RU2631317C1 - Selective inhibitors of cycloxygenase and method for their production - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: invention relates to selective inhibitors of the enzyme of cyclooxygenase-2 (COX-2) of the class of substituted 3(2H) -furanones of the general formula

and

and substituted phenanthro[9,10-b]furan-3(2H)-ones of the general formula

, as well as a pharmaceutical composition based thereon. These compounds are effective selective inhibitors of cyclooxygenase-2 (IC₅₀ to 0.004 μg ml, SI to 690).

EFFECT: treatment of chronic forms of arthritis, migraine, trauma, skin diseases, inhibition of angiogenesis and inhibition of cell growth in certain cancers such as neuroblastoma, breast, stomach, lung and large intestine cancers.

15 cl, 4 tbl, 9 ex, 14 dwg

Description

Technical field

This invention relates to the chemistry of organic compounds, pharmacology and medicine, and relates to new chemical compounds with high efficiency and selectivity in the inhibition of the enzyme COX-2. These compounds can be used in the treatment of diseases associated with the development of inflammation, as well as diseases mediated by excessive secretion of COX-2.

State of the art

Prostaglandins (PG) produced from arachidonic acid via the cyclooxygenase (COX) enzyme play an important role in the development of inflammatory reactions in humans and animals. Inhibition of the cyclooxygenase enzyme allows you to stop the biosynthesis of prostaglandins such as PGE ₂ , PGG ₂ and PGH ₂ and mitigate the symptoms of inflammation (edema, pain, hyperemia) associated with their action. At least two varieties of the cyclooxygenase enzyme are known: COX-1 and COX-2, of which only COX-2 is responsible for the development of the inflammatory process, while COX-1 is involved in the vital regulation of secretion in the gastrointestinal tract and kidneys (GIT). Structurally, these enzymes are extremely similar, and their selective inhibition is difficult [1]. Long-term inhibition of the functions of the SOX-1 enzyme, for example, when using non-selective non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, diclofenac, indomethacin, naproxen and others, often leads to the development of gastrointestinal ulcers, bleeding, and destruction of the gastrointestinal cell wall, may provoke perforation of the digestive system and the development of cancerous tumors [2, 3].

In the early 2000s, second-generation NSAIDs belonging to the class of selective inhibitors of the COX-2 enzyme (coxibs) were introduced to the pharmaceutical market. Typical examples of such human NSAIDs are rofecoxib (Vioxx, Merck), celecoxib (Celebrex, Pfizer), valdecoxib (Bextra, GD Searle & Company), etoricoxib (Arcoxia, Merck), and animals: firocoxib ( "Previcox"), deracoxib ("Deramaxx", Novartis), caprofen ("Rimadyl"). This class of drugs combines the structure of the molecule of the active substance - they are all 1,2-diaryl-substituted heterocyclic compounds containing SO ₂ NH ₂ or SO ₂ Me groups, which are responsible for the selectivity of COX-2 inhibition [4]. However, most of the known selective COX-2 inhibitors with prolonged use cause an increased risk of cardiovascular complications (tests VIGOR [5], APPROVe [6]), myocardial infarction and stroke, as a result, in 2004-2006 most of the selective COX- inhibitors 2 was withdrawn from the markets and the development of this field of pharmacology was somewhat difficult. Thus, today there is no satisfactory solution to the problem of long-term and safe anti-inflammatory therapy of various diseases, in particular, the treatment of various forms of chronic arthritis, osteoarthritis, rheumatoid arthritis and other joint diseases.

Nevertheless, the cause and severity of complications from the cardiovascular system varies quite widely depending on the structure of the inhibitor, since the effect of coxibs in the arachidonic acid cascade extends not only to the COX pathway, but also indirectly also to the LOX and CYT-P ₄₅₀ trajectories [7]. Large-scale studies of the comparative cardiovascular safety of NSAIDs, carried out after the prohibition of rofecoxib (2006-2012), showed [7] that such classic NSAIDs as ibuprofen, diclofenac, indomethacin often exceed selective COX-2 inhibitors in the severity of side effects. Moreover, the analgesic effect is more pronounced in the latter, the degree of danger of which, in general, is overrated [8-9]. Currently, special attention is also paid to new areas of application of COX-2 inhibitors - this is the treatment of certain forms of cancer (2,5-dimethyl celecoxib, apricoxib, tilmacoxib (JTE-522)) [10], as well as mental [11] and neurodegenerative diseases (Alzheimer's disease) [12].

It should also be noted that the majority (90%) of known heterocyclic cis-diaryl coxibs have a very specific order of aryl substituents - hydrophilic aryl is adjacent to a hydrophilic (and / or sterically bulky) group or heteroatom in the heterocycle. The rearrangement of the position of SO ₂ X-substituted aryl (ie, hydrophilic aryl) and hydrophilic aryl (eg, halogen-substituted phenyl) in some cases leads to a complete loss of activity of the compound with respect to the COX-2 enzyme [13]. Nevertheless, there are a number of inverse examples when the rearrangement of aryl groups does not lead to a loss of inhibitory ability [14]. In this case, one can expect the manifestation of some new properties of the inhibitor, for example, this structural feature may affect the severity of cardiovascular side effects of the use of such compounds.

In this regard, the search for new highly effective drugs, selective cyclooxygenase-2 inhibitors that do not cause the development of side effects, is one of the main directions for creating new pharmacological agents for the treatment of inflammatory diseases and acute pain, including the joint syndrome with rheumatism and exacerbation of gout, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, radiculitis, inflammatory processes of ligaments and tendons; inflammation caused by bites of poisonous snakes, scorpions and other animals; inflammation caused by sunburn, damage to the skin under the influence of ultraviolet light; inflammation caused by various forms of cancer, such as skin cancer, colorectal cancer, breast cancer, prostate cancer, and other forms of cancer.

Disclosure of invention

The objective of the present invention is to develop and obtain new effective inhibitors of cyclooxygenase-2 (COX-2), which are promising for the treatment of inflammatory diseases or diseases associated with excessive secretion of cyclooxygenase-2.

The technical result of this invention is the development and preparation of new compounds with high inhibitory activity and selectivity for the cyclooxygenase-2 enzyme. These compounds preferably inhibit cyclooxygenase-2 compared with cyclooxygenase-1, which, in turn, reduces the likelihood of side effects associated with destructive lesions of the gastrointestinal tract, kidneys and liver [2, 3]. These compounds are promising for use in the treatment of diseases of inflammatory genesis and / or diseases associated with excessive secretion of cyclooxygenase-2, in particular for the treatment of pain (both chronic and acute), fever and inflammation in various conditions and diseases.

The specified technical result is achieved by obtaining compounds of General formula (I):

or their stereoisomers, enantiomers, pharmaceutically acceptable salts, solvates or hydrates, where:

R ¹ represents a sulfonamide group —SO ₂ NHAlk, where Alk is selected from methyl, ethyl, isopropyl or n-propyl or an unsubstituted sulfonamide (—SO ₂ NH ₂ ) or sulfo (—SO ₂ OH) group;

R ² is independently selected and represents halogen or hydrogen, said substituents being in a meta or para position with respect to the attachment point of the phenyl group;

R ³ and R ⁴ are independently selected and are —C _1-5 alkyl or —C _3-7 cycloalkylalkyl, wherein R ³ and R ^4, together with the carbon atom to which they are attached, can form a saturated ring containing from 3 up to 7 atoms.

In some preferred embodiments, R ² is independently selected and is fluoro or chloro.

A separate subclass of compounds of interest includes compounds of formula (I) selected from the group:

2,2-Dimethyl-4- [4 '- (aminosulfonyl) phenyl] -5-phenyldihydrofuran-3 (2H) -one;

2,2-Dimethyl-4- [4 '- (aminosulfonyl) phenyl] -5- (4'-fluorophenyl) dihydrofuran-3 (2H) -one;

2,2-Dimethyl-4- [4 '- (aminosulfonyl) phenyl] -5- (3'-fluorophenyl) dihydrofuran-3 (2H) -one;

2,2-Dimethyl-4- [4 '- (aminosulfonyl) phenyl] -5- (4'-chlorophenyl) dihydrofuran-3 (2H) -one;

2,2-Dimethyl-4- [4 '- (aminosulfonyl) phenyl] -5- (3'-chlorophenyl) dihydrofuran-3 (2H) -one;

4- (5,5-dimethyl-4-oxo-2-phenyl-4,5-dihydrofuran-3-yl) benzenesulfonic acid;

4- (2- (4'-fluorophenyl) -5,5-dimethyl-4-oxo-4,5-dihydrofuran-3-yl) benzenesulfonic acid;

4- (2- (4'-chlorophenyl) -5,5-dimethyl-4-oxo-4,5-dihydrofuran-3-yl) benzenesulfonic acid;

4- (2- (3'-fluorophenyl) -5,5-dimethyl-4-oxo-4,5-dihydrofuran-3-yl) benzenesulfonic acid;

4- (2- (3'-chlorophenyl) -5,5-dimethyl-4-oxo-4,5-dihydrofuran-3-yl) benzenesulfonic acid;

The specified technical result is also achieved by obtaining compounds of General formula (II):

or their stereoisomers, enantiomers, pharmaceutically acceptable salts, solvates or hydrates, where:

R ¹ is independently selected and is a C _1-3 alkylsulfonyl or C _1-3 alkylsulfinyl group;

R ² is independently selected and is halogen;

R ³ and R ⁴ are independently selected and are —C _1-5 alkyl or —C _3-7 cycloalkylalkyl, wherein R ³ and R ^4, together with the carbon atom to which they are attached, can form a saturated ring containing from 3 up to 7 atoms.

In some preferred embodiments, R ² is independently selected and is fluoro or chloro.

Another separate subclass of compounds of interest includes compounds of formula (II) selected from the group:

2,2-Dimethyl-4- [4 '- (methylsulfinyl) phenyl] -5- (3'-fluorophenyl) dihydrofuran-3 (2H) -one;

2,2-Dimethyl-4- [4 '- (methylsulfonyl) phenyl] -5- (3'-fluorophenyl) dihydrofuran-3 (2H) -one;

2,2-Dimethyl-4- [4 '- (methylsulfinyl) phenyl] -5- (3'-chlorophenyl) dihydrofuran-3 (2H) -one;

2,2-Dimethyl-4- [4 '- (methylsulfonyl) phenyl] -5- (3'-chlorophenyl) dihydrofuran-3 (2H) -one.

In addition, the specified technical result is also achieved by obtaining compounds of the general formula (III):

or their stereoisomers, enantiomers, pharmaceutically acceptable salts, solvates or hydrates, where:

R ¹ is independently selected and is C _1-3 alkylsulfonyl, C _1-3 alkylsulfinyl substituted with sulfonamide (-SO ₂ NHAlk, where Alk is selected from methyl, ethyl, isopropyl or n-propyl) or unsubstituted sulfonamide (-SO ₂ NH ₂ ), a sulfo (—SO ₂ OH) group, a C _1-3 alkylthio group, hydrogen or halogen, said substituents being in the third or fourth position of the phenanthrene moiety;

R ² is independently selected and is C _1-3 alkylsulfonyl, C _1-3 alkylsulfinyl, substituted sulfonamide (-SO ₂ NHAlk, where Alk is selected from methyl, ethyl, isopropyl or n-propyl) or unsubstituted sulfonamide (-SO ₂ NH ₂ ), a sulfo (—SO ₂ OH) group, a C _1-3 alkylthio group, hydrogen or halogen, said substituents being in the fifth or sixth position of the phenanthrene moiety;

moreover, if R ¹ represents hydrogen, then R ² cannot be hydrogen and vice versa;

R ³ and R ⁴ are independently selected and are —C _1-5 alkyl or —C _3-7 cycloalkylalkyl, wherein R ³ and R ^4, together with the carbon atom to which they are attached, can form a saturated ring containing from 3 up to 7 atoms.

In some preferred embodiments, R ¹ and R ² are independently selected and are fluoro or chloro.

Another separate subclass of compounds of interest includes compounds of formula (III) selected from the group:

2 ', 2'-Dimethyl-3- (methylthio) phenantro [9,10-b] furan-3' (2'H) -one;

2 ', 2'-Dimethyl-3- (methylsulfinyl) phenantro [9,10-b] furan-3' (2'H) -one;

2 ', 2'-Dimethyl-3- (methylsulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

2 ', 2'-Dimethyl-3- (aminosulfonyl) phenantro [9,10-b] furan-3' (2'H) -one

2 ', 2'-Dimethyl-6- (methylthio) phenantro [9,10-b] furan-3' (2'H) -one;

2 ', 2'-Dimethyl-6- (methylsulfinyl) phenantro [9,10-b] furan-3' (2'H) -one;

2 ', 2'-Dimethyl-6- (methylsulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

2 ', 2'-Dimethyl-6- (aminosulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

6-fluoro-2 ', 2'-Dimethyl-3- (methylthio) phenantro [9,10-b] furan-3' (2'H) -one;

6-fluoro-2 ', 2'-Dimethyl-3- (methylsulfinyl) phenantro [9,10-b] furan-3' (2'H) -one;

6-fluoro-2 ', 2'-dimethyl-3- (methylsulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

6-fluoro-2 ', 2'-Dimethyl-3- (aminosulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

3-fluoro-2 ', 2'-dimethyl-6- (methylthio) phenantro [9,10-b] furan-3' (2H) -one;

3-fluoro-2 ', 2'-dimethyl-6- (methylsulfinyl) phenantro [9,10-b] furan-3' (2'H) -one;

3-fluoro-2 ', 2'-Dimethyl-6- (methylsulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

3-fluoro-2 ', 2'-dimethyl-6- (aminosulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

6-chloro-2 ', 2'-dimethyl-3- (methylthio) phenantro [9,10-b] furan-3' (2'H) -one;

6-chloro-2 ', 2'-dimethyl-3- (methylsulfinyl) phenantro [9,10-b] furan-3' (2'H) -one;

6-chloro-2 ', 2'-dimethyl-3- (methylsulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

6-chloro-2 ', 2'-dimethyl-3- (aminosulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

3-chloro-2 ', 2'-dimethyl-6- (methylthio) phenantro [9,10-b] furan-3' (2'H) -one;

3-chloro-2 ', 2'-dimethyl-6- (methylsulfinyl) phenantro [9,10-b] furan-3' (2'H) -one;

3-chloro-2 ', 2'-dimethyl-6- (methylsulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

3-chloro-2 ', 2'-dimethyl-6- (aminosulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

5-chloro-2 ', 2'-dimethyl-3- (methylthio) phenantro [9,10-b] furan-3' (2'H) -one;

5-chloro-2 ', 2'-dimethyl-3- (methylsulfinyl) phenantro [9,10-b] furan-3' (2'H) -one;

5-chloro-2 ', 2'-dimethyl-3- (methylsulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

5-chloro-2 ', 2'-dimethyl-3- (aminosulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

4-chloro-2 ', 2'-dimethyl-6- (methylthio) phenantro [9,10-b] furan-3' (2'H) -one;

4-chloro-2 ', 2'-dimethyl-6- (methylsulfinyl) phenantro [9,10-b] furan-3' (2'H) -one;

4-chloro-2 ', 2'-dimethyl-6- (methylsulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

4-chloro-2 ', 2'-dimethyl-6- (aminosulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

5-fluoro-2 ', 2'-Dimethyl-3- (methylthio) phenantro [9,10-b] furan-3' (2'H) -one;

5-fluoro-2 ', 2'-Dimethyl-3- (methylsulfinyl) phenantro [9,10-b] furan-3' (2'H) -one;

5-fluoro-2 ', 2'-Dimethyl-3- (methylsulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

5-fluoro-2 ', 2'-dimethyl-3- (aminosulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

4-fluoro-2 ', 2'-dimethyl-6- (methylthio) phenantro [9,10-b] furan-3' (2H) -one;

4-fluoro-2 ', 2'-dimethyl-6- (methylsulfinyl) phenantro [9,10-b] furan-3' (2'H) -one;

4-fluoro-2 ', 2'-dimethyl-6- (methylsulfonyl) phenantro [9,10-b] furan-3' (2'H) -one;

4-fluoro-2 ', 2'-dimethyl-6- (aminosulfonyl) phenantro [9,10-b] furan-3' (2'H) -one.

The present invention also relates to the use of the subject compounds as inhibitors of the cyclooxygenase-2 enzyme.

In some embodiments of the invention, the compounds of the present invention and exhibiting the properties of cyclooxygenase-2 inhibitors can be used as anti-inflammatory, analgesic, antipyretic, anti-arthritic, antitumor agents [15, 16], drugs that slow down the angiogenesis of new vessels of cancer tumors [17 ], drugs that increase the body’s immune response to cancer cells [18], drugs that slow down the proliferation of cancer cells [19, 20], and also for the treatment of Alzheim yep.

The compounds of the present invention can be used to treat pain (both chronic and acute), fever and inflammation in various conditions and diseases, in particular diseases such as arthritis, articular syndrome with rheumatism and exacerbation of gout, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, sciatica, Alzheimer's disease, headache, toothache or menstrual pain; inflammatory processes of ligaments, tendons, sciatica, lumbago, inflammation associated with sunburn, damage to the skin under the action eat ultraviolet light, various forms of oncological diseases, in particular oncological diseases of the skin.

The present invention also relates to the use of the subject compounds for the manufacture of a pharmaceutical composition for the treatment of inflammatory diseases of the genesis or diseases associated with excessive secretion of the cyclooxygenase-2 enzyme.

In addition, the invention provides pharmaceutical compositions for the treatment of diseases of inflammatory genesis or diseases associated with excessive secretion of the cyclooxygenase-2 enzyme, containing an effective amount of at least one compound of the present invention and at least one pharmaceutically acceptable carrier and / or diluent. In some particular embodiments of the invention, the pharmaceutical composition is characterized in that it contains the compounds of the invention and its regioisomer with respect to the interchanging of the substituents R ¹ and R ² .

In some embodiments, the pharmaceutical compositions of this invention can be used as anti-inflammatory, analgesic, antipyretic drugs.

In some other embodiments, the pharmaceutical compositions of the invention can be used to treat diseases comprising arthritis, skin inflammatory disease, inflammation in vascular diseases, pulmonary inflammation, thyroiditis, inflammation associated with general hypothermia, influenza, or viral infection. In addition, more specifically, arthritis is rheumatoid arthritis, osteoarthritis, gouty arthritis, juvenile arthritis, spondylolisthesis, and skin inflammatory disease is eczema, dermatitis, psoriasis.

The compounds of the invention may be useful in treating mammals, preferably humans, as well as animals, including, but not limited to, sheep, dogs, cats, horses, pigs, rats, mice, rabbits, and others.

The compounds of the invention may be used in combination with at least one other therapeutic agent.

The invention also includes the preparation of compounds of general formulas (I), (II) and (III).

The invention also relates to a method for treating inflammatory diseases of the genesis or diseases associated with excessive secretion of the cyclooxygenase-2 enzyme by administering to the patient a pharmaceutically effective amount of a compound of the invention or a pharmaceutical composition of the invention.

DETAILED DESCRIPTION OF THE INVENTION

As a result of the studies, it was found that the compounds of the invention selectively and effectively inhibit COX-2. These compounds are useful in the treatment of a very wide range of disorders mediated by COX-2, including, but not limited to, disorders characterized by inflammation, pain and / or fever. Such compositions are especially useful as anti-inflammatory agents, in particular in the treatment of arthritis, having the additional advantage of exhibiting significantly less dangerous side effects than the non-steroidal anti-inflammatory drugs known in the art, which have low selectivity to COX-2 relative to COX-1 . In particular, the compounds of the invention have a reduced potential for gastrointestinal toxicity and gastrointestinal irritation, including an ulceration in the upper gastrointestinal tract and bleeding, and a reduced potential for renal side effects. Therefore, compounds of the invention selectively inhibiting COX-2 are especially useful as an alternative to well-known non-steroidal anti-inflammatory drugs, where such drugs are contraindicated, for example, in patients with stomach ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with recurrent gastrointestinal disorders ; with gastrointestinal bleeding, bleeding disorders, including anemia, such as hypoprothrombinemia, hemophilia, or other bleeding problems; with kidney disease; or in patients prior to surgery, or in patients taking anticoagulants.

Such compounds are useful in the treatment of pain, including, but not limited to, pain after surgery, toothache, muscle pain, and pain arising from cancer. Such compositions are useful, for example, to relieve pain, fever and inflammation in various conditions, including lumbar and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout, bursitis, burns and injuries after surgical and dental interventions.

Definitions and Terms

The term “alkyl” as used herein means both straight and branched alkyls. In addition, the term “alkyl” as used herein refers to groups typically having one to three carbon atoms. For example, the term “C _1-3 alkyl” means methyl, ethyl, isopropyl, n-propyl.

The term “cycloalkyl” as used herein refers to groups having three to seven carbon atoms in a monocyclic structure. By way of illustration, cycloalkyls include, but are not limited to, the following radicals: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term “aryl” as used herein means groups containing an aromatic ring having six carbon atoms. An example of aryl ring groups is phenyl.

The term "halogen" by itself or in part of another term refers to an atom of fluorine, chlorine, bromine or iodine.

This invention contains only those combinations of substituents and derivatives that form a stable or chemically possible compound. A stable or chemically feasible compound is a compound whose stability is sufficient for its synthesis and analytical detection. Preferred compounds of this invention are sufficiently stable and do not decompose at temperatures up to 40 ° C in the absence of chemically active conditions, for at least one week.

The term “substituent” means a chemical radical that binds to a molecular skeleton (fragment), for example, “alkyl substituent”, “cyclic system substituent”, the meanings of which are defined herein.

Unless otherwise indicated, the structures depicted herein also include all stereoisomers, i.e., R- and S-isomers for each asymmetric center. In addition, individual stereochemical isomers, as well as enantiomers and diastereomeric mixtures of the present compounds, are also the subject of this invention. Thus, this invention encompasses each diastereomer or enantiomer substantially free of other isomers (> 90%, and preferably> 95% molar purity), as well as a mixture of such isomers.

A particular optical isomer can be obtained by resolving the racemic mixture in accordance with a standard procedure, for example, by preparing diastereoisomeric salts by treatment with an optically active acid or base, followed by crystallization of the diastereomer mixture, followed by isolation of the optically active bases from these salts. Another technique for separating optical isomers is to use a chiral chromatographic column.

The optically active compounds of this invention can be prepared using optically active starting materials. Such isomers may be in the form of a free acid, free base, ester or salt.

The term "regioisomer" encompasses herein the compounds obtained by interchanging the substituents R ¹ and R ² in the general formulas (I), (II), or (III) together with their positions in the benzene ring. So, for example, regioisomers, in this document, for compounds of formulas (I), (II), (III) will be compounds of formula (I *), (II *), (III *):

Moreover, for example, in formulas (II) and (II *), the substituent R ¹ retains the para position, and the substituent R ² retains the meta position, in accordance with this definition.

The numbering in the phenanthrene fragment of the compounds of general formula (III) in this document is assumed to be rigidly fixed, constant and independent of the substituents R ¹ and R ² , as shown in the following figure:

The term "patient" covers all types of mammals, preferably humans.

The terms “treatment”, “therapy” cover the treatment of pathological conditions in mammals, preferably in humans, and include: a) blocking (stopping) the course of the disease, b) alleviating the severity of the disease, i.e. induction of disease regression.

The term "inflammation" - (Latin inflammatio) is a complex, local and general pathological process that occurs in response to damage (alteratio) of the body's cellular structures or the action of a pathogenic irritant and manifests itself in reactions (exudatio, etc.) aimed at eliminating products damage, and if possible, of agents (irritants), as well as leading to the maximum recovery for these conditions (proliferatio, etc.) in the damage zone.

The term “therapeutically effective amount” means an amount of a compound which, when administered as a mono- or combination therapy, causes an inhibition of the COX-2 enzyme sufficient to treat a mammalian disease associated with the development of inflammation, as well as a disease mediated by excessive secretion of COX-2. When using the compounds of the invention in combination therapy, the term “therapeutically effective amount” refers to a combination of amounts of active ingredients, the administration of which leads to a preventive or therapeutic effect in consecutive or simultaneous administration. The exact amount required can vary from subject to subject depending on the type of mammal, age and general condition of the patient, the severity of the disease, the method of administration of the drug, combined treatment with other drugs, etc.

The term “solvate” refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvate forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term “hydrate” refers to a complex wherein the solvent molecules are water.

Brief Description of the Drawings

Figure 1. Values of normalized potential energies (kcal / mol) for amino acids in the composition of the hCOX-2 enzyme after the annealing procedure.

Figure 2. The normalized potential energies (kcal / mol) for the amino acids in the hCOX-1 enzyme after the annealing procedure.

Figure 3. Amino acids in hCOX-1 with high stress values (gray spheres), the binding site is shown by yellow spheres.

Figure 4. Reference set of known hCOX-1 and hCOX-2 inhibitors. Compounds E-8, E-9, E-13, E-14 belong to COX inhibitors with a changed sequence of aryl groups relative to the generally accepted.

Figure 5. Internal validation of the model using the celecoxib molecule, active conformation: orange - X-ray diffraction data, gray - docking: a) hCOX-2 (scoring: - 14.27 kcal / mol), RMSD = 0.13 b) hCOX-1 (scoring: - 13.39 kcal / mol); RMSD = 0.21.

Figure 6. General view of a three-center pharmacophore with celecoxib molecule. The pharmacophore is integrated into the in silico model (Acc is the potential acceptor of the hydrogen bond, Aro is the aromatic region).

Figure 7. QSAR model for SOX-2 in the form of a linear approximation.

Figure 8. QSAR model for SOX-1 in the form of a linear approximation.

Figure 9. Investigated structures of COX-1 and COX-2 inhibitors according to the invention.

Figure 10. Structures of some known cyclooxygenase inhibitors:

a) Rofecoxib: IC ₅₀ (SOX-2) = 0.06 μg / ml, IC ₅₀ (SOX-1) = 100 μg / ml, selectivity 1700;

b) Celecoxib: IC ₅₀ (SOX-2) = 0.02 μg / ml, IC ₅₀ (SOX-1) = 1.9 μg / ml, selectivity 100;

c) Ketoprofen: IC ₅₀ (SOX-2) = 0.13 μg / ml, IC ₅₀ (SOX-1) = 0.6 μg / ml, selectivity 4.6.

Figure 11. Docking of 2,2-dimethyl-4- [4 '- (aminosulfonyl) phenyl] -5- (3'-chlorophenyl) furan-3 (2H) -one (1u) at the COX-2 binding site. Comparison with celecoxib (orange structure). Scoring: - 8.631 kcal / mol.

Figure 12. Docking of 2,2-dimethyl-4- [4 '- (aminosulfonyl) phenyl] -5- (4'-chlorophenyl) furan-3 (2H) -one (1v) at the COX-2 binding site. Comparison with celecoxib (orange structure). Scoring: - 8.495 kcal / mol.

Figure 13. Docking of 3-chloro-2 ', 2'-Dimethyl-6- (methylsulfonyl) phenantro [9,10-b] furan-3' (2'H) -one (2e) at the COX-2 binding site. Comparison with celecoxib (orange structure). Scoring: - 7.499 kcal / mol.

Figure 14. Docking of 4-fluoro-2 ', 2'-Dimethyl-6- (methylsulfonyl) phenantro [9,10-b] furan-3' (2'H) -one (2h) at the COX-2 binding site. Comparison with celecoxib (orange structure). Scoring: - 7.138 kcal / mol.

The implementation of the invention

Overview of the methods for producing compounds of the invention

The compounds of the present invention can be prepared using the synthetic methods described below. The listed methods are not exhaustive and allow the introduction of reasonable modifications. These reactions should be carried out using suitable solvents and materials. When implementing these general procedures for the synthesis of specific substances, it is necessary to take into account the functional groups present in the substances and their influence on the reaction. To obtain some substances, it is necessary to change the order of the stages or give preference to one of several alternative synthesis schemes. It should be understood that these and all examples cited in the application materials are not limiting and are provided merely to illustrate the present invention.

¹ H (400 MHz) and ¹³ C (100 MHz) NMR spectra were recorded on a Bruker 400 MHz Avance spectrometer in deuterochloroform, CHCl ₃ (reference signal 7.26 ppm). IR spectra were obtained on a Perkin-Elmer BXII spectrophotometer in the range of 4000-400 cm ^-1 in a tetrachlorocarbon solvent or in a KBr tablet. To record the mass spectra, a Bruker microTOF chromato-mass spectrometer was used. The melting point was measured on a Buchi B-540 instrument.

). Аналитическую ТСХ проводили на пластинах Silufol UV-254, элюенты - гексан, петролейный эфир, хлористый метилен, ацетон, этилацетат и смесь растворителей в различном соотношении.The reactions were carried out in anhydrous solvents purified by standard procedures. For preparative separation of the reaction mixtures, column and flash chromatography on Silica gel 40/100 μm in gradient mode and preparative TLC on Silufol UV-254 plates (Kavalier,

) Analytical TLC was performed on Silufol UV-254 plates, eluents - hexane, petroleum ether, methylene chloride, acetone, ethyl acetate and a mixture of solvents in various proportions.

The compounds described in the description without reference, prepared according to standard laboratory methods or are commercially available substances.

Intermediates for the preparation of certain compounds of the invention can be prepared by the procedures described below.

Preparation of 2,2-Dimethyl-4- [4 '- (methylthio) phenyl] -5-phenylfuran-3 (2H) -one Intermediate (Scheme 1: 1a)

Step 0. Preparation of 4 '- (methylthio) phenyl (phenyl) methanone (3a).

To a solution of 25 ml (25.5 g, 0.2 mol) of thioanisole (2a) in 200 ml of methylene chloride cooled to 5 ° C, 30 g of anhydrous AlCl _{3 was} added with stirring. Then, over 1.5 h with vigorous cooling to 0-5 ° C, 23 ml (28 g, 0.2 mol) of benzoyl chloride were added dropwise, while the mixture turned orange and had a high viscosity. After adding all the benzoyl chloride, the mixture was refluxed for 3.5 hours. Upon completion of the reaction, the orange precipitate of the complex with aluminum chloride was filtered on a Schott filter, washed with dichloromethane and hydrolyzed: at the beginning of cold 7% HCl, and then hydrolysis was completed until the product was completely discolored by boiling. The ketone 3a hardened by cooling was dissolved in dichloromethane, washed with H ₂ O and dried over Na ₂ SO ₄ for 12 hours. After distilling off the solvent, 33.3 g of 4 '- (methylthio) phenyl (phenyl) methanone (3a) were obtained. The dark orange mother liquor of the complex in dichloromethane was hydrolyzed by boiling with a 7% aqueous HCl solution until completely discolored, then the organic layer was separated from the aqueous layer, the aqueous layer was extracted with dichloromethane (3 × 15 ml). The combined organic fractions were washed with water and dried over Na ₂ SO ₄ . After distilling off the solvent, the product was recrystallized from hexane and dried in air (1 day). Received 5.95 g of compound 3a. The total yield of 39.2 g (86%), colorless crystals, so pl. 79-80 ° C.

¹ H NMR spectrum (400 MHz, 32 mg in 0.8 ml CDCl ₃ ), δ, ppm: 2.53 s (3H, SCH ₃ ), 7.29 d (2H), 7.46 t (2H), 7.52-7.60 m ( 1H), 7.73 d (2H), 7.75 d (2H).

¹³ C NMR spectrum (100 MHz, 32 mg in 0.8 ml CDCl ₃ ), δ, ppm: 14.8 (SCH ₃ ), 124.8, 128.2, 129.7, 130.5, 132.1, 133.5, 137.7, 145.2 (all C _{ArAr '} ), 195.8 (C = O).

IR spectrum (in CCl ₄ ), cm ^-1 : 836 sr, 920 sr, 936 sr, 1090 s, 1175 sr, 1282 s, 1315 s, 1400 sr, 1445 sr, 1589 s ., 1658 p. (C = O), 2923 words, 2990 words, 3025 words, 3062 words, 3083 words

HRMS mass spectrum, m / z found: 229.0689 [MH] ⁺ , calculated: 229.0682.

Step I. Preparation of 2-methyl-5-phenyl-5- (4'-methylthiophenyl) pent-3-in-2,5-diol (5a).

To a solution of EtMgBr prepared from 5 g (0.21 mol) of magnesium and 22.7 g (0.21 mol) of ethyl bromide in 60 ml of absolute diethyl ether, while cooling in an ice bath, a solution of 7.85 ml (0.081 mol) of 2-methylbut-3- was slowly added dropwise. in-2-ol in 50 ml of absolute benzene. The mixture was boiled for 2 hours, then, while cooling, a solution of 13 g (0.0575 mol) of compound 3a in 50 ml of benzene was added dropwise and boiled for 5 hours. The mixture was then cooled in a water bath and carefully hydrolyzed with 150 ml of a 5% cold solution of hydrochloric acid. The organic layer was separated from the aqueous. The aqueous layer was extracted with benzene (3 × 20 ml). The combined organic fractions were washed with NaHCO ₃ solution, water and dried over Na ₂ SO ₄ . After distillation of the solvent, the obtained yellow oily substance was dried in vacuum at a pressure of 0.01–0.05 torr for 5 hours. Yield 5a 16.2 g (88%), colorless oily substance. Without further purification, the resulting compound was used in the next step.

¹ H NMR spectrum (400 MHz, 20 mg in 0.8 ml CDCl ₃ ), δ, ppm: 1.57 s (6H, 2CH ₃ ), 2.53 s (3H, SCH ₃ ), 7.17 d (2H), 7.22- 7.27 m (1H), 7.31 t (2H), 7.48 d (2H), 7.52-7.58 m (2H).

73.9, 84.7

91.8

125.8, 126.1, 126.4, 127.8, 128.4, 138.1, 141.8, 144.8. ¹³ C NMR spectrum (100 MHz, 20 mg in 0.8 ml CDCl ₃ ), δ, ppm: 15.5 (SCH ₃ ), 31.3 (2CH ₃ ), 65.2

73.9, 84.7

91.8

125.8, 126.1, 126.4, 127.8, 128.4, 138.1, 141.8, 144.8.

IR spectrum (in CCl ₄ ), cm ^-1 : 700.9 words, 908.5 words, 951.7 words, 999.6 words, 1167.6 words, 1325.6 words, 1449.0 words, 1490.0 words, 2854.7 words, 2926.6 s ., 3606.5 words

HRMS mass spectrum, m / z, calculated: 335.1077, found: 335.1087 [MNa] ⁺ .

Stage II. Preparation of 2,2-Dimethyl-5- [4 '- (methylthio) phenyl] -5-phenyl-dihydrofuran-3 (2H) -one (6a).

15.8 g (0.051 mol) of compound 5a was dissolved in 50 ml of boiling methanol and 2.5 ml (0.045 mol) of 98% sulfuric acid dissolved in 7.5 ml of methanol was added dropwise with stirring. The mixture was boiled for 2 hours until the end of the reaction (TLC control). Then the mixture was poured into 100 ml of water and thoroughly extracted with methylene chloride (3 × 50 ml). The organic layer was dried over Na ₂ SO ₄ , the solvent was driven off on a rotor, and the resulting substance was dried from methanol and dichloromethane in vacuo at a pressure of 0.02–0.05 torr for 5 h. The resulting oil was crystallized using a seed and re-dried in vacuo. Obtained 14.2 g of substance (yield 90%) 6a, colorless crystals, so pl. 64-65 ° C. Without further purification, the resulting compound was used in the next step.

¹ H NMR spectrum (400 MHz, 25 mg in 0.7 ml CDCl ₃ ), δ, ppm: 1.21 d (6H, 2CH ₃ ), 2.45 s (3H, SCH ₃ ), 3.30 s (2H, CH ₂ ) 7.17 d (2H), 7.21-7.26 m (1H), 7.26-7.36 m (4H), 7.40 d (2H).

82.4, 125.9, 126.1, 126.6, 127.3, 128.3, 137.7, 142.8, 146.0, 216.9 (С=O). ¹³ C NMR spectrum (100 MHz, 25 mg in 0.7 ml of CDCl ₃ ), δ, ppm: 15.6 (SCH ₃ ), 25.3 (2CH ₃ ), 47.9 (CH ₂ ), 81.4

82.4, 125.9, 126.1, 126.6, 127.3, 128.3, 137.7, 142.8, 146.0, 216.9 (C = O).

IR spectrum (in CCl ₄ ), cm ^-1 : 961 words, 994 words, 1095 words, 1133 words, 1173 words, 1281 words, 1376 words, 1447 words, 1493 words, 1599 words ., 1760 pp., 2925 words, 2984 words, 3028 words, 3064 words

HRMS mass spectrum, m / z, calculated: 313.1257, found: 313.1259 [MH] ⁺ .

Stage III. Preparation of 4-diazo-2,2-dimethyl-5- [4 '- (methylthio) phenyl] -5-phenyl-dihydrofuran-3 (2H) -one (7a).

To a mixture of 250 mg (0.8 mmol) of furanone 6a and 195 mg (0.99 mmol) of paratoluenesulfonylazide in 15 ml of dichloromethane was added dropwise a solution of 50 mg (0.33 mmol) of 1,8-diazobicyclo [5.4.0] undec-7-ene (DBU) in 1 ml of dichloromethane, and the mixture immediately turned orange-yellow. The reaction mixture was stirred at 35 ° C for 6 hours until completion of the reaction (control by TLC), then cooled, excess solvent removed in vacuo, the residue was transferred to a silica gel column, and gradient chromatography was performed with n-hexane-methylene chloride mixture . After removal of the solvent, the crystalline residue was dried in vacuo to give 191 mg (70%) of diazoketone 7a, a yellow crystalline solid, mp. 134-135 ° C.

¹ H NMR spectrum (400 MHz, 30 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 7.26 ppm), δ, ppm: 1.35 s (6H, 2CH ₃ ), 2.48 s (3H, SCH ₃ ), 7.23 s (4H), 7.29-7.41 m (5H).

126.1, 126.3, 126.9, 128.4, 128.5, 139.1, 140.4, 143.5 (все C_ArAr'), 196.9 (С=O). ¹³ C NMR spectrum (100 MHz, 30 mg in 0.8 ml of CDCl ₃ , reper: CHCl ₃ = 77.00 ppm), δ, ppm: 15.4 (SCH ₃ ), 25.2 s (2CH ₃ ), 83.9 ( C ₅ ), 85.5

126.1, 126.3, 126.9, 128.4, 128.5, 139.1, 140.4, 143.5 (all C _{ArAr '} ), 196.9 (C = O).

IR spectrum (in CCl ₄ ), cm ^-1 : 1025 words, 1094 words, 1165 words, 1226 words, 1346 cf., 1378 words, 1493 words, 1696 cf. (C = O), 2091 s. (C = N ₂ ), 2926 words, 2982 words

Mass spectrum, m / z, calculated: 361.0982, found: 361.0987 [MNa] ⁺ .

Stage IV. Preparation of 2,2-Dimethyl-4- [4 '- (methylthio) phenyl] -5-phenylfuran-3 (2H) -one (1a).

The reaction is carried out in a nitrogen atmosphere. To a solution of 200 mg (0.59 mmol) of diazoketone 7a in 10 ml of dichloromethane was added dropwise 0.1 ml of trifluoromethanesulfonic acid (TfOH) dissolved in 5 ml of methylene chloride. The mixture was boiled for 3 hours until the initial diazoketone completely disappeared (control by TLC), and upon completion of the reaction, the mixture was washed with an aqueous solution of NaHCO ₃ , water (2 × 5 ml) and dried over K ₂ CO ₃ . Removal of the solvent gave 180 mg (98%) of a mixture of two regioisomeric 2,2-dialkyl-4,5-diaryl-dihydrofuran-3 (2H) -ones in an approximate ratio of 3: 1 as a pale yellow oily product. The reaction mixture (180 mg) was separated on a silica gel column to give furanone 1a with a yield of 130 mg (72%), light yellow crystals, m.p. 120-121 ° C.

¹ H NMR spectrum (400 MHz, 20 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 7.26 ppm), δ, ppm: 1.55 s (6H, 2CH ₃ ), 2.49 s (3H, SCH ₃ ), 7.23-7.26 m (4H), 7.37 t (2H, ³ J _HH = 7.6 Hz), 7.44-7.49 m (1H), 7.67 d (2H, ³ J _HH = 7.4 Hz).

113.0 (С₄), 126.6, 128.5, 128.4, 129.7, 131.8, 137.7 (все C_ArAr'), 178.1 (С₅), 205.4 (С=O). ¹³ C NMR spectrum (100 MHz, 20 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 77.00 ppm), δ, ppm: 15.7 (SCH ₃ ), 23.4 (2CH ₃ ), 87.0

113.0 (C ₄ ), 126.6, 128.5, 128.4, 129.7, 131.8, 137.7 (all C _{ArAr '} ), 178.1 (C ₅ ), 205.4 (C = O).

IR spectrum (in CCl ₄ ), cm ^-1 : 1051 words, 1094 words, 1167 words, 1242 words, 1384 Wed, 1502 words, 1574 words, 1591 words, 1618 words, 1699 s ., 2926 words, 2982 words

HRMS mass spectrum, m / z, calculated: 311.1101, found: 311.1107 [MH] ⁺ .

Preparation of 2,2-dimethyl-4- [4 '- (methylsulfinyl) phenyl] -5-phenylfuran-3 (2H) -one intermediate (Scheme 2: 1b)

The preparation of compound 1a is described above.

Preparation of 2,2-Dimethyl-4- [4 '- (methylsulfinyl) phenyl] -5-phenylfuran-3 (2H) -one (1b).

10 ml of trifluoroacetic acid were placed in a round bottom flask with a magnetic stirrer and an air cooler, 300 mg (0.96 mmol) of compound 1a were dissolved in it at + 50 ° C, and a mixture of 100 mg 35% was carefully added dropwise with vigorous stirring over 1 h ( 0.96 mmol) of an aqueous solution of hydrogen peroxide in 3 ml of trifluoroacetic acid and 0.05 ml (1 mmol) of 98% H ₂ SO ₄ . In this reaction, it is very important to observe the exact equimolar ratio of hydrogen peroxide to 1a. The reaction mixture was stirred for another 3 hours at + 50-55 ° C (control by TLC), upon completion of the reaction, the mixture was poured into water, extracted with ethyl acetate (4 × 20 ml), the organic extracts were washed with NaHCO ₃ solution, water (3 × 5 ml), dried over Na ₂ SO ₄ and K ₂ CO ₃ , and after removal of the solvent and vacuum drying, 270 mg of crystalline material was obtained. The yield of target compound 1b was 270 mg (86%), a colorless oily substance.

¹ H NMR spectrum (400 MHz, 20 mg in 0.8 ml CDCl ₃ , benchmark: CHCl ₃ = 7.260 ppm), δ, ppm: 1.58 s (6H, 2CH ₃ ), 2.74 s (3H, SOCH ₃ ), 7.38 t (2H, ³ J _HH = 7.8 Hz), 7.49-7.51 m (3H), 7.63 t (4H, ³ J _HH = 7.3 Hz).

112.4 (С₄), 123.9, 127.9, 128.5, 128.7, 129.5, 130.3, 132.2, 144.6 (все C_ArAr'), 179.2 (С₅), 204.9 (С=O). ¹³ C NMR spectrum (100 MHz, 20 mg in 0.8 ml CDCl ₃ , benchmark: CHCl ₃ = 77.00 ppm), δ, ppm: 23.3 (CH ₃ ), 23.4 (CH ₃ ), 43.9 (SOCH ₃ ), 87.6

112.4 (C ₄ ), 123.9, 127.9, 128.5, 128.7, 129.5, 130.3, 132.2, 144.6 (all C _{ArAr '} ), 179.2 (C ₅ ), 204.9 (C = O).

IR spectrum (in CCl ₄ ), cm ^-1 : 955 sr, 1051 sr, 1090 sr, 1383 s, 1616 sr, 1701 s. (C = O), 2931 words, 2982 words

HRMS mass spectrum, m / z, calculated 349.0869, found: 349.0876 [MNa] ⁺ .

Preparation of 2,2-dimethyl-4- [4 '- (methylsulfonyl) phenyl] -5-phenylfuran-3 (2H) -one intermediate (Scheme 3: 1c)

The preparation of compound 1a is described above.

Preparation of 2,2-Dimethyl-4- [4 '- (methylsulfonyl) phenyl] -5-phenylfuran-3 (2H) -one (1c).

10 ml of trifluoroacetic acid were placed in a round bottom flask with a magnetic stirrer and an air cooler, 300 mg (0.96 mmol) of compound 1a were dissolved in it at + 40 ° C, and a mixture of 0.21 g (1.96 mmol) of a 35% aqueous solution of hydrogen peroxide in 5 was added dropwise. ml of trifluoroacetic acid and 0.05 ml (1 mmol) of 98% H ₂ SO ₄ . The reaction mixture was stirred for 45 min at + 65-70 ° C (control by TLC), upon completion of the reaction, the mixture was poured into water, extracted with CH ₂ Cl ₂ (4 × 20 ml), the organic extracts were washed with NaHCO ₃ solution, water ( 3 × 5 ml), dried over K ₂ CO ₃ . After removal of the solvent, 310 mg (94%) of compound 1c was obtained, a colorless crystalline solid, mp. 181-182 ° C.

¹ H NMR spectrum (400 MHz, 25 mg in 0.8 ml CDCl ₃ , reference: CHCl ₃ = 7.260 ppm), δ, ppm: 1.58 s (6H, 2CH ₃ ), 3.04 s (3H, SO ₂ CH ₃ ), 7.38 t (2H, ³ J _HH = 7.7 Hz), 7.50-7.54 m (3H), 7.61 d (2H, ³ J _HH = 8.5 Hz), 7.91 d (2H, ³ J _HH = 8.4 Hz )

111.6 (С₄), 127.5, 128.4, 128.6, 129.2, 130.1, 132.4, 136.1, 139.0 (все C_ArAr'), 179.8 (С₅), 204.4 (С=O). ¹³ C NMR spectrum (100 MHz, 25 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 77.00 ppm), δ, ppm: 23.3 (2CH ₃ ), 43.5 (SO ₂ CH ₃ ), 87.9

111.6 (C ₄ ), 127.5, 128.4, 128.6, 129.2, 130.1, 132.4, 136.1, 139.0 (all C _{ArAr '} ), 179.8 (C ₅ ), 204.4 (C = O).

IR spectrum (in CCl ₄ ), cm ^-1 : 955 sr, 1051 sr, 1157 s, 1327 sr, 1383 sr, 1614 sr, 1701 s. (C = O), 2932 words, 2982 words

HRMS mass spectrum, m / z, calculated: 365.0818, found 365.0823 [MNa] ⁺ .

Example 1

Preparation of 2 ', 2'-dimethyl-6- (methylthio) phenantro [9,10-b] furan-3' (2'H) -one (Scheme 4, 2a).

The preparation of compound 1a is described above.

Preparation of 2 ', 2'-dimethyl-6- (methylthio) phenantro [9,10-b] furan-3' (2'H) -one (2a).

A solution of 500 mg (1.61 mmol) of 4,5-diaryl-dihydrofuran-3 (2H) -one 1a in 50 ml of dichloromethane was placed in a water-cooled quartz photochemical reactor with a volume of 50 ml. Irradiation was carried out with a mercury lamp with a power of 150 W for 4 h in the presence of atmospheric oxygen. Upon completion of the reaction, the solvent was distilled off on a rotary evaporator, the mixture was separated by fraction chromatography, and the starting material could be used for repeated photolysis (eluent: hexane-ethyl acetate-dichloromethane). Yield 2a: 70 mg (14%). The conversion of the starting furanone 6a was 14%.

¹ H NMR spectrum (400 MHz, 25 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 7.260 ppm), δ, ppm: 1.62 s (6H, 2CH ₃ ), 2.64 s (3H, SCH ₃ ), 7.60 dd (1Н, ³ J _HH = 8.5 Hz, ⁴ J _HH = 1 8 Hz), 7.70 t (1Н, ³ J _HH = 7.3 Hz), 7.90-7.84 m (1Н), 8.33 dd (1Н, ³ J _HH = 8.0 Hz, ⁴ J _HH = 1.0 Hz), 8.45 d (1H, ⁴ J _HH = 1.5 Hz), 8.63 d (1H, ³ J _HH = 8.4 Hz), 8.76 d (1H, ³ J _HH = 8.4 Hz).

96.1 (С₄), 108.2, 121.0, 122.3, 123.4, 123.4, 124.2, 125.2, 127.3, 127.9, 131.4, 135.0, 135.6, 172.4, 203.4 (С=O). ¹³ C NMR spectrum (100 MHz, 25 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 77.00 ppm), δ, ppm: 16.6 (SCH ₃ ), 23.3 (2CH ₃ ), 89.6

96.1 (C ₄ ), 108.2, 121.0, 122.3, 123.4, 123.4, 124.2, 125.2, 127.3, 127.9, 131.4, 135.0, 135.6, 172.4, 203.4 (C = O).

IR spectrum: 2982 words, 2927 words, 2855 words, 1701 pages (C = O), 1626 sr., 1591 sr., 1521 s., 1431 sr., 1181 sr., 1126 sr., 1095 sr., 891 sr.

HRMS mass spectrum, m / z, calculated 331.0764, found: 331.0769 [MNa] ⁺ .

Example 2

Preparation of 2 ', 2'-dimethyl-3- (methylthio) phenantro [9,10-b] furan-3' (2'H) -one (Scheme 5, 2b).

The preparation of compound 5a is described above.

Stage II. Preparation of 2,2-Dimethyl-5- [4 '- (methylthio) phenyl] -5-phenyl-dihydrofuran-3 (2H) -one (6a).

15.8 g (0.051 mol) of compound 5a was dissolved in 40 ml of boiling methanol, and with stirring, a mixture of 15 ml of 98% phosphoric acid and 10 ml of methanol was added dropwise. The mixture was boiled for 3 hours until the end of the reaction (TLC control). Then the mixture was poured into 100 ml of water and thoroughly extracted with methylene chloride (3 × 50 ml). The organic layer was dried with Na ₂ SO ₄ , the solvent was driven off on a rotor, and the resulting substance was dried from methanol and dichloromethane in vacuo at a pressure of 0.02–0.05 torr for 5 h. The resulting oil was crystallized using a seed and re-dried in vacuo. Received 12.6 g of substance (yield 80%) 6a. Without further purification, the resulting compound was used in the next step.

Stage III. Preparation of 4-diazo-2,2-dimethyl-5- [4 '- (methylthio) phenyl] -5-phenyl-dihydrofuran-3 (2H) -one (7a).

To a mixture of 250 mg (0.8 mmol) of furanone 6a and 228 mg (0.99 mmol) of paranitrobenzenesulfonylazide in 15 ml of dichloromethane was added dropwise a solution of 50 mg (0.33 mmol) of 1,8-diazobicyclo [5.4.0] undec-7-ene (DBU) in 1 ml of dichloromethane, and the mixture immediately turned orange-yellow. The reaction mixture was stirred at 35 ° C for 6 h until completion of the reaction (control by TLC), then it was cooled and transferred to a silica gel column, and gradient chromatography was performed with n-hexane - methylene chloride mixture. After removal of the solvent (azeotropic distillation with ethanol), the crystalline residue was dried in vacuo to give 189 mg (70%) of diazoketone 7a.

Stage IV. Preparation of 2,2-Dimethyl-5- [4 '- (methylthio) phenyl] -4-phenylfuran-3 (2H) -one (1d).

The reaction is carried out in a nitrogen atmosphere. To a solution of 200 mg (0.59 mmol) of diazoketone 7a in 10 ml of dichloromethane was added dropwise 5 ml of 70% aqueous perchloric acid (HClO ₄ ). The mixture was refluxed with vigorous stirring for 3 hours until the initial diazoketone completely disappeared (control by TLC), and upon completion of the reaction, the organic layer was separated, the aqueous layer was extracted with 10 ml of dichloromethane, then the combined organic layer was washed with an aqueous solution of NaHCO ₃ and water (2 × 5 ml) and dried Na ₂ SO ₄ and K ₂ CO ₃ . Removal of the solvent gave 180 mg (98%) of a mixture of two regioisomeric 2,2-dialkyl-4,5-diaryl-dihydrofuran-3 (2H) -ones (1: 1 ratio) as a pale yellow oily product. The reaction mixture (180 mg) was separated on a silica gel column to give furanone 1d in 91 mg (50%) yield.

¹ H NMR spectrum (400 MHz, 20 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 7.26 ppm), δ, ppm: 1.55 s (6H, 2CH ₃ ), 2.47 s (3H, SCH ₃ ), 7.15-7.17 m (1H), 7.25 d (2H, ³ J _HH = 7.6 Hz), 7.30-7.41 m (4H), 7.57 d (2H, ³ J _HH = 7.4 Hz).

¹³ C NMR spectrum (100 MHz, 20 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 77.00 ppm), δ, ppm: 15.7 (SCH ₃ ), 23.4 (2CH ₃ ), 86.9 (C (CH ₃ ) ₂ ), 113.1 (C ₄ ), 125.0, 128.6, 128.6, 129.5, 131.7, 144.2 (all C _{ArAr '} ), 177.5 (C ₅ ), 205.2 (C = O).

IR spectrum (in CCl ₄ ), cm ^-1 : 676 words, 1052 words, 1095 words, 1147 words, 1168 words, 1239 words, 1264 words, 1386 Wed, 1485 words, 1598 Wed ., 1615 sr., 1698 s., 2858 ssl., 2927 sr., 2960 sr.

HRMS mass spectrum, m / z, calculated: 311.1101, found: 311.1113 [MH] ⁺ .

Stage VI. Preparation of 2 ', 2'-dimethyl-3- (methylthio) -phenantro [9,10-b] furan-3' (2'H) -one (2b)

A solution of 500 mg (1.61 mmol) of 4,5-diaryl-dihydrofuran-3 (2H) -one 1d in 40 ml of dichloromethane was placed in a water-cooled quartz photochemical reactor with a volume of 50 ml. Irradiation was carried out with a mercury lamp with a power of 150 W for 4 h in the presence of atmospheric oxygen. Upon completion of the reaction, the solvent was distilled off on a rotary evaporator, the mixture was applied to a preparative chromatography plate and divided into fractions (eluent: hexane-ethyl acetate-dichloromethane). Yield 2b. 60 mg (12%). The conversion of the starting furanone 1d was 60%.

¹ H NMR spectrum (400 MHz, 25 mg in 0.8 ml of CDCl ₃ , reference: CHCl ₃ = 7.26 ppm), δ, ppm: 1.62 s (6H, 2CH ₃ ), 2.71 s (3H, SCH ₃ ), 7.53-7.58 m (2H), 7.66 t (1H, ³ J _HH = 7.0 Hz), 8.23 d (1H, ³ J _HH = 8.5 Hz), 8.42 d (1H, ⁴ J _HH = 1.5 Hz), 8.51 d (1H, ³ J _HH = 8.3 Hz), 8.83 dd (1H, ³ J _HH = 8 Hz, ⁴ J _HH = 1 Hz).

96.1 (С₄), 107.5, 119.3, 122.7, 123.6, 123.9, 125.1, 125.4, 125.9, 128.2, 128.8, 136.1, 144.1, 172.6, 203.1 (С=O). ¹³ C NMR spectrum (100 MHz, 25 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 77.0 ppm), δ, ppm: 15.3 (SCH ₃ ), 23.3 (2CH ₃ ), 89.5

96.1 (C ₄ ), 107.5, 119.3, 122.7, 123.6, 123.9, 125.1, 125.4, 125.9, 128.2, 128.8, 136.1, 144.1, 172.6, 203.1 (C = O).

IR spectrum (in CCl ₄ ), cm ^-1 : 2982 s, 2929 s, 2857 s, 1700 s. (C = O), 1624 s., 1614 s., 1592 sr., 1507 sr., 1458 sr., 1430 s., 1324 sr., 1187 sr., 1145 sr., 1114 sr., 892 sr.

HRMS mass spectrum, m / z, calculated: 347.0503, found 347.0518 [MK] ⁺ .

Example 3

Preparation of 2 ', 2'-dimethyl-3- (methylsulfonyl) phenantro [9,10-b] furan-3' (2'H) -one (Scheme 6, 2c).

The conduct of compound 1d is described in example 2 above.

Step V. Preparation of 2,2-dimethyl-5- [4 '- (methylsulfonyl) phenyl] -4-phenylfuran-3 (2H) -one (1e).

10 ml of trifluoroacetic acid were placed in a round bottom flask with a magnetic stirrer and an air cooler, 300 mg (0.96 mmol) of compound 1d were dissolved in it at + 40 ° C, and a mixture of 0.21 g (1.96 mmol) of a 35% aqueous hydrogen peroxide solution was added dropwise 5 ml trifluoroacetic acid and 0.05 ml (1 mmol) 98% H ₂ SO ₄ . The reaction mixture was stirred for 1 h at + 65-70 ° C (control by TLC), upon completion of the reaction, the mixture was poured into water, extracted with CH ₂ Cl ₂ (4 × 20 ml), the organic extracts were washed with NaHCO ₃ solution, water ( 3 × 5 ml), dried over K ₂ CO ₃ . After removal of the solvent, 310 mg (94%) of compound 1e were obtained, colorless crystals, mp. 201-202 ° C.

¹ H NMR spectrum (400 MHz, 20 mg in 0.8 ml CDCl ₃ , benchmark: CHCl ₃ = 7.260 ppm) δ, ppm: 1.58 s (6H, 2CH ₃ ), 3.06 s (3H, SO ₂ CH ₃ ), 7.26 - 7.40 m (5H), 7.73 d (2H, ³ J _HH = 8.5 Hz), 8.03 d (2H, ³ J _HH = 8.4 Hz).

87.5 (С₂), 115.6 (С₄), 127.4, 128.2, 128.9, 129.2, 129.4, 135.1, 142.8, 175.2 (С₅), 205.2 (С=O). ¹³ C NMR spectrum (100 MHz, 20 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 77.00 ppm) δ, ppm: 23.3 (2CH ₃ ), 43.3

87.5 (C ₂ ), 115.6 (C ₄ ), 127.4, 128.2, 128.9, 129.2, 129.4, 135.1, 142.8, 175.2 (C ₅ ), 205.2 (C = O).

IR spectrum (in CCl ₄ ), cm ^-1 : 668 sr, 955 sr, 1152 s, 1332 sr, 1704 sr (C = O).

HRMS mass spectrum: m / z = 343.0996 [MH ⁺ ] (calculation: 343.0999).

Stage VI. Preparation of 2 ', 2'-dimethyl-3- (methylsulphonyl) -phenantro [9,10-b] furan-3' (2'H) -one (2c).

A solution of 50 mg (0.2 mmol) of iodine and 545 mg (4,5 mmol) of 4,5-diaryl-dihydrofuran-3 (2H) -one 1e in 50 ml of tetrahydrofuran was placed in a water-cooled quartz photochemical reactor with a volume of 50 ml. Irradiation was carried out with a mercury lamp with a power of 150 W for 4 hours. After completion of the reaction, the solvent was distilled off on a rotary evaporator, the mixture was applied to a preparative chromatography plate and divided into fractions (eluent: hexane-ethyl acetate-dichloromethane). Yield 2c: 125 mg (23%), colorless crystalline solid, violet fluorescence (at 254 nm). The degree of conversion of the starting furanone 1e was 90%.

¹ H NMR spectrum (400 MHz, 25 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 7.26 ppm), δ, ppm: 1.67 s (6H, 2CH ₃ ), 3.21 s (3H, SO ₂ CH ₃ ), 7.71 t (1H, ³ J _HH = 8.4 Hz), 7.79 t (1H, ³ J _HH = 8.1 Hz), 8.22 dd (1H, ³ J _HH = 8.4 Hz, ⁴ J _HH = 1.5 Hz) 8.57 d (1H, ³ J _HH = 8.4 Hz), 8.68 d (1H, ³ J _HH = 8.2 Hz), 8.91 dd (1H, ³ J _HH = 8 Hz, ⁴ J _HH = 1 Hz), 9.31 d ( 1H, ⁴ J _HH = 1-5 Hz).

¹³ C NMR spectrum (100 MHz, 25 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 77.00 ppm), δ, ppm: 23.2 (2CH ₃ ), 44.7 (SO ₂ CH ₃ ), 90.2 , 110.5, 123.2, 123.5, 124.0, 124.3, 124.8, 125.1, 126.5, 128.0, 129.8, 135.8, 142.5, 171.0, 203.5 (С = O).

IR spectrum (in CCl ₄ ), cm ^-1 : 3019 words, 2981 words, 2930 words, 1705 pages, 1627 words, 1517 Wed, 1427 Wed, 1326 e., 1215 s, 1154 s ., 955 Wed, 890 words, 669 Wed, 555 Wed

HRMS mass spectrum, m / z, calculated 363.0662, found: 363.0675 [MNa] ⁺ .

Preparation of 2,2-Dimethyl-4- [4 '- (methylthio) phenyl] -5- (4'-fluorophenyl) furan-3 (2H) -one Intermediate (Scheme 7.1f).

Step 0. Preparation of 4 '- (methylthio) phenyl (4'-fluorophenyl) methanone (3b).

10.7 g of parafluorobenzoic aldehyde was dissolved in 60 ml of acetic acid at 70 ° C with stirring on a magnetic stirrer. Then, a solution of 5.5 g of CrO ₃ in 60 ml of aqueous acetic acid was added dropwise over 1.5 hours. The mixture was stirred in a water bath for 3 hours. After completion of the reaction, 100 ml of ice-cold HCl (35%) was added to the solution, the precipitated acid precipitate was filtered off on a Schott filter, washed twice with 10% hydrochloric acid. For additional purification from residues of aldehyde and chromium salts, the resulting product was recrystallized from a mixture of methylene chloride-methanol, and the mother liquor was passed through a silica gel column. The product yield after vacuum drying was 4.96 g (42%). 4.96 g of parafluorobenzoic acid, 25 ml of tetrachlorocarbon were added to a round bottom flask with a magnetic stirrer, and then a mixture of 4 ml of distilled thionyl chloride SOCl ₂ with 0.05 ml of dimethylformamide in 25 ml of tetrachlorocarbon was carefully added. The mixture was refluxed for 5 hours until the evolution of gaseous products was complete. Then, the solvent and residues of thionyl chloride were removed in a vacuum of a rotary evaporator. The resulting oil, weighing 5.6 g (97% of theoretical yield), after short vacuum drying, without further purification, was dissolved in 20 ml of methylene chloride and, with cooling, 5 g of anhydrous aluminum chloride, 4.38 g (35 mmol) of thioanisole were added dropwise to the suspension and 30 ml of methylene chloride. After adding the entire amount of the acid chloride, the mixture was refluxed for 4 hours until the evolution of HCl was completely stopped. The resulting product was carefully hydrolyzed with 5% hydrochloric acid, extracted with methylene chloride (3 × 30 ml), dried over Na ₂ SO ₄ , and after distillation of the solvent, it was recrystallized from hexane to remove excess thioanisole. The yield of crystalline 4 '- (methylthio) phenyl (4'-fluorophenyl) methanone (3b) was 6.48 g (75%), colorless crystals, mp. 107-108 ° C.

¹ H NMR spectrum (400 MHz, 30 mg in 0.8 ml CDCl ₃ ), δ, ppm: 2.535 s (3H, SCH ₃ ), 7.15 t (2H, ³ J _HH = 8.6 Hz), 7.29 d (2H , ³ J _HH = 8.4 Hz), 7.71 d (2H, ³ J _HH = 8.5 Hz), 7.81 dd (2H, ³ J _HH = 8.7 Hz, ⁴ J _HF = 5.5 Hz).

¹³ C NMR spectrum (100 MHz, 30 mg in 0.8 ml CDCl ₃ ), δ, ppm: 14.8 (SCH ₃ ), 115.4 d (2С), 124.9 (2С), 130.4 (2С), 132.4 d (2С) ), 133.4, 133.8, 145.4, 137.7, 145.2, 165.2 d ( ¹ J _CF = 254 Hz), 194.3 (С = O).

¹⁹ F NMR spectrum (376 MHz, 30 mg in 0.8 ml CDCl ₃ ), δ, ppm: -106.3.

HRMS mass spectrum, m / z, calculated: 247.0588, found: 247.0598 [MH] ⁺ .

Perfluorobenzoic acid, ¹ H NMR spectrum (400 MHz, 30 mg in 0.8 ml CDCl ₃ ), δ, ppm: 7.154 t (2H, ³ J _HH = 8.6 Hz), 8.135 dd (2H, ³ J _HH = 8.7 Hz, ⁴ J _HF = 5.4 Hz).

Step I. Preparation of 2-methyl-5- (4'-fluorophenyl) -5- (4'-methylthiophenyl) pent-3-yn-2,5-diol (5b).

To a solution of EtMgBr prepared from 2.3 g (95 mmol) of magnesium and 10.3 g (95 mmol) of ethyl bromide in 40 ml of absolute diethyl ether, while cooling in an ice bath, a solution of 3.1 g (37 mmol) of 2-methylbut-3- was slowly added dropwise. in-2-ol in 25 ml of absolute benzene. The mixture was boiled for 3 hours, then, without stopping boiling, a solution of 6.4 g (26 mmol) of compound 3b in 25 ml of benzene was added dropwise over 2 hours and then boiled for 5 hours. Then the mixture was cooled and carefully hydrolyzed with 100 ml of 5% cold hydrochloric acid solution. The organic layer was separated from the aqueous. The aqueous layer was extracted with benzene (3 × 20 ml) and methylene chloride (1 × 20 ml). The combined organic fractions were washed with NaHCO ₃ solution, water and dried over Na ₂ SO ₄ . After distilling off the solvent, the obtained yellow oily product was chromatographed into 3 fractions: the target 1,4-diol, the initial unreacted substituted benzophenone and the byproduct of dimerization of benzophenone to 1,2-diol. In order to reduce the amount of by-products and increase the conversion percentage, it is necessary to use a lack of magnesium and a very slow addition of benzophenone during the reaction, so that its concentration remains insignificant. The purified γ-glycol was dried in vacuum at a pressure of 0.01–0.05 torr for 5 hours. Yield of 1,4-diol 5b 4.5 g (52%), yellow oily substance.

¹ H NMR spectrum (400 MHz, 20 mg in 0.8 ml CDCl ₃ ), δ, ppm: 1.54 s (6H, 2CH ₃ ), 2.45 s (3H, SCH ₃ ), 3.32 s (1H, -OH) , 6.97 t (2H, ³ J _HH = 8.7 Hz), 7.18 d (2H, ³ J _HH = 8.6 Hz), 7.44 d (2H, ³ J _HH = 8.6 Hz), 7.51 dd (2H, ³ J _HH = 8.9 Hz, ⁴ J _HF = 5.3 Hz).

73.4, 84.5

92.0

115.0 д (2С, ²J_HF=21.6 Гц), 126.3 д (2С), 127.8 д (2С), 138.2, 140.7, 141.7, 162.1 д (1С, ¹J_HF=246.6 Гц). Спектр ЯМР ¹⁹F (376 МГц, 30 мг в 0.8 мл CDCl₃), δ, м.д.: -114.8. ¹³ C NMR spectrum (100 MHz, 20 mg in 0.8 ml CDCl ₃ ), δ, ppm: 15.6 (SCH ₃ ), 31.2 (2CH ₃ ), 65.3

73.4, 84.5

92.0

115.0 d (2C, ² J _HF = 21.6 Hz), 126.3 d (2C), 127.8 d (2C), 138.2, 140.7, 141.7, 162.1 d (1C, ¹ J _HF = 246.6 Hz). ¹⁹ F NMR spectrum (376 MHz, 30 mg in 0.8 ml of CDCl ₃ ), δ, ppm: -114.8.

IR spectrum (in CCl ₄ ), cm ^-1 : 836 s, 957 sr, 1081 sr, 1158 s, 1232 s, 1365 s, 1506 s, 1601 s, 1682 s, 2930 s ., 2984 cf. (CH), 3469 words (broad., OH), 3605 words (IT).

HRMS mass spectrum, m / z, calculated: 353.0982, found: 353.1064 [MNa] ⁺ .

Stage II. Preparation of 2,2-Dimethyl-5- [4 '- (methylthio) phenyl] -5- (4'-fluorophenyl) dihydrofuran-3 (2H) -one (6b).

3.55 g of compound 5b was dissolved in 30 ml of boiling methanol, and with stirring, a solution of 2.5 ml of 98% sulfuric acid dissolved in 30 ml of methanol was added dropwise. The mixture was boiled for 3 hours until the end of the reaction (TLC control). Then the mixture was poured into 100 ml of water and thoroughly extracted with methylene chloride (3 × 50 ml). The organic layer was dried over Na ₂ SO ₄ , the solvent was driven off on a rotor, and the resulting substance was dried from methanol and dichloromethane in vacuo at a pressure of 0.02–0.05 torr for 5 h. 3.30 g (84%) of oily product 6b was obtained, colorless oily substance. Without further purification, the resulting compound was used in the next step.

¹ H NMR spectrum (400 MHz, 25 mg in 0.7 ml CDCl ₃ ), δ, ppm: 1.20 s (3H, CH ₃ ), 1.22 s (3H, CH ₃ ), 2.45 s (3H, SCH ₃ ) , 3.30 dd (2H, CH ₂ ), 7.00 t (2H, ³ J _HH = 8.7 Hz), 7.19 d (2H, ³ J _HH = 8.5 Hz), 7.30 d (2H, ³ J _HH = 8.5 Hz), 7.36 dd (2H, ³ J _HH = 8.8 Hz, ⁴ J _HF = 5.3 Hz).

82.0, 115.1 д (2С), 126.2 (2С), 126.4 (2С), 127.7 д (2С), 138.0, 141.9 д (1С), 142.6, 162.0 d (¹J_CF=254 Гц), 216.4 (С=O). ¹³ C NMR spectrum (100 MHz, 25 mg in 0.7 ml CDCl ₃ ), δ, ppm: 15.3 (SCH ₃ ), 25.2 d (2CH ₃ ), 48.0 (CH ₂ ), 81.4

82.0, 115.1 d (2С), 126.2 (2С), 126.4 (2С), 127.7 d (2С), 138.0, 141.9 d (1С), 142.6, 162.0 d ( ¹ J _CF = 254 Hz), 216.4 (С = O )

¹⁹ F NMR spectrum (376 MHz, 30 mg in 0.8 ml CDCl ₃ ), δ, ppm: -115.1. IR spectrum (in CCl ₄ ), cm ^-1 : 837 sr., 993 sr., 1097 sr., 1159 sr., 1236 s., 1508 s., 1604 s., 1761 s. (C = O), 2983 words (CH).

HRMS mass spectrum, m / z, calculated: 353.0982, found: 353.1026 [MNa] ⁺ .

Stage III. Preparation of 4-diazo-2,2-dimethyl-5- [4 '- (methylthio) phenyl] -5- (4'-fluorophenyl-dihydrofuran-3 (2H) -one (7b).

To a mixture of 3 g of furanone 6b and 1.8 g of paratoluenesulfonylazide in 50 ml of dichloromethane was added dropwise a solution of 350 mg of 1,8-diazobicyclo [5.4.0] undec-7-ene (DBU) in 25 ml of dichloromethane, and the mixture was immediately stained with orange yellow color. The reaction mixture was stirred at 35 ° C for 7 h until completion of the reaction (control by TLC), then cooled, excess solvent was distilled off, transferred to a silica gel column, and n-hexane - methylene chloride was subjected to gradient chromatography. After removing the solvent, the crystalline residue was dried in vacuo to give 2.80 g (84%) of diazoketone 7b, a yellow oily substance.

¹ H NMR spectrum (400 MHz, 25 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 7.260 ppm) δ, ppm: 1.33 s (3H, CH ₃ ), 1.34 s (3H, CH ₃ ), 2.48 s (3H, SCH ₃ ), 7.05 t (2H, ³ J _HH = 8.6 Hz), 7.25-7.18 m (4H, PhSCH ₃ ), 7.29 dd (2H, ³ J _HH = 8.8 Hz, ⁴ J _HF = 5.2 Hz). ¹³ C NMR spectrum (100 MHz, 25 mg in 0.8 ml of CDCl ₃ , reper: CHCl ₃ = 77.00 ppm) δ, ppm: 15.3 (SCH ₃ ), 25.2 (2CH ₃ ), 64.3 (C = N ₂ ), 83.6 (С ₅ ), 85.5 (С ₂ ), 115.4 d (2С, ² J _CF = 21.7 Hz), 126.1 (2С), 126.8 (2С), 128.3 d (2С, ³ J _CF = 8.3 Hz ), 139.3, 139.4 d (1С, ⁴ J _CF = 3.2 Hz), 140.1, 162.5 d (1С, ¹ J _CF = 248.2 Hz), 196.7 (С = O). Spectrum ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ, ppm: -113.40.

IR spectrum (in CCl ₄ ), cm ^-1 : 909 words, 1025 words, 1093 words, 1157 sr., 1231 sr., 1344 s., 1507 sr., 1695 s. (C = O), 2089 s. (CN ₂ ), 2928 words, 2986 words

HRMS mass spectrum, m / z, calculated for C ₁₉ H ₁₇ FN ₂ O ₂ SNa ⁺ : 379.0887; Found: 379.0922 [M + Na ⁺ ].

Stage IV. Preparation of 2,2-Dimethyl-4- (4 '- (methylthio) phenyl) -5- (4'-fluorophenyl) furan-3 (2H) -one (1f).

The reaction is carried out in a nitrogen atmosphere. A solution of 2.0 g of diazoketone 7a in 30 ml of trifluoroacetic acid was boiled for 3 hours until the initial diazoketone completely disappeared (control by TLC). Upon completion of the reaction, trifluoroacetic acid was removed in vacuo, the precipitate was dissolved in 25 ml of methylene chloride, washed thoroughly with an aqueous solution of NaHCO ₃ , water (2 × 5 ml) and dried over K ₂ CO ₃ . Removal of the solvent gave 1.80 g (98%) of a mixture of two regioisomeric 2,2-dialkyl-4,5-diaryl-dihydrofuran-3 (2H) -ones in an approximate ratio of 3: 1 as a pale yellow oily product. The reaction mixture (1.8 g) was separated on a silica gel column to give furanone 1f with a yield of 1.33 g (74%), a light yellow oily substance or crystals.

¹ H NMR spectrum (400 MHz, 25 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 7.26 ppm), δ, ppm: 1.54 s (6H, 2CH ₃ ), 2.49 s (3H, SCH ₃ ), 7.05 t (2H, ³ J _HH = 8.7 Hz), 7.20-7.25 m (4H, PhSCH ₃ ), 7.68 dd (2H, ³ J _HH = 8.9 Hz, ⁴ J _HF = 5.4 Hz).

112.8 (С₄), 115.7 д (2С, ²J_CF=21.9 Гц), 126.4, 126.6 (2С), 128.5, 129.8 (2С), 130.7 д (2С, ³J_CF=8.9 Гц), 138.0, 164.7 д (1С, ¹J_CF=254.0 Гц), 176.8 (С₅), 205.2 (С=O). ¹³ C NMR spectrum (100 MHz, 25 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 77.00 ppm), δ, ppm: 15.6 (SCH ₃ ), 23.4 (2CH ₃ ), 87.1

112.8 (С ₄ ), 115.7 d (2С, ² J _CF = 21.9 Hz), 126.4, 126.6 (2С), 128.5, 129.8 (2С), 130.7 d (2С, ³ J _CF = 8.9 Hz), 138.0, 164.7 d (1C, ¹ J _CF = 254.0 Hz), 176.8 (C ₅ ), 205.2 (C = O).

Spectrum ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ, ppm: -106.3.

HRMS mass spectrum, m / z, calculated 329.1007, found 329.1021 [MH] ⁺ .

Preparation of 2,2-dimethyl-4- [4 '- (methylsulfinyl) phenyl] -5- (4'-fluorophenyl) furan-3 (2H) -one intermediate (Scheme 8, 1g).

The preparation of compound 7b is described above.

Stage IV-V. Preparation of 2,2-Dimethyl-4- [4 '- (methylsulfinyl) phenyl] -5- (4'-fluorophenyl) furan-3 (2H) -one (1g).

The reaction was carried out in a nitrogen atmosphere. 10 ml of trifluoroacetic acid were placed in a round bottom flask with a magnetic stirrer and an air cooler and 342 mg (0.96 mmol) of compound 7b were dissolved in it and this solution was boiled for 3 hours. Then it was cooled to 50 ° C and a mixture of 100 mg of 35% (0.96 mmol) of a fresh aqueous solution of hydrogen peroxide in 5 ml of trifluoroacetic acid and 0.025 ml (0.5 mmol) of 98% H ₂ SO _{4 was} carefully added dropwise with vigorous stirring over 1 h. . In this reaction, it is very important to observe the exact equimolar ratio of hydrogen peroxide to 7b. The reaction mixture was stirred for another 1 h at + 50-55 ° C (control using TLC). Upon completion of the reaction, the mixture was poured into water, neutralized with sodium carbonate, extracted with ethyl acetate (4 × 20 ml). The organic extracts were washed with NaHCO ₃ solution, water (3 × 5 ml), dried over Na ₂ SO ₄ and K ₂ CO ₃ , and, after removal of the solvent and chromatographic separation of regioisomeric sulfoxides, 190 mg (61%) of compound 1e, light yellow oily substance.

¹ H NMR spectrum (400 MHz, 25 mg in 0.8 ml CDCl ₃ , reference: CHCl ₃ = 7.26 ppm), δ, ppm: 1.54 s (6H, 2CH ₃ ), 2.72 s (3H, SOCH ₃ ), 7.04 t (2H, ³ J _HH = 8.7 Hz), 7.45-7.47 m (2H), 7.60-7.65 dd (4H).

112.0, 115.9 д (2С, ²J_CF=21.9 Гц), 123.9 (2С), 130.3 (2С), 130.7 д (2С, ³J_CF=8.9 Гц), 133.1, 144.5, 164.8 д (1С, ¹J_CF=254.0 Гц), 177.7 (С₅), 204.5 (С=O). ¹³ C NMR spectrum (100 MHz, 25 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 77.00 ppm), δ, ppm: 23.4 (2CH ₃ ), 43.6 (SOCH ₃ ), 87.6

112.0, 115.9 d (2С, ² J _CF = 21.9 Hz), 123.9 (2С), 130.3 (2С), 130.7 d (2С, ³ J _CF = 8.9 Hz), 133.1, 144.5, 164.8 d (1С, ¹ J _CF = 254.0 Hz), 177.7 (C ₅ ), 204.5 (C = O).

Spectrum ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ, ppm: -105.4. IR spectrum (in CCl ₄ ), cm ^-1 : 842 cf., 902 cf., 1049 cf. (S = O), 1161 sr., 1242 s., 1381 s., 1515 sr., 1616 s., 1703 s. (C = O), 2980 (CH).

LCMS mass spectrum, m / z, calculated 345.0956, found 353.1015 [MH] ⁺ .

Preparation of 2,2-dimethyl-4- [4 '- (methylsulfonyl) phenyl] -5- (4'-fluorophenyl) furan-3 (2H) -one intermediate (Scheme 9, 1h).

The preparation of compound 7b is described above.

Stage IV-V. Preparation of 2,2-Dimethyl-4- [4 '- (methylsulfonyl) phenyl] -5- (4'-fluorophenyl) furan-3 (2H) -one (1h).

The reaction was carried out in a nitrogen atmosphere. 10 ml of trifluoroacetic acid were placed in a round bottom flask with a magnetic stirrer and an air cooler and 342 mg (0.96 mmol) of compound 7b were dissolved in it and this solution was boiled for 3 hours. Then, without stopping boiling, a mixture of 200 mg of 34% (1.98 mmol) of an aqueous solution of hydrogen peroxide in 5 ml of trifluoroacetic acid and 0.025 ml (0.5 mmol) of 98% H ₂ SO _{4 was} added dropwise over 10 min. In this reaction, it is very important to observe an exact 2-fold molar ratio of hydrogen peroxide to 7b to prevent oxidation of the double bond in compound 1h. The reaction mixture was stirred for another 2 hours at + 65-70 ° C (control by TLC). Upon completion of the reaction, the mixture was poured into water, the acid was neutralized with sodium carbonate, the organic substances were extracted with ethyl acetate (4 × 20 ml). The organic extracts were washed with NaHCO ₃ solution, water (3 × 5 ml), dried over Na ₂ SO ₄ and K ₂ CO ₃ , and, after removal of the solvent and chromatographic separation of regioisomeric sulfones, 225 mg (72%) of 1h, light yellow oily substance.

¹ H NMR spectrum (400 MHz, 25 mg in 0.8 ml CDCl ₃ , reference: CHCl ₃ = 7.26 ppm), δ, ppm: 1.57 s (6H, 2CH ₃ ), 3.06 s (3H, SO ₂ CH ₃ ), 7.09 t (2H, ³ J _HH = 8.5 Hz), 7.52 d (2H, ³ J _HH = 8.0 Hz), 7.63 dd (2H, ³ J _HH = 8.8 Hz, ⁴ J _HF = 5.4 Hz) 7.92 d (2H, ³ J _HH = 8.0 Hz).

116.2 д (2С, ²J_CF=22.0 Гц), 126.3 (1С), 127.8 (2С), 130.2 (2С), 130.9 д (2С, ³J_CF=9.0 Гц), 136.1, 139.3, 165.1 д (1С, ¹J_CF=255.4 Гц), 178.4 (С₅), 204.2 (С=O). Спектр ¹⁹F NMR (376 МГц, CDCl₃) δ, м.д.: -104.8. ¹³ C NMR spectrum (100 MHz, 25 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 77.00 ppm), δ, ppm: 23.3 (2CH ₃ ), 44.5 (SO ₂ CH ₃ ), 88.0

116.2 d (2С, ² J _CF = 22.0 Hz), 126.3 (1С), 127.8 (2С), 130.2 (2С), 130.9 d (2С, ³ J _CF = 9.0 Hz), 136.1, 139.3, 165.1 d (1С, ¹ J _CF = 255.4 Hz), 178.4 (C ₅ ), 204.2 (C = O). Spectrum ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ, ppm: -104.8.

IR spectrum (in CCl ₄ ), cm ^-1 : 955 sr, 1157 s. (SO ₂ ) 1243 sr., 1327 s. (SO ₂ ), 1383 sr., 1613 sr., 1704 s. (C = O), 2933 (CH).

LCMS mass spectrum, m / z, calculated 361.0905, found 361.0953 [MH] ⁺ .

Example 4

Preparation of 2 ', 2'-dimethyl-6- (methylsulfonyl) -3-fluorophenantro [9,10-b] furan-3' (2'H) -one (Scheme 10, 2d).

The preparation of compound 1f is as described above.

Stage VI. Preparation of 2 ', 2'-dimethyl-6- (methylsulfonyl) -3-fluorophenantro [9,10-b] furan-3' (2'H) -one (2d).

A solution of 50 mg (0.2 mmol) of iodine and 525 mg (1.46 mmol) of 4,5-diaryl-dihydrofuran-3 (2H) -one 1f in 50 ml of tetrahydrofuran was placed in a water-cooled quartz photochemical reactor with a volume of 50 ml. Irradiation was carried out with a mercury lamp with a power of 150 W for 4 hours. After completion of the reaction, the solvent was distilled off on a rotary evaporator, the mixture was applied to a preparative chromatography plate and divided into fractions (eluent: hexane-ethyl acetate-dichloromethane).

Preparation of 2,2-dimethyl-4- [4 '- (methylthio) phenyl] -5- (4'-chlorophenyl) furan-3 (2H) -one intermediate (Scheme 11, 1i).

Step 0. Preparation of 4 '- (methylthio) phenyl (4'-chlorophenyl) methanone (3c).

5 g (36 mmol) of parachlorobenzoic aldehyde was dissolved in 30 ml of acetic acid at 70 ° C and stirring on a magnetic stirrer. Then, a solution of 2.4 g (24 mmol) of CrO ₃ in 30 ml of aqueous acetic acid was added dropwise over 1.5 hours. The mixture was stirred in a water bath for 3 hours (100 ° C). After completion of the reaction, 50 ml of ice-cold HCl (35%) was added to the solution, the precipitated acid precipitate was filtered off on a Schott filter and washed twice with 10% hydrochloric acid. For additional purification from residues of aldehyde and chromium salts, the resulting product was recrystallized from a mixture of methylene chloride-methanol, and the mother liquor was passed through a silica gel column. The yield of parachlorobenzoic acid after vacuum drying was 3.71 g (66%). 3.71 g of parachlorobenzoic acid, 20 ml of tetrachlorocarbon was added to a round bottom flask with a magnetic stirrer, and then a mixture of 2.6 ml of distilled thionyl chloride SOCl ₂ with 0.025 ml of dimethylformamide in 20 ml of tetrachlorocarbon was carefully added. The mixture was refluxed for 5 hours until the evolution of gaseous products was complete. Then, the solvent and residues of thionyl chloride were removed in a vacuum of a rotary evaporator. The resulting oil, weighing 4.1 g (99% of theoretical yield), after short vacuum drying, without further purification, was dissolved in 15 ml of methylene chloride and 3.4 g of anhydrous aluminum chloride, 2.9 g (23 mmol) of thioanisole were added dropwise to the suspension. and 15 ml of methylene chloride. After adding the entire amount of the acid chloride, the mixture was refluxed for 4 hours until the evolution of HCl was completely stopped. The resulting product was carefully hydrolyzed with 5% hydrochloric acid, extracted with methylene chloride (3 × 30 ml), dried over Na ₂ SO ₄ , and after distillation of the solvent, it was recrystallized from hexane to remove excess thioanisole. The yield of crystalline 4 '- (methylthio) phenyl (4'-chlorophenyl) methanone (3c) was 4.3 g (70%), colorless crystals, mp. 132-133 ° C.

¹ H NMR spectrum (400 MHz, 20 mg in 0.8 ml CDCl ₃ ), δ, ppm: 2.524 s (3H, SCH ₃ ), 7.28 d (2H, ³ J _HH = 8.5 Hz), 7.44 d (2H , ³ J _HH = 8.5 Hz), 7.70 d (2H, ³ J _HH = 8.7 Hz), 7.71 d (2H, ³ J _HH = 8.8 Hz).

¹³ C NMR spectrum (100 MHz, 20 mg in 0.8 ml of CDCl ₃ ), δ, ppm: 14.7 (SCH ₃ ), 124.8 (2С), 128.5 (2С), 130.4 (2С), 131.2 (2С), 133.1, 136.1, 138.5, 145.6, 194.4 (C = O).

Parachlorobenzoic acid, ¹ H NMR spectrum (400 MHz, 10 mg in 0.8 ml (CD ₃ ) ₂ CO), δ, ppm: 7.57 d (2H, ³ J _HH = 8.8 Hz), 8.05 d (2H, ³ J _HH = 8.7 Hz).

Step I. Preparation of 2-methyl-5- (4'-chlorophenyl) -5- (4'-methylthiophenyl) pent-3-yn-2,5-diol (5b).

To a solution of EtMgBr prepared from 1.65 g (69 mmol) of magnesium and 7.5 g (69 mmol) of ethyl bromide in 30 ml of absolute diethyl ether, while cooling in an ice bath, a solution of 2.25 g (27 mmol) of 2-methylbut-3- was slowly added dropwise. in-2-ol in 20 ml of absolute benzene. The mixture was boiled for 3 hours, then, without stopping boiling, a solution of 4.9 g (19 mmol) of compound 3c in 20 ml of benzene was added dropwise over 2 hours and then boiled for 4 hours. Then the mixture was cooled and carefully hydrolyzed with 100 ml of 5% cold hydrochloric acid solution. The organic layer was separated from the aqueous. The aqueous layer was extracted with benzene (3 × 20 ml) and methylene chloride (1 × 20 ml). The combined organic fractions were washed with NaHCO ₃ solution, water and dried over Na ₂ SO ₄ . After distilling off the solvent, the obtained yellow oily product was chromatographed into 3 fractions: the target 1,4-diol, the initial unreacted substituted benzophenone and the byproduct of dimerization of benzophenone to 1,2-diol. In order to reduce the amount of by-products and increase the conversion percentage, it is necessary to use a lack of magnesium and a very slow addition of benzophenone during the reaction, so that its concentration remains insignificant. The purified γ-glycol was dried in vacuum at a pressure of 0.01–0.05 torr for 5 hours. Yield of 1,4-diol 5c 1.56 g (23%), yellow crystalline substance, mp. 112-113 ° C. The main reaction product is 1,2-bis (4-chlorophenyl) -1,2-bis (4- (methylthio) phenyl) ethane-1,2-diol.

¹ H NMR spectrum (400 MHz, 20 mg in 0.8 ml CDCl ₃ ), δ, ppm: 1.54 s (6H, 2CH ₃ ), 2.44 s (3H, SCH ₃ ), 7.17 d (2H, ³ J _HH = 8.7 Hz), 7.25 d (2H, ³ J _HH = 8.8 Hz), 7.43 d (2H, ³ J _HH = 8.8 Hz), 7.46 d (2H, ³ J _HH = 8.9 Hz).

73.4, 84.3

92.0

126.2 (2С), 126.3 (2С), 127.3 (2С), 128.3 (2С), 133.5, 138.3, 141.4, 143.4. ¹³ C NMR spectrum (100 MHz, 20 mg in 0.8 ml CDCl ₃ ), δ, ppm: 15.5 (SCH ₃ ), 31.2 (2CH ₃ ), 65.3

73.4, 84.3

92.0

126.2 (2C), 126.3 (2C), 127.3 (2C), 128.3 (2C), 133.5, 138.3, 141.4, 143.4.

IR spectrum (in KBr), cm ^-1 : 829 s., 993 s., 1015 s., 1093 s., 1135 sr., 1161 sr., 1239 sr., 1399 sr., 1491 s., 1592 sr. , 1707 words, 2923 words, 2979 sr., 3309 o.s., 3402 o.s.

LCMS mass spectrum, m / z, calculated 369.0687, found 369.0742 [MNa] ⁺ .

Stage II. Preparation of 2,2-dimethyl-5- [4 '- (methylthio) phenyl] -5- (4'-chlorophenyl) dihydrofuran-3 (2H) -one (6c).

1.15 g of compound 5c was dissolved in 20 ml of boiling methanol, and a solution of 1.9 ml of 98% sulfuric acid dissolved in 20 ml of methanol was added dropwise with stirring. The mixture was boiled for 4 hours until the end of the reaction (control by TLC). Then the mixture was poured into 50 ml of water and thoroughly extracted with methylene chloride (3 × 25 ml). The organic layer was dried over Na ₂ SO ₄ , the solvent was driven off on a rotor, and the resulting substance was dried from methanol and dichloromethane in vacuo at a pressure of 0.02–0.05 torr for 5 h. 1.19 g was obtained (NMR with the internal standard indicates 91% yield) of an oily product 6s Without further purification, the resulting compound was used in the next step.

¹ H NMR spectrum (400 MHz, 15 mg in 0.7 ml CDCl ₃ ), δ, ppm: 1.19 s (3H, CH ₃ ), 1.21 s (3H, CH ₃ ), 2.44 s (3H, SCH ₃ ) 3.31 dd (2H, CH ₂ ), 7.21-7.38 m (8H).

LCMS mass spectrum, m / z, calculated 369.0687, found 369.0720 [MNa] ⁺ .

Stage III. Preparation of 4-diazo-2,2-dimethyl-5- [4 '- (methylthio) phenyl] -5- (4'-chlorophenyl) dihydrofuran-3 (2H) -one (7c).

To a mixture of 1.1 g of furanone 6c and 0.63 g of paratoluenesulfonylazide in 25 ml of dichloromethane was added dropwise a solution of 120 mg of 1,8-diazobicyclo [5.4.0] undec-7-ene (DBU) in 25 ml of dichloromethane, and the mixture was immediately stained with orange yellow color. The reaction mixture was stirred at 35 ° C for 8 h until completion of the reaction (control by TLC), then the excess solvent was distilled off, transferred to a silica gel column and chromatographed in a gradient mode with n-hexane - methylene chloride mixture. After removing the solvent, the crystalline residue was dried in vacuo to give 0.9 g (75%) of diazoketone 7c, a yellow oily substance.

¹ H NMR spectrum (400 MHz, 25 mg in 0.8 ml CDCl ₃ , reference: CHCl ₃ = 7.260 ppm) δ, ppm: 1.33 s (6H, 2CH ₃ ), 2.48 s (3H, SCH ₃ ), 7.21-7.26 m (6Н), 7.34 d (2Н, ³ J _HH = 8.4 Hz).

¹³ C NMR spectrum (100 MHz, 25 mg in 0.8 ml of CDCl ₃ , reference: CHCl ₃ = 77.00 ppm) δ, ppm: 15.3 (SCH ₃ ), 25.2 (2CH ₃ ), 64.0 (C = N ₂ ), 83.5 (С ₅ ), 85.6 (С ₂ ), 126.1 (2С), 126.8 (2С), 127.8 (2С), 128.7 (2С), 134.4, 139.4, 139.8, 142.2, 196.6 (С = O) .

IR spectrum (in CCl ₄ ), cm ^-1 : 1093 sr., 1165 sr., 1227 sr., 1344 s., 1491 sr., 1697 s. (C = O), 2091 points. from. (CN ₂ ), 2924 words, 2982 words

HRMS mass spectrum, m / z calculated for C ₁₉ H ₁₇ ClN ₂ O ₂ SNa ⁺ : 395.0592, found 395.0612 [MNa ⁺ ].

Stage IV. Preparation of 2,2-Dimethyl-4- [4 '- (methylthio) phenyl] -5- (4'-chlorophenyl) furan-3 (2H) -one (1i).

The reaction is carried out in a nitrogen atmosphere. To a solution of 300 mg of diazoketone 7 s in 15 ml of dichloromethane was added dropwise 0.2 ml of trifluoromethanesulfonic acid (TfOH) dissolved in 5 ml of methylene chloride. The mixture was boiled for 3 hours until the initial diazoketone completely disappeared (control by TLC), and upon completion of the reaction, the mixture was washed with an aqueous solution of NaHCO ₃ , water (2 × 5 ml) and dried over K ₂ CO ₃ . Removal of the solvent gave 273 mg (98%) of a mixture of two regioisomeric 2,2-dialkyl-4,5-diaryl-dihydrofuran-3 (2H) -ones in an approximate ratio of 3: 1 as a light yellow oily product. The reaction mixture (273 mg) was separated on a silica gel column to give 205 mg (75%) of furanone 1i as a pale yellow oily substance.

¹ H NMR spectrum (400 MHz, 5 mg in 0.8 ml CDCl ₃ , reference: CHCl ₃ = 7.260 ppm), δ, ppm: 1.54 s (6H, 2CH ₃ ), 2.49 s (3H, SCH ₃ ), 7.20-7.24 m (4Н, PhSCH ₃ ), 7.33 d (2Н, ³ J _HH = 8.6 Hz), 7.60 d (2Н, ³ J _HH = 8.6 Hz).

113.3 (С₄), 126.6 (2С), 128.8 (2С), 128.9, 129.7 (2С), 129.8 (2С), 130.8, 138.0, 138.2, 176.6 (С₅), 205.2 (С=O). ¹³ C NMR spectrum (100 MHz, 25 mg in 0.8 ml CDCl ₃ , reference: CHCl ₃ = 77.00 ppm), δ, ppm: 15.6 (SCH ₃ ), 23.3 (2CH ₃ ), 87.1

113.3 (С ₄ ), 126.6 (2С), 128.8 (2С), 128.9, 129.7 (2С), 129.8 (2С), 130.8, 138.0, 138.2, 176.6 (С ₅ ), 205.2 (С = O).

HRMS mass spectrum, m / z calculated 345.0711, found 345.0728 [MN] ⁺ .

Preparation of 2,2-dimethyl-4- [4 '- (methylsulfinyl) phenyl] -5- (4'-chlorophenyl) furan-3 (2H) -one intermediate (Scheme 12, 1j).

The preparation of compound 7 c is described above.

Stage IV-V. Preparation of 2,2-Dimethyl-4- [4 '- (methylsulfinyl) phenyl] -5- (4'-chlorophenyl) furan-3 (2H) -one (1j).

The reaction was carried out in a nitrogen atmosphere. In a round bottom flask with a magnetic stirrer and an air cooler, 10 ml of trifluoroacetic acid were placed and 360 mg (0.96 mmol) of compound 7 s were dissolved in it and this solution was boiled for 3 hours. Then it was cooled to 40 ° C and a mixture of 100 mg of 35% (0.96 mmol) of a fresh aqueous solution of hydrogen peroxide in 5 ml of trifluoroacetic acid and 0.025 ml (0.5 mmol) of 98% H ₂ SO _{4 was} carefully added dropwise with vigorous stirring over 1 h. . In this reaction, it is very important to observe the exact equimolar ratio of hydrogen peroxide to 7 s. The reaction mixture was stirred for another 1 h at + 50-55 ° C (reaction control using TLC). Upon completion of the reaction, the mixture was poured into water, neutralized with sodium carbonate, carefully extracted with ethyl acetate (4 × 20 ml). The organic extracts were washed with NaHCO ₃ solution, water (3 × 5 ml), dried over Na ₂ SO ₄ and K ₂ CO ₃ , and, after removal of the solvent and chromatographic separation of regioisomeric sulfoxides, 217 mg (63%) of compound 1j, light yellow oily substance.

¹ H NMR spectrum (400 MHz, 25 mg in 0.8 ml of CDCl ₃ , reper: CHCl ₃ = 7.26 ppm), δ, ppm: 1.54 s (6H, 2CH ₃ ), 2.74 s (3H, SOCH ₃ ), 7.32 d (2H, ³ J _HH = 7.4 Hz), 7.45 (2H, ³ J _HH = 7.5 Hz), 7.58 d (2H, ³ J _HH = 7.4 Hz), 7.73 d (2H, ³ J _HH = 7.5 Hz).

Mass spectrum LCMS, m / z calculated 361.0660, found 361.0740 [MH] ⁺ .

Preparation of 2,2-dimethyl-4- [4 '- (methylsulfonyl) phenyl] -5- (4'-chlorophenyl) furan-3 (2H) -one intermediate (Scheme 13, 1k).

The preparation of compound 7c is described above.

Stage IV-V. Preparation of 2,2-Dimethyl-4- [4 '- (methylsulfonyl) phenyl] -5- (4'-chlorophenyl) furan-3 (2H) -one (1k).

The reaction was carried out in a nitrogen atmosphere. 10 ml of trifluoroacetic acid were placed in a round bottom flask with a magnetic stirrer and an air cooler and 360 mg (0.96 mmol) of compound 7c were dissolved in it and this solution was boiled for 3 hours. Then, without stopping boiling, a mixture of 200 mg of 34% (1.98 mmol) of an aqueous solution of hydrogen peroxide in 5 ml of trifluoroacetic acid and 0.025 ml (0.5 mmol) of 98% H ₂ SO _{4 was} added dropwise over 10 min. In this reaction, it is very important to observe an exact 2-fold molar ratio of hydrogen peroxide to 7c to prevent oxidation of the double bond in compound 1k. The reaction mixture was stirred for another 2 hours at + 65-70 ° C (control by TLC). Upon completion of the reaction, the mixture was poured into water, the acid was neutralized with sodium carbonate, the organic substances were extracted with ethyl acetate (4 × 20 ml). The organic extracts were washed with NaHCO ₃ solution, water (3 × 5 ml), dried over Na ₂ SO ₄ and K ₂ CO ₃ , and, after removal of the solvent and chromatographic separation of regioisomeric sulfones, 260 mg (73%) of 1k, light yellow oily substance.

¹ H NMR spectrum (400 MHz, 20 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 7.26 ppm), δ, ppm: 1.57 s (6H, 2CH ₃ ), 3.06 s (3H, SO ₂ CH ₃ ), 7.37 d (2H, ³ J _HH = 8.8 Hz), 7.53 dd (4H, ³ J _HH = 8.8 Hz, ⁴ J _HF = 5.4 Hz), 7.92 d (2H, ³ J _HH = 8.8 Hz) .

112.0, 127.7 (2С), 129.2 (2С), 129.7 (2С), 130.2 (2С), 130.6, 135.9, 138.8, 139.3, 178.3 (С₅), 204.2 (С=O). ¹³ C NMR spectrum (100 MHz, 25 mg in 0.8 ml CDCl ₃ , reference: CHCl ₃ = 77.00 ppm), δ, ppm: 23.3 (2CH ₃ ), 44.5 (SO ₂ CH ₃ ), 88.1

112.0, 127.7 (2С), 129.2 (2С), 129.7 (2С), 130.2 (2С), 130.6, 135.9, 138.8, 139.3, 178.3 (С ₅ ), 204.2 (С = O).

IR spectrum (in CCl ₄ ), cm ^-1 : 956 cf., 1095 cf., 1158 s. (SO ₂ ), 1329 s. (SO ₂ ), 1384 s., 1616 sr., 1703 s. (C = O), 2931 words, 2982 words (CH).

Mass spectrum LCMS, m / z calculated 377.0609, found 377.0679 [MH] ⁺ .

Example 5

Preparation of 2 ', 2'-dimethyl-6- (methylsulfonyl) -3-chlorophenantro [9,10-b] furan-3' (2'H) -one (Scheme 14, 2e).

The preparation of compound 1k is described above.

Stage VI. Preparation of 2 ', 2'-dimethyl-6- (methylsulfonyl) -3-chlorophenantro [9,10-b] furan-3' (2'H) -one (2e).

A solution of 50 mg (0.2 mmol) of iodine and 550 mg (1.46 mmol) of 4,5-diaryl-dihydrofuran-3 (2H) -one 1k in 50 ml of tetrahydrofuran was placed in a water-cooled quartz photochemical reactor with a volume of 50 ml. Irradiation was carried out with a mercury lamp with a power of 150 W for 4 hours. After completion of the reaction, the solvent was distilled off on a rotary evaporator, the mixture was applied to a preparative chromatography plate and divided into fractions (eluent: hexane-ethyl acetate-dichloromethane).

Preparation of 2,2-Dimethyl-4- [4 '- (methylthio) phenyl] -5- (3'-fluorophenyl) furan-3 (2H) -one Intermediate (Scheme 15, 1l).

Step 0. Preparation of 4 '- (methylthio) phenyl (3'-fluorophenyl) methanone (3d).

6.2 g of boric acid (H ₃ BO ₃ ) and 23 g of an aqueous 35% hydrofluoric acid (HF) solution were mixed in a plastic dish and allowed to cool to 0 ° C for 20 minutes. Then, in 7 grams of the resulting solution, 3.24 g of metaaminobenzoic acid was dissolved with stirring, then a solution of 1.7 g of sodium nitrite (NaNO ₂ ) in 5-7 ml of water was added dropwise. The precipitated tetrafluoroborate precipitate was filtered off on a paper filter using vacuum, washed with water and dried, passing absolute benzene and then absolute toluene through a salt layer (careful removal of water is necessary to prevent the formation of phenols). Received 3.48 g (62%) of diazonium tetrafluoroborate. The resulting salt was in portions of 100-200 mg carefully added to 100 ml of boiling toluene. The process is accompanied by thermal decomposition of salt with rapid evolution of BF ₃ (in the form of smoke) and proceeds in the range of 100-110 ° C for 2.5 hours. Upon completion of the reaction, toluene was removed by azeotropic distillation in vacuo, and the residue was transferred to a water-soluble salt by treatment with sodium hydroxide solution (or soda). To the resulting solution was added 30-50 ml of concentrated hydrochloric acid, the separated white flakes of acid were filtered on a paper filter, washed with glacial hydrochloric acid, hexane and benzene. The mass of metafluorobenzoic acid after vacuum drying was 1.18 g (35%).

1.18 g of parafluorobenzoic acid, 10 ml of tetrachlorocarbon were added to a round bottom flask with a magnetic stirrer, and then a mixture of 1 ml of distilled thionyl chloride SOCl ₂ with 0.01 ml of dimethylformamide in 5 ml of tetrachlorocarbon was carefully added. The mixture was refluxed for 4 hours until the evolution of gaseous products was complete. Then, the solvent and residues of thionyl chloride were removed in a vacuum of a rotary evaporator. The resulting oil, after short vacuum drying and without further purification, was dissolved in 10 ml of methylene chloride and 1.2 g of anhydrous aluminum chloride, 0.91 g (7.3 mmol) of thioanisole, and 8 ml of methylene chloride were added dropwise to a suspension. After adding the entire amount of the acid chloride, the mixture was refluxed for 5 hours until the HCl evolution ceased. The resulting product was carefully hydrolyzed with 5% hydrochloric acid, extracted with methylene chloride (3 × 20 ml), dried with Na ₂ SO ₄ , and after distillation of the solvent, it was passed through a silica gel column for further purification. The yield of crystalline 4 '- (methylthio) phenyl (3'-fluorophenyl) methanone (3d) was 0.71 g (39%), colorless crystals, mp. 67-68 ° C.

¹ H NMR spectrum (400 MHz, 30 mg in 0.8 ml CDCl ₃ ), δ, ppm: 2.54 s (3H, SCH ₃ ), 7.30 d (2H, ³ J _HH = 8.4 Hz), 7.46-7.48 m (2H), 7.53 d (1H, ³ J _HH = 7.6 Hz), 7.74 d (2H, ³ J _HH = 8.5 Hz).

¹³ C NMR spectrum (100 MHz, 30 mg in 0.8 ml of CDCl ₃ ), δ, ppm: 14.8 (SCH ₃ ), 116.5 d (2C), 119.1 d, 124.9 (2C), 125.5 d (1C), 129.9 d (1C), 130.5 (2C), 133.0, 140.0 d, 145.9, 162.4 d ( ¹ J _CF = 247 Hz), 194.3 (C = O).

¹⁹ F NMR spectrum (376 MHz, 30 mg in 0.8 ml of CDCl ₃ ), δ, ppm: -112.0.

Metafluorobenzoic acid, ¹ H NMR spectrum (400 MHz, 30 mg in 0.8 ml CDCl ₃ ), δ, ppm: 7.32 t (1Н, ³ J _HH = 8.6 Hz), 7.40-7.50 m (1Н), 7.80 d (1H, ³ J _HH = 8.8 Hz), 7.92 d (1H, ³ J _HH = 7.6 Hz). ¹⁹ F NMR spectrum (376 MHz, 30 mg in 0.8 ml of CDCl ₃ ), δ, ppm: -112.0.

Step I. Preparation of 2-methyl-5- (3'-fluorophenyl) -5- (4'-methylthiophenyl) pent-3-yn-2,5-diol (5d).

To a solution of EtMgBr, prepared from 250 mg of magnesium and 1.13 g of ethyl bromide, in 10 ml of absolute diethyl ether, while cooling in an ice bath, a solution of 340 mg of 2-methylbut-3-in-2-ol in 10 ml of absolute benzene was slowly added dropwise. The mixture was boiled for 4 hours, then, without stopping boiling, a solution of 700 mg of 3d compound in 5 ml of benzene was added dropwise over 2 hours and then boiled for 5 hours. Then the mixture was cooled and carefully hydrolyzed with 100 ml of 5% cold hydrochloric acid solution. The organic layer was separated from the aqueous. The aqueous layer was extracted with benzene (3 × 20 ml) and methylene chloride (1 × 20 ml). The combined organic fractions were washed with NaHCO ₃ solution, water and dried over Na ₂ SO ₄ . After distilling off the solvent, the resulting yellow oily product (813 mg) was chromatographed into 3 fractions: the target 1,4-diol, the initial unreacted substituted benzophenone, and a byproduct of dimerization of benzophenone to 1,2-diol. In order to reduce the amount of by-products and increase the conversion percentage, it is necessary to use a lack of magnesium and a very slow addition of benzophenone during the reaction, so that its concentration remains insignificant. The purified γ-glycol 5d was dried in a vacuum of 0.01–0.05 torr for 5 hours. The yield of 1,4-diol 5d was 235 mg (25%), a light yellow oily substance. The degree of conversion of the starting ketone 3d is 75%.

¹ H NMR spectrum (400 MHz, 15 mg in 0.8 ml CDCl ₃ ), δ, ppm: 1.52 s (6H, 2CH ₃ ), 2.43 s (3H, SCH ₃ ), 3.17 s (1H, -OH) 4.05 s (1H, -OH), 7.16 d (2H, ³ J _HH = 8.4 Hz), 7.22-7.32 m (4H), 7.45 d (2H, ³ J _HH = 8.4 Hz).

73.3, 84.1

91.9

113.0 д (2С, ²J_HF=21.6 Гц), 114.4 д, 121.5 д, 126.2 д (2С), 129.6 д, 138.1, 141.4, 162.5 д (1С, ¹J_HF=246.6 Гц). ¹³ C NMR spectrum (100 MHz, 20 mg in 0.8 ml CDCl ₃ ), δ, ppm: 15.5 (SCH ₃ ), 31.0 (2CH ₃ ), 65.2

73.3, 84.1

91.9

113.0 d (2C, ² J _HF = 21.6 Hz), 114.4 d, 121.5 d, 126.2 d (2C), 129.6 d, 138.1, 141.4, 162.5 d (1C, ¹ J _HF = 246.6 Hz).

¹⁹ F NMR spectrum (376 MHz, 20 mg in 0.8 ml CDCl ₃ ), δ, ppm: -112.5.

Mass spectrum LCMS, m / z calculated 331.1163, found 331.1173 [MN] ⁺ .

Stage II. Preparation of 2,2-Dimethyl-5- [4 '- (methylthio) phenyl] -5- (3'-fluorophenyl) dihydrofuran-3 (2H) -one (6d).

230 mg of compound 5d was dissolved in 10 ml of boiling methanol, and a solution of 0.7 ml of 98% sulfuric acid dissolved in 5 ml of methanol was added dropwise with stirring. The mixture was boiled for 5 hours until the end of the reaction (TLC control). Then the mixture was poured into 100 ml of water and thoroughly extracted with methylene chloride (3 × 10 ml). The organic layer was dried over Na ₂ SO ₄ , the solvent was driven off on a rotor, and the resulting mixture was separated into components by chromatographic method. The main reaction product is a mixture of isomeric α-oxyenones. The isolated target furanone was dried from methanol and dichloromethane in vacuo at a pressure of 0.02–0.05 torr for 5 h. 70 mg (31%) of oily product 6d, a colorless oily substance, were obtained.

¹ H NMR spectrum (400 MHz, 20 mg in 0.7 ml CDCl ₃ ), δ, ppm: 1.19 s (3H, CH ₃ ), 1.26 s (3H, CH ₃ ), 2.46 s (3H, SCH ₃ ) , 3.24 d (1H, CH ₂ , ² J _HH = 17.6 Hz), 3.33 d (1 H, CH ₂ , ² J _HH = 17.7 Hz), 7.13-7.33 m (8H).

81.9 д, 113.1 д, 114.3 д, 121.3, 126.3 д (2С), 129.8 д, 138.1, 142.1, 149.0, 162.7 д (¹J_CF=254 Гц), 216.2 (С=O). ¹³ C NMR spectrum (100 MHz, 20 mg in 0.7 ml CDCl ₃ ), δ, ppm: 15.5 (SCH ₃ ), 25.2 d (2CH ₃ ), 47.7 (CH ₂ ), 81.5

81.9 d, 113.1 d, 114.3 d, 121.3, 126.3 d (2C), 129.8 d, 138.1, 142.1, 149.0, 162.7 d ( ¹ J _CF = 254 Hz), 216.2 (C = O).

¹⁹ F NMR spectrum (376 MHz, 30 mg in 0.8 ml of CDCl ₃ ), δ, ppm: -112.2.

Mass spectrum LCMS, m / z calculated 331.1163, found 331.1187 [MH] ⁺ .

Stage III. Preparation of 4-diazo-2,2-dimethyl-5- [4 '- (methylthio) phenyl] -5- (3'-fluorophenyl) dihydrofuran-3 (2H) -one (7d).

To a mixture of 70 mg (0.21 mmol) of furanone 6d and 42 mg of paratoluenesulfonylazide in 5 ml of dichloromethane was added dropwise a solution of 10 mg of 1,8-diazobicyclo [5.4.0] undec-7-ene (DBU) in 5 ml of dichloromethane, the mixture being immediately dyed orange yellow. The reaction mixture was stirred at 35 ° C for 24 h until completion of the reaction (control by TLC), then cooled, excess solvent was distilled off, transferred to a silica gel column, and gradient chromatography was performed with n-hexane - methylene chloride mixture. After removing the solvent, the crystalline residue was dried in vacuo to give 54 mg (71%) of diazoketone 7d, a yellow oily substance.

¹ H NMR spectrum (400 MHz, 25 mg in 0.8 ml CDCl ₃ , reference: CHCl ₃ = 7.260 ppm) δ, ppm: 1.34 s (3H, CH ₃ ), 1.36 s (3H, CH ₃ ), 2.49 s (3H, SCH ₃ ), 7.03-7.10 m (2H), 7.20-7.25 m (4H), 7.30-7.35 m (2H).

¹³ C NMR spectrum (100 MHz, 25 mg in 0.8 ml of CDCl ₃ , reference: CHCl ₃ = 77.00 ppm) δ, ppm: 15.4 (SCH ₃ ), 25.2 (2CH ₃ ), 64.1 (C = N ₂ ), 85.6 (С ₅ ), 113.7 d (J = 23 Hz), 115.4 d (J = 21.3 Hz), 121.9 d (1С, ⁴ J _CF = 2.9 Hz), 126.2 (2С), 126.8 (2С) , 130.2 d, 139.4 d (J = 3.2 Hz), 139.6 d (J = 26.2 Hz) 146.4 d, 162.8 d (1C, ¹ J _CF = 247.6 Hz), 196.6 (C = O).

Spectrum ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ, ppm: -111.5.

HRMS mass spectrum, m / z calculated for 357.1068, found 357.1075 [MN] ⁺ .

.Stage IV. Preparation of 2,2-Dimethyl-4- (4 '- (methylthio) phenyl) -5- (3'-fluorophenyl) furan-3 (2H) -one

.

с выходом 32 мг (66%), светло-желтое маслообразное вещество.The reaction is carried out in a nitrogen atmosphere. A solution of 54 mg of diazoketone 7d in 5 ml of trifluoroacetic acid was boiled for 3 hours until the initial diazoketone completely disappeared (control by TLC). Upon completion of the reaction, trifluoroacetic acid was removed in vacuo, the precipitate was dissolved in 5 ml of methylene chloride, washed thoroughly with aqueous NaHCO ₃ solution, water (2 × 1 ml) and dried over K ₂ CO ₃ . Removal of the solvent gave 37 mg (75%) of a mixture of two regioisomeric 2,2-dialkyl-4,5-diaryl-dihydrofuran-3 (2H) -ones in an approximate ratio of 7: 1 as a pale yellow oily product. The reaction mixture (37 mg) was separated on a silica gel column to obtain furanone

in 32 mg yield (66%), a light yellow oily substance.

¹ H NMR spectrum (400 MHz, 25 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 7.26 ppm), δ, ppm: 1.56 s (6H, 2CH ₃ ), 2.50 s (3H, SCH ₃ ), 7.10-7.45 m (8H).

Spectrum ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ, ppm: -111.4.

Preparation of 2,2-dimethyl-4- [4 '- (methylthio) phenyl] -5- (3'-chlorophenyl) furan-3 (2H) -one intermediate (Scheme 16, 1m).

Step 0. Preparation of 4 '- (methylthio) phenyl (3'-chlorophenyl) methanone (3e).

10 g of methachlortoluene was mixed with a hot solution of 30 g of potassium permanganate in 300 ml of water. The reaction mixture was refluxed for 4 hours, and then the remaining unreacted metachlortoluene was distilled off with steam for 1 hour. Then, the reaction mixture was filtered from manganese dioxide, the solid phase was further washed with hot water, and 50 ml of glacial concentrated hydrochloric acid was added to the combined cooled filtrates. The precipitated white precipitate of methachlorobenzoic acid was filtered, washed with ice water and dried by triple distillation of the azetrop water-isopropanol (ethanol) in a vacuum of a rotary evaporator. The yield of metachlorobenzoic acid was 4.88 g (45% of the chlorotoluene involved).

4.86 g of methachlorobenzoic acid, 40 ml of tetrachlorocarbon were placed in a round bottom flask with a magnetic stirrer, and then a mixture of 5 ml of distilled thionyl chloride SOCl ₂ with 0.05 ml of dimethylformamide in 20 ml of tetrachlorocarbon was carefully added. The mixture was refluxed for 5 hours until the evolution of gaseous products was complete. Then, the solvent and residues of thionyl chloride were removed in a vacuum of a rotary evaporator. The oil obtained, after short vacuum drying, without further purification, was dissolved in 40 ml of methylene chloride and 4.5 g of anhydrous aluminum chloride, 3.7 g of thioanisole and 40 ml of methylene chloride were added dropwise to the suspension. After adding the entire amount of the acid chloride, the mixture was refluxed for 5 hours until the HCl evolution ceased. The resulting product was hydrolyzed with 5-10% hydrochloric acid, extracted with methylene chloride (3 × 40 ml), dried over Na ₂ SO ₄ , and after distillation of the solvent, it was recrystallized from hexane to remove excess thioanisole and aluminum complexes (green). The yield of crystalline 4 '- (methylthio) phenyl (3'-chlorophenyl) methanone (3e) was 5.15 g (66%), colorless crystals, mp. 73-74 ° C.

¹ H NMR spectrum (400 MHz, 20 mg in 0.8 ml CDCl ₃ ), δ, ppm: 2.54 s (3H, SCH ₃ ), 7.30 d (2H, ³ J _HH = 8.5 Hz), 7.41 t (1H , ³ J _HH = 7.8 Hz), 7.54 dm (1H, J _HH = 8.0 Hz), 7.63 d (1H, ³ J _HH = 7.7 Hz), 7.73 d (3H, ³ J _HH = 8.5 Hz).

¹³ C NMR spectrum (100 MHz, 20 mg in 0.8 ml CDCl ₃ ), δ, ppm: 14.8 (SCH ₃ ), 124.9 (2С), 127.8, 129.6, 129.7, 130.5 (2С), 132.1, 132.9, 134.5, 139.5, 146.0, 194.2 (C = O).

Step I. Preparation of 2-methyl-5- (4'-chlorophenyl) -5- (4'-methylthiophenyl) pent-3-in-2,5-diol (5e).

To a solution of EtMgBr prepared from 1.65 g (69 mmol) of magnesium and 7.5 g (69 mmol) of ethyl bromide in 30 ml of absolute diethyl ether, while cooling in an ice bath, a solution of 2.25 g (27 mmol) of 2-methylbut-3- was slowly added dropwise. in-2-ol in 20 ml of absolute benzene. The mixture was boiled for 3 hours, then, without stopping boiling, a solution (suspension) of 5.0 g (19 mmol) of compound 3e in 40 ml of benzene was added dropwise over 2 hours and then boiled for 4-5 hours. Then the mixture was cooled and carefully hydrolyzed with 100 ml of cold 5% hydrochloric acid solution. The organic layer was separated from the aqueous. The aqueous layer was extracted with benzene (3 × 30 ml) and methylene chloride (2 × 20 ml). The combined organic fractions were washed with NaHCO ₃ solution, water and dried over Na ₂ SO ₄ . After distilling off the solvent, the obtained yellow oily product was chromatographed into 3 fractions: the target 1,4-diol, the initial unreacted substituted benzophenone and the byproduct of dimerization of benzophenone to 1,2-diol. In order to reduce the amount of by-products and increase the conversion percentage, it is necessary to use a lack of magnesium and a very slow addition of benzophenone during the reaction, so that its concentration remains insignificant. The purified γ-glycol was dried in vacuum at a pressure of 0.01–0.05 torr for 5 hours. Yield of 1,4-diol 5e 3.56 g (54%), yellow oily substance.

¹ H NMR spectrum (400 MHz, 20 mg in 0.8 ml CDCl ₃ ), δ, ppm: 1.57 s (6H, 2CH ₃ ), 2.45 s (3H, SCH ₃ ), 3.14 (1H, -OH), 7.18-7.25 m (4H), 7.40-7.48 m (3H), 7.56-7.57 m (1H).

73.4, 84.1

92.3

124.1, 126.1, 126.2 (2С), 126.4 (2С), 127.8, 129.5, 134.2, 138.4, 141.2, 146.9. ¹³ C NMR spectrum (100 MHz, 20 mg in 0.8 ml CDCl ₃ ), δ, ppm: 15.6 (SCH ₃ ), 31.2 (2CH ₃ ), 65.3

73.4, 84.1

92.3

124.1, 126.1, 126.2 (2C), 126.4 (2C), 127.8, 129.5, 134.2, 138.4, 141.2, 146.9.

IR spectrum (in CCl ₄ ), cm ^-1 : 3603 sr., 3381 s. Shir., 2984 sr., 2924 sr., 1595 sr., 1491 sr., 1423 sr., 1323 s., 1167 s., 1095 sr., 1006 sr.

Mass spectrum of LCMS, m / z, calculated: 369.0687, found 369.0729 [MNa ⁺ ].

Stage II. Preparation of 2,2-Dimethyl-5- [4 '- (methylthio) phenyl] -5- (3'-chlorophenyl) dihydrofuran-3 (2H) -one (6e).

3.56 g of compound 5e were dissolved in 30 ml of boiling methanol, and a solution of 2.9 ml of 98% sulfuric acid dissolved in 30 ml of methanol was added dropwise with stirring. The mixture was boiled for 5 hours until the end of the reaction (TLC control). Then the mixture was poured into 70 ml of water and thoroughly extracted with methylene chloride (4 × 25 ml). The organic layer was dried with Na ₂ SO ₄ , the solvent was driven off on a rotor, and the resulting oil was dried from methanol and dichloromethane in vacuo at a pressure of 0.02–0.05 torr for 5 h. 3.49 g (98% yield) of oily product 6е were obtained. Without further purification, the resulting compound was used in the next step.

¹ H NMR spectrum (400 MHz, 15 mg in 0.7 ml of CDCl ₃ ), δ, ppm: 1.18 s (3H, CH ₃ ), 1.26 s (3H, CH ₃ ), 2.46 s (3H, SCH ₃ ) , 3.21 d (1Н, СН ₂ , ² J _HH = 18 Hz), 3.33 d (1Н, СН ₂ , ² J _HH = 18 Hz), 7.16-7.27 m (5Н), 7.31 d (2Н, ³ J _HH = 8.8 Hz), 7.41-7.44 m (1H).

81.9, 123.9, 126.0, 126.3 (2С), 126.5 (2С), 127.5, 129.6, 134.4, 138.2, 142.1, 148.4, 216.2 (С=O). ¹³ C NMR spectrum (100 MHz, 25 mg in 0.7 ml CDCl ₃ ), δ, ppm: 15.5 (SCH ₃ ), 25.1 (CH ₃ ), 25.4 (CH ₃ ), 47.7 (CH ₂ ), 81.6

81.9, 123.9, 126.0, 126.3 (2С), 126.5 (2С), 127.5, 129.6, 134.4, 138.2, 142.1, 148.4, 216.2 (С = O).

IR spectrum (in CCl ₄ ), cm ^-1 : 880 sr., 997 sr., 1135 sr., 1172 sr., 1422 sr., 1493 sr., 1596 sr., 1762 s. (C = O), 2982 cf. (CH).

HRMS mass spectrum, m / z, calculated: 369.0687, found 369.0696 [MNa ⁺ ].

Stage III. Preparation of 4-diazo-2,2-dimethyl-5- [4 '- (methylthio) phenyl] -5- (3'-chlorophenyl) dihydrofuran-3 (2H) -one (7e).

To a mixture of 3.49 g of furanone 6e and 2.0 g of paratoluenesulfonylazide in 50 ml of dichloromethane was added dropwise a solution of 400 mg of 1,8-diazobicyclo [5.4.0] undec-7-ene (DBU) in 25 ml of dichloromethane, and the mixture was immediately stained with orange yellow color. The reaction mixture was stirred at 35 ° C for 8 h until completion of the reaction (control by TLC), then the excess solvent was distilled off, transferred to a silica gel column and chromatographed in a gradient mode with n-hexane - methylene chloride mixture. After removing the solvent, the product was dried in vacuo to give 3.10 g (83%) of diazoketone 7e, a yellow oily substance.

¹ H NMR spectrum (400 MHz, 25 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 7.260 ppm) δ, ppm: 1.34 s (3H, CH ₃ ), 1.35 s (3H, CH ₃ ), 2.49 s (3H, SCH ₃ ), 7.15-7.35 m (8H).

¹³ C NMR spectrum (100 MHz, 25 mg in 0.8 ml of CDCl ₃ , reference: CHCl ₃ = 77.00 ppm) δ, ppm: 15.3 (SCH ₃ ), 25.2 (2CH ₃ ), 64.0 (C = N ₂ ), 83.5 (С ₅ ), 85.7 (С ₂ ), 124.5, 126.2 (2С), 126.6, 126.8 (2С), 128.6, 129.8, 134.7, 139.5, 139.6, 145.8, 196.5 (С = O).

IR spectrum (in CCl ₄ ), cm ^-1 : 1026 words, 1094 words, 1163 words, 1225 words, 1344 pages, 1377 words, 1595 words, 1697 s (C = O), 2093 points .from. (CN ₂ ), 2930 words, 2982 words

HRMS mass spectrum, m / z, calculated for C ₁₉ H ₁₇ ClN ₂ O ₂ SNa ⁺ : 395.0592, found 395.0598 [MNa ⁺ ].

Stage IV. Preparation of 2,2-Dimethyl-4- [4 '- (methylthio) phenyl] -5- (3'-chlorophenyl) furan-3 (2H) -one (1m).

The reaction is carried out in a nitrogen atmosphere. To a solution of 1.0 g of diazoketone 7e in 35 ml of dichloromethane was added dropwise 0.3 ml of trifluoromethanesulfonic acid (TfOH) dissolved in 10 ml of methylene chloride. The mixture was boiled for 3 hours until the initial diazoketone completely disappeared (control by TLC), and upon completion of the reaction, the mixture was washed with an aqueous solution of NaHCO ₃ , water (2 × 10 ml) and dried with K ₂ CO ₃ . Removal of the solvent gave 870 mg (94%) of a mixture of two regioisomeric 2,2-dialkyl-4,5-diaryl-dihydrofuran-3 (2H) -ones in an approximate ratio of 5: 1 as a pale yellow oily product. The reaction mixture (273 mg) was separated on a silica gel column to give furanone 1m in 720 mg (78%), a light yellow oily substance or crystals.

¹ H NMR spectrum (400 MHz, 5 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 7.260 ppm), δ, ppm: 1.55 s (6H, 2CH ₃ ), 2.49 s (3H, SCH ₃ ), 7.21-7.26 m (4H, PhSCH ₃ ), 7.36 s (1H), 7.43 d (1H, ³ J _HH = 9.1 Hz), 7.48 d (1H, ³ J _HH = 7.8 Hz), 7.72 s (1H )

¹³ C NMR spectrum (100 MHz, 25 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 77.0 ppm), δ, ppm: 15.6 (SCH ₃ ), 23.3 (2CH ₃ ), 87.2 (C (СН ₃ ) ₂ ), 113.7 (С ₄ ), 126.6 (2С), 126.7, 128.0, 128.3, 129.7, 129.8 (2С), 131.7, 131.8, 134.7, 138.2, 176.1 (С ₅ ), 205.3 (С = O )

HRMS mass spectrum, m / z, calculated 345.0711, found 345.0718 [MH] ⁺ .

Example 6

Preparation of 2,2-dimethyl-4- [4 '- (methylsulfinyl) phenyl] -5- (3'-chlorophenyl) furan-3 (2H) -one (Scheme 17, 1n).

The preparation of compound 7e is described above.

Stage IV-V. Preparation of 2,2-Dimethyl-4- [4 '- (methylsulfinyl) phenyl] -5- (3'-chlorophenyl) furan-3 (2H) -one (1n).

The reaction was carried out in a nitrogen atmosphere. 15 ml of trifluoroacetic acid were placed in a round bottom flask with a magnetic stirrer and an air cooler and 360 mg (0.96 mmol) of compound 7e were dissolved in it and this solution was boiled for 3 hours. Then it was cooled to 40 ° C and a mixture of 100 mg of 35% (0.99 mmol) of a fresh aqueous solution of hydrogen peroxide in 5 ml of trifluoroacetic acid and 0.025 ml (0.5 mmol) of 98% H ₂ SO _{4 was} carefully added dropwise with vigorous stirring over 1 h. . In this reaction, it is very important to observe the exact equimolar ratio of hydrogen peroxide to 7e. The reaction mixture was stirred for another 1.5 h at + 50-55 ° C (reaction control using TLC). Upon completion of the reaction, the mixture was poured into water, neutralized with sodium carbonate, carefully extracted with ethyl acetate (4 × 20 ml). The organic extracts were washed with NaHCO ₃ solution, water (3 × 5 ml), dried over Na ₂ SO ₄ and K ₂ CO ₃ , and, after removal of the solvent and chromatographic separation of regioisomeric sulfoxides, 240 mg (70%) of 1n, light yellow oily substance.

¹ H NMR spectrum (400 MHz, 25 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 7.26 ppm), δ, ppm: 1.53 s (6H, 2CH ₃ ), 2.79 s (3H, SOCH ₃ ), 7.23-7.27 m (1H), 7.37-7.50 m (4H), 7.60-7.70 m (3H).

113.0 (С₄), 124.2, 126.8, 128.1, 130.0, 130.3 (2С), 131.2, 132.2, 132.9, 134.9, 144.0, 177.4 (С₅), 204.7 (С=O). ¹³ C NMR spectrum (100 MHz, 20 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 77.00 ppm), δ, ppm: 23.3 (2CH ₃ ), 43.6 (SOCH ₃ ), 87.9

113.0 (С ₄ ), 124.2, 126.8, 128.1, 130.0, 130.3 (2С), 131.2, 132.2, 132.9, 134.9, 144.0, 177.4 (С ₅ ), 204.7 (С = O).

IR spectrum (in CCl ₄ ), cm ^-1 : 1051 cf. (S = O), 1145 sr., 1238 ss., 1384 s., 1618 sr., 1706 s. (C = O), 2983 words (CH).

HRMS mass spectrum, m / z, calculated 361.0660, found 361.0740 [MH] ⁺ .

Example 7

Preparation of 2,2-dimethyl-4- [4 '- (methylsulfonyl) phenyl] -5- (3'-chlorophenyl) furan-3 (2H) -one (Scheme 18, 1 °).

The preparation of compound 7e is described above.

Stage IV-V. Preparation of 2,2-Dimethyl-4- [4 '- (methylsulfonyl) phenyl] -5- (3'-chlorophenyl) furan-3 (2H) -one (1 °).

The reaction was carried out in a nitrogen atmosphere. 10 ml of trifluoroacetic acid were placed in a round bottom flask with a magnetic stirrer and an air cooler and 360 mg (0.96 mmol) of compound 7e were dissolved in it and this solution was boiled for 3 hours. Then, without stopping boiling, a mixture of 200 mg of a 34% (2 mmol) aqueous solution of hydrogen peroxide in 5 ml of trifluoroacetic acid and 0.025 ml (0.5 mmol) of 98% H ₂ SO _{4 was} added dropwise over 10 minutes. In this reaction, it is very important to observe an exact 2-fold molar ratio of hydrogen peroxide to 7e to prevent oxidation of the double bond in compound 1o. The reaction mixture was stirred for another 2 hours at + 65-70 ° C (control by TLC). Upon completion of the reaction, the mixture was poured into water, the acid was neutralized with sodium carbonate, the organic substances were extracted with ethyl acetate (4 × 20 ml). The organic extracts were washed with a solution of NaHCO ₃ , water (3 × 5 ml), dried over Na ₂ SO ₄ and K ₂ CO ₃ , and, after removal of the solvent and chromatographic separation of regioisomeric sulfones, 278 mg (77%) of 1o was obtained, colorless or light yellow oily substance.

¹ H NMR spectrum (400 MHz, 20 mg in 0.8 ml CDCl ₃ , reper: CHCl ₃ = 7.26 ppm), δ, ppm: 1.56 s (6H, 2CH ₃ ), 3.04 s (3H, SO ₂ CH ₃ ), 7.29 d (1H, ³ J _HH = 7.8 Hz), 7.38 d (1H, ³ J _HH = 7.9 Hz), 7.51 d (2H, ³ J _HH = 8.4 Hz), 7.67 s (1H), 7.91 d (2H, ³ J _HH = 8.4 Hz).

112.4, 126.7, 127.6 (2С), 128.0, 130.0, 130.1 (2С), 131.0, 132.3, 135.0, 135.6, 139.3, 177.8 (С₅), 204.2 (С=O). ¹³ C NMR spectrum (100 MHz, 25 mg in 0.8 ml of CDCl ₃ , reper: CHCl ₃ = 77.00 ppm), δ, ppm: 23.2 (2CH ₃ ), 44.4 (SO ₂ CH ₃ ), 88.1

112.4, 126.7, 127.6 (2С), 128.0, 130.0, 130.1 (2С), 131.0, 132.3, 135.0, 135.6, 139.3, 177.8 (С ₅ ), 204.2 (С = O).

IR spectrum (in CCl ₄ ), cm ^-1 : 957 sr, 1157 s. (SO ₂ ), 1330 s. (SO ₂ ), 1384 sr., 1616 sr., 1705 s. (C = O), 2931 words, 2982 words (CH).

LCMS mass spectrum, m / z, calculated 377.0609, found 377.0667 [MH] ⁺ .

Example 8

Preparation of 2,2-dimethyl-4- (4 '- (aminosulfonyl) phenyl) -5-phenylfuran-3 (2H) -one (Scheme 19, 1q).

Stage II. Preparation of 2-methyl-5,5-diphenylpent-3-in-2,5-diol (5f).

To a solution of EtMgBr prepared from 10 g (0.41 mol) of magnesium and 46 g (0.42 mol) of ethyl bromide in 160 ml of absolute diethyl ether, while cooling in an ice bath, a solution of 15.7 ml (0.16 mol) of 2-methylbut-3- was slowly added dropwise. in-2-ol in 90 ml of absolute benzene. Next, the mixture was boiled for 3 hours, after which 21 g (0.12 mol) of benzophenone (3f) was added and boiled for 8 hours. After the reaction mixture was cooled in a water bath, 250 ml of a hydrochloric acid solution prepared from 200 ml of water was added through a dropping funnel. and 50 ml of 36% hydrochloric acid. The organic layer was separated from the aqueous layer, the latter was subjected to extraction with absolute methylene chloride (3 × 30 ml). The combined organic extracts were washed with NaHCO ₃ then water and dried over K ₂ CO ₃ . The solvent was distilled off in vacuo, the obtained residue was recrystallized from a mixture of hexane and chloroform. Yield 28.8 g (90%) of compound 5f, mp. 119-120 ° C (published data 118-119 ° C [21]).

Stage III. Preparation of 2,2-dimethyl-5,5-diphenyldihydrofuran-3 (2H) -one (6f).

To a solution of 19.13 g (72 mmol) of compound 5f in 140 ml of CH ₃ OH, 55 ml of a solution of 15 ml of concentrated sulfuric acid in 40 ml of methanol were carefully added. The mixture was refluxed for 1-2 hours. Upon completion of the reaction, the mixture was poured into 400 ml of water and subjected to extraction with dichloromethane (4 × 40 ml). The organic phases were washed with 50 ml of a Na ₂ CO ₃ solution (sat _.) , Then with a saturated NaCl solution (2 × 20 ml) and dried over Na ₂ SO ₄ . Having driven off the solvent in a vacuum of a rotary evaporator, the precipitated precipitate was recrystallized from hexane. Yield 18 g (95%) of compound 6f, colorless crystals mp. 64-65 ° C.

¹ H NMR spectrum (400 MHz, 5 mg in 0.7 ml of CDCl ₃ , TMS = 0 ppm), δ, ppm: 1.210 s (6H, 2CH ₃ ), 3.330 s (2H, CH ₂ ), 7.240 d (2H, ³ J _HH = 6.7 Hz), 7.307 t (4H, ³ J _HH = 7.6 Hz), 7.410 d (4H, ³ J _HH = 8.2 Hz).

48.04

81.35 (1С, С²), 82.64 (1С, С⁵), 126.0 (4С), 127.34 (2С), 128.28 (4С), 146.09 (2С), 217.0

Spectrum ¹³ C NMR (100 MHz, 30 mg in 0.7 ml CDCl ₃ ), δ, ppm: 25.31

48.04

81.35 (1С, С ² ), 82.64 (1С, С ⁵ ), 126.0 (4С), 127.34 (2С), 128.28 (4С), 146.09 (2С), 217.0

IR spectrum (in CCl ₄ ), cm ^-1 : 699.4 m, 740.2 words, 994.5 words, 1131.1 words, 1173.0 words, 1376.1 words, 1448.4 words, 1492.6 words, 1760.1 words, 2931.6 words ., 2983.2 words, 3027.8 words, 3064.9 words HRMS, m / z, calculated: 267.1380, found: 267.1381 [MH] ⁺ .

Stage IV. Preparation of 4-diazo-2,2-dimethyl-5,5-diphenyldihydrofuran-3 (2H) -one (7f).

To a mixture of 1 gram (3.76 mmol) of a compound of furanone 6f, 770 mg (3.9 mmol) of paratoluenesulfanyl azide in 70 ml of dichloromethane, 200 mg of 1,8-diazobicyclo [5.4.0] undec-7-ene (DBU) in 10 ml of dichloromethane. The mixture was stirred at 35 ° C for 4 hours. After completion of the reaction, the organic layer was washed with brine (2 × 20 ml), aqueous extracts were subjected to extraction with methylene chloride (2 × 20 ml). The combined organic phases were washed with water (5 × 10 ml) to a neutral medium and dried over magnesium sulfate. The solvent was distilled off, the residue was passed through a silica gel column (eluent: hexane / methylene chloride in a gradient mode). Yield: 760 mg (69%) of compound 7f, yellow crystalline solid, mp. 118.7-118.9 ° C.

¹ H NMR spectrum (400 MHz, 5 mg in 0.7 ml of CDCl ₃ , TMS = 0 ppm), δ, ppm: 1.35 s (6H, 2CH ₃ ); 7.30-7.38 m (10H, 2Ph).

¹³ C NMR spectrum (100 MHz, 30 mg in 0.7 ml of CDCl ₃ ), δ, ppm: 25.3 (2CH ₃ ), 64.4 (C = N ₂ ), 84.2, 85.5, 128.5, 128.3, 126.4, 143.8, 197.0 (C = O).

IR spectrum (in KBr), cm ^-1 : 3065 words, 3045 words, 2981 words, 2932 words, 2866 words, 2093 points from. (C = N ₂ ), 1832 words, 1806 words, 1692 points. from. (C = O), 1599 words, 1490 sr., 1446 s., 1377 s., 1347 points. s., 1226 s., 1185 sr., 1165 sr., 1153 sr., 1083 ss., 1022 s., 1005 s., 931 ss., 921 ss., 910 sr., 894 sr., 761 s. , 701 p.

CHN analysis calculated for C ₁₈ H ₁₆ N ₂ O ₂ : C, 73.96; H, 5.52; N, 9.58; found: C, 73.93; H, 5.52; N, 9.57.

Stage V. Obtaining 2,2-dimethyl-4,5-diphenylfuran-3 (2H) -one (1p).

To a solution of 290 mg (1 mmol) of compound 7f in 10 ml of dichloromethane was added dropwise a solution of 0.1 ml of trifluoromethanesulfonic acid (TfOH) in 5 ml of dichloromethane. The mixture was boiled for 2 hours until the initial diazoketone completely disappeared (reaction control by TLC). Upon completion of the reaction, the mixture was washed with a solution of NaHCO ₃ , water (2 × 10 ml) and dried over K ₂ CO ₃ . After distillation of the solvent, 260 mg (98%) of 1p, a colorless crystalline solid, are obtained.

¹ H NMR spectrum (400 MHz, 5 mg in 0.7 ml CDCl ₃ , TMS = 0 ppm), δ, ppm: 1.58 s (6H, 2CH ₃ ), 7.28-7.68 m (10H, 2Ph) .

¹³ C NMR spectrum (100 MHz, 30 mg in 0.7 ml of CDCl ₃ ), δ, ppm: 23.8, 87.4, 114.0, 127.9, 128.8, 129.0, 129.9, 130.4, 132.2, 178.4, 205.8. HRMS, m / z, calculated: 265.1224, found: 265.1231 [MH] ⁺ .

Stage VI. Preparation of 2,2-Dimethyl-4- (4 '- (aminosulfonyl) phenyl) -5-phenylfuran-3 (2H) -one (1q).

325 mg of furanone 1p were carefully added to 1.5 g (10-fold molar excess) of chlorosulfonic acid, then 10 ml of tetrachlorocarbon and 100 mg of sodium chloride were added. The mixture was stirred at 60 ° C for 3 hours. After completion of the sulfochlorination reaction, the mixture was placed in an ice bath and, with vigorous stirring, unreacted chlorosulfonic acid was hydrolyzed by slowly dropping 50% sulfuric acid (10 ml) to the reaction mixture. Then dry ammonia was passed through the reaction vessel at 0 ° C until all acids were neutralized, then 10 ml of a 25% solution of ammonia in water was added and stirred at 50-60 ° C for 3 hours. Upon completion of the amidation reaction, water and carbon tetrachloride were removed by azeotropic distillation on a rotary evaporator. The resulting crystalline mixture was applied to a silica gel column and the unreacted starting furanone (eluent: dichloromethane) was separated from the target amide 1q (eluent: methyl alcohol). Inorganic salts and sulfonic acid salts remain at the start of the column. The amide thus separated was further recrystallized from ethanol and dried in vacuo at a pressure of 0.02–0.05 torr for 5 hours. Yield 1q: 330 mg (79%), colorless crystalline substance.

Note 1. In the proposed method, carbon tetrachloride serves as an inert diluent of the reaction mixture, reducing its viscosity. Dilution with 50% sulfuric acid is carried out, since direct hydrolysis with water or hydrolysis with amidation with an ammonia solution very often proceeds uncontrollably and with an explosion, despite intensive cooling. The neutralization of acids with gaseous ammonia is carried out for the same purpose of reducing the intensity of thermal effects. In this method, we do not use the extraction of the obtained substance from an aqueous solution because of the possible large losses of amide 1q due to its good solubility in water. Attention should also be paid to the ability of 1q to form solvates with alcohols. Amides are poorly soluble in chloroform; therefore, NMR spectra were taken in acetone. In the spectrum, there is only one set of signals corresponding to one regioisomer.

¹ H NMR spectrum (400 MHz, 5 mg in 0.7 ml acetone-d ₆ , reference acetone multiplet = 2.05 ppm), δ, ppm: 1.53 s (6H, 2CH ₃ ), 6.60 s (2H, -NH ₂ ass.), 7.44-7.49 m (4H), 7.58 t (1H, ³ J _HH = 7.4 Hz), 7.65 d (2H, ³ J _HH = 7.2 Hz), 7.87 d (2H, ³ J _HH = 8.5 Hz).

¹ H NMR spectrum (400 MHz, 3 mg in 0.6 ml CDCl ₃ ), δ, ppm: 1.58 s (6H, 2CH ₃ ), 4.78 s (2H, NH ₂ ), 7.40 t (2H, ³ J _HH = 7.7 Hz), 7.50 t (3H, ³ J _HH = 8.2 Hz), 7.62 d (2H, ³ J _HH = 7.2 Hz), 7.90 d (2H, ³ J _HH = 8.5 Hz).

¹³ C NMR spectrum (100 MHz, 15 mg in 0.7 ml acetone-d ₆ , reference acetone multiplet = 29.84 ppm), δ, ppm: 23.4 (2C), 88.0 (C ₂ ), 113.0 (C ₄ ), 127.0 (2С), 129.2 (2С), 129.6 (2С), 130.6 (2С), 130.7, 133.0, 135.3, 143.7, 179.7 (С ₅ ), 204.5 (С = O).

IR spectrum (in KBr), cm ^-1 : 3346 broad. (-SO ₂ NH ₂ ), 3234 broad. (-SO ₂ NH ₂ ), 2988 tr. (CH ₃ , Ar), 2938 (CH ₃ , Ar), 1662 pts. s., 1607 s., 1568 s., 1485 sr., 1386 s., 1342 s., 1238 sr., 1170 s., 1058 sr., 904 sr., 746 sr., 658 sr., 597 sr. , 553 cf.

HRMS, m / z, calculated: 344.0952, found: 344.1006 [MH] ⁺ .

Example 9

Preparation of 2,2-Dimethyl-4- (4 '- (aminosulfonyl) phenyl) -5- (4'-chlorophenyl) furan-3 (2H) -one and 4- (2' - (4 '' - chlorophenyl) - 5,5-dimethyl-4-oxo-4,5-dihydrofuran-3-yl) benzenesulfonic acids (Scheme 20, 1v and 1vv).

Stage II. Preparation of 1- (4-chlorophenyl) -4-methyl-1-phenylpent-2-in-1,4-diol (5v).

To a solution of EtMgBr prepared from 10 g (0.41 mol) of magnesium and 46 g (0.42 mol) of ethyl bromide in 160 ml of absolute diethyl ether, while cooling in an ice bath, a solution of 15.7 ml (0.16 mol) of 2-methylbut-3- was slowly added dropwise. in-2-ol in 90 ml of absolute benzene. Then the mixture was boiled for 3 hours, after which 25.9 g (0.12 mol) (4-chlorophenyl) (phenyl) methanone (3v) was added and boiled for 7 hours. After cooling the reaction mixture in a water bath, 230 ml of the solution was added via a dropping funnel. hydrochloric acid prepared from 180 ml of water and 50 ml of 36% hydrochloric acid. The organic layer was separated from the aqueous layer, the latter was subjected to extraction with absolute methylene chloride (3 × 30 ml). The combined organic extracts were washed with NaHCO ₃ then water and dried over K ₂ CO ₃ . The solvent was distilled off in vacuo, the obtained residue was recrystallized from a mixture of hexane and chloroform. Yield 27.7 g (77%) of compound 5v, mp. 91-92 ° C (published data 89-95 ° C, [22]).

Stage III. Preparation of 2,2-Dimethyl-5-phenyl-5- (4'-chlorophenyl) dihydrofuran-3 (2H) -one (6v).

To a solution of 21.6 g (72 mmol) of compound 5v in 140 ml of CH ₃ OH, 55 ml of a solution, which is a mixture of 15 ml of concentrated sulfuric acid and 40 ml of methanol, were carefully added. The mixture was refluxed for 1-2 hours. Upon completion of the reaction, the mixture was poured into 400 ml of water and subjected to extraction with dichloromethane (4 × 40 ml). The organic phases were washed with 50 ml of a Na ₂ CO ₃ solution (sat _.) , Then with a saturated NaCl solution (2 × 20 ml) and dried over Na ₂ SO ₄ . Having driven off the solvent in a vacuum of a rotary evaporator, the precipitate was recrystallized from hexane. Yield 18 g (92%) of compound 6v, colorless crystals mp. 68 ° C. (published data 67.5–69 ° C, [22]).

Stage IV. Preparation of 4-diazo-2,2-dimethyl-5-phenyl-5- (4'-chlorophenyl) dihydrofuran-3 (2H) -one (7v).

To a mixture of 1.13 grams (3.76 mmol) of furanone 6v, 770 mg (3.9 mmol) of paratoluene sulfanilazide in 60 ml of dichloromethane, 190 mg of 1,8-diazobicyclo [5.4.0] undec-7-ene (DBU) in 10 were added dropwise with vigorous stirring ml of dichloromethane. The mixture was stirred at 30 ° C for 6 hours. After completion of the reaction, the organic layer was washed with brine (2 × 20 ml), aqueous extracts were subjected to extraction with methylene chloride (2 × 20 ml). The combined organic phases were washed with water (5 × 10 ml) to a neutral medium and dried over magnesium sulfate. The solvent was distilled off, the residue was passed through a silica gel column (eluent: hexane / methylene chloride in a gradient mode). Yield: 749 mg (66%) of compound 7v, yellow crystalline solid, mp. 131-132 ° C.

¹ H NMR spectrum (400 MHz, 6 mg in 0.7 ml of CDCl ₃ , TMS = 0 ppm), δ, ppm: 1.35 s (6H, 2CH ₃ ); 7.30-7.36 m (9H).

CHN analysis calculated for C ₁₈ H ₁₅ N ₂ O ₂ Cl: C - 66.16, H - 4.63, N - 8.57, found: C - 66.0, H - 4.65, N - 9.59.

Step V. Preparation of 2,2-Dimethyl-4-phenyl-5- (4'-chlorophenyl) furan-3 (2H) -one (8v).

To a solution of 326 mg (1 mmol) of compound 7v in 15 ml of dichloromethane was added dropwise a solution of 0.1 ml of trifluoromethanesulfonic acid (TfOH) in 5 ml of dichloromethane. The mixture was boiled for 2 hours until the initial diazoketone completely disappeared (reaction control by TLC). Upon completion of the reaction, the mixture was washed with a solution of NaHCO ₃ , water (2 × 10 ml) and dried over K ₂ CO ₃ . The solvent was distilled off, a mixture of 2 regioisomers was separated on a silica gel column (eluent: hexane / methylene chloride in a gradient mode). Received 155 mg (52%) of compound 8v, a colorless crystalline substance.

¹ H NMR spectrum (400 MHz, 7 mg in 0.7 ml CDCl ₃ , TMS = 0 ppm), δ, ppm: 1.55 s (6H, 2CH ₃ ), 7.30-7.61 m (9H).

HRMS, m / z, calculated: 299.0834, found: 299.0885 [MH] ⁺ .

Preparation of 4- (2 '- (4' '- chlorophenyl) -5,5-dimethyl-4-oxo-4,5-dihydrofuran-3-yl) benzenesulfonic acid (1vv).

To 1.5 g (10-fold molar excess) of chlorosulfonic acid, 298 mg (1 mmol) of furanone 8v was carefully added, then 10 ml of tetrachlorocarbon and 10 mg of sodium chloride were added. The mixture was stirred at 60 ° C for 3 hours. After completion of the sulfochlorination reaction, the mixture was placed in an ice bath and, with vigorous stirring, unreacted chlorosulfonic acid was hydrolyzed by slowly dropping first ice water (10 ml) and then a 30% aqueous KOH solution until completely neutralized. Upon completion of the reaction, water and carbon tetrachloride were removed by azeotropic distillation on a rotary evaporator. The resulting crystalline mixture of salts was dissolved in a minimum amount of boiling water (1-3 ml) and 4-5 ml of ice-cold 30% HCl was added. The precipitated flocculent precipitate of sulfonic acid 1vv was filtered on a Schott filter, washed with ice-cold 25% HCl and dried in a vacuum of 0.1 torr for 24 hours to constant weight. Alternatively, drying of the sulfonic acid can be accomplished by dissolving it in a sufficient amount of dichloromethane and holding it for 12 hours over anhydrous Na ₂ SO ₄ . 1vv sulfonic acid yield: 340 mg (90%), a colorless crystalline solid.

¹ H NMR spectrum (400 MHz, 5 mg in 0.7 ml acetone-d ₆ , reference acetone multiplet = 2.05 ppm), δ, ppm: 1.53 s (6H, 2CH ₃ ), 7.44-7.51 m ( 4H), 7.55-7.90 m (4H).

HRMS, m / z, calculated: 401.0221, found: 401.0210 [MNa] ⁺ .

Preparation of 2,2-Dimethyl-4- (4 '- (aminosulfonyl) phenyl) -5- (4'-chlorophenyl) furan-3 (2H) -one (1v).

To 1.5 g (10-fold molar excess) of chlorosulfonic acid, 298 mg of furanone 1v was carefully added, then 10 ml of tetrachlorocarbon and 100 mg of sodium chloride were added. The mixture was stirred at 60 ° C for 3 hours. After completion of the sulfochlorination reaction, the mixture was placed in an ice bath and, with vigorous stirring, unreacted chlorosulfonic acid was hydrolyzed by slowly dropping 50% sulfuric acid (10 ml) to the reaction mixture. Then dry ammonia was passed through the reaction vessel at 0 ° C with vigorous stirring until all acids were neutralized, then 10 ml of a 25% solution of ammonia in water was added and stirred at 50-60 ° C for 3 hours. Upon completion of the amidation reaction, water and carbon tetrachloride were removed by azeotropic distillation with isopropyl alcohol on a rotary evaporator. The resulting crystalline mixture was applied to a silica gel column and the unreacted starting furanone (eluent: dichloromethane) was separated from the target amide 1v (eluent: methyl alcohol). Inorganic salts and sulfonic acid salts remain at the start of the column. The amide thus separated was further recrystallized from ethanol and dried in vacuo at a pressure of 0.02–0.05 torr for 6 hours. Yield 1v: 268 mg (71%), colorless crystalline substance.

¹ H NMR spectrum (400 MHz, 5 mg in 0.7 ml acetone-d ₆ , reference multiplet of acetone = 2.05 ppm), δ, ppm: 1.53 s (6H, 2CH ₃ ), 4.82 s (2H, -NH ₂ ), 7.44-7.49 m (4H), 7.64 d (2H, ³ J _HH = 7.2 Hz), 7.86 d (2H, ³ J _HH = 8.5 Hz).

HRMS, m / z, calculated: 378.0562, found: 378.0578 [MH] ⁺ .

Note 2. Obtaining the remaining paraffluoro, metafluoro and metachlor substituted benzenesulfonic acids and sulfamides is carried out according to the above methods based on substituted benzophenones and does not present difficulties. Substituted sulfamides are obtained by using instead of ammonia primary amines, such as methylamine and ethylamine, in the form of solutions in suitable solvents, for example, tetrachlorocarbon.

Pharmaceutically Acceptable Derivatives of Compounds

The compounds of this invention may exist in free form during processing or, if desired, in the form of a pharmaceutically acceptable salt or other derivative.

As used herein, the term “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 specifically based on 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 [23]). 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.

Pharmaceutical Compositions

The invention also relates to pharmaceutical compositions that contain at least one of the compounds described herein (or a prodrug, a pharmaceutically acceptable salt or other pharmaceutically acceptable derivative) and one or more pharmaceutically acceptable carriers, solvents and / or excipients. These compositions may also contain one or more additional therapeutic agents. On the other hand, the compound of this invention can be administered to a patient in need of appropriate therapy in combination with one or more other therapeutic agents, for example, in combination with antiplatelet agents, drugs for the treatment of concomitant diseases (including antitumor drugs), etc.

The pharmaceutical compositions of this invention comprise the compounds of this invention together with pharmaceutically acceptable carriers, which may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, astringents, lubricants materials, etc., suitable for a particular dosage form. [24] discloses various carriers used in the development of pharmaceutical compositions and known methods for their preparation. Except in such cases where the medium of conventional carriers is incompatible with the compound of the invention, for example, upon the appearance of any undesirable biological effects and other undesirable interactions with any other component (s) of the pharmaceutical composition, the use of such compositions is within the scope of this invention. Materials that may serve as pharmaceutically acceptable carriers include, but are not limited to, mono- and oligosaccharides, as well as their derivatives; malt, gelatin; talcum powder; excipients such as: cocoa butter and suppository wax; oils such as peanut, cottonseed, safrole, sesame, olive, corn and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic solution, Ringer's solution; ethyl alcohol and phosphate buffers. Also in the composition of the composition may be other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as dyes, release fluids, film-forming agents, sweeteners, flavors and fragrances, preservatives and antioxidants.

The use of compounds in combination therapy

Although the compounds of this invention can be administered as an individual active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention and / or one or more other agents. When administered orally, the therapeutic agents can be different dosage forms that are administered simultaneously or sequentially at different times, or the therapeutic agents can be combined into a single dosage form.

The phrase "combination therapy" in relation to the compounds of this invention in combination with other pharmaceutical agents, means the simultaneous or sequential administration of all agents, which, one way or another, will provide a beneficial effect of the combination of drugs. Co-administration includes, in particular, co-delivery, for example, in one tablet, capsule, injection, or in another form, having a fixed ratio of active substances, as well as simultaneous delivery in several separate dosage forms for each compound, respectively.

Thus, the introduction of the compounds of this invention can be carried out in combination with additional treatment methods known to specialists in the treatment of diseases associated with the development of inflammation, as well as diseases mediated by excessive secretion of COX-2.

Characterization of the biological activity of the compounds

Computer simulation of the inhibition of cyclooxygenase-1 and -2 enzymes by the compounds of the invention.

Since to date, a fairly large number of biological tests of various classes of human and animal cyclooxygenase inhibitors have been carried out [14], and a significant amount of experimental data has been accumulated to evaluate the activity of certain molecules with respect to COX-1 and -2, parameters such as IC ₅₀ ( the concentration of the substance leading to 50% inhibition of cyclooxygenase of standard concentration) and SI (selectivity index, IC ₅₀ (SOX-1) / IC ₅₀ (SOX-2)) can be calculated with sufficient accuracy by computer simulation using QSAR model structures according to a number of the closest studied structures [25]. The following is a computer simulation of the inhibitory activity of the compounds of the invention as an example.

A list of common abbreviations and terms in the field of virtual screening.

- Docking (Docking) - a method that allows, based on the three-dimensional structure of the target (enzyme), to predict possible supramolecular interactions with the ligand (the molecule of the COX inhibitor).

- Preparation - a procedure for minimizing potential energy and geometric optimization of a three-dimensional structure for small and biomolecules, using standard approaches of molecular mechanics and dynamics.

- Annealing - a method of obtaining a three-dimensional conformation of a target (protein molecule) with minimal calculated values of potential energy using molecular dynamics approaches.

- Stress of amino acids - conformational stress (energy term) of amino acids in the tertiary structure of the target protein.

- Scoring (Score) - energy (kcal / mol) function, characterizing the affinity of the ligand with respect to the binding site.

- RMSD - standard deviation of three-dimensional atomic coordinates.

- A pharmacophore is a set of spatial and electronic features of a molecule necessary to ensure its optimal supramolecular interactions with a specific biological target, which can cause (or block) a biological response.

The preparation and construction of homologous models of target proteins was performed in the ICM Pro v program. 1.8a (MolSoft, official website: http://www.molsoft.com), docking was carried out in the program MY v. 09.09.01 (Molecular Operating Environment, CCG, official website: http://www.chemcomp.com). To construct three-dimensional models of the hCOX-1 and hCOX-2 isoforms, the crystallographic data obtained previously for the celecoxib drug (Celebrex®, Pfizer), which is the most famous selective cyclooxygenase-2 inhibitor, were used as initial data. Numbers of entries in the PDB database (Protein Data Bank, http://www.rcsb.org) 3KK6 (COX-1 sheep isoform, DOI: 10.2210 / pdb3kk6 / pdb) and 3LN1 (COX-2 mouse isoform, DOI: 10.2210 / pdb3ln1 / pdb). These proteins were obtained recombinantly in the Spodoptera frugiperda insect cell line.

Homologous models were constructed using the Homology Model function. We used the standard FASTA primary amino acid sequence code hCOX-1 (number sp_P23219_PGH1_HUMAN, source http://www.uniprot.org/uniprot/P23219) and hCOX-2 (number sp_P35354_PGH2_HUMAN, source http://www.uniprot.org/uniprot/ P35354). Water molecules were excluded from consideration in order to simplify the modeling procedure and build the QSAR model. At the first stage, three-dimensional conformations of the target amino acid sequences were obtained by “rough” overlaying on the appropriate template (ie, secondary and tertiary structures of 3KK6 and 3LN1 enzymes), then proteins were “annealed” at various initial temperatures until the minimum amino acid stress values were reached. Stress diagrams for final three-dimensional conformations are shown in Figures 1, 2.

).As follows from Figures 1 and 2, the two isoforms hCOX-1 and hCOX-2 are characterized by a relatively low stress value, which indicates the reliability of the constructed model. The most stressed amino acids are located relatively far from the binding site (Figure 3). Particular attention was paid to minimizing the potential energy of the radicals of the closest amino acids (HOOC (R) CHNH ₂ ) and hydrogen atoms at the binding site to the inhibitor (celecoxib), as well as in its immediate vicinity (cell size

)

Thus, as a result of the stress minimization procedure, two three-dimensional conformations of the enzymes hCOX-1 and hCOX-2 with potential energy lying in the vicinity of the calculated minimum were obtained. Note that celecoxib binding sites in template structures are characterized by high homology with respect to their human counterparts.

The constructed models were tested using a series of known selective COX-1 and -2 inhibitors (Table 1). To obtain the reference value of energy scoring, celecoxib was docked to the hCOX-1 and -2 binding site (Figure 5). During the experiment, 50 different active conformations were generated corresponding to the optimal positions of the ligand at the indicated binding site. Docking was carried out in a dynamic mode (the active site of the protein is the mobile system). As can be seen from Figure 5, in both cases, the results of molecular docking correlate well with the data of X-ray diffraction analysis (according to RMSD).

Then, using the constructed model, activity was predicted for a number of reference molecules (Table 2). Docking was carried out in dynamic mode with an integrated three-center pharmacophore (Figure 6), based on the peculiarities of celecoxib binding, which is necessary to limit the degree of freedom of the tested ligand at the binding site. For each structure, 50 different possible conformations were generated with corresponding in silico energy scoring values. The arithmetic mean values of scoring for all predicted conformations were taken as true. They were used to construct the corresponding QSAR models (Figures 7, 8). As can be seen from Table 2 and Figures 7 and 8, the models showed high correlation values (RMSD): R ² = 0.82 (SOX-2) and 0.87 (SOX-1).

The developed models were used to evaluate the activity of new molecules in silico. So, for the compounds of the invention (Figure 9), molecular docking was carried out by analogy with the procedures described previously. The obtained energy scoring values were averaged and using the two QSAR models shown in Figures 7 and 8, the IC ₅₀ parameter values were calculated for the studied compounds (Table 3).

Based on the values of the linear approximation error (1-R ² ), it can be argued that within the framework of the class of inhibitors under consideration, the constructed QSAR models have high predictive ability.

As can be seen from table 3, structures 1q, 1t, 1u, 1v, 1w of the general formula (I) containing the NH ₂ SO ₂ group have especially high scoring values, selectivity index (up to 690 for 1u) and, as a result, the most lower values of IC ₅₀ (COX-2), compared with similar molecules with sulfonylmethyl fragment. Thus, the use of sulfamides is preferable from the point of view of introducing a minimum amount of active ingredient in the finished dosage form. The use of compounds (I) as an active substance is also promising for the reason that, as is known from the prior art, sulfamides and salts of sulfonic acids of the general formula (I) have significantly greater solubility in water and physiological solution than alkyl sulfones and alkyl sulfoxides.

The compounds of general formula (I) proposed in this invention are regioisomeric to the compounds of US Pat. No. 6,492,416 B1 [28] with which they are structurally closest (Examples 150-165). However, the compounds of the invention have significantly lower (3-5 times) in vitro concentrations of inhibition of COX-2 (1t, 1u: 0.004-0.007 μg / ml) compared with the above examples of US Pat. No. 6,492,416 B1 [28] (No. 151) - 0.02 μg / ml, No. 155 - 0.016 μg / ml, No. 157 - 0.038 μg / ml, No. 164 - 0.03 μg / ml), which gives an advantage to the compounds of this invention, since it allows to dispense with lower therapeutic doses in case of using the compounds of the present patent in a pharmaceutical composition.

Also from table 3 it follows that the structures of General formula (II) and (III) have an average inhibitory activity and selectivity, both in relation to the known compound celecoxib, and in relation to compounds of the general formula (I). However, it is known from the prior art [5-7] that the high activity of sulfoamides can lead to more pronounced side effects from the cardiovascular system, namely, to excessive aggregation of platelets in blood vessels and the formation of blood clots with the development of ischemia and strokes. Rofecoxib [5, 6] is an example of such an “excess” action, its selective inhibitory activity is extremely high (SI> 1700), however, it also occupies one of the first places according to the severity of side effects [7] and is prohibited for use. Thus, substances with lower SI selectivities characteristic of alkyl sulfones (e.g., -SO ₂ Me) should also be investigated in terms of creating the safest drug. At the moment, there is no universally accepted point of view regarding the mechanism of the development of side effects when using selective cyclooxygenase-2 inhibitors, and the possibilities for their leveling by modifying the structure of the inhibitor. This issue should be solved experimentally.

Sulfoxides of the general formula (II) are of interest as a prodrug form ("prodrugs") of alkyl sulfones, which, despite its lower activity, easily turns into an active sulfonic form in the body as a result of normal oxidative metabolism [29]. Despite its lower activity, sulfoxide has a significantly greater bioavailability, which leads to a decrease in the risk of complications due to an overdose, as well as an improvement in the kinetic parameters of the compound (prolonged action). Thus, sulfoxides are also of interest in this invention and the question of the possibility of their use in the treatment of inflammatory diseases should be decided experimentally.

The closest compounds to the alkyl sulfones of the general formula (II) are compounds of the patent RU 2563876 [30], in which the halogenation of the hydrophobic aryl substituent refers to the para position. However, our computer simulation shows that para-substituted alkyl sulfones exhibit 2-3 times less inhibitory activity than metasubstituted ones. So, for example, for parasubstituted compounds 1c, 1h, 1k from patent RU 2563 876 [30] we see IC ₅₀ at the level of 0.36-0.42 μM, while metasubstitution (1s, 1о) significantly improves IC ₅₀ (3-4 times) up to 0.11 μM. In addition, the selectivity index for para-substituted compounds is also lower (2-3 times, at the level of 22-43) than in the case of metasubstituted compounds (65-101) (see Table 4). Thus, there are several significant reasons for the preference for introducing halogen to the meta position in the compounds of the present invention compared to its introduction to the para position.

Procedure for performing an in vitro experiment to determine the inhibition parameters of IC ₅₀ for the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes for the studied compounds.

The inhibition activity of COX-1 and COX-2 for the claimed compounds will be measured using the sheep isoform of the COX-1 enzyme and the human recombinant isoform of the COX-2 enzyme, which are included in the kit (kit) COX Inhibitor Screening Assay supplied by Cayman ( Cayman Chemical Co., Ann Arbor, Ml), according to the standard procedure for this experimental kit. In this experiment, the concentration of prostaglandin PGF2a produced during the reduction of tin (SnCl ₂ ) prostaglandin PGH2, the formation of which is controlled by COX enzymes, is directly measured fluorometrically. The production of prostaglandins in the system is evaluated by their reaction with widely specific antibodies that interact with all major prostaglandins [31]. An experiment to determine the inhibitory activity is carried out at various concentrations of arachidonic acid (from 0.1 to 100 μM). The target% IC ₅₀ , relative to placebo, is determined at a significantly lower concentration of the inhibitor under study than its concentration in a saturated solution. In order to better visualize and improve the accuracy of the experimental results, the inhibitory activity with respect to the COX-1 enzyme is measured at a concentration of arachidonic acid of about 1 μM (micromole per liter), while the concentration of 0.1 μM is used for the case of COX-2 enzyme. The used concentration of the studied inhibitors in the solution is 200 μM. The IC ₅₀ parameters for naproxen and indomethacin (used at the same concentration of 200 μM) are used as reference values.

Procedure for performing an in vivo experiment to determine the degree of inhibition of carrageenin-induced edema of the paws of mice (CPE%) by injection of the test compounds.

Edema is induced by subcutaneous injection into the right hind paw of the mouse 0.05 ml of a 2% solution of carrageenan in water. Mice of both sexes are used except for pregnant females. Each compound is tested in a group of 6-10 animals, which are kept under standard conditions before the experiment and receive a standard commercial feed for laboratory animals. After the start of the experiment, animals do not receive food. The studied compounds, at a concentration of 0.01 mmol per 1 kg of animal weight), are pre-suspended in water with a few drops of the TWIN-80 surfactant and, after filtering, are administered intraperitoneally, simultaneously with carrageenne injection. 3.5 hours after injection, the mice are euthanized. Differences in the weight of the edematous paw and healthy are determined for all animals, averaged (standard deviation should be less than 10%) and compared with the same parameter in the control group (intraperitoneal injection of saline instead of inhibitor solution). This determines CPE% - the percentage of inhibition of swelling of the paws of mice.

General procedure for performing an in vitro experiment to determine the degree of inhibition of the growth rate of cancer cells by the studied compounds

Activity against cell lines derived from solid tumors (HT-29, NCl-H460, MCF-7, etc.) is evaluated in exponentially growing cultures seeded at a concentration of 5 * 10 ⁴ cells / ml, which are allowed to adhere to the bottom tablet for 18 hours before adding drugs. Cell viability is determined after 72 hours at 37 ° C using the MTT method [32]. The colon cancer cell line (alternatively: gastric cancer, lung cancer, breast cancer, pancreatic cancer), resistant to the action of doxorubicin - LoVo / Doxo, cultured in Hama F12; while doxorubicin (100 ng / ml) is added to the persistent subline of cancer at each pass. The cell growth rate at each concentration of the drug is expressed as a percentage of the growth rate of the control culture; the concentration providing 50% growth inhibition (IC ₅₀ ) is determined using linear regression analysis.

Bibliography:

[1] P.N. Praveen Rao, E.E. Knaus, J. Pharm. Pharmaceut. Sci. 2008, 11, 81.

[2] E.L. Nasonov, Consilium Medicum, 1999, Volume 1, No. 5.

[3] Yu. Muravyov, V. Lebedeva, Russian Gastroenterological Journal, 2000, No. 4.

[4] J.J. Talley, Prog. Med. Chem. Res. 1999, 36, 201.

[5] Bombardier, Laine, Reicin et al., N. Engl. J. Med. 2000, 343, 1520.

[6] R.S. Bresalier, R.S. Sandler, H. Quan et al., N. Engl. J. Med. 2005, 352, 1092.

[7] Sven Trelle et al., BMJ 2011, 342, 7086.

[8] Svetla Gadzhanova, et al., Drugs Aging 2013, 30, 23.

[9] Meheroz, Rabadi et al., Ann Indian Acad Neurol. 2013, 16 (1), 47.

[10] H. Sheng et al., J. Clin. Invest. 1997, 99, 2254.

, Curr Opin Investig Drugs, 2010, W(1), 31-42.[11] N.

, Curr Opin Investig Drugs, 2010, W (1), 31-42.

[12] W.F. Stewart, Neurology, 1997, 48, 626.

[13] P. Prasit et al., Bioorg. Med. Chem. Lett., 1999, 9, 1773-1778.

[14] A.K. Chakraborti et al., Current Medicinal Chemistry, 2010, 17, 1563-1593.

[15] B. Rigas, I. Goldman, L. Levine, "Altered eicosanoid levels in human colon cancer", J. Lab. Clin. Med, 122, 1993, p. 518-523.

[16] S. Koehne, R. Dubois "COX-2 inhibition and colorectal cancer", Semin. Oncol., 2004, p. 12-21.

[17] K. Leahy, A. Koki, J. Masferrer, "Role of cyclooxygenases in angiogenesis", Curr. Med. Chem., 7, 2000, p. 1163-1170.

[18] S. Zelenay et al., "Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity", Cell, 162, 6, 2015, p. 1257-1270.

[19] M. Dore, Vet. Pathol., 48, 2011, p. 254.

[20] Brunelle, Vet. Pathol., 43, 2006, p. 656-666.

[21] S.A. Malashikhin et. al., Helv. Chim. Acta, 91, 2008, p. 1662.

[22] G. Bennett et al., Journal of Medicinal Chemistry, 19 (5), 1976, p. 709.

[23] S.M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 66, 1977, p. 1-19.

[24] E.W. Martin "Remington's pharmaceutical sciences", 15th edition, Mack Publishing Co.,

Easton, Pa., 1975.

[25] Philippe Chavatte et al., J. Med. Chem., 2001, 44, 3223-3230.

[26] Song Seok Shin and coworkers, Bioorganic & Medicinal Chemistry Letters 2001, 11, 165.

[27] Song Seok Shin and coworkers, J. Med. Chem, 2004, 47, 792.

[28] Patent S. Shin et al., US 6492416 B1 (2002).

[29] J.H. Moh et al., Bioorg. Med. Chem. Lett., 14, 2004, p. 1757.

[30] Yu. Medvedev, D. Semenok, V. Nikolaev, L. Rodina, RU 2563876 (priority 11.11.2014).

[31] G. Ziakas et al., Bioorg. Med. Chem., 14 (16), 2006, p. 5616-5624.

[32] T. Mosmann, J. Immunol. Methods, 1983, 65, p. 55-63.

Claims (61)

1. The compound of General formula (I)

or its pharmaceutically acceptable salt, where R ¹ represents a substituted sulfonamide group —SO ₂ NHAlk, where Alk is selected from methyl, ethyl, isopropyl or n-propyl, or an unsubstituted sulfonamide (—SO ₂ NH ₂ ) or sulfo (—SO ₂ OH) group; R ² is independently selected and represents halogen or hydrogen, said substituents being in a meta or para position with respect to the attachment point of the phenyl group; R ³ and R ⁴ are independently selected and are C _1-5 alkyl. 2. The compound according to claim 1, selected from the group: 2,2-Dimethyl-4- [4 '- (aminosulfonyl) phenyl] -5-phenyldihydrofuran-3 (2H) -one; 2,2-Dimethyl-4- [4 '- (aminosulfonyl) phenyl] -5- (4'-fluorophenyl) dihydrofuran-3 (2H) -one; 2,2-Dimethyl-4- [4 '- (aminosulfonyl) phenyl] -5- (3'-fluorophenyl) dihydrofuran-3 (2H) -one; 2,2-Dimethyl-4- [4 '- (aminosulfonyl) phenyl] -5- (4'-chlorophenyl) dihydrofuran-3 (2H) -one; 2,2-Dimethyl-4- [4 '- (aminosulfonyl) phenyl] -5- (3'-chlorophenyl) dihydrofuran-3 (2H) -one; 4- (5,5-dimethyl-4-oxo-2-phenyl-4,5-dihydrofuran-3-yl) benzenesulfonic acid; 4- (2- (4'-fluorophenyl) -5,5-dimethyl-4-oxo-4,5-dihydrofuran-3-yl) benzenesulfonic acid; 4- (2- (4'-chlorophenyl) -5,5-dimethyl-4-oxo-4,5-dihydrofuran-3-yl) benzenesulfonic acid; 4- (2- (3'-fluorophenyl) -5,5-dimethyl-4-oxo-4,5-dihydrofuran-3-yl) benzenesulfonic acid; 4- (2- (3'-chlorophenyl) -5,5-dimethyl-4-oxo-4,5-dihydrofuran-3-yl) benzenesulfonic acid. 3. The compound of General formula (II)

or its pharmaceutically acceptable salt, where R ¹ is independently selected and is a C _1-3 alkylsulfonyl or C _1-3 alkylsulfinyl group; R ² is independently selected and is halogen; R ³ and R ⁴ are independently selected and are C _1-5 alkyl. 4. The compound according to claim 2, in which R ² is independently selected and is fluoro or chloro. 5. The compound according to claim 4, selected from the group: 2,2-Dimethyl-4- [4 '- (methylsulfinyl) phenyl] -5- (3'-fluorophenyl) dihydrofuran-3 (2H) -one; 2,2-Dimethyl-4- [4 '- (methylsulfonyl) phenyl] -5- (3'-fluorophenyl) dihydrofuran-3 (2H) -one; 2,2-Dimethyl-4- [4 '- (methylsulfinyl) phenyl] -5- (3'-chlorophenyl) dihydrofuran-3 (2H) -one; 2,2-Dimethyl-4- [4 '- (methylsulfonyl) phenyl] -5- (3'-chlorophenyl) dihydrofuran-3 (2H) -one. 6. The compound of General formula (III)

or its pharmaceutically acceptable salt, where R ¹ is independently selected and is C _1-3 alkylsulfonyl, C _1-3 alkylsulfinyl, unsubstituted sulfonamide (-SO ₂ NH ₂ ), C _1-3 alkylthio group, hydrogen or halogen, wherein said substituents are in the third or the fourth position of the phenanthrene fragment; R ² is independently selected and is C _1-3 alkylsulfonyl, C _1-3 alkylsulfinyl, unsubstituted sulfonamide (-SO ₂ NH ₂ ), C _1-3 alkylthio group, hydrogen or halogen, said substituents being in the fifth or the sixth position of the phenanthrene fragment; moreover, if R ¹ represents hydrogen, then R ² cannot be hydrogen and vice versa; R ³ and R ⁴ are independently selected and are C _1-5 alkyl. 7. The compound according to claim 6, in which R ¹ and R ² are independently selected and are fluoro or chloro. 8. The compound according to claim 6, selected from the group: 2 ', 2'-dimethyl-3- (methylthio) phenantro [9,10-b] furan-3' (2'H) -one; 2 ', 2'-dimethyl-3- (methylsulfinyl) phenantro [9,10-b] furan-3' (2'H) -one; 2 ', 2'-dimethyl-3- (methylsulfonyl) phenantro [9,10-b] furan-3' (2'H) -one; 2 ', 2'-dimethyl-6- (methylthio) phenantro [9,10-b] furan-3' (2'H) -one; 2 ', 2'-dimethyl-6- (methylsulfinyl) phenantro [9,10-b] furan-3' (2'H) -one; 2 ', 2'-dimethyl-6- (methylsulfonyl) phenantro [9,10-b] furan-3' (2'H) -one; 3-fluoro-2 ', 2'-dimethyl-6- (methylthio) phenantro [9,10-b] furan-3' (2H) -one; 3-fluoro-2 ', 2'-dimethyl-6- (methylsulfinyl) phenantro [9,10-b] furan-3' (2'H) -one; 3-fluoro-2 ', 2'-dimethyl-6- (methylsulfonyl) phenantro [9,10-b] furan-3' (2'H) -one; 3-chloro-2 ', 2'-dimethyl-6- (methylthio) phenantro [9,10-b] furan-3' (2'H) -one; 3-chloro-2 ', 2'-dimethyl-6- (methylsulfinyl) phenantro [9,10-b] furan-3' (2'H) -one; 3-chloro-2 ', 2'-dimethyl-6- (methylsulfonyl) phenantro [9,10-b] furan-3' (2'H) -one; 3-chloro-2 ', 2'-dimethyl-6- (aminosulfonyl) phenantro [9,10-b] furan-3' (2'H) -one; or their pharmaceutically acceptable salts. 9. A pharmaceutical composition for treating inflammatory diseases of the genesis or diseases associated with excessive secretion of cyclooxygenase-1 and cyclooxygenase-2 enzymes, having the property of inhibiting preferably COX-2 compared to COX-1 and containing an effective amount of at least one compound according to any one of p. 1-8 and at least one pharmaceutically acceptable carrier and / or diluent. 10. The pharmaceutical composition according to p. 9, characterized in that it contains a compound according to any one of paragraphs. 1-8 and further comprises its regioisomer. 11. The pharmaceutical composition according to claim 9, characterized in that it has anti-inflammatory, analgesic and / or antipyretic effects. 12. The pharmaceutical composition according to claim 9, characterized in that the disease is arthritis, joint syndrome with rheumatism and exacerbation of gout, skin inflammatory disease, inflammation in vascular diseases, pulmonary inflammation, thyroiditis, inflammation associated with general hypothermia, flu or other acute respiratory viral infection, inflammatory processes of ligaments, tendons, sciatica, lumbago. 13. The pharmaceutical composition according to p. 12, characterized in that the arthritis is rheumatoid arthritis, osteoarthritis, gouty arthritis, juvenile arthritis, psoriatic arthritis, spondylolisthesis. 14. The pharmaceutical composition according to p. 12, characterized in that the skin inflammatory disease is eczema, dermatitis, psoriasis. 15. The pharmaceutical composition according to claim 9, characterized in that it has antitumor activity.

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