RU2685501C1 - Amide-containing derivatives of 2-oxindole, method for production and application thereof - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: group of inventions relates to amide-containing 2-oxindole derivatives of the general formula (I), where Ris H, benzyl, C-C-alkyl, Ris H, OH, OR, Ris COOH, CN, Ris H, OC-C-alkyl, halogen, C-C-alkyl, COOC-C-alkyl, NHC(X)R, Ris C-C-aryl, C-C-heteroaryl, NHC-C-alkyl, NHC-C-haloalkyl, NHC-C-cycloalkyl, NHC-C-aryl, NHC-C-heteroaryl, OC-C-aryl, where C-C-heteroaryl contains 1 or 2 heteroatoms selected from O, N, S, Ris C-C-alkyl, C(O)C-C-alkyl, Ris C-C-alkyl, C-C-haloalkyl, OC-C-alkyl, C-C-cycloalkyl, C-C-aryl, C-C-heteroaryl, NHC-C-alkyl, NHC-C-haloalkyl, NHC-C-cycloalkyl, NHC-C-aryl, NHC-C-heteroaryl, OC-C-aryl, where C-C-heteroaryl contains 1 or 2 heteroatoms selected from O, N, S, X is O, S, to a method of obtaining these compounds and their use as medicines, as a component of the pharmaceutical composition for the treatment of ophthalmic diseases, as well as a method of treating ophthalmic diseases using a pharmaceutical composition based on compounds of formula (I)..EFFECT: use as pharmaceuticals, as a component of a pharmaceutical composition for the treatment of ophthalmic diseases, as well as a method of treating ophthalmic diseases using a pharmaceutical composition based on compounds of formula (I).32 cl, 2 dwg, 29 ex, 2 tbl

Description

Technical field

The invention relates to the fields of organic chemistry, namely the chemistry of heterocyclic compounds, medical chemistry, pharmacology and ophthalmology. The proposed compounds can be used as antihypertensive and antioxidant drugs for the treatment of glaucoma and other eye diseases, as well as eye diseases accompanied by oxidative stress.

The level of technology

Melatonin is an epiphyseal hormone, is one of the regulators of circadian rhythms in many animals, enhances the efficiency of the immune system, has pronounced antioxidant, neuroprotective properties, and is also able to reduce intraocular pressure. Many countries now produce drugs hormone melatonin (N-acetyl-5-methoxytryptamine). Its well-known dosage form Melaxen is used for sleep disorders in patients with impaired cerebral circulation, with autoimmune therapy, with the treatment of hypertension, for the prevention of cardiovascular diseases, with complex anticancer therapy and neurodegenerative diseases. The widespread introduction of melatonin into medical practice is hampered by its rapid metabolism and instability in the light. However, despite all its positive properties, like most endogenous molecules, melatonin does not act selectively, because it has many binding sites in the human body. In animals, there are 3 subtypes of melatonin receptors: transmembrane GPCR receptors MT1 and MT2 subtypes and the low affinity receptor MT3, which, according to some studies, is an enzyme - quinone-reductase 2, as well as nuclear receptors ROR / RZR. Melatonin also has an antioxidant effect, which, according to some studies, is associated with the mechanism of interception of reactive oxygen species in the body.

Therefore, the design and synthesis of selective ligands with respect to each melatonin binding site is necessary. The melatonin modification, including the replacement of the central indole core with, for example, oxindole, which is much more stable, may be the basis. In addition, the selectivity of the action of the future ligand is easily achieved by introducing various substituents into the main nucleus.

Given the great potential of selective ligands of melatonin receptors of various subtypes, the design of new melatonin analogues, the development of a synthesis method and their synthesis, as well as the study of their activity is an important task. Thus, the present invention relates to amide-containing analogues of 2-oxindole (indolinone, oxindole, indolin-2-one).

MS Volkova et al. (Synthesis of the novel receptor via an unusual Knoevenagel condensation, Bioorganic & Medicinal Chemistry Letters, 2012, v. 22, 7578-7581) describes 2-oxindole derivatives, such as (5-acetamido-2-oxindol-3-yl) acetonitrile , (5-acetamido-3-hydroxy-2-oxindol-3-yl) acetonitrile, and others, as inhibitors of the MT3 melatonin receptor subtype. A method for their preparation by condensation of nitroisatins with cyanoacetic acid is also described, followed by reduction and simultaneous acylation of the nitro group. However, according to this method, it is impossible to obtain derivatives of 2-oxindole with substituents other than NC (O) R, where R means C ₁ -C ₄ -alkyl, since the reduction with simultaneous acylation of the nitro group is carried out in a carboxylic acid medium in the presence of the corresponding acid anhydride . Accordingly, the set of carboxylic acids with the corresponding anhydrides strongly limits the number of promising ligands for the MT3 subtype of melatonin receptors. Data on other biological activity of the compounds obtained are not presented.

Silva B.N.M et al. (Synthesis of Novel Isatin-Type 5 '- (4-Alkyl / Aryl-1H-1,2,3-triazoles)) 1,3-Dipolar Cycloaddition Reactions, Journal of Brazilian Chemical Society, 2013, v. 24, No. 2, 179-183) describes a process for the preparation of the 5-amino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one by catalytic reduction of the 5-nitro-spiro [1,3 -dioxolan-2,3'-indole] -2 '(1'N) -one, which in turn was obtained by the action of ethylene glycol in the presence of p-toluenesulfonic acid on 5-nitroisatin with azeotropic distillation of water. However, the selection of the product was carried out by extraction of the product from the reaction mixture. The proposed production method is characterized in that the isolation is carried out by precipitating the product by adding water to the reaction mixture, and then the washings are further extracted, and the yield of the target compound is significantly increased. The resulting product is also washed with diethyl ether, which allows to obtain a more pure product.

The closest in the prior art to the present invention are compounds of similar structure proposed in MS Volkova (Synthesis of novel receptor ligands via an unusual Knoevenagel condensation, Bioorganic & Medicinal Chemistry Letters, 2012, v. 22, 7578-7581) used as ligands MT ₃ . However, the invention allows to significantly expand the range of the obtained derivatives with an increase in the probability of finding more selective analogues and analogues with greater biological activity. In addition, the proposed method of obtaining can significantly increase the yield of the target compounds. An extremely important difference is the presence of an additional property, namely a pronounced antioxidant activity in new compounds.

DISCLOSURE OF INVENTION

The present invention is the synthesis of derivatives of indolinone with increased affinity for melatonin receptors compared with the endogenous ligand, and a more pronounced ability to reduce intraocular pressure in comparison with existing drugs, as well as with a pronounced antioxidant effect.

The invention relates to compounds of general formula (I), a method for their preparation and their use as medicaments in the treatment of ophthalmic diseases, as ligands for MT1, MT2 and MT3 subtypes of melatonin receptors, as inhibitors of MT3 subtype of melatonin receptors, as well as antioxidant means. In addition, it is proposed to use compounds of formula (I) as an active ingredient of a pharmaceutical composition that can be used to treat various ophthalmic diseases, in particular glaucoma, due to their ability to reduce intraocular pressure (IOP), as well as diseases associated with oxidative stress, due to their pronounced antioxidant activity.

The proposed compounds of General formula (I), its stereoisomers and pharmaceutically acceptable salts:

Where:

R ¹ means H, benzyl, C ₁ -C ₄ -alkyl,

R ² means H, HE, OR ⁶ ,

R ³ means COOH, CN,

R ⁴ means H, OS ₁ -C ₄ -alkyl, halogen, C ₁ -C ₄ -alkyl, SOOC ₁ -C ₄ -alkyl, NHC (X) R ⁷ ,

R ⁵ means ₃ -C ₆ -cycloalkyl, C ₅ -C ₆ -aryl, C ₅ -C ₆ -heteroaryl, NHC ₁ -C ₄ -alkyl, NHC ₁ -C ₄ -haloalkyl, NHC ₃ -C ₆ -cycloalkyl , NHC ₅ -C ₆ -aryl, NHC ₅ -C ₆ -heteroaryl, OC ₅ -C ₆ -aryl, where C ₅ -C ₆ -heteroaryl means a 5-6-membered aryl with 1 or 2 heteroatoms selected from group O , N, S,

R ⁶ means ₁ -C ₄ -alkyl, C (O) C ₁ -C ₄ -alkyl,

R ⁷ means C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, OC ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₅ -C ₆ -aryl, C ₅ -C ₆ -heteroaryl , NHC ₁ -C ₄ -alkyl, NHC ₁ -C ₄ -halogen alkyl, NHC ₃ -C ₆ -cycloalkyl, NHC ₅ -C ₆ -aryl, NHC ₅ -C ₆ -heteroaryl, OC ₅ -C ₆ -aryl, where C ₅ -C ₆ -heteroaryl means a 5-6-membered aryl with 1 or 2 heteroatoms selected from the group O, N, S,

X means O, S.

A method for preparing compounds of formula (I) according to scheme (1) is provided:

where R ¹ -R ⁷ , X have the above values.

The proposed method includes the steps described below. All equivalents (equiv.) Of the reagents are relative to 1 equiv. starting compound (1), (2), (3), (4) or (5), depending on the stage.

In the first (i) stage, the carbonyl group is protected at the 3 position of isatins of the general formula (1). To do this, mix (1), diol - ethylene glycol (at least 12 eq.) And a catalytic amount of p-toluenesulfonic acid (PTSK, at least 0.1 eq.) And in a high-boiling solvent medium (the minimum amount of solvent used is diol ), forming an azeotropic mixture with water, boil with stirring with azeotropic distillation of water. After cessation of water evolution, the reaction mixture is cooled to room temperature, cold water is added in an amount equal to the amount of solvent used. The precipitate formed is filtered and washed with water and air dried. Thus, a product with the general formula (2) is obtained. As a high-boiling solvent, forming an azeotropic mixture with water, use, for example, toluene or xylene.

Other diols can also be used to protect the carbonyl group, such as, for example, 1,3-propandiol, 2,2-dimethyl-1,3-propandiol and their homologs. In addition to PTSA, ortho- and meta-toluenesulfonic acids, methylsulfonic acids, benzenesulfonic acids, trifluoromethanesulfonic acids and others can be used as catalysts.

To increase the yield of the product (2), the aqueous fraction is further extracted with a suitable solvent. After removing the solvent in vacuo, the dry residue is triturated with diethyl ether, filtered and dried in air and combined with the first portion of the product (2).

In the second (ii) stage, the resulting product (ketal) is reduced with formula (2) with hydrogen (pressure 3-10 atm.) In the presence of a suitable catalyst for the reduction of the nitro group (for example, Pd / C, Pd / Ni, Re-Ni etc.) in an anhydrous protic solvent, for example ethyl acetate at room temperature. Hydrogenation can be carried out both in a large volume and in a flow reactor, and in both cases the amount of solvent is adjusted so that the compound of formula (2) is completely dissolved; Hydrogenation is carried out until the disappearance of traces of the starting compound, which is monitored by thin layer chromatography. After the termination of the hydrogenation, the solvent is removed in vacuum, and the resulting dry residue is completely dissolved in anhydrous tetrahydrofuran. An organic base is added to the resulting solution as an interceptor for the liberated acid (1.05-1.10 eq.), For example, triethylamine or piperidine. Then, an acylating agent (1.05-1.10 eq.) With the general formulas (R ⁵ C (O)) ₂ O or R ⁵ C (O) Hal, or R ⁵ NCS, or R ⁵ is added in small portions with vigorous stirring. NCO at room temperature, preventing the reaction mixture from heating. After complete addition of the acylating agent, the reaction mixture is stirred at room temperature for another 10-15 minutes, then cold water is added in an amount equal to the amount of solvent used (tetrahydrofuran), and extraction is carried out with a suitable solvent. After removing the solvent in vacuo, a product with the general formula (3) is obtained.

At the third (iii) stage, acid hydrolysis of the compound (3) is performed. To do this, prepare a mixture of compound (3) with aqueous acetone (0.1 g of compound (3) - 3-5 ml of acetone), then with stirring add concentrated hydrochloric acid (at least 12 eq.). Avoiding evaporation and weathering of hydrochloric acid, i.e. in a tightly closed container, the mixture is stirred at room temperature for 24-96 hours. Then the reaction mixture is poured into ice (the amount of ice is approximately equal to the total volume of the reaction mixture). If the product is poorly soluble in water, the precipitate formed is filtered off, washed 1-2 times with a small amount of cold water and dried in air. If the product is highly soluble in water, the isolation is carried out by extraction with a suitable solvent. Thus, a product with the general formula (4) is obtained.

In the fourth (iv) stage, the compound (4) is condensed with the CH-acid compounds of the general formula CH ₂ (COOH) R ³ . To this end, compound (4) and the CH-acid compound (1.1-1.5 eq.) Are dissolved in pyridine, and then with stirring at room temperature, a catalytic amount of an organic base, amine (0.05-0, 15 eq.), For example, piperidine. The resulting mixture is boiled with vigorous stirring until the end of the reaction. The end of the reaction is monitored by thin layer chromatography until the starting compound (4) disappears. On average, the reaction time is from 2 to 60 hours. After completion of the reaction, the mixture is cooled to room temperature, dioxane saturated with hydrogen chloride (1-2 eq.) Is added and stirred at room temperature for 5-10 minutes. Then add cold water in an amount equal to the amount of solvent used (pyridine), and extracted with a suitable solvent. After concentration in vacuo, the product is obtained with the general formula (5), i.e. the compound of formula (I), where R ² means HE, R ¹ , R ³ -R ⁵ and X have the above values.

In the following, if necessary, carry out one of two modifications of the obtained product (stage (v) or (vi)):

(v) dehydration of the compound followed by reduction of the double C = C bond. The product (5) is completely dissolved in anhydrous tetrahydrofuran and an acylating agent (1.05-1.50 eq.) With the general formula (R ⁶ ) ₂ O, R ⁶ Cl or (R ⁶ ) ₂ SO ₄ is added in small portions with vigorous stirring. and other agents suitable for modification of the hydroxy group. After complete addition, the solution is stirred at room temperature for another 10-15 minutes, cold water is added in an amount equal to the amount of solvent used and extracted with an appropriate solvent. After concentration in vacuum, a product with the general formula (6) is obtained, i.e. the compound of formula (I), where R ² means OR ⁶ ; R ¹ , R ³ -R ⁵ , R ⁷ and X are as defined above.

(vi) modification of the hydroxyl group. The product (5) is boiled in a solution of concentrated hydrochloric acid (at least 12 eq.) Until the end of the reaction. The end of the reaction is monitored by thin layer chromatography until the starting compound (5) disappears. On average, the reaction time is from 2 to 60 hours. After completion of the reaction, the mixture is cooled to room temperature, and the intermediate product is isolated by filtration, followed by washing with water 1-2 times and air drying. Next, the intermediate compound is completely dissolved in a solvent suitable for hydrogenation and the reduction of the double bond is carried out by catalytic hydrogenation under the action of hydrogen (pressure 1-5 atm.), For example, using such catalysts as Pd, Pt, Ni-Ra and other double C hydrogenation catalysts = With communication. As a solvent, any solvent can be used in which the intermediate product is completely soluble, for example, ethyl acetate, methanol, ethanol and others. Hydrogenation can be carried out both in a large volume and in a flow reactor, and in both cases the amount of solvent is adjusted so that the compound of formula (2) is completely dissolved; Hydrogenation is carried out until the disappearance of traces of the starting compound, which is monitored by thin layer chromatography. Thus, a product is obtained with the general formula (6), i.e. the compound of formula (I), where R ² means H; R ¹ , R ³ -R ⁷ and X are as defined above.

The above scheme for the preparation of compounds of formula (I) may include the additional step (vii) of nitration while removing dioxolane protection in compound (3), in which R ⁴ = H, followed by repeating steps (ii) - (vii). Thus, a product is obtained with the general formula (1), where R ⁴ = NHC (X) R ⁷ .

The reaction is carried out under the action of potassium or sodium nitrate in an environment of concentrated sulfuric acid. To do this, prepare a solution of the compound (3) in concentrated sulfuric acid, then cooling it to 0-5 ° C. A nitrating agent (potassium nitrate or sodium nitrate, 1.1-1.5 eq.) Is added to the cooled solution slowly with vigorous stirring in small portions, preventing the mixture from heating above 5 ° C. After complete addition, stop cooling the mixture and continue stirring for 10-60 minutes. Then, the reaction mixture is poured into ice with stirring (in an amount sufficient to ensure that the solution formed after it has a temperature not higher than 30 ° C, 2.5-5 g of ice are used per 1 ml of sulfuric acid). If the product is poorly soluble in water, the precipitate formed is filtered off, washed 1-3 times with a small amount of cold water and dried in air. If the product is highly soluble in water, the isolation is carried out by extraction with a suitable solvent.

As suitable for the extraction of the solvent can be used, for example, ethyl acetate, chloroform, dichloromethane, benzene, toluene, diethyl ether and other solvents that are immiscible with water.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, for example, salts of acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chloroforophyllate, citrate, citrate, citrate, citrate, citrate, citrate, citrate, citrate, bromide / hydrobromide / hydrobromide , fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, naps lata, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and triftoraatsetata.

Inorganic acids from which salts can be obtained include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be obtained include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, and mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluene sulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic fragment, by conventional chemical methods. Typically, such salts can be obtained by reacting the free acid forms of these compounds with a stoichiometric amount of an appropriate base (such as hydroxide, carbonate, bicarbonate, or the like, Na, Ca, Mg, or K), or by reacting the free basic forms of these compounds with the stoichiometric amount of the corresponding acid. Such reactions are usually carried out in water or in an organic solvent, or in a mixture of both. Usually, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable where practicable. Lists of additional suitable salts may be found, for example, in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in the Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

It is proposed to use a compound of formula (I) as a ligand of melatonin receptors, in particular as an inhibitor of the MT3 subtype of melatonin receptors.

It is proposed to use a compound of formula (I) as a medicine for the treatment of diseases mediated by maleononin receptors, including ophthalmic diseases.

The proposed pharmaceutical composition of the compounds of formula (I), which may contain an effective amount of the compounds of formula (I) (up to 75 wt%, preferably up to 30 wt%, more preferably up to 10 wt%, even more preferably up to 0.1-0 , 5 mass%), and the rest - additional pharmaceutically acceptable additives: diluents, solvents, stabilizers, pH regulators, buffers, antioxidants, preservatives, compounds, prolonging the effect of the drug, etc., for example, selected from the group: water, benzalkonium chloride, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride, sodium citrate, sodium edetate, sodium bisulfite, sodium thiosulfate, sodium carbonate, magnesium stearate, mannitol, benzalkonium hydrochloride, citrate hydrochloride, citrate, citrate, citrate, hydrochloride, citrate, citrate, citrate, citrate, citrate, citrate, citrate, hydrochloride acid, polyethylene glycol, glycerin, dextrose, dextran 40, dextran 70, polyvinylpyrrolidone, tween-80, starch, lactose, and other pharmaceutically acceptable carriers and components. The composition can be presented in the form of eye drops, gel, ointment, polymer matrix with the active substance included, etc. The composition may also include the active substance in the form of a quick or delayed / prolonged release, which can be achieved by methods known to experts in this field. The proposed pharmaceutical compositions can be used to treat diseases mediated by melatonin receptors, including ophthalmic diseases.

Ophthalmological diseases in which the use of the compounds of formula (I) may be used include, but are not limited to: diseases associated with a state of increased intraocular pressure, for example, glaucoma, diseases associated with oxidative stress, for example, uveitis.

The present invention also relates to a method for treating a patient suffering from diseases mediated by melatonin receptors, including ophthalmic, consisting in administering a therapeutically effective amount of the pharmaceutical composition to a patient in need thereof. In this case, the introduction is carried out one-time or at certain intervals in such a way that an effective concentration of the active compound in the body is achieved, which allows to obtain the necessary biological response. The frequency and duration of use depends on the nature and severity of the disease, and may also depend on the individual sensitivity to the drug, weight, age, and other factors.

Brief Description of the Drawings

(+)Контроль), мелатонина (

), (5-бензоиламино-3-гидрокси-2-оксиндол-3-ил)ацетонитрила (

- пример 1), (5-фуроиламино-3-гидрокси-2-оксиндол-3-ил)ацетонитрила (

- пример 2), (-)Контроля (

носитель - раствор 0,05 М фосфатного буфера с содержанием ДМСО равным таковому в растворе тестируемого соединения) и нормальных суточных колебаний ВГД (

интактные животные) от времени после введения испытуемым животным одной капли тестируемого раствора. ошибка является величиной стандартного отклонения (n=6, Р=0,95).FIG. 1 shows the dependence of the average decrease in IOP in normotensive rabbits under the action of timolol (

(+ Control), melatonin (

), (5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile (

- example 1), (5-furoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile (

- example 2), (-) Control (

the carrier is a solution of 0.05 M phosphate buffer with a DMSO content equal to that in the solution of the test compound) and normal daily fluctuations in IOP (

intact animals) from the time after the test animals injected one drop of the test solution. the error is the standard deviation (n = 6, P = 0.95).

), (5-бензоиламино-3-гидрокси-2-оксиндол-3-ил)ацетонитрила (

- пример 1) и (5-фуроиламино-3-гидрокси-2-оксиндол-3-ил)ацетонитрила (

- пример 2) от концентрации. Аппроксимация методом МНК показана прямыми.FIG. 2 shows the dependence of the AOA melatonin (

), (5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile (

- example 1) and (5-furoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile (

- example 2) on concentration. The OLS approximation is shown straight.

The implementation of the invention

The invention is illustrated by the following examples:

Receiving intermediates.

Synthesis of nitro-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -ones

(compounds of the formula (2) in the scheme (1))

Intermediate 1

5'-nitro-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

A solution of 1 g (0.005 mol) of 5-nitroisatin, 4.6 ml (0.08 mol) of ethylene glycol, 0.08 g (0.00004 mol) of p-toluenesulfonic acid in toluene was placed in a flask equipped with a Dean-Stark nozzle. (12 ml). The mixture was boiled until the evolution of water ceased (6 hours). Then the reaction mixture is cooled to room temperature, water (12 ml) is added. The precipitation is filtered off and washed with water and dried in air. The aqueous fraction was extracted with ethyl acetate (3 × 15 ml), the organic extracts were combined, and sewed over anhydrous sodium sulfate. After removing the solvent in vacuo, the dry residue was triturated with diethyl ether, filtered and dried in air. The obtained dry product was combined with the first sediment fraction. Thus, 5'-nitro-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one was obtained with a yield of 69% (0.85 g).

T. pl. (exp.) = 215 ° C.

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 4.35 (s, 4H), 7.05 (d, J = 8.59, 1H), 8.16 (d ., J = 2.27, 1H), 8.27 (dd., J = 2.40, J = 8.59, 1H), 11.16 (s, 1H).

Intermediate 2

7'-nitro-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

Synthesis was carried out similarly to intermediate 1, using 3 g (0.016 mol) of 7-nitroisatin, 7'-nitro-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one was obtained with a yield of 64% (2.37 g).

T. pl. (exp.) = 207-208 ° C.

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 4.30-4.40 (m, 4H), 7.24 (dd, J = 7.20, J = 8, 59, 1H), 7.77 (dd., J = 0.63, J = 7.20, 1H), 8.12 (dd., J = 1.01, J = 8.59, 1H), 11 , 17 (s., 1H).

NMR ¹³ C (DMSO-d ₆ , ppm), main signals: 66.38; 123.25; 126.90; 131.58.

IR (KBr, cm ^-1 ): 1119; 1322; 1346 (CH ₂ ); 1465; 1528; 1630 (NO ₂ ); 1762 (C = O); 3219 (NH).

Mass spectrum (electron impact, 70 eV), m / z (I,%): 236 (41, M +), 219 (96), 208 (46), 191 (100), 175 (22), 161 ( 20), 147 (29), 131 (11), 117 (58), 106 (12), 90 (29), 75 (26), 63 (30), 43 (19), 30 (60).

Intermediate 3

5'-methoxy-7'-nitro-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 1, using 3 g (0.014 mol) of 5-methoxy-7-nitroisatin; 5'-methoxy-7'-nitro-spiro [1,3-dioxalan-2,3'-indole] - 2 '(1'H) -one with a yield of 75% (2.68 g).

T. pl. (exp.) = 170-172 ° C.

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 3.83 (s, 3H), 4.28-4.40 (m, 4H), 7.47 (d, J = 2.15, 1H), 7.53 (d, 1 = 2.40, 1H), 11.04 (s, 1H).

NMR ¹³ C (DMSO-d ₆ , ppm): 56.76; 66.48; 100.10; 108.88; 120.51; 130.10; 131.90; 132.97; 155.21; 174.91.

IR (KBr, cm ^-1 ): 1272, 1546; 1485 (NO ₂ ), 1770 (C = O), 2847 (OCH ₃ ), 3253 (NH).

Mass spectrum (electron impact, 70 eV), m / z (I,%): 222 (83), 205 (68), 194 (41), 175 (58), 164 (38), 147 (37), 132 (21), 104 (65), 93 (47), 76 (35), 62 (32), 50 (31), 30 (100), 15 (70).

Intermediate 4

5'-bromo-7'-nitro-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 1, using 3 g (0.011 mol) of 5-bromo-7-nitroisatin; 5'-bromo-7'-nitro-spiro [1,3-dioxalan-2,3'-indole] - was obtained 2 '(1'N) -one with a yield of 82% (2.86 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 4.20 (s, 4H), 7.66 (d, J = 2.20, 1H), 7.99 (d, J = 2.20, 1H), 11.63 (s, 1H).

Intermediate 5

5'-nitro-7'-methyl-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one

Synthesis was carried out similarly to intermediate 1, using 3 g (0.014 mol) of 5-nitro-7-methyl-isatin, 5'-nitro-7'-methyl-spiro [1,3-dioxalan-2,3'-indole] - was obtained 2 '(1'N) -one with a yield of 76% (2.77 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.64 (s, 3H); 3.98 (s, 4H), 7.38 (d, J = 2.20, 1H), 7.56 (d, J = 2.20, 1H), 10.64 (s, 1H ).

Intermediate 6

5-methoxycarbonyl-7-nitro-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

Synthesis was carried out similarly to intermediate 1, using 3 g (0.012 mol) of 5-methoxycarbonyl-7-nitroisatin, 5'-methoxycarbonyl-7'-nitro-spiro [1,3-dioxalan-2,3'-indole] 2 '(1'N) -one with a yield of 54% (1.91 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 3.98 (s, 3H), 4.46 (s, 4H), 7.13 (s, 1H); 7.86 (s, 1H), 11.60 (s, 1H).

Intermediate 7

N-allyl-5'-nitro-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one

Synthesis was carried out similarly to intermediate 1, using 3 g (0.014 mol) of N-allyl-5-nitroisatin; N-allyl-5'-nitro-spiro [1,3-dioxalan-2,3'-indole] -2 was obtained '(1'N) -one with a yield of 36% (1.30 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 4.02 (d, J = 14.18, 1H), 4.12 (d, J = 8.44, 1H), 4.22 (s., 4H), 6.80-6.90 (m, 1H), 7.05 (d, J = 8.59, 1H), 8.16 (d, J = 2 , 27, 1H), 8.27 (dd., J = 2.40, J = 8.59, 1H).

Intermediate 8

N-benzyl-5'-nitro-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one

Synthesis was carried out similarly to intermediate 1, using 3 g (0.011 mol) of N-benzyl-5-nitro-isatin, N-benzyl-5'-nitro-spiro [1,3-dioxalan-2,3'-indole] -2 was obtained '(1'N) -one with a yield of 55% (1.91 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.02 (s, 2H), 4.22 (s, 4H), 7.05 (d, J = 8, 59, 1H), 7.32-7.42 (m, 2H), 7.47-7.58 (m, 2H), 7.64-7.77 (m, 1H), 8.16 (d, J = 2.27, 1H), 8.27 (dd., J = 2.40, J = 8.59, 1H).

Intermediate 9

N-methyl-5'-nitro-spiro [1,3-dioxalan-2,3'-indole] -2 '(1'H) -one

Synthesis was carried out similarly to intermediate 1, using 3 g (0.015 mol) of N-methyl-5-nitroisatin, to obtain N-methyl-5'-nitro-spiro [1,3-dioxalan-2,3'-indole] -2 '(1'N) -one with a yield of 48% (1.75 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 2.02 (s, 3H), 4.22 (s, 4H), 7.05 (d, J = 8, 59, 1H), 8.16 (d, J = 2.27, 1H), 8.27 (dd, J = 2.40, J = 8.59, 1H).

Intermediate 10

5'-nitro-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 1, using 3 g (0.010 mol) of 5-nitro-7-benzoylamino-isatin (intermediate 78), 5'-nitro-7'-benzoylamino-spiro [1,3-dioxalan-2,3 ' -indole] -2 '(1'N) -one with a yield of 50% (1.71 g).

NMR ¹ H (DMSO-cl ₆ , ppm, J, Hz): 3.98 (s, 4H), 6.68-6.78 (m, 2H), 7.31 (m, 2H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H), 7.91 (m, 1H), 10.20 (s ., 1H), 10.64 (s., 1H).

Intermediate 11

5'-nitro-7'-acetylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 1, using 3 g (0.012 mol) of 5-nitro-7-acetylamino-isatin (intermediate 79), 5'-nitro-7'-acetylamino-spiro [1,3-dioxalan-2,3 ' -indole] -2 '(1'N) -one with a yield of 55% (1.94 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.02 (s, 3H), 3.98 (s, 4H), 7.59 (d, J = 2, 67, 1H), 7.87 (d, J = 2.83, 1H), 10.20 (s, 1H), 10.64 (s, 1H).

Intermediate 12

5'-nitro-7'-methoxycarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 1, using 3 g (0.011 mol) of 5-nitro-7-methoxycarbonylamino-isatin (intermediate 79), 5'-nitro-7'-methoxycarbonylamino-spiro [1,3-dioxalan-2,3 ' -indole] -2 '(1'N) -one with a yield of 50% (1.75 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.12 (s, 3H), 3.98 (s, 4H), 7.59 (d, J = 2, 67, 1H), 7.87 (d, J = 2.83, 1H), 10.20 (s, 1H), 10.64 (s, 1H).

Intermediate 13

5'-nitro-7'-cyclopropylcarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

Synthesis was performed similarly to intermediate 1, using 3 g (0.011 mol) of 5-nitro-7-cyclopropylcarbonylamino-isatin (intermediate 80), 5'-nitro-7'-cyclopropylcarbonylamino-spiro [1,3-dioxalan-2,3 ' -indole] -2 '(1'N) -one with a yield of 45% (1.57 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 0.73-0.83 (m, 2H), 1.01-1.11 (m, 2H), 2.46-2 , 54 (m., 1H), 3.98 (s., 4H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H) 10.20 (s, 1H), 10.64 (s, 1H).

Intermediate 14

5'-nitro-7 '- (3-pyridine) aminocarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2' (1'H) -one

Synthesis was carried out similarly to intermediate 1, using 3 g (0.009 mol) of 5-nitro-7- (3-pyridine) aminocarbonylamino-isatin (intermediate 81), 5'-nitro-7 '- (3-pyridine) aminocarbonylamino-spiro was obtained [ 1,3-dioxolane-2,3'-indole] -2 '(1'H) -one with a yield of 68% (2.31 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.98 (s, 4H), 7.32-7.42 (m, 2H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H), 8.01 (m, 2H), 10.20 (s, 1H), 10.33 (s ., 1H), 10.64 (s, 1H).

Intermediate 15

5'-nitro-7'-phenylaminocarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

Synthesis was performed similarly to intermediate 1, using 3 g (0.009 mol) of 5-nitro-7-phenylaminocarbonylamino-isatin (intermediate 82), 5'-nitro-7'-phenylaminocarbonylamino-spiro [1,3-dioxalan-2,3 'was obtained -indole] -2 '(1'N) -one with a yield of 70% (2.38 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.98 (s, 4H), 6.68-6.78 (m, 2H), 7.31 (m, 2H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H), 7.91 (m, 1H), 10.20 (s ., 1H), 10.33 (s, 1H), 10.64 (s, 1H).

Reduction of nitro-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -ones

Intermediate 16

5'-amino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

A solution of 0.2 g (0.0008 mol) of 5'-nitro-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one (intermediate 1) in ethyl acetate (40 ml ) Hydrogenated in a H-Cube hydrogenation flow reactor (Hungary): a flow rate of 1 ml / min, H ₂ pressure 3 atm., Pd / C catalyst (10%). After complete hydrogenation, the solvent was removed in a rotary evaporator vacuum, 5'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'N) -one was obtained in a yield of 95% (0, 17g)

T. pl. (exp.) = 203 ° C.

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 4.15-4.25 (m, 2H), 4.27-4.37 (m, 2H), 6.58 (s, 1H), 6.51 (s, 1H), 6.57-6.59 (m, 1H), 9.96 (s, 1H).

Intermediate 17

7'-amino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 16, using 0.2 g (0.0008 mol) of 7'-nitro-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 2 ), 7'-amino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one was obtained in 95% (0.17 g) yield.

T. pl. (exp.) = 205-210 ° C.

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 4.16-4.24 (m, 2H), 4.28-4.36 (m, 2H), 4.94 ( s, 2H), 6.66 (d, J = 7.33, 1H), 6.64 (d, J = 8.08, 1H), 6.77 (t, J = 7.70 , 1H), 9.95 (s., 1H).

NMR ¹³ C (DMSO-d ₆ , ppm): 113.09; 117.71; 123.57; 125.12; 128.14; 132.81; 174.72.

IR (KBr, cm ^-1 ): 1005; 1193; 1286; 1720 (C = O); 3062 (NH); 3330; 3391 (NH ₂ ).

Mass spectrum (electron impact, 70 eV), m / z (I,%): 206 (66, M +), 189 (5), 178 (100), 161 (9), 147 (8), 133 ( 49), 117 (19), 106 (84), 105 (61), 79 (25), 52 (23), 45 (19), 29 (28).

Intermediate 18

5'-methoxy-7'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 16, using 0.2 g (0.0007 mol) of 5'-methoxy-7'-nitro-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one (intermediate 3), obtained 5'-methoxy-7'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one in 95% yield (0, 17g) NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.83 (s, 3H), 4.16–4.24 (m, 2H), 4.28–4.36 ( m., 2H), 4.94 (s., 2H) ,. 7.47 (d, 1H; J = 2.15), 7.53 (d, 1H, J = 2.40), 11.04 (s, 1H).

Intermediate 19

5'-bromo-7'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 16, using 0.2 g (0.0006 mol) of 5'-bromo-7'-nitro-spiro [1,3-dioxol-2,3'-indole] -2 '(1'N) -one (intermediate 4), obtained 5'-bromo-7'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one in 95% yield (0, 16g) NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 4.16-4.24 (m, 2H), 4.28-4.36 (m, 2H), 4.94 ( s., 2H) ,. 7.66 (d, J = 2.20, 1H), 7.99 (d, J = 2.20, 1H), 11.63 (s, 1H).

Intermediate 20

5'-amino-7'-methyl-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 16, using 0.2 g (0.0008 mol) of 5'-nitro-7'-methyl-spiro [1,3-dioxol-2,3'-indole] -2 '(1'N) -one (intermediate 5), received 5'-amino-7'-methyl-spiro [1,3-dioxol-2,3'-indole] -2 '(GN) -one in 95% yield (0.17 g ). NMR (DMSO-sb, ppm, J, Hz): 2.52 (s, 3H), 4.16-4.24 (m, 2H), 4.28-4.36 (m, 2H), 4.94 (s., 2H) ,. 7.38 (d, J = 2.20, 1H), 7.56 (d, J = 2.20, 1H), 10.64 (s, 1H).

Intermediate 21

5'-methoxycarbonyl-7'-amino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

Synthesis was carried out similarly to intermediate 16, using 0.2 g (0.0007 mol) of 5'-methoxycarbonyl-7'-nitro-spiro [1,3-dioxol-2,3'-indole] -2 '(1'N) -one (intermediate 6), obtained 5'-methoxycarbonyl-7'-amino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one in 96% yield (0, 17g)

NMR ¹ ′ H (DMSO-d ₆ ppm, J, Hz): 2.36 (s, 3H), 4.16–4.24 (m, 2H), 4.28–4.36 (m, 2H), 4.94 (brs, 2H), 7.13 (s, 1H); 7.86 (s, 1H), 11.60 (s, 1H).

Intermediate 22

N-allyl-5'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 16, using 0.2 g (0.0008 mol) of N-allyl-5'-nitro-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) - she (intermediate 7) received N-allyl-5'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one in 94% yield (0.17 g ). NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 4.02 (d, J = 14.18, 1H), 4.12 (d, J = 8.44, 1H), 3.58-4.16 (s., 4H), 4.94 (brs, 2H), 6.80-6.90 (m., 1H), 7.05 (d, J = 8 , 59, 1H), 8.16 (d, J = 2.27, 1H), 8.27 (dd., J = 2.40, J = 8.59, 1H).

Intermediate 23

N-benzyl-5'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 16, using 0.2 g (0.0006 mol) of N-benzyl-5'-nitro-spiro [1,3-dioxol-2,3'-indole] -2 '(1'N) - she (intermediate 8), received N-benzyl-5'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one in 95% yield (0.17 g ). NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 2.02 (s, 2H), 3.57-4.09 (s, 4H), 4.94 (s br ., 2H), 7.05 (d, J = 8.59, 1H), 7.32-7.42 (m, 2H), 7.47-7.58 (m, 2H), 7 , 64-7.77 (m, 1H), 8.16 (d, J = 2.27, 1H), 8.27 (dd., J = 2.40, J = 8.59, 1H) .

Intermediate 24

N-methyl-5'-amino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 16, using 0.2 g (0.0008 mol) of N-methyl-5'-nitro-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) - she (intermediate 9) received N-methyl-5'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one in 98% yield (0.17 g ). NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 2.02 (s, 3H), 3.68-4.15 (s, 4H), 4.94 (bs ., 2H), 7.05 (d, J = 8.59, 1H), 8.16 (d, J = 2.27, 1H), 8.27 (dd., J = 2.40, J = 8.59, 1H).

Intermediate 25

5'-amino-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 16, using 0.2 g (0.0006 mol) of 5'-nitro-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 10), obtained 5'-amino-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one in 95% yield (0, 17g)

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 3.58-4.16 (m, 4H), 4.91 (bs, 2H), 6.68-6 , 78 (m, 2H), 7.31 (m, 2H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H) , 7.91 (m, 1H), 10.20 (s, 1H), 10.64 (s, 1H).

Intermediate 26

5'-amino-7'-acetylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

Synthesis was performed similarly to intermediate 16, using 0.2 g (0.0007 mol) of 5'-nitro-7 ^, -acetylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 11), received 5'-amino-7'-acetylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(GN) -one in 98% yield (0.18 g ).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 2.02 (s, 3H), 3.56-4.14 (m, 4H), 4.93 (broad s ., 2H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H), 10.20 (s, 1H), 10.64 (s., 1H).

Intermediate 27

5'-amino-7'-methoxycarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 16, using 0.2 g (0.0006 mol) of 5'-nitro-7'-methoxycarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 12), obtained 5'-amino-7'-methoxycarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one with a yield of 97% (0, 18 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 3.12 (s, 3H), 3.54-4.10 (m, 4H), 4, 92 (broad s ., 2H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H), 10.20 (s, 1H), 10.64 (s., 1H).

Intermediate 28

5'-amino-7'-cyclopropylcarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 16, using 0.2 g (0.0006 mol) of 5'-nitro-7'-cyclopropylcarbonylamino-spiro [1,3-dioxolan-2,3'-indole] -2 '(1'N) -one (intermediate 13), obtained 5'-amino-7'-cyclopropylcarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one in 95% yield (0, 17g)

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 0.73-0.83 (m, 2H), 1.01-1.11 (m, 2H), 2.46-2 , 54 (m., 1H), 3.54-4.14 (m, 4H), 4, 89 (bs, 2H), 7.59 (d, J = 2.67, 1H) , 7.87 (d, J = 2.83, 1H), 10.20 (s, 1H), 10.64 (s, 1H).

Intermediate 29

5'-amino-7 '- (3-pyridine) aminocarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2' (1'H) -one

The synthesis was carried out similarly to intermediate 16, using 0.2 g (0.0005 mol) of 5'-nitro-7 '- (3-pyridine) aminocarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2' (1'N) -one (intermediate 14), 5'-amino-7 '- (3-pyridine) aminocarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2' (1'N ) -one with a yield of 95% (0.17 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 3.58-4.16 (m, 4H), 4.88 (bs, 2H), 7.32-7 , 42 (m., 2H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H), 8.01 (m, 2H) , 10.20 (s, 1H), 10.33 (s, 1H), 10.64 (s, 1H).

Intermediate 30

5'-amino-7'-phenylaminocarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 16, using 0.2 g (0.0005 mol) of 5'-nitro-7'-phenylaminocarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 15), received 5'-amino-7'-phenylaminocarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one in 98% yield (0, 18 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 3.80-4.16 (m, 4H), 4.94 (bs, 2H), 6.68-6 , 78 (m, 2H), 7.31 (m, 2H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H) , 7.91 (m, 1H), 10.20 (s, 1H), 10.33 (s, 1H), 10.64 (s, 1H).

Acylation of amino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -ones (synthesis of compounds of formula (3) in the diagram)

Intermediate 31

5'-benzoylamino-spiro [1,3-dioxolan-2,3'-indole] -2 '(1'H) -one

To a solution of 0.2 g (0.001 mol) 5'-amino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one (intermediate 16) and 0.14 ml (0.001 mol a) triethylamine in anhydrous tetrahydrofuran (6 ml) was slowly dripped 0.11 ml (0.001 mol) of benzoyl chloride. After complete addition, the reaction mixture was stirred for 10 minutes, then 6 ml of cold water was added. The product was isolated by extraction with ethyl acetate (3 ^× 15 ml), the organic extracts were combined, dried over anhydrous sodium sulfate. After removing the solvent in vacuo, 5'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one was obtained in 70% yield (0.21 g).

T. pl. (exp.) = 210 ° C.

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 4.23-4.32 (m, 2H), 4.34-4.42 (m, 2H), 6.84 (d, J = 8.34, 1H), 7.47-7.60 (m, 3H), 7.67 (dd., J = 2.15, J = 8.34, 1H), 7 , 84 (d, J = 1.89, 1H), 7.91-8.00 (m, 2H), 10.21 (s, 1H), 10.43 (s, 1H).

NMR ¹³ C (DMSO-d ₆ , ppm): 65.93; 110.90; 118.47; 124.18; 124.99; 128.01; 128.86; 132.00; 134.67; 135.23; 139.08; 165.71; 175.01.

Mass spectrum (electron impact, 70 eV), m / z (I,%): 310 (18, M +), 282 (64), 238 (1), 210 (2), 177 (16), 133 ( 33), 106 (13), 105 (100), 77 (78), 51 (13), 28 (4).

Intermediate 32

5 '- (2-furoyl) amino-spiro [1,3-dioxolane-2,3'-indole] -2' (1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.001 mol) of 5'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'N) -one (intermediate 16) and 0.09 ml (0.001 mol) of 2-furoyl chloride, obtained 5 '- (2-furoyl) amino-spiro [1,3-dioxol-2,3'-indole] -2' (1'H) -one with the yield 65% (0.17 g).

T. pl. (exp.) = 169 ° C.

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 4.20-4.30 (m, 2H), 4.30-4.40 (m, 2H), 6.68 (dd., J = 1.59, J = 3.30, 1H), 6.82 (d, J = 8.44, 1H), 7.29 (d, J = 3.06, 1H) , 7.63 (dd., J = 1.96, J = 8.44, 1H), 7.77 (d, J = 1.59, 1H), 7.91 (bs, 1H) , 10.14 (s., 1H), 10.42 (s., 1H).

NMR ¹³ C (DMSO-d ₆ , ppm): 65.92; 102.25; 110.95; 112.59; 115.00; 118.44; 124.19; 125.02; 133.98; 139.15; 146.12; 147.89; 156.51; 174.96. IR (KBr, cm ^-1 ): 1200, 1212, 1655, 1736, 3127, 3278.

Mass spectrum (electron impact, 70 eV), m / z (I,%): 300 (15, M +), 272 (50), 228 (2), 200 (2), 177 (13), 144 ( 6), 133 (30), 105 (16), 95 (100), 52 (9), 39 (26), 29 (10).

Intermediate 33

7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.001 mol) of 7'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'N) -one (intermediate 17) and 0.17 ml (0.001 mol) of benzoyl chloride, obtained 7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one in 65% yield (0.20 g ).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 3.60-4.15 (m, 4H), 7.06 (t, J = 7.34, 1H), 7 , 34 (d, J = 7.09, 1H), 7.44-7.62 (m, 3H), 8.00 (d, J = 7.09, 2H), 8.89 (d ., J = 5.14, 1H), 9.96 (s, 1H), 10.53 (s, 1H).

Intermediate 34

7'-acetylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

Synthesis was carried out similarly to intermediate 31, using 0.2 g (0.001 mol) of 7-amino-isatin (intermediate 17) and 0.10 ml (0.001 mol) of acetic anhydride; 7'-acetylamino-spiro [1,3-dioxalane- 2,3'-indole] -2 '(1'H) -one with a yield of 55% (0.13 g). NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.02 (s, 3H), 3.98 (s, 4H), 7.06 (t, J = 7, 34, 1H), 7.34 (d, J = 7.09, 1H), 8.00 (d, J = 7.09, 1H), 10.20 (s, 1H), 10.64 (s., 1H).

Intermediate 35

7'-methoxycarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

Synthesis was carried out similarly to intermediate 31, using 0.2 g (0.001 mol) of 7-amino-isatin (intermediate 17) and 0.08 ml (0.001 mol) of methyl chloroformate; 7'-methoxycarbonylamino-spiro [1,3-dioxolane- 2,3'-indole] -2 '(1'H) -one with a yield of 60% (0.15 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 3.12 (s, 3H), 3.98 (s, 4H), 7.06 (t, J = 7, 34, 1H), 7.34 (d, J = 7.09, 1H), 8.00 (d, J = 7.09, 1H), 10.20 (s, 1H), 10.64 (s., 1H).

Intermediate 36

7'-cyclopropylcarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.001 mol) of 7-amino-isatin (intermediate 17) and 0.09 ml (0.001 mol) of cyclopropylcarbonyl chloride, to obtain 7'-cyclopropylcarbonylamino-spiro [1,3-dioxalan 2,3'-indole] -2 '(1'H) -one with a yield of 55% (0.15 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 0.73-0.83 (m, 2H), 1.01-1.11 (m, 2H), 2.46-2 , 54 (m., 1H), 3.98 (s., 4H), 7.06 (t, J = 7.34, 1H), 7.34 (d, J = 7.09, 1H) , 8.00 (d, J = 7.09, 1H), 10.20 (s, 1H), 10.64 (s, 1H).

Intermediate 37

7 '- (3-pyridine) aminocarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2' (1'H) -one

Synthesis was carried out similarly to intermediate 31, using 0.2 g (0.001 mol) of 7-amino-isatin (intermediate 17) and 0.12 g (0.001 mol) of pyridine-3-isocyanate; 7 '- (3-pyridine) aminocarbonylamino- spiro [1,3-dioxolan-2,3'-indole] -2 '(1'H) -one with a yield of 68% (0.22 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.98 (s, 4H), 7.32-7.42 (m, 2H), 7.06 (t, J = 7.34, 1H), 7.34 (d, J = 7.09, 1H), 8.00 (d, J = 7.09, 2H), 8.08 (m, 1H) , 10.20 (s, 1H), 10.33 (s, 1H), 10.64 (s, 1H).

Intermediate 38

7'-phenylaminocarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.001 mol) of 7-amino-isatin (intermediate 17) and 0.11 ml (0.001 mol) of phenyl isocyanate; 7'-phenylaminocarbonylamino-spiro [1,3-dioxalan-2 was obtained , 3'-indole] -2 '(1'H) -one with a yield of 70% (0.22 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.98 (s, 4H), 6.68-6.78 (m, 2H), 7.31 (m, 2H), 7.06 (t, J = 7.34, 1H), 7.34 (d, J = 7.09, 1H), 7.91 (m, 1H), 8.00 ( ., J = 7.09, 1H), 10.20 (s, 1H), 10.33 (s, 1H), 10.64 (s, 1H).

Intermediate 39

N-allyl-5'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

Synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0009 mol) of N-allyl-5'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) - she (intermediate 22) and 0.10 ml (0.0009 mol) of benzoyl chloride, obtained N-allyl-5'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N ) -one with a yield of 75% (0.22 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.62-4.10 (m, 4H), 4, 22 (d, J = 14.18, 1H), 4 , 44 (d, J = 8.44, 1H), 6.80-6.90 (m., 1H), 7.45-7.60 (m, 3H), 7.63-7.74 ( m., 1H), 7.81 (dd., J = 8.30, J = 14.20, 1H), 7.85-8.05 (m., 3H), 10.26 (s., 1H ).

Intermediate 40

N-benzyl-5'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0007 mol) of N-benzyl-5'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) - she (intermediate 23) and 0.08 ml (0.0007 mol) of benzoyl chloride, obtained N-benzyl-5'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N ) -one with a yield of 73% (0.20 g). NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.02 (s, 2H), 3.57-4.09 (s, 4H), 6.80-6.90 (m, 1H), 7.05 (d, J = 8.59, 1H), 7.32-7.42 (m, 2H), 7.47-7.62 (m, 5H) , 7.65-7.77 (m, 2H), 8.16 (d, J = 2.27, 1H), 8.27 (dd., J = 2.40, J = 8.59, 1H), 10.26 (s, 1H).

Intermediate 41

N-methyl-5'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0009 mol) of N-methyl-5'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) - she (intermediate 24) and 0.11 ml (0.0009 mol) of benzoyl chloride obtained N-methyl-5'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N ) -one with a yield of 70% (0.21 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.17 (s, 3H), 3.55-4.16 (m, 4H), 6.80-6.90 (m, 1H), 7.45-7.60 (m, 3H), 7.63-7.74 (m, 1H), 7.85-8.05 (m, 3H), 10 , 26 (s., 1H).

Intermediate 42

5'-methoxy-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0008 mol) of 5'-methoxy-7'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'N) -one (intermediate 18) and 0.10 ml (0.0008 mol) of benzoyl chloride, 5'methoxy-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1' H) -one with a yield of 60% (0.17 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.45 (s, 3H), 3.58-4.16 (m, 4H), 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H) , 7.88 (d, J = 2.71, 1H), 10.26 (s, 1H), 10, 53 (s, 1H).

Intermediate 43

5'-bromo-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0007 mol) 5'-bromo-7'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'N) -one (intermediate 19) and 0.09 ml (0.0007 mol) of benzoyl chloride, 5'-bromo-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1 'H) -one with a yield of 80% (0.22 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.60-4.15 (m, 4H), 6.80-6.90 (m, 1H), 7.34 -7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s, 1H), 10, 53 (s, 1H).

Intermediate 44

5'-benzoylamino-7'-methyl-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0009 mol) 5'-amino-7'-methyl-spiro [1,3-dioxol-2,3'-indole] -2 '(1'N) -one (intermediate 20) and 0.11 ml (0.0009 mol) of benzoyl chloride, 5'-benzoylamino-7'-methyl-spiro [1,3-dioxolane-2,3'-indole] -2 '(1 'H) -one with a yield of 75% (0.22 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 2.31 (s, 1H), 3.57-4.10 (m, 4H), 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H) , 7.88 (d, J = 2.71, 1H), 10.26 (s, 1H), 10, 53 (s, 1H).

Intermediate 45

5'-methoxycarbonyl-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0008 mol) of 5'-methoxycarbonyl-7'-amino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one (intermediate 21) and 0.09 ml (0.0008 mol) of benzoyl chloride, 5'-methoxycarbonyl-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1 'H) -one with a yield of 70% (0.20 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.22 (s, 3H), 3.66-4.18 (m, 4H), 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H) , 7.88 (d, J = 2.71, 1H), 10.26 (s, 1H), 10, 53 (s, 1H).

Intermediate 46

5'-cyclopropylcarboinlamino-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0006 mol) of 5'-amino-7'-benzoylamino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'N) -one (intermediate 25) and 0.06 ml (0.0006 mol) of cyclopropylcarbonyl chloride, 5'-cyclopropylcarboynylamino-7'-benzoylamino-spiro [1,3-dioxalan-2,3'-indole] -2 '(1 'H) -one with a yield of 60% (0.15 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 0.73-0.83 (m, 2H), 1.01-1.11 (m, 2H), 2.46-2 , 54 (m, 1H), 3.56-4.10 (m, 4H), 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H) , 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s, 1H), 10.33 (s, 1H), 10, 53 (s, 1H).

Intermediate 47

5'-methylaminothiocarbonylamino-7'-benzoylamino-spiro [1,3-dioxolan-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0006 mol) of 5'-amino-7'-benzoylamino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'N) -one (intermediate 25) and 0.04 ml (0.0006 mol) of methyl isothiocyanate, 5'-methylaminothiocarbonylamino-7'-benzoylamino-spiro [1,3-dioxalan-2,3'-indole] -2 '(1 'H) -one with a yield of 75% (0.18 g). NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.17 (s, 3H), 3.55-4.15 (m, 4H), 6.68-6.78 (m, 2H), 7.31 (m, 2H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H), 7 , 91 (m, 1H), 10.20 (s, 1H), 10.33-10.42 (m, 2H), 10.53 (s, 1H).

Intermediate 48

5'-trifluoromethylaminocarbonylamino-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0006 mol) of 5'-amino-7'-benzoylamino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'N) -one (intermediate 25) and 0.05 ml (0.0006 mol) of trifluoromethylisocyanate, 5'-trifluoromethylaminocarbonylamino-7'-benzoylamino-spiro [1,3-dioxalan-2,3'-indole] -2 '(1 'H) -one with a yield of 75% (0.21 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.66-4.22 (m, 4H), 6.80-6.90 (m, 1H), 7.34 -7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s, 1H), 10.33-10.39 (m, 2H), 10, 53 (s, 1H).

Intermediate 49

5'-cyclopropylaminocarbonylamino-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0006 mol) of 5'-amino-7'-benzoylamino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'N) -one (intermediate 25) and 0.06 ml (0.0006 mol) of cyclopropylisocyanate, 5'-cyclopropylaminocarbonylamino-7'-benzoylamino-spiro [1,3-dioxalan-2,3'-indole] -2 '(1 'H) -one with a yield of 70% (0.18 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 0.73-0.83 (m, 2H), 1.01-1.11 (m, 2H), 2.46-2 , 54 (m, 1H), 3.56-4.12 (m, 4H), 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H) , 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s, 1H), 10.33 (s, 1H), 10, 53 (s, 1H).

Intermediate 50

5'-trifluoroacetylamino-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0006 mol) of 5'-amino-7'-benzoylamino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'N) -one (intermediate 25) and 0.09 ml (0.0006 mol) of trifluoroacetic anhydride, 5'-trifluoroacetylamino-7'-benzoylamino-spiro [1,3-dioxalan-2,3'-indole] -2 '(1 'H) -one with a yield of 80% (0.21 g). NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.54-4.10 (m, 4H), 6.80-6.90 (m, 1H), 7.34 -7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s, 1H), 10.33 (s, 1H), 10, 53 (s, 1H).

Intermediate 51

5'-benzoylamino-7'-acetylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0008 mol) of 5'-amino-7'-acetylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 26) and 0.09 ml (0.0008 mol) of benzoyl chloride, 5'-benzoylamino-7'-acetylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1 'H) -one with a yield of 85% (0.24 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.07 (s, 1H), 3.56-4.10 (m, 4H), 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H) , 7.88 (d, J = 2.71, 1H), 10.26 (s, 1H), 10.33 (s, 1H), 10, 53 (s, 1H).

Intermediate 52

5'-phenoxycarbonylamino-7'-acetylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0008 mol) of 5'-amino-7'-acetylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 26) and 0.10 ml (0.0008 mol) of phenoxycarbonyl chloride, 5'-phenoxycarbonylamino-7'-acetylamino-spiro [1,3-dioxalan-2,3'-indole] -2 '(1 'H) -one with a yield of 75% (0.22 g). NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.07 (s, 3H), 3.56-4.18 (m, 4H), 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H) , 7.88 (d, J = 2.71, 1H), 10.26 (s, 1H), 10.33 (s.DH), 10, 53 (s, 1H).

Intermediate 53

5 '- (2-thiophene) carbonylamino-7'-methoxycarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2' (1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0007 mol) of 5'-amino-7'-methoxycarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 27) and 0.08 ml (0.0007 mol) (2-thiophene) carbonyl chloride, obtained 5 '- (2-thiophene) carbonylamino-7'-methoxycarbonylamino-spiro [1,3-dioxalan-2, 3'-indole] -2 '(1'H) -one with a yield of 65% (0.18 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 3.17 (s, 3H), 3.55-4.12 (m, 4H), 6.68 (dd., J = 1.71, J = 3.42, 1H), 7.31 (d, J = 3.42, 1H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H), 7.91 (d, J = 0.86, 1H), 10.20 (e., 1H), 10.33 (s, 1H), 10 53 (s, 1H).

Intermediate 54

5 '- (2-pyridine) carbonylamino-7'-cyclopropylcarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2' (1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0007 mol) of 5'-amino-7'-cyclopropylcarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 28) and 0.13 g (0.0007 mol) (2-pyridine) carbonyl chloride, obtained 5 '- (2-pyridine) carbonylamino-7'-cyclopropylcarbonylamino-spiro [1,3-dioxalan-2, 3'-indole] -2 '(1'H) -one with a yield of 75% (0.20 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 0.73-0.83 (m, 2H), 1.01-1.11 (m, 2H), 2.46-2 , 54 (m., 1H), 3.55-4.16 (m, 4H), 6.68 (dd., J = 1.71, J = 3.42, 1H), 7.31 (d ., J = 3.42, 1H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H), 7.91-8.16 (m, 5H), 10.20 (s, 1H), 10.33 (s, 1H), 10.53 (s, 1H).

Intermediate 55

5 ', 7'-bis (phenylaminocarbonylamino) -spiro [1,3-dioxolane-2,3'-indole] -2' (1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0006 mol) of 5'-amino-7'-phenylaminocarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 30) and 0.07 ml (0.0007 mol) of phenyl isocyanate, 5 ', 7'-bis (phenylaminocarbonylamino) -spiro [1,3-dioxolan-2,3'-indole] -2' ( 1'N) -one with a yield of 80% (0.22 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 3.66-4.25 (m, 4H), 6.80-6.90 (m, 2H), 7.34 -7.56 (m, 6H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 2H), 7.88 (d, J = 2.71, 1H), 10.26-10.30 (m, 2H), 10.33-10.39 (m, 2H), 10, 53 (s, 1H).

Intermediate 56

5 ', 7'-bis ((3-pyridine) aminocarbonylamino) -spiro [1,3-dioxolane-2,3'-indole] -2' (1'H) -one

The synthesis was carried out similarly to intermediate 31, using 0.2 g (0.0006 mol) of 5'-amino-7 '- (3-pyridine) aminocarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2' (1'N) -one (intermediate 29) and 0.07 g (0.0007 mol) (3-pyridine) of an isocyanate, 5 ', 7'-bis ((3-pyridine) aminocarbonylamino) -spiro [1, 3-dioxolane-2,3'-indole] -2 '(1'H) -one with a yield of 85% (0.23 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.56-4.16 (m, 4H), 7.43-7.55 (m, 4H), 7.59 (d, J = 2.67, 1H), 7.69-7.81 (m, 4H), 7.88 (d, J = 2.71, 1H), 10.26-10.30 (m, 2H), 10.33-10.39 (m, 2H), 10, 53 (s, 1H).

Removal of dioxalan protective group

(synthesis of compounds of formula (4) in the diagram)

Intermediate 57

5-benzoylamino-isatin

0.23 g (0.0007 mol) of 5'-benzoylamino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'H) -one (intermediate 31) was dissolved in a round-bottomed flask in 4 ml of aqueous acetone (75%). Then to the solution was added a solution of concentrated hydrochloric acid (1 ml), after the reaction mixture was stirred at room temperature for 24 hours. After the end of the reaction (judged by thin layer chromatography), the reaction mixture was poured into a beaker containing 5 g of finely divided ice, the precipitated precipitate was filtered, washed with a small amount of cold water and dried in air. Thus, 5-benzoylamino-isatin was obtained with a yield of 63% (0.12 g).

T. pl. (exp.) = 310 ° C.

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 6.91 (d, J = 8.07, 1H), 7.45-7.65 (m, 3H), 7 , 82-8.03 (m., 4H), 10.31 (s., 1H), 11.00 (s., 1H).

NMR ¹³ C (DMSO-d ₆ , δ, ppm): 112.73; 117.09; 118.09; 128.07; 128.90; 130.66; 132.15; 134.93; 135.02; 147.03; 160.11; 165.95; 185.00.

IR (KBr, cm ^-1 ): 1642, 1733, 1757, 3299, 3372.

Mass spectrum (electron impact, 70 eV), m / z (I,%): 266 (19, M +), 238 (13), 210 (1), 181 (0.5), 161 (1), 133 (7), 105 (100), 77 (71), 51 (23), 29 (1.5).

Intermediate 58

5- (2-furoyl) amino-isatin

Synthesis was carried out similarly to intermediate 57, using 1 g (0.003 mol) of 5 '- (2-furoyl) amino-spiro [1,3-dioxol-2,3'-indole] -2' (1'H) -one (intermediate 32), 5- (2-furoyl) amino-isatin was obtained with a yield of 44% (0.38 g).

M.p. (exp.) = 297-299 ° C.

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 6.70 (s, 1H), 6.01 (d, J = 8.09, 1H), 7.32 (s ., 1H), 7.80-8.00 (m, 3H), 10.30 (s, 1H), 11.01 (s, 1H).

NMR ¹³ C (DMSO-d ₆ , δ, ppm): 112.68; 112.75; 115.38; 117.12; 118.09; 130.67; 134.24; 146.26; 147.08; 147.69; 156.66; 160.07; 184.94.

IR (KBr, cm ^-1 ): 1727, 1739, 1768, 3107, 3302.

Mass spectrum (electron impact, 70 eV), m / z (I,%): 256 (86, M +), 228 (99), 200 (9), 171 (20), 144 (18), 112 ( 17), 95 (100), 79 (6), 39 (29), 29 (9).

Intermediate 59

7-benzoylamino-isatin

The synthesis was carried out similarly to intermediate 57, using 1 g (0.003 mol) 7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one (intermediate 33), received 7 '-benzoylamino-isatin with a yield of 60% (0.51 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 7.06 (t, J = 7.34, 1H), 7.34 (d, J = 7.09, 1H) , 7.44-7.62 (m., 3H), 8.00 (d, J = 7.09, 2H), 8.89 (d, J = 5.14, 1H), 9.96 (s, 1H), 10.53 (s, 1H).

Intermediate 60

N-allyl-5-benzoylamino-isatin

The synthesis was carried out similarly to intermediate 57, using 1 g (0.003 mol) of N-allyl-5'-benzoylamino-spiro [1,3-dioxol-2,3'-indole] -2 '(1'N) -one (intermediate 39 ) received N-allyl-5'-benzoylamino-isatin with a yield of 65% (0.56 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 4, 22 (d, J = 14.18, 1H), 4.44 (d, J = 8.44, 1H), 6.80-6.90 (m, 1H), 7.45-7.60 (m, 3H), 7.63-7.74 (m, 1H), 7.81 (dd, J = 8.30, J = 14.20, 1H), 7.85-8.05 (m., 3H), 10.26 (s, 1H).

Intermediate 61

N-benzyl-5-benzoylamino-isatin

The synthesis was carried out similarly to intermediate 57, using 1 g (0.003 mol) of N-benzyl-5'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 40 ), N-benzyl-5'-benzoylamino-isatin was obtained with a yield of 60% (0.53 g). NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.02 (s, 2H), 6.80-6.90 (m, 1H), 7.05 (d, J = 8.59, 1H), 7.32-7.42 (m, 2H), 7.47-7.62 (m, 5H), 7.65-7.77 (m, 2H) , 8.16 (d, J = 2.27, 1H), 8.27 (dd., J = 2.40, J = 8.59, 1H), 10.26 (s, 1H).

Intermediate 62

N-methyl-5-benzoylamino-isatin

The synthesis was carried out similarly to intermediate 57, using 1 g (0.003 mol) of N-methyl-5'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 41 ), N-methyl-5'-benzoylamino-isatin was obtained with a yield of 66% (0.57 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 3.17 (s, 3H), 6.80-6.90 (m, 1H), 7.45-7.60 (m, 3H), 7.63-7.74 (m, 1H), 7.85-8.05 (m, 3H), 10.26 (s, 1H).

Intermediate 63

5-methoxy-7-benzoylamino-isatin

The synthesis was carried out similarly to intermediate 57, using 1 g (0.003 mol) of 5'-methoxy-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 42), received 5'-methoxy-7'-benzoylamino-isatin with a yield of 68% (0.59 g). NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.45 (s, 3H), 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s, 1H), 10, 53 (s, 1H).

Intermediate 64

5-bromo-7-benzoylamino-isatin

Synthesis was carried out similarly to intermediate 57, using 1 g (0.003 mol) of 5'-bromo-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 43), received 5'-bromo-7'-benzoylamino-isatin with a yield of 65% (0.58 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s, 1H), 10, 53 (s., 1H).

Intermediate 65

5-benzoylamino-7-methyl-isatin

The synthesis was carried out similarly to intermediate 57, using 1 g (0.003 mol) of 5'-benzoylamino-7'-methyl-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one (intermediate 44), received 5'-benzoylamino-7'-methyl-isatin with a yield of 67% (0.58 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 2.31 (s, 1H), 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s., 1H), 10, 53 (s, 1H).

Intermediate 66

5-methoxycarbonyl-7-benzoylamino-isatin

The synthesis was carried out similarly to intermediate 57, using 1 g (0.003 mol) of 5'-methoxycarbonyl-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 45), 5'-methoxycarbonyl-7'-benzoylamino-isatin was obtained in 70% yield (0.62 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.22 (s, 3H), 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s., 1H), 10, 53 (s, 1H).

Intermediate 67

5-cyclopropylcarboinlamino-7-benzoylamino-isatin

The synthesis was carried out similarly to intermediate 57, using 1 g (0.003 mol) of the 5'-cycle of the opropylcarboyl-amino-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one ( intermediate 46), 5'-cyclopropylcarboinlamino-7'-benzoylamino-isatin was obtained in 65% yield (0.58 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 0.73-0.83 (m, 2H), 1.01-1.11 (m, 2H), 2.46-2 , 54 (m, 1H), 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m., 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s, 1H), 10.33 (s., 1H), 10, 53 (s., 1H).

Intermediate 68

5-methylaminothiocarbonylamino-7-benzoylamino-isatin

The synthesis was carried out similarly to intermediate 57, using 1 g (0.003 mol) of the 5'-cycle of the opropylcarboyl-amino-7'-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one ( intermediate 47), 5'-cyclopropylcarboinlamino-7'-benzoylamino-isatin was obtained in 60% yield (0.53 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.17 (s, 3H), 6.68-6.78 (m, 2H), 7.31 (m, 2H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H), 7.91 (m, 1H), 10.20 (s 1H), 10.33-10.42 (m, 2H), 10.53 (s, 1H).

Intermediate 69

5-trifluoromethylaminocarbonylamino-7-benzoylamino-isatin

The synthesis was carried out similarly to intermediate 57, using 1 g (0.002 mol) of 5'-trifluoromethylaminocarbonylamino-7'-benzoylamino-spiro [1,3-dioxalan-2,3'-indole] -2 '(1'H) -one (intermediate 48), 5'-trifluoromethylaminocarbonylamino-7'-benzoylamino-isatin was obtained in 65% yield (0.58 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s., 1H), 10.33-10.39 (m, 2H), 10, 53 (s, 1H).

Intermediate 70

5-cyclopropylaminocarbonylamino-7-benzoylamino-isatin

Synthesis was carried out similarly to intermediate 57, using 1 g (0.002 mol) of 5'-cyclopropylaminocarbonylamino-7'-benzoylamino-spiro [1,3-dioxalan-2,3'-indole] -2 '(1'N) -one (intermediate 49), 5'-cyclopropylaminocarbonylamino-7'-benzoylamino-isatin was obtained with a yield of 65% (0.58 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 0.73-0.83 (m, 2H), 1.01-1.11 (m, 2H), 2.46-2 , 54 (m, 1H), 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m., 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s, 1H), 10.33 (s., 1H), 10, 53 (s., 1H).

Intermediate 71

5-trifluoroacetylamino-7-benzoylamino-isatin

The synthesis was carried out similarly to intermediate 57, using 1 g (0.002 mol) of 5'-trifluoroacetylamino-7'-benzoylamino-spiro [1,3-dioxolan-2,3'-indole] -2 '(1'N) -one (intermediate 50), received 5'-trifluoroacetylamino-7'-benzoylamino-isatin with a yield of 65% (0.58 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s., 1H), 10.33 (s., 1H), 10, 53 (s, 1H).

Intermediate 72

5-benzoylamino-7-acetylamino-isatin

The synthesis was carried out similarly to intermediate 57, using 1 g (0.003 mol) of 5'-benzoylamino-7'-acetylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one (intermediate 51), 5'-benzoylamino-7'-acetylamino-isatin was obtained in 67% yield (0.59 g). NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.07 (s, 1H), 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s, 1H), 10.33 (s, 1H), 10, 53 (s, 1H).

Intermediate 73

5-phenoxycarbonylamino-7-acetylamino-isatin

The synthesis was carried out similarly to intermediate 57, using 1 g (0.003 mol) of 5'-phenoxycarbonylamino-7'-acetylamino-spiro [1,3-dioxalan-2,3'-indole] -2 '(1'N) -one (intermediate 52), received 5'-phenoxycarbonylamino-7'-acetylamino-isatin with a yield of 63% (0.56 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.07 (s, 3H), 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s, 1H), 10.33 (s, 1H), 10, 53 (s, 1H).

Intermediate 74

5- (2-thiophene) carbonylamino-7-methoxycarbonylamino-isatin

The synthesis was carried out similarly to intermediate 57, using 1 g (0.003 mol) of 5 '- (2-thiophene) carbonylamino-7'-methoxycarbonylamino-spiro [1,3-dioxalan-2,3'-indole] -2' (1'N ) -one (intermediate 53), 5 '- (2-thiophene) carbonylamino-7'-methoxycarbonylamino-isatin was obtained in 65% yield (0.58 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.17 (s, 3H), 6.68 (dd., J = 1.71, J = 3.42, 1H) , 7.31 (d, J = 3.42, 1H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H), 7 , 91 (d, J = 0.86, 1H), 10.20 (s, 1H), 10.33 (s, 1H), 10.53 (s, 1H).

Intermediate 75

5- (2-pyridine) carbonylamino-7-cyclopropylcarbonylamino-isatin

The synthesis was carried out similarly to intermediate 57, using 1 g (0.003 mol) 5 '- (2-pyridine) carbonylamino-7'-cyclopropylcarbonylamino-spiro [1,3-dioxalan-2,3'-indole] -2' (1'N ) -one (intermediate 54), 5 '- (2-pyridine) carbonylamino-7'-cyclopropylcarbonylamino-isatin was obtained with a yield of 67% (0.60 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 0.73-0.83 (m, 2H), 1.01-1.11 (m, 2H), 2.46-2 , 54 (m, 1H), 6.68 (dd., J = 1.71, J = 3.42, 1H), 7.31 (d, J = 3.42, 1H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H), 7.91-8.16 (m, 5H), 10.20 (s, 1H), 10.33 (s., 1H), 10.53 (s, 1H).

Intermediate 76

5,7-bis (phenylaminocarbonylamino) -isatin

The synthesis was carried out similarly to intermediate 57, using 1 g (0.002 mol) 5 ', 7'-bis (phenylaminocarbonylamino) -spiro [1,3-dioxolane-2,3'-indole] -2' (1'N) -one ( intermediate 55), 5 ', 7'-bis (phenylaminocarbonylamino) -isatin was obtained in 65% yield (0.59 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 6.80-6.90 (m, 2H), 7.34-7.56 (m, 6H), 7.59 (d, J = 2.67, 1H), 7.63-7.80 (m, 2H), 7.88 (d, J = 2.71, 1H), 10.26-10.30 (m, 2H), 10.33-10.39 (m, 2H), 10, 53 (s, 1H).

Intermediate 77

5,7-bis ((3-pyridine) aminocarbonylamino) -isatin

The synthesis was carried out similarly to intermediate 57, using 1 g (0.002 mol) of 5 ', 7'-bis ((3-pyridine) aminocarbonylamino) -spiro [1,3-dioxolan-2,3'-indole] -2' (1 ' H) -one (intermediate 56), 5 ', 7'-bis ((3-pyridine) aminocarbonylamino) -isatin was obtained in 70% yield (0.63 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 7.47-7.55 (m, 4H), 7.59 (d, J = 2.67, 1H), 7 , 69-7.81 (m., 4H), 7.88 (d, J = 2.71, 1H), 10.26-10.30 (m, 2H), 10.33-10.39 (m, 2H), 10, 53 (s., 1H).

Nitration of isatins with simultaneous removal of dioxolane protection (synthesis of compounds of formula (1) in the scheme, where R ⁴ = NHC (X) R ⁷ )

Intermediate 78

5-nitro-7-benzoylamino-isatin

In a round-bottomed flask in 2 ml of concentrated sulfuric acid, while stirring, 0.09 g (0.0003 mol) of 7-benzoylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) - she (intermediate 33), the resulting solution is cooled to 0 ° C. Then in small portions with constant stirring, preventing the reaction mixture from heating above 5 ° C, 0.044 g (0.0004 mol) of potassium nitrate is introduced. After the addition was complete, the cooling was stopped and the reaction mixture was stirred for an additional 30 minutes. Then it was poured into finely crushed ice (5 g) with stirring. The product was isolated by extraction with ethyl acetate (3 * 7 ml). After removing the solvent in vacuo, 5-nitro-7-benzoylamino-isatin was obtained with a yield of 65% (0.06 g). NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 6.68-6.78 (m, 2H), 7.31 (m, 2H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H), 7.91 (m, 1H), 10.20 (s, 1H), 10.64 (s ., 1H).

Intermedia 79

5-nitro-7-acetylamino-isatin

The synthesis was carried out similarly to intermediate 78, using 0.1 g (0.0004 mol) of 7'-acetylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 34 ) 5-nitro-7-acetylamino-isatin was obtained with a yield of 55% (0.06 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.02 (s, 3H), 7.59 (d, J = 2.67, 1H), 7.87 (d ., J = 2.83, 1H), 10.20 (s, 1H), 10.64 (s, 1H).

Intermediate 80

5-nitro-7-methoxycarbonylamino-isatin

The synthesis was carried out similarly to intermediate 78, using 0.1 g (0.0004 mol) of 7'-methoxycarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 35 ) 5-nitro-7-methoxycarbonylamino-isatin was obtained in 55% yield (0.06 g). NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 3.12 (s, 3H), 7.59 (d, J = 2.67, 1H), 7.87 (d ., J = 2.83, 1H), 10.20 (s, 1H), 10.64 (s, 1H).

Intermediate 81

5-nitro-7-cyclopropylcarbonylamino-isatin

The synthesis was carried out similarly to intermediate 78, using 0.1 g (0.0004 mol) of 7'-cyclopropylcarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'N) -one (intermediate 36 ), 5-nitro-7-cyclopropylcarbonylamino-isatin was obtained in 60% yield (0.06 g). NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 0.73-0.83 (m, 2H), 1.01-1.11 (m, 2H), 2.46-2 , 54 (m., 1H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H), 10.20 (s, 1H) , 10.64 (s., 1H).

Intermediate 82

5-nitro-7- (3-pyridine) aminocarbonylamino-isatin

The synthesis was carried out similarly to intermediate 78, using 0.1 g (0.0003 mol) 7 '- (3-pyridine) aminocarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2' (1'N) -one (intermediate 37), obtained 5-nitro-7- (3-pyridine) aminocarbonylamino-isatin with a yield of 63% (0.06 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 7.32-7.42 (m, 2H), 7.59 (d, J = 2.67, 1H), 7 , 87 (d, J = 2.83, 1H), 8.01 (m, 2H), 10.20 (s, 1H), 10.33 (s, 1H), 10.64 (s ., 1H).

Intermediate 83

5-nitro-7-phenylaminocarbonylamino-isatin

The synthesis was carried out similarly to intermediate 78, using 0.1 g (0.0003 mol) of 7'-phenylaminocarbonylamino-spiro [1,3-dioxolane-2,3'-indole] -2 '(1'H) -one (intermediate 38 ) 5-nitro-7-phenylaminocarbonylamino-isatin was obtained with a yield of 58% (0.06 g). NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 6.68-6.78 (m, 2H), 7.31 (m, 2H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H), 7.91 (m, 1H), 10.20 (s, 1H), 10.33 (s ., 1H), 10.64 (s., 1H).

Synthesis of compounds of formula (I)

Example 1. (5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile

0.1 g (0.0004 mol) of 5-benzenamine-isatin and 0.03 g (0.0004 mol) of cyanoacetic acid in pyridine (2 ml) were dissolved in a round bottom flask equipped with a reflux condenser. Then, 0.05 ml of piperidine was added to the reaction mixture and boiled for 3 hours. The end of the reaction was judged by thin layer chromatography. Then the reaction mixture was cooled to room temperature, slowly added 2 ml of a saturated solution of hydrogen chloride in 1,4-dioxane, preventing the mixture from overheating. To the resulting mixture was added 2 ml of cold water. The product was obtained by extraction with ethyl acetate (5 * 7 ml). The organic extracts were combined, dried over anhydrous sodium sulfate, the solvent was removed in vacuo. (5-Benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile was obtained in 61% yield (0.07 g).

T. pl. (exp.) = 173-176 ° C.

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.94 (d, J = 16.51, 1H), 3.04 (d, J = 16.14, 1H) , 6.66 (s., 1H), 6.80-6.90 (m., 1H), 7.45-7.60 (m., 3H), 7.63-7.74 (m, 1H), 7.85-8.05 (m, 3H), 10.26 (s, 1H), 10.53 (s, 1H).

NMR ¹³ C (DMSO-d ₆ , δ, ppm): 26.67; 72.82; 110.34; 117.43; 118.00; 122.83; 128.04; 128.83; 130.37; 131.94; 134.36; 135.34; 137.86; 165.68; 177.24.

Mass spectrum (electron impact, 70 eV), m / z (I,%): 307 (22, M +), 289 (6), 267 (6), 239 (2), 202 (0.5), 174 ( 1), 133 (2), 105 (100), 77 (45), 51 (5), 14 (1).

Example 2. (5- (2-furoyl) amino-3-hydroxy-2-oxindol-3-yl) acetonitrile

Synthesis was carried out similarly to example 1, using 0.1 g (0.0004 mol) of 5- (2-furoyl) amino-isatin, (5- (2-furoyl) amino-3-hydroxy-2-oxindol-3-yl was obtained ) acetonitrile with a yield of 50% (0.06 g).

M.p. (exp.) = 298-300 ° C.

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.94 (d, J = 16.63, 1H), 3.03 (d, J = 16.63, 1H) , 6.65 (br.S, 1H), 6.68 (dd., J = 1.71, J = 3.42, 1H), 6.84 (d, J = 8.44, 1H) , 7.31 (d., J = 3.42, 1H), 7.64 (dd., J = 1.96, J = 8.44, 1H), 7.87 (d, J = 1, 83, 1H), 7.91 (d, J = 0.86, 1H), 10.20 (s, 1H), 10.53 (s, 1H).

NMR ¹³ C (DMSO-d ₆ , δ, ppm): 26.63; 72.76; 110.37; 112.56; 114.91; 117.46; 118.01; 122.84; 130.41; 133.63; 137.93; 146.07; 147.99; 156.60; 177.23.

IR (KBr, cm ^-1 ): 1557, 1724, 2268, 2852, 3240, 3305.

Mass spectrum (electron impact, 70 eV), m / z (I,%): 297 (66, M +), 279 (9), 257 (65), 229 (23), 189 (13), 174 ( 5), 133 (10), 105 (12), 95 (100), 79 (29), 52 (18), 43 (20), 39 (33), 28 (18).

Example 3. (7-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile

Synthesis was carried out similarly to example 1, using 0.1 g (0.0004 mol) of 7-benzoylamino-isatin, (7-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile was obtained in 40% yield (0.05 d).

T. pl. (exp.) = 115-120 ° C.

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.96 (d, J = 16.63, 1H), 3.07 (d, J = 16.51, 1H) , 7.06 (t., J = 7.34, 1H), 7.34 (d, J = 7.09, 1H), 7.44-7.62 (m, 3H), 8.00 (d, J = 7.09, 2H), 8.89 (d, J = 5.14 1H), 9.96 (s, 1H), 10.53 (s, 1H).

NMR ¹³ C (DMSO-d ₆ , δ, ppm): 26.67; 72.82; 110.34; 117.43; 118.00; 122.83; 128.04; 128.83 130.37; 131.94; 134.36; 135.34; 137.86; 165.68; 177.24.

Mass spectrum (electron impact, 70 eV), m / z (I,%): 307 (32), 267 (4), 242 (2), 202 (1), 19: (1), 161 (3) , 129 (1), 105 (100), 77 (45), 51 (6).

Example 4. (N-allyl-5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile

The synthesis was carried out similarly to example 1, using 0.1 g (0.0003 mol) of N-allyl-5-benzoylamino-isatin, was obtained (N-allyl-5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile with a yield of 50% (0.06 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.94 (d, J = 16.51, 1H), 3.04 (d, J = 16.14, 1H) , 4, 22 (d., J = 14.18, 1H), 4.44 (d, J = 8.44, 1H), 6.66 (s., 1H), 6.80-6.90 ( m., 1H), 7.45-7.60 (m., 3H), 7.63-7.74 (m, 1H), 7.81 (dd., J = 8.30, J = 14 , 20, 1H), 7.85-8.05 (m., 3H), 10.26 (s., 1H).

Example 5. (N-benzyl-5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile

The synthesis was carried out similarly to example 1, using 0.1 g (0.0003 mol) of N-benzyl-5-benzoylamino-isatin, was obtained (N-benzyl-5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile with a yield of 60% (0.07 g). NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.94 (d, J = 16.51, 1H), 3.04 (d, J = 16.14, 1H) , 4.91 (s., 2H), 6.66 (s., 1H), 6.80-6.90 (m., 1H), 7.34-7.60 (m, 5H), 7 , 63-7.80 (m., 2H), 7.81-7.85 (m., 2H), 7.87-8.05 (m., 3H), 10.26 (s., 1H) .

Example 6. (N-methyl-5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile

The synthesis was carried out analogously to example 1, using 0.1 g (0.0004 mol) of N-methyl-5-benzoylamino-isatin, was obtained (N-methyl-5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile with a yield of 48% (0.06 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.94 (d, J = 16.51, 1H), 3.04 (d, J = 16.14, 1H) , 3.17 (s., 3H), 6.66 (s., 1H), 6.80-6.90 (m, 1H), 7.45-7.60 (m, 3H), 7 , 63-7.74 (m, 1H), 7.85-8.05 (m, 3H), 10.26 (s., 1H).

Example 7. (5-benzoylamino-2-oxindol-3-yl) acetonitrile

In a round bottom flask equipped with a reflux condenser, 0.3 g (0.001 mol) (5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile (product of Example 1) was boiled in a solution of for 10 hours. After completion of the reaction (control by TLC, until the starting material disappeared), the reaction mixture was cooled to room temperature. The intermediate product was isolated by filtration, washed with cold water and dried in air (the mass of dry residue was 0.27 g). Next, the intermediate product was completely dissolved in ethyl acetate (5 ml) and catalytic reduction of the double bond under the action of hydrogen in an on-line hydrogenation reactor H-Cube (Hungary) was carried out: flow rate 1 ml / min, pressure H ₂ 2 atm., Catalyst Pd / C ( ten%). After complete hydrogenation, the solvent was removed in a rotary evaporator vacuum, was (5-benzoylamino-2-oxindol-3-yl) acetonitrile with a yield of 90% (0.26 g). NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.77 (d, J = 17.00, 1H), 3.09 (d, J = 16.96, 1H) , 3.62-3.66 (m, 1H), 6.80-6.90 (m., 1H), 7.45-7.60 (m., 3H), 7.63-7.74 ( m., 1H), 7.85-8.05 (m., 3H), 10.26 (s., 1H), 10.53 (s., 1H).

Example 8. (5-benzoylamino-3-methoxy-2-oxindol-3-yl) acetonitrile

0.2 g (0.0006 mol) (5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile (product of example 1) was dissolved in anhydrous tetrahydrofuran (5 ml) in a round-bottomed flask. Then, in small portions with vigorous stirring at room temperature, (Me) ₂ SO ₄ (0.07 ml, 0.0007 mol) was added. After complete addition, the solution was stirred at room temperature for another 15 minutes, then cold water (5 ml) was added and extracted with ethyl acetate (3 * 5 ml). The organic extracts were combined, dried over anhydrous sodium sulfate. After concentrating the rotary evaporator in vacuo, (5-benzoylamino-3-methoxy-2-oxindol-3-yl) acetonitrile was obtained with a yield of 85% (0.18 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.94 (d, J = 16.51, 1H), 3.04 (d, J = 16.14, 1H) , 3.26 (s., 3H), 6.80-6.90 (m., 1H), 7.45-7.60 (m., 3H), 7.63-7.74 (m, 1H), 7.85-8.05 (m., 3H), 10.26 (s, 1H), 10.53 (s., 1H).

Example 9. (5-benzoylamino-3-acetoxy-2-oxindol-3-yl) acetonitrile

The synthesis was carried out analogously to example 7, using 0.1 g (0.0003 mol) (5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile and 0.05 ml (0.0005 mol) of acetic anhydride as an acylating agent, and (5-benzoylamino-3-acetoxy-2-oxindol-3-yl) acetonitrile was obtained in 77% yield (0.09 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.05 (s, 3H), 2.94 (d, J = 16.51, 1H), 3.04 (d ., J = 16.14, 1H), 6.80-6.90 (m., 1H), 7.45-7.60 (m., 3H), 7.63-7.74 (m, 1H), 7.85-8.05 (m, 3H), 10.26 (s, 1H), 10.53 (s, 1H).

Example 10. (5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetic acid

The synthesis was carried out analogously to example 1, using 0.1 g (0.0003 mol) of 5-benzoylamino-isatin and 0.03 g (0.0003 mol) of malonic acid as a CH-acid compound, to obtain (5-benzoylamino-3- hydroxy-2-oxindol-3-yl) acetic acid with a yield of 63% (0.10 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.94 (d, J = 16.51, 1H), 3.04 (d, J = 16.14, 1H) , 4.91 (s., 2H), 6.66 (s., 1H), 6.80-6.90 (m., 1H), 7.34-7.60 (m, 5H), 7 , 63-7.80 (m., 2H), 7.81-7.85 (m., 2H), 7.87-8.05 (m., 3H), 10.26 (s., 1H) , 12, 15 (ws, 1H).

Example 11. (5-methoxy-7-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile

Synthesis was carried out analogously to example 1, using 0.1 g (0.0003 mol) of 5-methoxy-7-benzoylamino-isatin, (5-methoxy-7-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile was obtained with a yield of 48% (0.05 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.94 (d, J = 16.51, 1H), 3.04 (d, J = 16.14, 1H) , 3.45 (s., 3H), 6.66 (s., 1H), 6.80-6.90 (m., 1H), 7.34-7.56 (m, 3H), 7 , 59 (d, J = 2.67, 1H), 7.63-7.80 (m., 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s ., 1H), 10, 53 (s, 1H).

Example 12. (5-Bromo-7-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile

Synthesis was carried out similarly to example 1, using 0.1 g (0.0003 mol) of 5-bromo-7-benzoylamino-isatin, (5-bromo-7-benzoyllamino-3-hydroxy-2-oxindol-3-yl) was obtained acetonitrile with a yield of 68% (0.08 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.94 (d, J = 16.51, 1H), 3.04 (d, J = 16.14, 1H) , 6.66 (s., 1H), 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d., J = 2, 67, 1H), 7.63-7.80 (m., 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s., 1H), 10, 53 (s ., 1H).

Example 13. (5-benzoylamino-7-methyl-3-hydroxy-2-oxindol-3-yl) acetonitrile

Synthesis was carried out similarly to example 1, using 0.1 g (0.0004 mol) of 5-benzoylamino-7-methyl-isatin, (5-benzoylamino-7-methyl-3-hydroxy-2-oxindol-3-yl) acetonitrile was obtained with a yield of 47% (0.05 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 2.31 (s, 1H), 2.94 (d, J = 16.51, 1H), 3.04 (d ., J = 16.14, 1H), 6.66 (s, 1H), 6.80-6.90 (m., 1H), 7.34-7.56 (m, 3H), 7 , 59 (d, J = 2.67, 1H), 7.63-7.80 (m., 1H), 7.88 (d, J - 2.71, 1H), 10.26 (s ., 1H), 10, 53 (s, 1H).

Example 14. (5-Benzoylamino-7-aceamido-3-hydroxy-2-oxindol-3-yl) acetonitrile

The synthesis was carried out similarly to example 1, using 0.1 g (0.0003 mol) of 5-benzoylamino-7-acetamido-isatin, was obtained (5-benzoylamino-7-acetamido-3-hydroxy-2-oxindol-3-yl) acetonitrile with a yield of 65% (0.07 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 2.07 (s, 1H), 2.94 (d, J = 16.51, 1H), 3.04 (d ., J = 16.14, 1H), 6.66 (s, 1H), 6.80-6.90 (m., 1H), 7.34-7.56 (m, 3H), 7 , 59 (d, J = 2.67, 1H), 7.63-7.80 (m., 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s ., 1H), 10.33 (s, 1H), 10, 53 (s, 1H).

Example 15. (5-cyclopropylcarbonylamino-7-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile

Synthesis was carried out similarly to example 1, using 0.1 g (0.0003 mol) of 5-cyclopropylcarbonylamino-7-benzoylamino-isatin, to obtain (5-cyclopropylcarbonylamino-7-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile with a yield of 70% (0.08 g). NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 0.73-0.83 (m, 2H), 1.01-1.11 (m, 2H), 2.46-2 , 54 (m., 1H), 2.94 (d, J = 16.51, 1H), 3.04 (d, J = 16.14, 1H), 6.66 (s, 1H) , 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7 , 80 (m., 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s., 1H), 10.33 (s., 1H), 10, 53 (s ., 1H).

Example 16. (5- (2-thiophenecarbonyl) amino-7-methoxycarbonylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile

Synthesis was carried out as in Example 1, using 0.1 g (0.0003 mol) of 5- (2-thiophenecarbonyl) amino-7-methoxycarbonylamino-isatin, to obtain (5- (2-thiophenecarbonyl) amino-7-methoxycarbonylamino-3-hydroxy -2-oxindol-3-yl) acetonitrile with a yield of 68% (0.08 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.94 (d, J = 16.63, 1H), 3.03 (d, J = 16.63, 1H) , 3.17 (s, 3H), 6.65 (s, 1H), 6.68 (dd., J = 1.71, J = 3.42, 1H), 7.31 (d., J = 3.42, 1H), 7.59 (d, J = 2.67, 1H), 7.87 (d, J = 2.83, 1H), 7.91 (d, J = 0.86, 1H), 10.20 (s, 1H), 10.33 (s, 1H), 10.53 (s, 1H).

Example 17. (5- (2-pyridinecarbonyl) amino-7-cyclopropylcarbonylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile

The synthesis was carried out similarly to example 1, using 0.1 g (0.0003 mol) of 5- (2-pyridinecarbonyl) amino-7-cyclopropylcarbonylamino-isatin, to obtain (5- (2-pyridinecarbonyl) amino-7-cyclopropylcarbonylamino-3-hydroxy -2-oxindol-3-yl) acetonitrile with a yield of 72% (0.08 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 0.73-0.83 (m, 2H), 1.01-1.11 (m, 2H), 2.46-2 , 54 (m, 1H), 2.94 (d, J = 16.63, 1H), 3.03 (d, J = 16.63, 1H), 6.65 (s, 1H) 6.68 (dd., J = 1.71, J = 3.42, 1H), 7.31 (d, J = 3.42, 1H), 7.59 (d, J = 2, 67, 1H), 7.87 (d, J = 2.83, 1H), 7.91-8.16 (m, 5H), 10.20 (s, 1H), 10.33 (s ., 1H), 10.53 (s., 1H).

Example 18. (5-Methylaminothiocarbonylamino-7-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile

The synthesis was carried out analogously to example 1, using 0.1 g (0.0003 mol) of 5-methylaminothiocarbonylamino-7-benzoylamino-isatin, (5-methyl aminothiocarbonylamino-7-benzoylamino-3-hydroxy-2-oxindol-3-yl) was obtained acetonitrile with a yield of 60% (0.07 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.94 (d, J = 16.63, 1H), 3.03 (d, J = 16.63, 1H) , 3.17 (s., 3H), 6.65 (s., 1H), 6.68-6.78 (m, 2H), 7.31 (m, 2H), 7.59 (d ., J = 2.67, 1H), 7.87 (d, J = 2.83, 1H), 7.91 (m, 1H), 10.20 (s, 1H), 10.33 -10.42 (m, 2H), 10.53 (s, 1H).

Example 19. (5-trifluoromethylaminocarbonylamino-7-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile

Synthesis was carried out similarly to example 1, using 0.1 g (0.0002 mol) of 5-trifluoromethylaminocarbonylamino-7-benzoylamino-isatin, (5-trifluoromethylaminocarbonylamino-7-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile was obtained with a yield of 70% (0.08 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.94 (d, J = 16.51, 1H), 3.04 (d, J = 16.14, 1H) , 6.66 (s., 1H), 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d., J = 2, 67, 1H), 7.63-7.80 (m., 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s., 1H), 10.33-10 , 39 (m, 2H), 10, 53 (s., 1H).

Example 20. (5-cyclopropylaminocarbonylamino-7-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile

Synthesis was carried out as in Example 1, using 0.1 g (0.0003 mol) of 5-cyclopropylaminocarbonylamino-7-benzoylamino-isatin, (5-cyclopropylamino-carbonylamino-7-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile was obtained with a yield of 50% (0.06 g).

NMR ¹ H (DMSO-d ₆ , ppm, J, Hz): 0.73-0.83 (m, 2H), 1.01-1.11 (m, 2H), 2.46-2 , 54 (m., 1H), 2.94 (d, J = 16.51, 1H), 3.04 (d, J = 16.14, 1H), 6.66 (s, 1H) 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d, J = 2.67, 1H), 7.63-7 , 80 (m., 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s., 1H), 10.33-10.39 (m, 2H), 10 53 (s., 1H).

Example 21. (5,7-bis (phenylaminocarbonylamino) -3-hydroxy-2-oxindol-3-yl) acetonitrile

The synthesis was carried out analogously to example 1, using 0.1 g (0.0002 mol) of 5,7-bis (phenylaminocarbonylamino) -isatin, to obtain (5,7-bis (phenylaminocarbonylamino) -3-hydroxy-2-oxindol-3-yl ) acetonitrile with a yield of 55% (0.06 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.94 (d, J = 16.51, 1H), 3.04 (d, J = 16.14, 1H) , 6.66 (s., 1H), 6.80-6.90 (m, 2H), 7.34-7.56 (m, 6H), 7.59 (d., J = 2, 67, 1H), 7.63-7.80 (m., 2H), 7.88 (d, J = 2.71, 1H), 10.26-10.30 (m, 2H), 10 , 33-10.39 (m, 2H), 10, 53 (s., 1H).

Example 22. (5,7-bis ((3-pyridine) aminocarbonylamino) -3-hydroxy-2-oxindol-3-yl) acetonitrile

Synthesis was carried out analogously to example 1, using 0.1 g (0.0002 mol) of 5,7-bis ((2-pyridine) aminocarbonylamino) -isatin, to obtain (5,7-bis ((2-pyridine) aminocarbonylamino) -3 α-hydroxy-2-oxindol-3-yl) acetonitrile with a yield of 54% (0.06 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.94 (d, J = 16.51, 1H), 3.04 (d, J = 16.14, 1H) 6.66 (s., 1H), 7.43-7.55 (m, 4H), 7.59 (d, J = 2.67, 1H), 7.69-7.81 (m ., 4H), 7.88 (d, J = 2.71, 1H), 10.26-10.30 (m, 2H), 10.33-10.39 (m, 2H), 10 53 (s., 1H).

Example 23. (5-Phenyloxycarbonylamino-7-aceamido-3-hydroxy-2-oxindol-3-yl) acetonitrile

Synthesis was carried out similarly to example 1, using 0.1 g (0.0003 mol) of 5-phenyloxycarbonylamino-7-acetamido-isatin to give (5-phenyloxycarbonylamino-7-acetamido-3-hydroxy-2-oxindol-3-yl) acetonitrile with a yield of 65% (0.07 g). NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.07 (s, 3H), 2.94 (d, J = 16.51, 1H), 3.04 (d ., J = 16.14, 1H), 6.66 (s, 1H), 6.80-6.90 (m., 1H), 7.34-7.56 (m, 3H), 7 , 59 (d, J = 2.67, 1H), 7.63-7.80 (m., 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s ., 1H), 10.33 (s, 1H), 10, 53 (s, 1H).

Example 24. (5-trifluoromethylcarbonylamino-7-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile

Synthesis was carried out similarly to example 1, using 0.1 g (0.0003 mol) of 5-trifluoromethylcarbonylamino-7-benzoylamino-isatin, (5-trifluoromethylcarbonylamino-7-benzoylamino-3-hydroxy-2-oxindia-3-yl) acetonitrile was obtained with a yield of 70% (0.08 g).

NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.94 (d, J = 16.51, 1H), 3.04 (d, J = 16.14, 1H) , 6.66 (s., 1H), 6.80-6.90 (m, 1H), 7.34-7.56 (m, 3H), 7.59 (d., J = 2, 67, 1H), 7.63-7.80 (m., 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s., 1H), 10.33 (s ., 1H), 10, 53 (s., 1H).

Example 25. (5-methoxycarbonyl-7-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile

Synthesis was carried out similarly to Example 1, using 0.1 g (0.0003 mol) of 5-methoxycarbonyl-7-benzoylamino-isatin, to obtain (5-methoxycarbonyl-7-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile with a yield of 70% (0.08 g). NMR ¹ H (DMSO-d ₆ ppm, J, Hz): 2.94 (d, J = 16.51, 1H), 3.04 (d, J = 16.14, 1H) , 3.22 (s., 3H), 6.66 (s., 1H), 6.80-6.90 (m., 1H), 7.34-7.56 (m, 3H), 7 , 59 (d, J = 2.67, 1H), 7.63-7.80 (m., 1H), 7.88 (d, J = 2.71, 1H), 10.26 (s ., 1H), 10, 53 (s., 1H).

Example 26. Hydrochloride (5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile

In a round-bottomed flask to a solution of 0.5 g (0.002 mol) of (5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile (Example 1) in tetrahydrofuran (15 ml) while cooling in an ice bath, dropwise with intensive while stirring, add a saturated solution of hydrogen chloride in diethyl ether (0.75 ml). After complete addition, cooling is stopped and the reaction mixture is stirred for another 10 minutes. The solution is then concentrated in vacuo to obtain (5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile hydrochloride in quantitative yield.

Example 27. (5-Benzoylamino-3-hydroxy-2-oxindol-3-yl) sodium acetate In a round bottom flask to a solution of 0.5 g (0.002 mol) (5-benzoylamino-3-hydroxy-2-oxindol-3- dl) acetic acid (example 10) in tetrahydrofuran (15 ml) while cooling in an ice bath, a saturated solution of sodium hydroxide in methanol (0.28 ml) is added dropwise with vigorous stirring. After complete addition, cooling is stopped and the reaction mixture is stirred for another 10 minutes. The solution is then concentrated in vacuo to obtain (5-benzoylamino-3-hydroxy-2-oxindol-3-yl) sodium acetate in quantitative yield.

Pharmaceutical compositions in accordance with the claimed invention can be presented in the form of eye drops, gel, ointment, polymer matrix with the active substance included, and so on.

The claimed invention is illustrated, but not limited, by the following examples of pharmaceutical compositions.

Example 28. A pharmaceutical composition comprising (5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile in the form of eye drops.

The preparation of eye drops is carried out in a standard way of preparing eye drops, by mixing all the components included in their composition until a homogeneous mass, soluble in water. The resulting eye drops meet the requirements of the pharmaceutical agent.

These components of eye drops are taken in the following ratio in mass. %:

In this case, the pH of the resulting solution should be 7.4.

Example 29. Pharmaceutical composition (5-furoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile

Preparation analogously to example 28, but (5-furoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile was used as the active component.

DESIGN RESEARCH

To confirm the possibility of binding compounds of formula (I) with melatonin receptors, molecular modeling (docking) of the interaction of compounds of formula (I) with the active site of the MT3 subtype of melatonin receptors was carried out.

For the docking procedure and the calculation of the affinity of compounds of formula (I), the crystal structure of the MT3 subtype of melatonin receptors (PDB ID 4GQI, http://www.rcsb.org/pdb/explore/explore.do?structureId=4GQI), known from prior art, namely described in MS Volkova (Synthesis of the receptor ligands via the unusual Knoevenagel condensation, Bioorganic & Medicinal Chemistry Letters, 2012, v. 22, 7578-7581). Preparation of ligands and macromolecules was carried out using the software ACD / Labs (Version 10.04, Advanced Chemistry Development, Inc.), AutoDockTools (ADT Version 1.5.6, The Scripps Research Institute), visualization - The PyMOL Molecular Graphics System (Version 1.74, Schrodinger , LLC). The binding energy was calculated using AutoDock Vina software (Version 1.1.2, Trott O., AJ AutoDock Vina: using a new scoring function), Journal of Computational Chemistry, 2010, pp 455-461) and AutoDock4 (Version 4.2.6, The Scripps Research Institute). To compare the efficiency of binding, the binding constants of K ligands were used, the calculation of which was carried out according to equation (1):

where dG is the binding energy (J), R is the universal gas constant (8.31 J / (mol * K), T is the temperature (298 K) (Table 1).

Thus, based on the calculation of the binding constant, it can be concluded that the proposed compounds of formula (I) demonstrate a stronger affinity for the MT3 subtype of melatonin receptors compared to the endogenous ligand (melatonin) and, presumably, will have a stronger biological response and / or a prolonged effect .

The results obtained by docking were confirmed experimentally. The novel indolinone derivatives of formula (I) effectively reduce IOP, as confirmed in the in vivo experiments shown below.

STUDY OF BIOLOGICAL ACTIVITY OF COMPOUNDS OF THE FORMULA (I)

The ability of melatonin, (5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetoniryl and (5-furoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile to reduce intraocular pressure was evaluated on normotensive rabbits of the chinchilla breed, males weighing about 2 kg. To do this, the above compounds were dissolved in DMSO, and then diluted with 0.05 M phosphate buffer (pH 7.4) to a concentration of 1 mg / ml (0.1 mass%). To measure the biological activity (decrease in intraocular pressure), a single installation of 1 drop (0.05 ml) of the obtained test compound was performed in both eyes of the animal (negative control — carrier — solution of 0.05 M phosphate buffer with the same DMSO content as in test compound). To control daily fluctuations, IOP was measured in a group of animals that did not receive treatment. Timolol solution (0.1 mass%) was used as a positive control. The intraocular pressure was measured before instillation and further after instillation for 6 hours with an interval of 1 hour, and also 24 hours after the installation. The measurements were performed using an automatic Tonovet veterinary applanation tonometer (Icare, Finland). Evaluation of the hypotensive effect of each substance and positive / negative control was carried out in a group of 3 animals (6 eyes) (Table 2). In the next experiment, animals were taken after a break of at least 7 days. Animals were kept in individual cages with free access to food and water. All animal studies were conducted in accordance with the statement of the Association for Research in Vision and Ophthalmology (ARVO) on the use of animals in ophthalmological research and the directive of the European Community Council (86/609 / ЕЕС). All procedures were approved by the local ethical committee of the Research Institute of Eye Diseases. Helmholtz.

* n = 6, P = 0.95, the interval is the standard deviation

From the above graph (Fig. 2) it can be seen that at the points of maximum IOP reduction, the values of biological activity for the studied derivatives (5-benzoylamino-3-hydroxy-2-oxingyl-3-yl) acetonitrile and (5-furoylamino-3-hydroxy- 2-oxindol-3-yl) acetonitrile) intersect taking into account the magnitude of the standard deviation with the values for the referential compounds (Melatonin and Timolol) and all the values of the IOP decrease significantly differ from those for the control groups ((-) Control and normal days. ). This suggests the possibility of using the group of proposed compounds of formula (I) as agents affecting (namely, reducing) the intraocular pressure, in particular as antiglaucoma preparations.

STUDY OF ANTIOXIDANT ACTIVITY OF COMPOUNDS OF THE FORMULA (I)

A significant advantage of the compounds of formula (I) over drugs for reducing IOP, including over Timolol, is their pronounced antioxidant activity. Oxidative stress is an important link in the pathogenesis of glaucoma, because it leads to the death of retinal neurons and the development of glaucomatous optic neuropathy [Nesterov A.P. Glaucoma, Moscow: Medicine, 1995.]. According to the testimony of both domestic and foreign researchers, the inclusion of antioxidants in the complex therapy of glaucoma significantly increases the effectiveness of treatment [Rational pharmacotherapy in ophthalmology, ed. E.A. Egorov, (2004) Medicine, M .; Moreno MC., Campanelli J, Sande P et al. Retinal oxidative stress induced by high intraocular pressure. Free Radic Biol Med 2004; 37: 803-812.]. The use of compounds of formula (I) will allow to achieve higher results in the treatment of glaucoma and at the same time reduce the number of drugs used by the patient.

Evaluation of antioxidant activity (AOA) of (5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile and (5-furoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile was carried out by changing the parameters of chemiluminescence in model system hemoglobin-H ₂ O ₂ -luminol [Gulidova O.V., Lyubitsky OB, Klebanov G.I., Chesnokova N.B. Changes in the antioxidant activity of the tear fluid in experimental burn eye disease. Bulletin of experimental biology and medicine. 1999; 128 (11): 571-574. doi.org/10.1007/bf02433426]. Kinetics were recorded using a Biotox-7 chemiluminometer (ANO "Engineering Center - Ecology", Russia).

The main parameters of the CL kinetics are: the magnitude of the latent period, the light sum, the maximum CL intensity. In the present work, as a parameter characterizing the AOA of the synthesized compounds, the period of complete protection of Lm from oxidation, which reflects the latent period of CL, was chosen.

The introduction of antioxidants (AO) into the model system leads to inhibition of the free radical oxidation of luminol. This is manifested in an increase in the latent period of CL. The directly proportional dependence of the change in the latent period of the CL (t / t ₀ ) on the concentration of the substance added to the system makes it easy to express the AOA of the analyte through the molar concentration of another (standard) antioxidant. The concentration of the standard, the addition of which to the model system leads to the same change in the latent period of CL, as with the addition of the analyte of a given concentration, is an equivalent value when presenting the results. As a standard antioxidant, a water-soluble vitamin E analogue - Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, Sigma-Aldrich, Germany) was used.

The obtained experimental data can be approximated by a straight line using the OLS method (Fig. 2).

For the calculation of the AOA of the test substances, the corresponding values of the change constant of the latent period of the test substances (K _t ) and the reference trolox AO (K _t ^T ) were found. AOA was expressed in terms of the final concentration of trolox (C _eq ^T ). The final result is presented in units of equivalent concentration of trolox, which is calculated taking into account the preliminary dilution (D) (equation 2, 3) [O. Lyubitsky - Determination of the antioxidant activity of biological fluids by the chemiluminescent method. Moscow: Cand. dis. RSMU .. 1999].

The greater the value of the coefficient K _t in the linear equation (3) for a particular substance, the greater the increase in the latent period is observed with an increase in the concentration of the added substance and, therefore, its antioxidant effect. For comparison, the AOA of the tested substances was used the tangent of the slope of the dependence of the AOA on the concentration of the analyte α (Fig. 2).

In the literature there are many works devoted to the successful use in the treatment of glaucoma melatonin - a powerful natural antioxidant [Korkmaz A., Reiter R.J., Topal T., Manchester L.C., Oter S., Tan D.X. Melatonin: an established antioxidant, Mol. 2009. Vol. 15. №1-2. P. 43-50 .; Rosenstein R.E., Pandi-Perumal, S.R., Srinivasan V., Spence, D.W., Brown, G.M., Cardinali D. Melatonin as a therapeutic tool in ophthalmology: implications for glaucoma and uveitis. J Pineal Res. 2010; 49 (1): 1-13.].

FIG. 2 shows that AOA (5-benzoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile (example 1) and (5-furoylamino-3-hydroxy-2-oxindol-3-yl) acetonitrile (example 2) many times the activity of melatonin.

Thus, the compounds of formula (I) immediately possess two properties that make them promising candidates for the creation of drugs for the treatment of glaucoma and other eye diseases accompanied by oxidative stress due to their ability to reduce IOP and their pronounced antioxidant activity.

Claims (60)

1. Amide-containing derivative of 2-oxindole of General formula (I), its stereoisomers and pharmaceutically acceptable salts:

Where: R ¹ means H, benzyl, C ₁ -C ₄ -alkyl, R ² means H, HE, OR ⁶ , R ³ means COOH, CN, R ⁴ means H, OC ₁ -C ₄ -alkyl, halogen, C ₁ -C ₄ -alkyl, SOOC ₁ -C ₄ -alkyl, NHC (X) R ⁷ , R ⁵ means C ₅ -C ₆ -aryl, C ₅ -C ₆ -heteroaryl, NHC ₁ -C ₄ -alkyl, NHC ₁ -C ₄ -halogen alkyl, NHC ₃ -C ₆ -cycloalkyl, NHC ₅ -C ₆ -aryl , NHC ₅ -C ₆ -heteroaryl, OC ₅ -C ₆ -aryl, where C ₅ -C ₆ -heteroaryl contains 1 or 2 heteroatoms selected from O, N, S, R ⁶ means C ₁ -C ₄ -alkyl, C (O) C ₁ -C ₄ -alkyl, R ⁷ means C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, OC ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₅ -C ₆ -aryl, C ₅ -C ₆ -heteroaryl , NHC ₁ -C ₄ -alkyl, NHC ₁ -C ₄ -halogen alkyl, NHC ₃ -C ₆ -cycloalkyl, NHC ₅ -C ₆ -aryl, NHC ₅ -C ₆ -heteroaryl, OC ₅ -C ₆ -aryl, where C ₅ -C ₆ heteroaryl contains 1 or 2 heteroatoms selected from O, N, S, X means O, S. 2. The method of obtaining amide-containing derivative of 2-oxindole of formula (I) according to claim 1, characterized in that (i) protect the carbonyl group in the 3rd position of the nitroisatin of formula (1):

where R ¹ means H, benzyl, C ₁ -C ₄ -alkyl; R ⁴ means H, OC ₁ -C ₄ -alkyl, halogen, C ₁ -C ₄ -alkyl, SOOC ₁ -C ₄ -alkyl, NHC (X) R ⁷ ; R ⁷ means C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, OC ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₅ -C ₆ -aryl, C ₅ -C ₆ -heteroaryl , NHC ₁ -C ₄ -alkyl, NHC ₁ -C ₄ -halogen alkyl, NHC ₃ -C ₆ -cycloalkyl, NHC ₅ -C ₆ -aryl, NHC ₅ -C ₆ -heteroaryl, OC ₅ -C ₆ -aryl, where C ₅ -C ₆ heteroaryl contains 1 or 2 heteroatoms selected from O, N, S; (ii) then catalytic reduction of the ketal of the formula (2) is carried out

obtained in stage (i), where R ¹ and R ⁴ have the above values, with subsequent modification of the intermediate amino-derivative with the formation of the amido-derived formula (3)

where R ¹ and R ⁴ have the above values; (iii) then remove the protective group in the amido-derived (3) to obtain amido-isatin of formula (4)

where R ¹ and R ⁴ have the above values, R ⁵ means C ₅ -C ₆ -aryl, C ₅ -C ₆ -heteroaryl, NHC ₁ -C ₄ -alkyl, NHC ₁ -C ₄ -haloalkyl, NHC ₃ -C ₆ -cycloalkyl, NHC ₅ -C ₆ -aryl, NHC ₅ -C ₆ -heteroaryl, OC ₅ -C ₆ -aryl, where C ₅ -C ₆ -heteroaryl contains 1 or 2 heteroatoms selected from O, N, S; (iv) amido-isatin (4) is condensed from step (iii) with CH-acid compounds of general formula CH ₂ (COOH) R ³ , where R ³ is COOH, CN, to give the compound of formula (5)

which essentially is a compound of formula (I), where R ² is OH, R ¹ , R ³ , R ⁴ and R ⁵ are as defined above; (v) if necessary, carry out the dehydration of the compound (5) obtained in stage (iv), followed by reduction of the double C = C bond with the formation of the compound of formula (6)

which is essentially a compound of formula (I), in which R ² is H, R ¹ , R ³ , R ⁴ and R ⁵ are as defined above; (vi) if necessary, carry out a modification of the hydroxyl group at position 3 of compound (5) obtained in step (iv) to form a compound of formula (6), which essentially is a compound of formula (I), in which R ² is OR ⁶ , R ⁶ means C ₁ -C ₄ -alkyl, C (O) C ₁ -C ₄ -alkyl, R ¹ , R ³ , R ⁴ and R ⁵ have the above values. 3. The method according to p. 2, characterized in that the protection of the carbonyl group in the 3rd position in stage (i) is carried out by boiling a mixture of compound (1), a diol selected from the group of ethylene glycol, 1,3-propane diol, 2.2 -dimethyl-1,3-propanediol and their homologues, and a catalytic amount of an organic acid selected from the group of p-toluenesulfonic acid, ortho- or meta-toluenesulfonic acid, methylsulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, in the medium of high boiling solvent, forming a nitrogen solvent, it is asylipropic, forms a nitrogen and hydrogen sulfide. termination of vyde water and isolating the resulting ketal of formula (3). 4. The method according to p. 3, characterized in that the high-boiling solvent is selected from the group including toluene, xylene. 5. The method according to claim 2, characterized in that the catalytic reduction of the ketal of formula (3) in step (ii) is carried out under the action of hydrogen in the presence of a catalyst for the reduction of the nitro group at room temperature. 6. The method according to p. 5, characterized in that the hydrogen pressure in stage (ii) is 3-10 atm. 7. The method according to p. 5, characterized in that the reduction is carried out in an anhydrous aprotic solvent. 8. The method according to p. 7, characterized in that the recovery is carried out in an environment of ethyl acetate, tetrahydrofuran, acetonitrile. 9. The method according to p. 5, characterized in that Pd / C is used as a catalyst for the reduction of the nitro group. 10. The method according to claim 2, characterized in that the modification of the intermediate amino derivative in step (ii) is carried out with an acylating agent with the general formula (R ⁵ C (O)) ₂ O, or R ⁵ C (O) Hal, or R ⁵ NCS, or R ⁵ NCO, where R ⁵ is as defined above. 11. The method according to p. 10, characterized in that the modification of the intermediate amino-derivative at stage (ii) is carried out in the presence of an organic base, the amount of which is 1.05-1.10 equivalents relative to the intermediate amino-derivative. 12. The method according to p. 10, characterized in that the modification of the intermediate amino-derivative at stage (ii) is carried out in anhydrous tetrahydrofuran at room temperature, preventing the reaction mixture from heating. 13. The method according to p. 2, characterized in that the removal of the protective group at stage (iii) is carried out by acid hydrolysis. 14. The method according to p. 13, characterized in that the acid hydrolysis is carried out in aqueous acetone under the action of concentrated hydrochloric acid. 15. The method according to p. 2, characterized in that the condensation of the compound (4) with the CH-acid compounds in step (iv) is carried out in pyridine in the presence of a catalytic amount of an organic base. 16. The method according to p. 15, characterized in that the CH-acidic compounds are compounds selected from the group of cyanoacetic acid, malonic acid. 17. The method according to claim 2, characterized in that the dehydration of the compound (5) at the stage (v) is carried out by boiling a solution of the product (5) in concentrated hydrochloric acid. 18. The method according to claim 2, characterized in that the reduction of the double C = C bond in step (v) is carried out catalytically under the action of hydrogen. 19. The method according to p. 17, characterized in that the hydrogen pressure is 1-5 atm. 20. The method according to p. 17, characterized in that Pd / C is used as a catalyst for the reduction of the double C = C bond in step (v). 21. The method according to p. 2, characterized in that the modification of the hydroxyl group in position 3 of compound (5) in step (vi) is carried out under the action of an acylating agent with the general formula (R ⁶ ) ₂ O, R ⁶ Cl or (R ⁶ ) ₂ SO ₄ . 22. The method according to p. 2, characterized in that the compounds of formula (1), where R ⁴ means NHC (X) R ⁷ , are obtained from the compounds of formula (3), where R ⁴ means H, by nitration in an acidic medium. 23. The method according to p. 22, characterized in that the nitration of the compounds of formula (3) is carried out in concentrated sulfuric acid at 0-5 ° C under the action of potassium nitrate or sodium nitrate. 24. The method according to p. 11 or 15, characterized in that the organic base is piperidine or triethylamine. 25. The use of the compound of formula (I) according to claim 1 as a drug for the treatment of ophthalmologic diseases associated with an increase in intraocular pressure (IOP) and / or oxidative stress. 26. The use according to claim 25, wherein the ophthalmologic disease is glaucoma. 27. The use according to claim 25, wherein the ophthalmologic disease is uveitis. 28. Pharmaceutical composition for the treatment of ophthalmologic diseases associated with an increase in intraocular pressure (IOP) and / or oxidative stress, comprising a therapeutically effective amount of the compound of formula (I) according to claim 1 and pharmaceutically acceptable additives. 29. The pharmaceutical composition of claim 28, wherein the ophthalmologic disease is glaucoma. 30. The pharmaceutical composition of claim 28, wherein the ophthalmic disease is uveitis. 31. A method of treating ophthalmic diseases associated with an increase in intraocular pressure (IOP) and / or oxidative stress, which consists in administering the pharmaceutical composition according to claim 28 in a therapeutically effective amount. 32. The method of treatment according to claim 31, characterized in that the frequency and duration of use is chosen depending on the nature and severity of the disease.

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