.56 s (C ⁴ ), 151.22 d (C ^{7 '} ), 151.78 s (C ⁷ ), 156.10 (C ¹ ), 158.20 s (C ³ ), 177.92 s (C = O), 179.86 s (C ¹⁰ ), 183.02 s (C ⁹ ). Found,%: C 74.52; H 7.88; N, 2.36. C ₃₄ H ₄₃ NO ₅ . Calculated,%: C 74.83; H 7.94; N, 2.57. The total yield of compound (Ie) based on the starting levopimaric acid (III) is 28%.

Example 7. The effect of the compounds on formalin edema was studied in mice at a dose of 1/280 and / or 1/100 from LD ₅₀ . Inflammation was caused by the introduction of 0.05 ml of a 3% formalin solution under the plantar aponeurosis of the right hind paw. The studied compounds were administered orally 2 hours before the introduction of formalin, immediately before administration and after 3 and 6 hours after phlogogenic exposure. The research results are shown in table 2.

Example 8. The effect of compounds on carrageenan edema was studied in white mice. Inflammation was caused by the introduction of 0.05 ml of a 1% carrageenin solution under the plantar aponeurosis of the right hind paw. Compounds were administered orally 2 hours before administration of carrageenin, 3 and 6 hours after administration. The research results are shown in table 3.

Thus, the claimed invention has the following advantages, namely:

- obtaining new low-toxic optically active 4-hydroxy-2-azaanthraquinones with anti-inflammatory activity;

- the proposed method for the preparation of optically active derivatives of 4-hydroxy-2-aza-9,10-anthraquinone is based on the use of available raw materials - pine resin, amino acids and 1,4-benzoquinone;

- the use in the inventive method of producing new substances at a key stage in the reaction of diene synthesis of optically active polyfunctional 1,4-naphthoquinones with 4-alkyl-2-methyl-5-methoxyoxazoles catalyzed by Lewis acid.

Claims (2)

1. Optically active derivatives of 4-hydroxy-2-aza-9,10-anthraquinone of the formula (Ia-e):

R = H, R ¹ = Me (Ia); R = H, R ¹ -Et (Ib); R = H, R ¹ = i-Pr (Ic); R = R ¹ = Me (Ig); R = Me, R ¹ = Et (Id); R = Me, R ¹ = i-Pr (Ie)
possessing anti-inflammatory activity. 2. A method of obtaining optically active derivatives of 4-hydroxy-2-aza-9,10-anthraquinone of the formula (Ia-e):

R = H, R ¹ = Me (Ia); R = H, R ¹ = Et (Ib); R = H, R ¹ = i-Pr (Ic); R = R ¹ = Me (Ig); R = Me, R ¹ = Et (Id); R = Me, R ¹ = i-Pr (Ie)
from levopimaric acid contained in the resin of conifers, which under the action of 1,4-benzoquinone gives 7,10a-dimethyl-13-isopropyl-7-carboxy-4,4a, 5,6,6a, 7,8,9,10, 10a, 10b, 11,12,12a-tetradecahydro-4b, 12-ethenochrysene-1H-1,4-dione, the indicated compound or its ether is treated with alkali, isomerizing into the corresponding hydroquinones, which are further oxidized to 7,10a-dimethyl-7- carboxy or 7,10a-dimethyl-7-methoxycarbonyl-13-isopropyl-4b, 5,6,6a, 7,8,9,10,10a, 10b, 11,12-dodecahydro-4b, 12-ethenochrysene-1 , 4-diones, the subsequent thermal cleavage of which gives 5- [2- (6-vinyl-2,6-dimethyl-2-carboxycyclohexyl) tyl] - or 5- [2- (6-vinyl-2,6-dimethyl-2-methoxycarbonylcyclohexyl) ethyl] -7-isopropyl-1,4-naphthoquinone, which in interaction with 4-alkyl-2-methyl-5 -methoxyoxazole under conditions of catalysis with boron trifluoride etherate and subsequent acid treatment of the resulting adducts lead to the desired products.