RU2675237C1 - COMPOUND (6-{[(1S)-1(5-FLUORO-4-OXO-3-PHENYL-3,4-DIHYDROQUINAZOLIN-2-YL)PROPYL]AMINO}-9H-PURIN-9-YL)METHYL ACETATE AS INHIBITOR OF P110δ- DELTA ISOFORM OF PHOSPHOINOSITIDE-3-KINASE (PI3K), METHODS FOR ITS PRODUCTION (OPTIONS) AND APPLICATIONS - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to (6-{[(1S)-1(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl]amino}-9H-purin-9-yl)methyl acetate (compound of formula I) with properties of inhibitor of p110δ – delta isoform of phosphoinositide-3-kinase (PI3K). In addition, invention relates to a method for producing a compound of formula I, an active ingredient, a pharmaceutical composition, and a drug based on it.EFFECT: invention may be applicable to the treatment of follicular lymphoma and other malignant lymphoproliferative diseases from a number of non-Hodgkin lymphomas.10 cl, 4 tbl, 10 ex

Description

The invention relates to new physiologically active substances, new inhibitors of rPOb - the delta isoform of phosphoinositide-3-kinase (PI3K), active components for pharmaceutical compositions, to pharmaceutical compositions and drugs containing (6 - {[(1S) -1 (5 -fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl] amino} -9H-purin-9-yl) methyl acetate as an inhibitor of p110δ - delta isoform of phosphoinositide-3-kinase (PI3K ), which can be used in the treatment of follicular lymphoma and other malignant lymphoproliferative diseases from a number of non-Hodgkin lymphomas.

Non-Hodgkin type lymphomas are caused by cancerous tumors of the B- and T-cell type. The source of such a pathology is able to originate in any lymph node or other organ, and then "infect" the lymph. Subsequently, metastasis occurs in three ways: hematogenous, lymphogenous, hematogenous-lymphogenous. The name "Follicular lymphoma" arose because in most cases a malignant neoplasm began to form and develop in the covering cells of the epidermis, pathologically changing the hair follicles, otherwise called follicles. Risk group - age category up to forty years.

According to the type of localization, follicular lymphomas are divided into nodal - lymphatic sarcomas localized in the lymph nodes, and extranodal - in the case of another localization site (salivary glands, tonsils, thyroid gland, epidermis, brain, lungs, etc.). The follicular (nodular) or diffuse them makes the structural component of the neoplasm.

Today, follicular lymphoma is the most common form of indolent (sluggish) lymphomas. Each year, more than 75 thousand people suffering from this malignant disease are registered in the world. In Russia, 3,500 patients experience a diagnosis of follicular lymphoma every year.

A tumor in follicular lymphoma consists of mature B-lymphocytes, which are formed in the follicular center of the lymph node, in which the growth and development of lymphocytes, the main cells of the human immune defense, takes place.

One of the universal signaling pathways characteristic of most human cells, responsible for avoiding apoptosis, growth, cell proliferation, metabolism, is a group of enzymes that are components of the intracellular signaling pathway PI3K / AKT / mTOR. Activation of this pathway is observed in the vast majority of tumors human, development of tumor cell resistance is often associated with it, therefore PI3K is a promising target for antitumor therapy ..

There are 4 isoforms of PI3K: α, β, γ, and δ. Isoforms of α and β are common in many tissues of the body, while δ and γ are more specifically expressed in white blood cells. Thus, the inhibition of these isoforms is a promising specific method for the treatment of various types of hemoblastoses, including follicular lymphoma.

In recent years, high efficacy of tyrosine kinase inhibitors Btk (ibrutinib and others) and PI3K δ (idelalisib and others) has been shown. Idealalisib, which served as the prototype of the present invention, was developed as a second-line drug, usually for use in combination with rituximab, but was also planned for independent use also in patients in whom rituximab therapy is contraindicated or ineffective due to concomitant diseases or intolerance to rituximab, as well as for use in the treatment of patients with recurrence of the follicular form. Unfortunately, Idealalisib is currently withdrawn from the market due to its high toxicity. Therefore, the superiority of the safety of the compounds of formula I over the prototype is its undeniable advantage.

It was unexpectedly found that (6 - {[(1S) -1 (5-fluoro-4-oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl) propyl] amino} -9H-purin-9 -yl) methyl acetate - a compound of formula I

It is an effective inhibitor of p110δ - the delta isoform of phosphoinositide-3-kinase (RBC) and can be used to develop drugs for the treatment of follicular lymphoma and other non-Hodgkin lymphomas.

The following are definitions of terms that are used in the description of this invention.

“Agonists” means compounds that, by binding to receptors of a particular type, actively contribute to the transmission by these receptors of their specific signal and thereby elicit a biological response from the cell.

"Active component" (drug substance, drug substance, drug-substance) means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, having pharmacological activity and is the active principle of the pharmaceutical composition used for the manufacture and manufacture medicinal product (means).

"Active substance" (drug substance, drug substance, drug-substance) means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, having pharmacological activity and is the active principle of the pharmaceutical composition used for the manufacture and manufacture medicinal product.

“Inhibitors” (lat. Inhibere - to delay) - the general name of substances that suppress or delay the course of physiological and physico-chemical (mainly enzymatic) processes, the study of enzyme inhibition plays an important role in creating drugs, in studying the mechanism of action and structure of enzymes,

“Combined medicinal product (preparation)” - a combination of several medicinal substances for simultaneous use in the form of tablets, capsules, injections, ointments, rectal suspensions and gels and other finished forms, designed to restore, correct or change physiological functions in humans and animals, as well as for the treatment and prevention of diseases, diagnosis, anesthesia, contraception, cosmetology and other things. Medicinal substances in one set can be presented in the form of various ready-made forms intended for administration into an animal or human body in various ways, for example, orally and rectally.

"Receptors" (from the Latin recipere - to receive, to recognize) are biological macromolecules located on the cytoplasmic membrane of a cell or intracellular, capable of specifically interacting with a limited set of physiologically active substances (ligands) and transforming the signal about this interaction into a specific cellular response.

"PI3K" is a family of enzymes phosphorylating phosphatidylinositol in the position of the 3D inositol ring. They are a key element of the PI3K signaling pathway. The phosphoinositide-3-kinase pathway is one of the universal signaling pathways characteristic of most human cells. It controls such processes as: apoptosis, cell growth and proliferation, metabolism. Hyperactivation of the phosphoinositide-3-kinase pathway in most cases leads to the development of oncological pathologies. In this regard, phosphoinositide-3-kinases are of increased interest as objects of anticancer therapy.

“Signal cascade” (signal system, signal transmission cascade) means a set of interconnected sequential and parallel molecular processes of regulation of cellular metabolism by external (primary) signals that carry information into the cell, which fundamentally distinguishes them from other chemical compounds entering the cell that serve as its source matter and energy. The molecular mechanisms of transmission (transduction) of external signals into the cell imply not only the transmission of signals as such, but also the whole complex of events associated with it, including amplification, attenuation and suppression (or switching off) of signals.

"Pharmaceutical composition" means a composition comprising a compound of general formula 1 and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceiving agents, delivery vehicles, such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterials tal agents, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be provided with a variety of antibacterial and antifungal agents, for example, parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of grinders and distributors are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms. Pharmaceutical compositions are generally prepared using standard procedures involving the mixing of the active compound with a liquid or finely divided solid carrier. For the manufacture of suppositories, in addition to the active components, cocoa butter, its alloys with paraffin and hydrogenated fats, vegetable and animal hydrogenated fats, solid fat, lanol, alloys of hydrogenated fats with wax, hard paraffin and other bases approved for medical use are also used.

“Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds or prepared specially. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like. (A detailed description of the properties of such salts is given in Berge S. M., et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like. In addition, tetraalkylammonium hydroxides, for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. As amino acids, the main amino acids can be used - lysine, ornithine and arginine.

"Pharmaceutically acceptable excipients" by pharmaceutically acceptable excipients refers to pharmaceutical diluents, excipients and / or carriers.

The purpose of the present invention is to provide new inhibitors of p110δ - the delta isoform of phosphoinositide-3-kinase as potential drugs for the treatment of follicular lymphoma.

The goal is achieved (6 - {[(1S) -1 (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquin-azolin-2-yl) propyl] amino} -9H-purin-9-yl ) methyl acetate of the formula I

The subject of the present invention is a new inhibitor of p110δ - delta isoform of phosphoinositide-3-kinase, which is a compound of formula I.

The subject of this invention is a method for producing (6 - {[(1S) -1 (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquin-azolin-2-yl) propyl] amino} -9H-purine - 9-yl) methyl acetate of formula I starting from 2-fluoro-6-nitrobenzoic acid (2), (2S) -2 - [(tert-butoxycarbonyl) amino] butanoic acid (4) and 6-chloro-9H-purine (8 ) (diagram 1).

Scheme 1

The scheme involves the production of secondary fluoronitrobenzoic acid anilide, which under activation conditions is secondary amidated with (2S) -2 - [(tert-butoxycarbonyl) amino] butanoic acid (4). The resulting intermediate cyclizes with the formation of a key intermediate, an amine substituted quinazolinone ring (7). 6-chloro-9H-purine (8) is modified by imidazole nitrogen by the sequential action of acetyl chloride and formaldehyde with the formation of chloride (9), the second key intermediate. The dropping of intermediates 7 and 9 leads to the formation of (6 - {[(1S) -1 (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquin-azolin-2-yl) propyl] amino} -9H- purin-9-yl) methyl acetate of formula I.

A preferred embodiment of the production method comprises the following steps:

a) a solution of oxalyl chloride in dichloromethane is added to a solution of 2-fluoro-6-nitrobenzoic acid in a mixture of dichloromethane and dimethylformamide. Then the reaction mass is redissolved in dioxane and a suspension of aniline and K ₂ CO _{3 is} added with cooling to form a precipitate of 2-fluoro-6-nitro-N-phenylbenzamide;

b) a solution of 2-fluoro-6-nitro-N-phenylbenzamide obtained in the previous step in dimethylformamide is treated with thionyl chloride under heating, and then (2S) -2 - [(tert-butoxycarbonyl) amino] butanoic acid in dichloromethane at 10 ° C. The reaction mixture is filtered off and the mother liquor is chromatographed to form (S) - [1- (2-fluoro-6-nitrobenzoyl) phenyl aminocarbonyl] propyl carbamic acid tert-butyl ester

c) the (S) - [1- (2-fluoro-6-nitrobenzoyl) phenyl-aminocarbonyl] propylcarbamic acid tert-butyl ester from the previous step is dissolved in acetic acid in the presence of zinc powder. The reaction mass is filtered off, concentrated, the product - (S) - [1- (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) -propyl] -carbamic acid product - is extracted and purified chromatographic.

d) tert-butyl ether (S) - [1- (5-fluoro-4-oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl) -propyl] -carbamic acid from the previous step is dissolved in dichloromethane and cyclized under the influence of trifluoroacetic acid. The reaction mass is neutralized and concentrated to form (S) -2- (1-aminopropyl) -5-fluoro-3-phenyl-3H-quinazolin-4-one.

d) A mixture of 6-chloro-9H-purine paraform, acetic acid and acetic anhydride is heated in toluene, then filtered and concentrated to give crystalline 6-chloro-9H-purin-9-yl) methyl acetate.

e) (S) -2- (1-Aminopropyl) -5-fluoro-3-phenyl-3H-quinazolin-4-one and (6-Chloro-9H-purin-9-yl) methyl acetate are dissolved in tertbutanol in the presence of diisopropylethylamine (DIPEA) when heated. The reaction mixture was concentrated and the product was isolated - (6 - {[(1S) -1 (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquin-azolin-2-yl) propyl] amino} -9H-purine -9-yl) methyl acetate chromatography.

Scheme 2

a) 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4 (3H) -one is added to a solution of acetyl chloride in acetonitrile to form a precipitate of 2- { (1S) -1 - [(9-acetyl-9H-purin-6-yl) amino] propyl} -5-fluoro-3-phenylquinazolin-4 (3H) -one;

b) to the toluene solution of 2 - {(1S) -1 - [(9-acetyl-9H-purin-6-yl) amino] propyl} -5-fluoro-3-phenylquinazolin-4 (3H) -one obtained on stage a) add paraform. At the end of the interaction, the product - (6 - {[(1S) -1 (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquin-azolin-2-yl) propyl] amino} -9H-purin-9 -yl) methyl acetate of the formula I - is isolated by successive concentration, chromatography and a number of recrystallizations from suitable solvents.

Specific modes / conditions for the implementation of the method of obtaining can be selected by a specialist experimentally.

The subject of the present invention is an active component having the property of a p110δ inhibitor, the delta isoform of phosphoinositide 3-kinase (PI3K), which is a compound (6 - {[(1S) -1 (5-fluoro-4-oxo-3-phenyl-3 , 4-dihydroquin-azolin-2-yl) propyl] amino} -9H-purin-9-yl) methyl acetate of formula I.

The subject of this invention is a pharmaceutical composition intended for the treatment of follicular lymphoma and other malignant lymphoproliferative diseases from a number of non-Hodgkin's lymphomas, containing in an effective amount an active component having the property of a p110δ inhibitor, the delta isoform of phosphoinositide-3-kinase (PI3K). The pharmaceutical composition may be in the form of tablets, capsules, and injections in a pharmaceutically acceptable package.

The pharmaceutical composition may include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients are meant diluents, excipients and / or carriers used in the pharmaceutical field. The pharmaceutical composition along with the active component of the present invention may include other active ingredients, provided that they do not cause undesirable effects, for example, allergic reactions.

If it is necessary to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed for the manufacture of various forms, while they can include traditional pharmaceutical carriers; for example, oral forms (such as tablets, gelatine capsules, pills, solutions or suspensions); injection forms (such as injectable solutions or suspensions, or dry powder for injection, which only requires the addition of water for injection before use); local forms (such as ointments or solutions).

The carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to obtain common forms, including: in oral forms, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, colorless are used agents, flavoring agents of taste; antiseptic agents, solubilizers, stabilizers are used in injection forms; in local forms, bases, diluents, lubricants, antiseptic agents are used.

Preferably, the pharmaceutical composition contains, in an effective amount, a compound of formula I, in an amount of 25 mg, and pharmaceutically acceptable additives: microcrystalline cellulose in an amount of 35.0 mg, lactose monohydrate 26.0 mg, hydroxypropyl cellulose in an amount of 5 mg, sodium carboxymethyl starch in an amount of 4 mg , croscarmellose sodium in an amount of 4 mg, magnesium stearate in an amount of 1 mg, and Opadray II white (polyvinyl alcohol - 60%, titanium dioxide - 25%, polyethylene glycol-10%, talc - 5%) in an amount of 3 mg.

A new pharmaceutical composition can be obtained by mixing with an inert excipient and / or solvent of the active component, which is a compound of formula I.

The subject of this invention is a medicament containing the compound (6 - {[(1S) -1 (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl] amino} -9H-purine -9-yl) methyl acetate of the formula I as an active component.

Medicines may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, topically or rectally). The clinical dosage of the active component (s), pharmaceutical composition or combination drug comprising a pharmaceutically effective amount of the active component in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion from the body, as well as on the age, sex and stage of the patient’s disease, with a daily dose in adults usually being 1-300 mg, preferably 50-100 mg. Therefore, during the preparation of the pharmaceutical compositions of the present invention in the form of dosage units, the above effective dosage must be taken into account, with each dosage unit of the preparation containing 1-300 mg, preferably 5-100 mg. In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times).

The subject of this invention is a method for treating follicular lymphoma and other malignant lymphoproliferative diseases from a number of non-Hodgkin's lymphomas by administering in an effective amount of a new active ingredient or a new pharmaceutical composition or new drug.

The subject of this invention is the use of a compound of formula I for the manufacture of a medicament for the treatment of follicular lymphoma and other malignant lymphoproliferative diseases from a number of non-Hodgkin lymphomas.

The subject of this invention is a method of inhibiting p110δ-delta isoform of phosphoinositide-3-kinase (PI3K) by administering in an effective amount of a compound of formula I to a recipient in need thereof

The claimed invention also relates to a compound of formula I for use in a method for the treatment of follicular lymphoma and other malignant lymphoproliferative diseases from a number of non-Hodgkin lymphomas.

The following examples illustrate but do not limit the invention.

The structures of the compounds obtained were confirmed by chemical, chromatographic and spectral analysis.

Example 1. Obtaining 2-fluoro-6-nitro-N-phenylbenzamide (3)

To a solution of 2-fluoro-6-nitrobenzoic acid (10 g, 54 mmol) (2) in a mixture of dichloromethane (60 ml) and dimethylformamide (0.5 ml), a solution of oxalyl chloride in dichloromethane (2M, 41 ml) is added using a dropping funnel , 80 mmol, 1.5 equiv.). The reaction mass is stirred for 2 hours at room temperature, after which the solvents are distilled off on a rotary evaporator. The residue was dissolved in dioxane (8 ml), cooled to 6 ° C and aniline (4.9 ml, 54 mmol, 1 equiv) and K ₂ CO ₃ (9 g) suspended in an aqueous solution of dioxane (25 ml: 25 ml) were slowly added. , 108 mmol, 2 equiv.). The temperature of the reaction mass in this case rises to 27 ° C. The reaction mass is stirred for 30 minutes, after which 120 ml of water are added. The precipitate formed is filtered off, washed with water, hexane, dried, and 2-fluoro-6-nitro-N-phenylbenzamide is obtained in 93% yield (13 g).

¹ H NMR spectrum (400.13 MHz, DMSO-d6, δ, ppm, J / Hz): 10.82 (s 1H), 8.12 (d, J = 7.7 Hz, 1H), 7.91-7.77 (m, 2H) 7.64 (d, J = 7.7 Hz, 2H); 7.38 (t, J = 7.9 Hz, 2H); 7.15 (t, J = 7.4 Hz, 1H);

LCMS: one peak with a retention time of 4.36 min. (M + H ⁺ = 261) with a substance content of 99.3 ... 99.9% for UV detectors and 96.2% for ELSD.

Example 2 Preparation of (S) - [T- (2-fluoro-6-nitrobenzoyl) phenyl-aminocarbonyl] propylcarbamic acid tert-butyl ester (5)

To 2-Fluoro-6-nitro-M-phenylbenzamide (3) (50 mmol) was added dimethylformamide (0.5 ml), thionyl chloride (25.6 ml, 250 mmol, 5 equiv) and the reaction mixture was stirred for 5 hours at 85 ° C, after which the excess thionyl chloride is distilled off on a rotary evaporator. To the residue dissolved in dichloromethane (20 ml), a solution of (2S) -2 - [(tert-butoxycarbonyl) amino] butanoic acid (4) (11.2 g, 55 mmol, 1.1 eq) and triethylamine (slowly 7.7 ml, 0.55 mol, 1.1 eq.) In dichloromethane (60 ml) at 10 ° C. The reaction mass is stirred at room temperature for 3 hours, the insoluble precipitate is filtered off, the mother liquor is washed with water, sodium bicarbonate solution, 5% citric acid solution and sodium chloride solution. The organic layer was dried using magnesium sulfate and the solvent was distilled off on a rotary evaporator. The product was isolated by column chromatography using a solution of hexane: ethyl acetate (10% -25%) as an eluent. The product yield is 66% (14.7 g).

¹ H NMR spectrum (400.13 MHz, DMSO-d6, δ, ppm, J / Hz): 8.13 (d, J = 8.0 Hz, 1H), 7.84 (t, J = 8.6 Hz, 1H), 7.78- 7.67 (m, 1H), 7.65-7.49 (m, 3H), 7.40-7.28 (m, 2H), 7.19 (d, J = 7.5 Hz, 1H), 4.05 (bs 1H), 1.75-1.30 (m, 2H) ), 1.34 (s 9H), 0.93 (br 3H).

LCMS: one peak with a retention time of 6.96 min. (M + H ⁺ = 446.3) with a substance content of 99.3 ... 99.9% for UV detectors and 96.2% for ELSD.

Example 3. Preparation of (S) - [1- (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) -propyl] -carbamic acid tert-butyl ester (6)

To a solution of (S) - [1- (2-fluoro-6-nitrobenzoyl) phenyl-aminocarbonyl] -propylcarbamic acid (5) (12.5 mmol, 1 equiv) solution in acetic acid (50 ml), zinc powder is added (4.8 g, 74 mmol, 6 equiv). The reaction mass is stirred for 2 hours at room temperature, the precipitate is filtered off and washed with acetic acid. The mother liquor was evaporated on a rotary evaporator, the residue was dissolved in ethyl acetate (400 ml), the solution was washed with water and the aqueous layer was extracted with ethyl acetate. The organic layers are combined, washed with water, sodium bicarbonate solution, sodium chloride solution and dried using magnesium sulfate. The solvent was distilled off on a rotary evaporator, and the product was isolated from the residue by column chromatography using a solution of hexane: ethyl acetate (10% -25%) as an eluent. The product yield is 69% (3.3 g).

¹ H NMR spectrum (400.13 MHz, CDCl ₃ , δ, ppm, J / Hz): 7.66-7.75 (m, 1H), 7.50-7.64 (m, 4H), 7.38 (m, 1H), 7.29 ( m, 1H), 7.13 (t, J = 9 Hz, 1H), 5.46 (m, 1H), 4.42 (m, 1H), 1.68-1.8 (m, 1H), 1.52-1.62 (m, 1H), 1.41 (s 9H), 0.77 (t, J = 7.3 Hz, 3H).

LCMS one peak with a retention time of 13.00 min. (M + H ⁺ = 398.3) with a substance content of 96.4 ... 99.3% for UV detectors and 83.9% for ELSD.

Example 4. Obtaining (S) -2- (1-aminopropyl) -5-fluoro-3-phenyl-3H-quinazolin-4-one (7)

To a solution of (S) - [1- (5-fluoro-4-oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl) -propyl] -carbamic acid solution (6) (8.5 mmol) ) trichloroacetic acid (6 ml) is added in dichloromethane (6 ml). The reaction mass is stirred for 1 hour at room temperature, after which it is diluted with dichloromethane (15 ml), and the organic layer is washed with a 10% aqueous potassium bicarbonate solution. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with water, sodium chloride solution and dried using magnesium sulfate. The solvent was distilled off on a rotary evaporator to give the product in 88% yield (2.2 g).

¹ H NMR spectrum (400.13 MHz, CDCl ₃ , δ, ppm, J / Hz): 7.73-7.65 (m, 1H), 7.62-7.49 (m, 4H), 7.32-7.22 (m, 2H), 7.13-7.06 (m, 1H), 3.42 (dd, J = 7.5, 5.2 Hz, 1H), 1.87-1.70 (m, 1H), 1.58-1.43 (m, 1H), 0.80 (t, J = 7.4 Hz, 3H).

LCMS one peak with a retention time of 7.00 min. (M + H ⁺ = 298.2) with a substance content of 96.4 ... 99.3% for UV detectors and 83.9% for ELSD.

Example 5. Obtaining (6-Chloro-9H-purin-9-yl) methyl acetate (9)

A mixture of 6-chloro-9H-purine 8 (300 mg, 2 mmol), paraform (120 mg, 4 mmol, 2 equiv), acetic acid (0.12 g, 2 mmol, 1 equiv) and acetic anhydride (400 mg, 4 mmol, 2 eq.) Are dissolved in toluene (10 ml). The reaction mass is stirred at 80 ° C for 5 hours, after which it is cooled to room temperature. The precipitate formed is filtered off, the mother liquor is evaporated on a rotary evaporator, obtaining light yellow crystals of the product with a yield of 34% (150 mg).

¹ H NMR spectrum (400.13 MHz, CDCl ₃ , δ, ppm, J / Hz): 2.13 (s 3H), 6.21 (s 2H), 8.4 (s 1H), 8.84 (s 1H).

Example 6. Preparation of (6 - {[(1S) -1- (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl] amino} -9H-purin-9-yl ) methyl acetate (1).

(S) -2- (1-Aminopropyl) -5-fluoro-3-phenyl-3H-quinazolin-4-one 7 (300 mg, 1 mmol) was dissolved in tert-butanol (4 ml), (6-Chloro-9H was added Purin-9-yl) methyl acetate 9 (1.1 mmol, 1.1 equiv), and also diisopropylethylamine (DIPEA) (260 mg, 2 mmol, 2 equiv). The reaction mass is heated to 80 ° C and stirred at this temperature for 24 hours, then cooled, and the solvent is distilled off on a rotary evaporator. The technical product is dissolved in 5 ml of methylene chloride and applied to 40 g of silica gel, diluted and compacted with 90 ml of methylene chloride. Wash off with a mixture of methylene chloride - tetrahydrofuran (10: 1) in an amount of 0.3 l. The first fraction of 100 ml was discarded. A 200 ml fraction containing the product is then collected. The fractions containing the product are evaporated on a rotary evaporator and get a colorless oil. 5 ml of ethyl alcohol was added to the product and stirred for one hour at room temperature. The precipitated product is filtered off. The product is dried in a vacuum oven at 45 ° C and a residual pressure of 10 ± 5 mm Hg. within 4 hours. Product yield (6 - {[(1S) -1 (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl] amino} -9H-purin-9-yl) methyl acetate 8 was 13% (12 mg).

¹ H NMR spectrum (400.13 MHz, CDCl ₃ , δ, ppm, J / Hz): 0.84 (t, 3H), 1.75-1.82 (m, 1H), 1.9-1.398 (m, 1H), 2.08 ( s 3H), 5.18 (br, 1H), 6.09 (br, 2H), 6.74 (br, 1H), 7.1 (t, 1H), 7.34 (d, 1H), 7.44-7.61 (m, 5H), 7.65 ( m, 1H), 8.04 (bs 1H), 8.33 (s 1H).

LCMS one peak with a retention time of 5.50 min. (M + H ⁺ = 487.9) with a substance content of 96.4 ... 99.3% for UV detectors and 99.9% for ELSD.

Example 7. Obtaining 2 - {(1S) -1 - [(9-acetyl-9H-purin-6-yl) amino] propyl} -5-fluoro-3-phenylquinazolin-4 (3H) -one (11)

A mixture of 45 ml of toluene, 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] -quinazolin-4 (3H) -one 10 (1, 5 g, 3 , 6 mmol), acetic anhydride (0.55 g, 5.4 mmol, 1.5 eq) and anhydrous sodium acetate (0.59 g, 7.2 mmol, 2 eq) are refluxed for 2 hours. The reaction mixture was cooled to room temperature and washed twice with water (in 10 ml portions). The solvent is distilled off on a rotary evaporator and the precipitate formed is filtered off, washed with ether and dried in air to constant weight. The yield of 2 - {(1S) -1 - [(9-acetyl-9H-purin-6-yl) amino] propyl} -5-fluoro-3-phenylquinazolin-4 (3H) -one 11 was 92% (1 5 g).

¹ H NMR spectrum (400.13 MHz, DMSO-d6, δ, ppm, m / Hz): 0.75 (t, 3H), 1.92 (m, 2H), 2.86 (s 3H), 4.68 (m, 1H) 7.28 (t, 1H), 7.42-7.45 (m, 3H), 7.5-7.6 (m, 3H), 8.24-8.30 (m, 1H), 8.31 (s 1H), 8.66 (s 1H).

Example 8. Obtaining (6 - {[(1S) -1- (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl] amino} -9H-purin-9-yl ) methyl acetate (1).

2 - {(1S) -1 - [(9-acetyl-9H-purin-6-yl) amino] propyl} -5-fluoro-3-phenylquinazolin-4 (3H) -one 11 (1.4 g, 3 mmol), acetic acid (0.18 g, 3 mmol, 1 equiv), paraform (0.18 g, 6 mmol, 2 equiv) and anhydrous sodium acetate (0.25 g, mmol, 1 equiv) are dissolved in 30 ml toluene. The reaction mass is stirred at 80 ° C for 5 hours, then cooled, and the solvent is distilled off on a rotary evaporator. The technical product is dissolved in 5 ml of methylene chloride and applied to 40 g of silica gel, diluted and compacted with 90 ml of methylene chloride. Wash off with a mixture of methylene chloride - tetrahydrofuran (10: 1) in an amount of 0.3 l. The first fraction of 100 ml was discarded. A 200 ml fraction containing the product is then collected. The fractions containing the product are evaporated on a rotary evaporator and get a colorless oil. 5 ml of ethyl alcohol was added to the product and stirred for one hour at room temperature. The precipitated product is filtered off. The product is dried in a vacuum oven at 45 ° C and a residual pressure of 10 ± 5 mm Hg. within 4 hours. Product yield (6 - {[(1S) -1 (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl] amino} -9H-purin-9-yl) methyl acetate 8 is 73% (1.1 g).

¹ H NMR spectrum (400.13 MHz, CDCl ₃ , δ, ppm, J / Hz): 0.84 (t, 3H), 1.75-1.82 (m, 1H), 1.9-1.398 (m, 1H), 2.08 ( s 3H), 5.18 (br, 1H), 6.09 (br, 2H), 6.74 (br, 1H), 7.1 (t, 1H), 7.34 (d, 1H), 7.44-7.61 (m, 5H), 7.65 ( m, 1H), 8.04 (bs 1H), 8.33 (s 1H).

LCMS one peak with a retention time of 5.50 min. (M + H ⁺ = 487.9) with a substance content of 96.4 ... 99.3% for UV detectors and 99.9% for ELSD.

Example 9. The study of activity in vivo.

The antitumor activity of the compound of formula 1 was studied in vivo in a model of human B-cell lymphoma. Idealalisib was used as a comparison drug. To form a lymphoma model, SCID cells were implanted subcutaneously with Ramos B cell lymphoma cells to immunodeficient SCID mice. After the formation of tumors, the animals were randomized into groups (9 mice per group) and treatment was started. The compound of formula 1 was administered intragastrically at doses of 10, 25, 50 and 100 mg / kg, Idealisib at a dose of 50 mg / kg, a solvent was administered to the control group of animals, and the volume of administration was 10 mg / kg. Observation of the animals continued for 28 days after cell injection. During the study, we monitored the behavior and condition of animals, weight and mortality of animals.

The compound of formula 1 was shown to dose-dependently inhibit tumor growth. The maximum effect was achieved at a dose of 100 mg / kg. Moreover, the antitumor effect of the compound of formula 1 at a dose of 50 mg / kg was comparable to the effect of Idealisib in an equivalent dose.

Example 10. The study of subchronic toxicity in vivo

The aim of the study was to assess the chronic toxicity of the compound of formula I when administered daily intragastrically at a dose similar to that of Idealalisib (TD), 5 and 10-fold TD in rats of both sexes - namely, in doses of 25 mg / kg, 50 mg / kg and 100 mg / kg for 3 months, followed by a follow-up period of 1 month after the end of administration.

The main objective of the preclinical study of chronic toxicity was to establish the severity of the toxic effect and tolerance of the drug in its chronic administration to rats compared with Idealisib.

A Pharmacology review of Idelalisib (Mau 1, 2014) reports that in a 28-day rat toxicity study, intragastric administration of Idealisib at doses of 100 and 150 mg / kg / day resulted in animal deaths (3 deaths at a dose of 100 and 5 deaths at a dose 150 mg / kg). Target organs of toxicity were recorded bone marrow, heart, liver and testes.

In a 3-month rat toxicity study, the use of IDALALISIB at a dose of 90 mg / kg led to an increase in heart weight. The target organs of toxicity were the heart, pancreas, tongue and testes

Intragastric administration of a compound of formula I at a dose of 100 mg / kg for three months did not cause toxic effects and death of animals, which indicates less toxicity of a compound of formula I compared to Idealisib with the same route of administration in the same doses.

Detailed toxicity test results for a compound of formula I

The following are the results of macroscopic and microscopic studies of the internal organs of rats obtained in the experiment.

Mass of organs

The results are presented in tables 2-5.

A pathomorphological study revealed no differences in the relative mass of the organs of male and female rats treated with FS of the drug ZC065-0001 in TD, 2TD, and 4TD for 3 months, compared with the parallel control. No differences were noted at the end of the recovery period.

Histological examination

Rats, whose organs were presented for the study, were divided into two experimental series (A and B), eight groups each. Series A consisted of males and females who received compound I for 3 months. Series "B" - consisted of males and females, who for 1 month were in the recovery period after a three-month use of compound I.

SERIES "A"

- Group 1A - control, males receiving the solvent;

- Group 2A - males treated with compound I at a dose of 25 mg / kg;

- Group 3A - males treated with compound I at a dose of 50 mg / kg;

- Group 4A - males receiving compound I at a dose of 100 mg / kg;

- Group 5A - control, females treated with solvent;

- Group 6A - females receiving compound I at a dose of 25 mg / kg;

- Group 7A - females treated with compound I at a dose of 25 mg / kg;

- Group 8A - females receiving compound I at a dose of 100 mg / kg;

SERIES "B"

- Group 1B - control males that received the solvent and went through the recovery period;

- Group 2B - males treated with compound I at a dose of 25 mg / kg and undergoing a recovery period;

- Group 3B - males receiving compound I at a dose of 50 mg / kg and undergoing a recovery period;

- Group 4B - males receiving compound I at a dose of 100 mg / kg and undergoing a recovery period;

- Group 5B - control of the female who received the solvent and went through the recovery period;

- Group 6B - females receiving compound I at a dose of 25 mg / kg and undergoing a recovery period;

- Group 7B - females receiving compound I at a dose of 50 mg / kg and undergoing a recovery period;

- Group 8B - females receiving compound I at a dose of 100 mg / kg and undergoing a recovery period.

The following organs were taken for the study: liver, kidneys, heart, lungs, spleen, thymus, adrenal glands, testes, ovaries, brain, thyroid gland, stomach, small and large intestine, pancreas.

The results of the study. Histological examination of the thymus, spleen, heart, adrenal glands, liver, kidneys, thyroid gland, testes, ovaries, lungs, brain, stomach, small and large intestines, pancreas of animals of the control groups, as during the period of administration of the solvent (groups 1A and 5A) , and during the recovery period (groups 1B and 5B), showed the absence of structural features indicating the presence of pathology.

At the injection site - the stomach, small intestine, large intestine, pancreas - there are no signs of irritating effect, pathological changes in control animals.

When studying the structure of the organs of experimental animals treated with compound I, the following results were obtained:

Liver - when applying all the studied doses of the drug, pronounced pathological disorders in the organ were not detected. Hepatic trabeculae in animals are well defined. The degree of development of interlobular connective tissue in experimental animals did not differ compared with the control.

Kidneys - the use of the drug in all doses studied did not cause significant structural impairment of the kidneys in the experimental groups. The renal corpuscles are not damaged. The blood filling of the glomerular capillaries, peritubular network and veins did not differ from the control. The epithelium of the distal and proximal tubules in the cortical substance was not damaged.

Myocardium - the structure of the myocardium is typical, did not significantly differ from the myocardium of control animals. No dystrophic changes in the nuclei and cardiomyocytes, as well as damage to myofibrils, were found.

Lungs - in rats of experimental groups, the structure of the lungs corresponded to the norm. Pathological changes in the structure of the organ were absent.

Spleen - follicular structure was preserved in experimental animals. The degree of blood supply to the red pulp in the experimental animals did not differ from the blood supply in the animals of the control group. At the end of the recovery period, pathological changes in the structure of the organ were absent.

Thymus (thymus gland) - the thymus in animals of the experimental groups when using the drug did not have structural disturbances. Lobes of the thymus of a typical form, varied in size. The border between the cortical and medulla is distinct. At the end of the recovery period, pathological changes in the structure of the organ were absent.

Adrenal glands - the severity of the glomerular, reticular and bundle zones of the cortex in the experimental groups did not differ from the animals of the control groups. Changes in the structure of endocrinocytes of the cortical and medulla were not detected. Blood vessels were identical to animals in the control group. At the end of the recovery period, pathological changes in the structure of the organ were absent.

Testes - in all experimental groups, the spermatogenic cells of the basal and adluminal parts of the convoluted seminiferous tubules had no damage. Leydig cells unchanged. Differences in structure from the control group of animals were not identified. After the recovery period, pathological changes in the structure of the organ were not detected.

Ovaries - in all experimental groups when applying the studied doses of the drug, no differences were found from the control group of animals in the structure of the organ: the cortical substance is of a normal structure, mainly represented by follicles at various stages of development. The brain substance was preserved, in a small amount, contained rather large convoluted blood vessels, a stroma of the usual microscopic structure. After the recovery period, pathological changes in the structure of the organ were not detected.

Brain - when using the drug in all studied doses, the structure of the brain was preserved. White and gray matter are within normal limits. No signs of dystrophy of neurons, areas of gliosis, signs of neuronophagy, inflammatory infiltration, focuses of destruction, pathological hyperemia were found. After the recovery period, pathological changes in the structure of the organ are minimal or completely absent.

The thyroid gland - in animals of all experimental groups, the structure of the organ is typical. Follicles of various sizes. A homogeneous colloid in all observed follicles. Thyrocytes of a cubic form. There were no differences with the control group. At the end of the recovery period, pathological changes in the structure of the organ were absent.

Stomach - in all experimental groups, the structure of the wall of the stomach is preserved. In the structure of their own glands, in experimental animals there were no signs of glandular cell dystrophy or hypertrophy, erosive or ulcerative lesions of the mucous membrane were not observed, inflammatory changes were not detected. At the end of the recovery period, pathological changes in the structure of the organ were absent.

Small intestine - the wall of the small intestine in all experimental groups has the usual structure. The epithelium of the villi is preserved, inflammatory infiltration in all layers of the wall was not found. Erosion and ulcers not found. At the end of the recovery period, pathological changes in the structure of the organ were absent.

Large intestine - the structure of the intestinal wall corresponded to the norm in all experimental groups. Crypts are saved. The number of goblet cell secretion between the experimental groups does not differ. There was no inflammatory infiltration of a single layer of the intestinal wall, erosion and ulcers. After the recovery period, pathological changes in the structure of the organ were not detected

Pancreas - the structure of the organ in animals of the experimental groups did not differ significantly and did not differ from the control group. No signs of atrophy or sclerosis were observed in the acini and excretory ducts. Signs of destruction of the islets of Langerhans were absent. At the end of the recovery period, pathological changes in the structure of the organ were absent.

Conclusion As a result of histological examination of the organs of rats of males and females treated with compound I, it was shown that with the use of drug TD (25 mg / kg), as well as doses of 50 mg / kg (twice TD) and 100 mg / kg (four times TD), signs of intoxication in rats were absent. At the end of the recovery period, signs of intoxication in the experimental groups were not detected.

The results of the study indicate that daily intragastric administration of a compound of formula I for 3 months in TD, 2TD and 4TD did not cause the death of animals and did not affect the integral indicators of their vital activity. The general condition of the animals, appearance, mobility, attitude to food and water throughout the experiment were satisfactory and did not differ in the experimental and control groups.

The introduction of the compounds of formula I did not have a significant effect on the dynamics of body weight of rats of both sexes compared with the control during the entire experiment period.

In female rats, the administration of a compound of formula I for 3 months at doses of 50 mg / kg and 100 mg / kg caused a significant increase in the amplitude R relative to the control group; when administered at a dose of 25 mg / kg, a significant decrease in the amplitude of T and an increase in the QRS interval were observed. In addition, when a compound of formula I was administered over a period of three months at a dose of 50 mg / kg, a significant increase in the R-R interval was observed while reducing the heart rate. At the end of the recovery period, the amplitude K was also significantly increased in groups of females receiving a compound of formula I at doses of 50 and 100 mg / kg. In addition, there was a significant increase in the amplitude of T in groups of females treated with compounds of formula I at doses of 25 and 50 mg / kg.

With intragastric administration of a compound of formula I to male rats for three months, significant changes in the leukocyte formula were detected in groups of males treated with the drug at doses of 50 mg / kg and 100 mg / kg. There was also a significant decrease in the average hemoglobin content in erythrocytes and an increase in the width of the distribution of red blood cells in the group of males treated with a compound of formula I at a dose of 100 mg / kg. At the end of the recovery period, significant differences from the control group were not observed.

With intragastric administration of a compound of formula I, female rats showed changes in the leukocyte formula as well as in other indicators of peripheral blood in all studied doses. At the end of the recovery period, significant changes in the leukocyte formula were found in a group of female rats treated with a compound of formula I at a dose of 50 mg / kg — a decrease in the number of lymphocytes and an increase in the number of granulocytes.

The drug of the compound of formula I, when administered intragastrically for 3 months, caused changes in the biochemical parameters of the blood serum of rats of both sexes, which returned to the control group at the end of the recovery period.

It was shown that the compound of formula I, when administered intragastrically for 3 months in TD, 2TD and 4TD, did not affect the urinary system of male rats; There were no statistically significant differences between the experimental groups and the control. Female rats in the groups treated with the compound of formula I for 3 months at doses of 25 mg / kg and 100 mg / kg showed a significant increase in the specific gravity of urine. At the end of the recovery period, there were no significant differences from the control group in the urine indices of the experimental groups

The compound of formula I with a 3-month intragastric administration and after a recovery period did not cause changes in the mass coefficients of the internal organs.

As a result of histological examination of rat organs treated with a compound of formula I, it was shown that when used for 3 months in TD (25 mg / kg), as well as in doses of 50 mg / kg (2TD) and 100 mg / kg (4TD) a) there were no signs of intoxication in rats. At the end of the recovery period, signs of intoxication and reactive changes from the organs of the immune system in the experimental groups were not detected.

Macroscopic examination of the gastrointestinal tract (local irritant effect) - stomach, small intestine, colon, pancreas - no signs of irritant effect were found. The absence of a local irritant effect was also confirmed by histological examination.

Summarizing the results obtained, it can be concluded that a 3-month administration of the drug of the compound of formula I in TD, as well as in doses equal to 2 TD and 4TD, causes moderately pronounced changes that fully or partially normalize in the recovery period. No deaths were observed in any of the studied groups.

In a study of 28-day toxicity of Idealalisib in rats, intragastric administration of the drug at doses of 100 and 150 mg / kg / day led to the death of animals (3 deaths at a dose of 100 and 5 deaths at a dose of 150 mg / kg). Target organs of toxicity were recorded bone marrow, heart, liver and testes.

In a 3-month rat toxicity study, the use of IDALALISIB at a dose of 90 mg / kg led to an increase in heart weight. The target organs of toxicity were the heart, pancreas, tongue and testes

Intragastric administration of a compound of formula I at a dose of 100 mg / kg for three months did not cause toxic effects and death of animals, which indicates a lower toxicity of the compound of formula I compared to Idealisib with the same route of administration in the same doses, which indicates less toxicity of the compound of the formula I compared with the known analogue.

Claims (13)

1. The compound (6 - {[(1S) -1 (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl] amino} -9H-purin-9-yl) methyl acetate formulas I

2. A method of obtaining a compound of formula I, which consists in the interaction of 2-fluoro-6-nitrobenzoic acid in a mixture of dichloromethane and dimethylformamide with oxalyl chloride in dichloromethane to obtain a solution of 2-fluoro-6-nitro-N-phenylbenzamide, followed by sequential treatment with sulfonyl chloride in dimethylformamide and (2S) -2 - [(tert-butoxycarbonyl) amino] butanoic acid in dichloromethane, producing (S) - [1- (2-fluoro-6-nitrobenzoyl) phenyl-aminocarbonyl] propyl- carbamic acid, and its subsequent reduction under de the action of zinc powder in acetic acid and cyclization of the resulting (S) - [1- (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) -propyl] -carbamic acid obtained under the influence of trifluoroacetic acid acid to form (S) -2- (1-aminopropyl) -5-fluoro-3-phenyl-3H-quinazolin-4-one and then reacting it with (6-chloro-9H-purin-9-yl) methyl acetate with the preparation and isolation of the product - (6 - {[(1S) -1 (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquin-azolin-2-yl) propyl] amino} -9H-purine- 9-yl) methyl acetate of the formula I chromatographically. 3. The method according to p. 2, comprising the following steps: a) 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamino) propyl] quinazolin-4 (3H) -one is added to a solution of acetyl chloride in acetonitrile to form a precipitate of 2- { (1S) -l - [(9-acetyl-9H-purin-6-yl) amino] propyl} -5-fluoro-3-phenylquinazolin-4 (3H) -one; b) to a toluene solution of 2 - {(1S) -1 - [(9-acetyl-9H-purin-6-yl) amino] propyl} -5-fluoro-3-phenylquinazolin-4 (3H) -one obtained on step a), paraform is added. At the end of the interaction, the product - (6 - {[(1S) -1 (5-fluoro-4-oxo-3-phenyl-3,4-dihydroquin-azolin-2-yl) propyl] amino} -9H-purin-9 -yl) methyl acetate of the formula I - is isolated by successive concentration, chromatography and a number of recrystallizations from suitable solvents. 4. The active component having the property of a p110δ inhibitor, the delta isoform of phosphoinositide 3-kinase (PI3K), comprising a compound of formula I in a pharmaceutically effective amount. 5. A pharmaceutical composition having the property of a p110δ inhibitor, the delta isoform of phosphoinositide 3-kinase (PI3K), for treating follicular lymphoma and other malignant lymphoproliferative diseases from a number of non-Hodgkin's lymphomas, containing in a pharmaceutically effective amount a compound of formula I according to claim 1 or the active component p. 4 and pharmaceutically acceptable additives. 6. The pharmaceutical composition according to claim 5, containing in an effective amount a compound of formula I according to claim 1 in an amount of 25 mg and pharmaceutically acceptable additives: microcrystalline cellulose in an amount of 35.0 mg, lactose monohydrate 26.0 mg, hydroxypropyl cellulose in an amount of 5 mg , sodium carboxymethyl starch in an amount of 4 mg, croscarmellose sodium in an amount of 4 mg, magnesium stearate in an amount of 1 mg, and Opadry II white (polyvinyl alcohol - 60%, titanium dioxide - 25%, polyethylene glycol - 10%, talc - 5%) in the amount of 3 mg. 7. A medicament containing a compound of formula I in an effective amount as an active component. 8. A method of treating follicular lymphoma and other malignant lymphoproliferative diseases from a number of non-Hodgkin lymphomas by administering in an effective amount a compound of formula I according to claim 1, or an active component according to claim 4, or a pharmaceutical composition according to claims. 5-6, or the drug according to claim 7, to the recipient in need thereof. 9. The use of the compounds of formula I according to claim 1 for the manufacture of a medicament for the treatment of follicular lymphoma and other malignant lymphoproliferative diseases from a number of non-Hodgkin lymphomas. 10. A method of inhibiting p110δ-delta isoforms of phosphoinositide-3-kinase (PI3K) by administering in an effective amount of a compound of formula I according to claim 1 to a recipient in need thereof.