KR20140033643A - Flavonoid derivatives selectively inhibiting the activity of janus kinase 3 - Google Patents

Abstract

The present invention relates to flavonoid derivatives selectively inhibiting an activity of janus kinase 3, a method for manufacturing the same, and a use of the compound as immunosuppressive agents. The compound can be used as a safe immunosuppressive agent since the compound does not cause problems like pernicious anemia which is a side effect of a conventional immunosuppressant using JAK3 inhibitors.

Description

[0002] Flavonoid derivatives selectively inhibit the activity of Janus kinase 3, which selectively inhibits the activity of Janus kinase 3,

The present invention relates to the selective inhibition of the activity of flavonoid derivatives and Janus kinase 3 thereof and their use as immunosuppressants.

In general, an immunosuppressant is a generic term for an agent that inhibits the immune response of a living body and is mainly used as a drug for the treatment and prevention of organ transplant rejection and autoimmune diseases.

Organ transplantation is the best treatment for the treatment of end-stage insufficiency unless there is a development of new therapies. Immunosuppressants are used to protect the transplanted tissues / organs against immune rejection, and today there are 25 organ transplants.

Autoimmune disease (autoimmune disease) is a disease caused by the destruction of tissues in response to antigens of antibodies or immune cells formed by the immune system's recognition of endogenous proteins as external antigens. Rheumatoid arthritis, atopic dermatitis, Psoriasis, Crohn's disease, and the like. It has not been clarified about the clear pathogenesis and mechanism. Currently, it is reported that the effect of the immunosuppressive drug such as steroids is temporarily improved without the fundamental treatment, and immunosuppressive therapy has been proved to be effective in suppressing such autoimmune response.

Immunosuppressants, on the other hand, are divided into chemical immunosuppressants and biological immunosuppressants.

Chemical immunosuppressants are the most commonly prescribed immunosuppressive agents for organ transplant rejection and autoimmune diseases. Fujisawa's FK506 has almost the same mechanism of action as Novartis' cyclosporin A (CsA, 85% of the total). However, the signaling process that is the drug action point of the chemical immunosuppressive agent is not specific to the activated immune cells and thus has a problem that various and serious side effects are caused by non-selective signaling inhibition.

On the other hand, TNF-α inhibitors (etanercept, infliximab, adalimumab), which are used as therapeutic agents for autoimmune diseases such as rheumatoid arthritis (RA), psoriasis and Crohn's disease, are typical among biological immunosuppressive agents. In addition, Daclizumab (Zenapax) and Basiliximab (Simulect) are the therapeutic antibody preparations represented by monoclonal or polyclonal antibodies against the immune system of organ transplant patients. In addition, Siplizumab (MEDI-507) and ABXCBL is being developed. Antibody preparations suppress the immune response by abolishing the function of the patient's immune system elements. The most commonly used antibodies are antibodies against B cells and T cells. In addition, IL-2 receptors (CD25) and CTLA -4, antibodies to CD40 and CD40 ligand, and the like.

However, biological immunosuppressants have many problems, such as: 1) TNF-α is ineffective in all RA patients and exceeds 30% refractory, and 2) selectivity to activated immune cells. The absence of side effects remains a problem, and 3) it is very expensive to develop and treat. Since immunosuppressants have to be taken for a lifetime, they can be very costly for patients. Patient compliance is very low and there is a risk of injection and infection.

On the other hand, as the number of transplant surgery increases and the patient's remaining survival time increases, efforts have recently been made to improve the 'quality of life' of patients undergoing transplant surgery by minimizing the side effects of immunosuppressants. An ideal immunosuppressive agent should be a specific immunosuppressive agent that selectively inhibits only clones that specifically react to the antigen, but is not yet clinically available, and currently used drugs have specificity for activated immune cells. As an immunosuppressive agent, it inhibits the host's normal immune response and shows fatal side effects such as kidney and liver, and causes complications such as infectious diseases and malignant tumors. Until now, since a single drug does not provide sufficient efficacy to prevent rejection, a combination of several methods is required. Accordingly, the demand for immunosuppressive agents that long-term transplant patients have to take for a lifetime is also increasing in tandem with the increasing demand, but the demand for the development of new immunosuppressive agents is increasing due to the side effects and the high price due to long-term administration.

Janus Kinase 3 (JAK3) is a target protein specifically expressed and regulated in immune cells. It has been reported that selective JAK3 (JAK3) is a target protein that is specifically expressed and regulated in immune cells, The discovery of inhibitors is expected to result in the development of oral low-molecular immunosuppressants with minimal side effects.

Immune cells are signaled by cytokines, so there are receptors specific for each cytokine. The cytokine receptors that bind to IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 have a central part called the common cytokine receptor γ-chain γc family, which is known to play a crucial role in the formation and function of lymphocytes. Therefore, a mutation occurs in the gene coding for γc, or the cytoplasmic tyrosine kinase JAK3 (janus kinase 3) (SCID) is known to occur when a mutation in a gene coding for a mutation occurs. As a result, studies on the development of immunosuppressive agents using a substance capable of selectively inhibiting the activity of JAK3 have been actively attempted.

As a result, JAK3 plays a very important role in the immune system, as confirmed by SCC generation by mutation of γc and JAK3, and other JAK kinases (JAK1, JAK2, Tyk2) While JAK3 is restricted and regulated in the immune cell system. Therefore, unlike the targets of all immunosuppressants developed so far, JAK3 is selectively expressed in the immune cell system, so it is expected that a selective immunosuppressive agent can be developed through JAK3 inhibitor.

Although most multinational pharmaceutical companies around the world have worked hard to develop JAK3 inhibitors, Pfizer's CP-690,550 is the most likely new drug candidate. CP-690,550 exhibits an excellent inhibitory activity against the JAK family ( Science 2003, 302: 875) and a JAK family inhibitory activity 1,000 times higher than the non-JAK family kinase inhibitory activity ( Blood 2008, 111: 2155). In addition, the murine heterotopic heart transplantation model also has the effect of preventing organ rejection and increasing the survival rate of individuals. CP-690,550 has demonstrated efficacy as an immunosuppressive agent similar to cyclosporin A or tacolimus (FK506) in preclinical and clinical studies, with very few side effects, especially in clinical studies in patients with rheumatoid arthritis. CP-690,550 is currently undergoing extensive clinical trials for rheumatoid arthritis (Phase 3), kidney transplantation, Crohn's disease, psoriasis, ocular hypertension (Phase 2), and asthma (Phase 1).

However, CP-690,550 exhibits very low inhibitory activity against JAK kinases and exhibits high selectivity for other kinases, but has a disadvantage of low selectivity within the JAK family. In particular, the selectivity for JAK2 is low (IC ₅₀ = 1 nM for JAK3 and 20 nM for JAK2), resulting in hematopoietic effects such as anemia, thrombocytopenia and leukopenia. Inflammatory cytokines IL-1, TNF-α, and TGF-β are found in 8-70% of autoimmune disease patients and in 8-71% of organ transplant patients. Etc. can reduce red blood cell production in anemia situations. JAK2 plays a crucial role in the signaling process involving erythropoiesis, and inhibition of JAK2 activity may exacerbate inflammatory anemia. Immunosuppressants, such as JAK3 inhibitors, are taken for a lifetime, and selectivity to JAK2 should be ensured to prevent the deterioration of inflammatory anemia.

Korean Priority Patent No. 1020100061666 discloses a method and a composition for treating immunological and inflammatory diseases and disorders, and a specific method and composition includes an agent that inhibits S1P lyase activity, and one or more additional immunity Inhibiting < / RTI > and / or anti-inflammatory agents,

As another related prior patent, Korean Patent Publication No. 1020060050555 discloses that a compound containing a diphenoyl (DP) structure has a number of regulatory T cells (Tregs) that act to regulate agonized immunity and an active And is useful for preventing or treating immunological diseases such as organ rejection, graft-versus-host disease, autoimmune disease, irritable inflammatory disease, and the like.

The present invention solves the above problems and aims to provide a novel inhibitor of JAK2 / JAK3 selectivity using a natural compound, a flavonoid derivative, to provide an immunosuppressive agent with minimal side effects The goal is to develop.

In order to achieve the above object, the present invention provides a compound of the following formula 1: < EMI ID =

[Formula 1]

In a preferred embodiment of the present invention, R ₁ and R ₂ in the general formula (1) are substituents selected from the group consisting of hydrogen, CH ₃ -, and CH ₂ CN and are preferably present in an ortho-position,

Also, in the above formula, R ₃ is preferably a substituent selected from the group consisting of hydrogen or -C≡CCH ₂ OH, and is preferably present in the para-position, but is not limited thereto.

In another embodiment of the present invention, the compound preferably inhibits the activity of Janus kinase 3, but is not limited thereto.

The compounds of the present invention and their pharmaceutically acceptable salts preferably have immunosuppressive activity, but are not limited thereto.

The present invention also provides a pharmaceutical composition comprising a compound of the formula [1] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier:

[Formula 1]

Wherein R ₁ and R ₂ are substituents selected from the group consisting of hydrogen, CH ₃ -, CH ₂ CN, and the like and are present in the ortho-position. Also, in the above formula, R ₃ is a substituent selected from the group consisting of hydrogen, -C≡CCH ₂ OH, and the like and is present at the para-position.

The present invention also provides pharmaceutically acceptable compositions, wherein these compositions comprise any of the compounds as disclosed herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

It is also to be appreciated that certain of the compounds of the present invention may exist in a free form for treatment, or where appropriate, exist as pharmaceutically acceptable derivatives thereof. In accordance with the present invention, the pharmaceutically acceptable derivatives include the pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or compounds or metabolites as described herein or otherwise, But are not limited to, any other additive or derivative that can directly or indirectly provide the compound.

The term "pharmaceutically acceptable salts ", as used herein, refers to salts which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc. within the scope of sound medical judgment, Means salts that are proportional to the benefit / risk ratio. "Pharmaceutically acceptable salt" means any of the compounds of the present invention, or any passive salt of a compound of the present invention, which, upon administration to a recipient, is capable of providing, either directly or indirectly, Means a salt of an ester of a compound.

Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and perchloric acid or with organic acids such as acetic, oxalic, maleic, tartaric, citric, Salts of amino groups formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include those derived from pharmaceutically acceptable salts such as adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, hydrogen sulphates, borates, butyrates, camphor, camphorsulfonates, citrates, cyclopentanepropionates, Hydrogencarbonate, gluconate, hemic sulfate, heptanoate, hexanoate, hydrogen iodide, 2-hydroxy-ethanesulfonic acid, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptate, glycerophosphate, Salts of lactic acid, salts of lactic acid, salts of lactic acid, salts of lactic acid, salts of lactic acid, salts of lactic acid, salts of lactic acid, salts of lactic acid, salts of lactic acid, salts of lactic acid, Pamoate, pamoate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, Include sulfonate, undecane acid, valeric acid, and the like. Salts derived from suitable bases include alkali metals, alkaline earth metals, and ammonium salts. The present invention also envisions quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water-soluble or oil-soluble or dispersible products can be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine salts formed with counter ions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates and arylsulfonates, Lt; / RTI >

As mentioned above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, and as used herein, is meant to include any and all solvents, diluents or other Liquid vehicles, dispersing or suspending aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, which apply to the specific dosage form desired. Remington ' s Pharmaceutical Sciences, 16th Edition, E.W. Martin (1980, Mack Publishing, Easton, PA) discloses pharmaceutically acceptable compositions and various carriers used in known techniques for its preparation. Except insofar as any conventional carrier medium is incompatible with the compounds of the present invention it is possible to produce undesirable biological effects or in a detrimental manner with any other component (s) of the otherwise pharmaceutically acceptable composition It is anticipated that its use will be within the scope of the present invention, as is done by interacting. Some examples of materials which may act as pharmaceutically acceptable carriers are ion exchange materials, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer matrix Such as, for example, phosphates, glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride , Zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; Starches such as corn starch and potato starch; Cellulose and derivatives thereof such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Powdered tragaganth; malt; gelatin; talc; Excipients such as cocoa butter and suppository wax; Oils, for example peanut oil, cottonseed oil; Safflower oil; Sesame oil; Olive oil; Corn oil and soybean oil; Glycols such as propylene glycol or polyethylene glycol; Esters such as ethyl oleate and ethyl laurate; Agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; Alginic acid; Water without heat source; Isotonic saline; Ringer's solution; Ethyl alcohol, and phosphate buffers as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate as well as colorants, relaxants, coatings, sweeteners, flavors and fragrances, preservatives and antioxidants But are not limited to, these.

The pharmaceutically acceptable compositions of the present invention may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (including powders, granules, Ointments or drops), into the ball, orally or intranasally. In certain embodiments, the compounds of the present invention are administered at dosage levels of from 0.01 mg / kg to about 50 mg / kg, preferably from about 1 mg / kg to about 25 mg / kg, to the patient's body weight per day to achieve the desired therapeutic effect. May be administered orally or parenterally one or more times a day.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate , Ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil) , Glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral compositions may also include adjuvants such as, for example, moisturizers, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Injectable preparations, for example sterile injectable aqueous or oleaginous suspension preparations, may be formulated according to the known art using suitable dispersing or moisturizing agents or suspending agents. The sterile injectable preparation may be, for example, a solution in a non-toxic parenterally acceptable diluent or solvent, as a solution in 1,3-butanediol, an injectable solution, a suspension or an emulsion. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, U.S.P. And isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose any mixed fixed oil may be used, including synthetic mono- or glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable formulations.

Injectable formulations may be sterilized, for example, by filtration through a bacteria-preserving filter or by incorporating sterilizing agents in the form of sterile solid compositions that may be dissolved or dispersed in sterile water or other sterile injectable medium prior to use .

In order to prolong the effect of the compounds of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by the use of liquid suspensions of crystalline or amorphous material with poor water solubility. The rate of absorption of this compound then depends on its dissociation rate, which again may depend on crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in the oily vehicle. Priming depot forms are prepared by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration may be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers, for example cocoa butter, polyethylene glycol or a liquid at ambient temperature, but liquid at body temperature, It is preferred that the suppositories be prepared by mixing with a suppository wax releasing the compound.

Solid dosage forms for oral administration include capsules, tablets, tablets, powders, and granules. In such solid dosage forms, the active compound may contain at least one inert, pharmaceutically acceptable excipient or carrier, for example sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches Such as carboxymethylcellulose, alginates, gelatine, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d-lactose, sucrose, sucrose, glucose, mannitol, E) a solution retarder such as paraffin, f) an absorption accelerator such as quaternary ammonium < RTI ID = 0.0 > G) moisturizers such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, stearic acid Calcium, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and tablets, the dosage form may also contain buffering agents.

Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose as well as high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, tablets and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating arts. These forms may optionally comprise opacifying agents, and they may also consist of a composition which releases only the active ingredient (s) or, in a parenterally specific part of the intestinal tract, in an optionally delayed manner. Examples of embedded compositions that can be used include polymeric substrates and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose as well as high molecular weight polyethylene glycols.

The active compounds may be present in microencapsulated form with one or more excipients as described above. Solid dosage forms of tablets, dragees, capsules, capsules, tablets, and granules may be prepared with coatings and shells such as enteric coatings, release-controlled coatings, and other coatings well known in the pharmaceutical formulating arts . In such solid dosage forms, the active compound may be mixed with at least one diluent such as sucrose, lactose or starch. Such dosage forms may comprise additional substrates other than inert diluents, such as tablet lubricants and other tablet adjuvants such as magnesium stearate and microcrystalline cellulose, as is commonly practiced. In the case of capsules, tablets, and tablets, the dosage forms may contain buffering agents. They may optionally comprise opacifying agents and may consist of a composition which emits only the active ingredient (s) or, in a parenterally specific portion of the intestinal tract, optionally in a delayed manner. Examples of embedded compositions that can be used include polymeric substrates and waxes.

Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active compound is mixed under sterile conditions with the pharmaceutically acceptable carrier and any necessary preservatives or buffers as required. Ophthalmic formulations, ear drops and eye drops are also contemplated as falling within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches with the added advantage of controlling the delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

In another aspect, the present invention a) the quercetin N, N - after adding potassium carbonate dissolved in a solution in dimethylformamide (N, N -Dimethylformamide) was added benzyl bromide mideueul, Purification of the residue obtained by concentration under reduced pressure and the reaction mixture of methane / Tris (benzyloxy) -2- (3,4-bis (benzyloxy) phenyl) -4H-chromen-4-one obtained by recrystallization from ethyl acetate was dissolved in anhydrous pyridine, After adding glycol and potassium hydroxide, the reaction mixture was extracted with dichloromethane and the organic layer was concentrated under reduced pressure to give 2- (benzyloxy) -1- (2,4-bis (benzyloxy) -6-hydroxyphenyl ) Ethanone;

b) dissolving the 2- (benzyloxy) -1- (2,4-bis (benzyloxy) -6-hydroxyphenyl) ethanone in methanol and tetrahydrofuran, adding palladium / charcoal, The mixture was stirred in the presence of hydrogen to dissolve 2-hydroxy-1- (2,4,6-trihydroxyphenyl) ethanone in dichloromethane and then pyridinium-para-toluenesulfonic acid and 3,4-dihydro- 2H-pyran was added and the stirred reaction mixture was concentrated under reduced pressure to obtain 2- (tetrahydropyranyl) -1- (2,4-bis (tetrahydropyranyl) -6-hydroxyphenyl) ethanone;

c) reacting the 2- (tetrahydropyranyl) -1- (2,4-bis (tetrahydropyranyl) -6-hydroxyphenyl) ethanone compound with an aromatic carboxylic acid in N, N -dimethylformamide After the reaction mixture was dissolved, a mixture of 4-dimethylaminopyridine (DMAP) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) was added to the reaction mixture and the reaction mixture was concentrated under reduced pressure. Was dissolved in toluene, potassium carbonate and tetrabutylammonium bromide were added to the mixture, and the mixture was stirred under reduced pressure to form 3,5 ', 7'-tri (tetrahydropyranyl) -flavonoid derivative And

d) dissolving the above 3,5 ', 7'-tri (tetrahydropyranyl) -flavonoid derivative in methanol, adding para-toluenesulfonic acid and stirring the resultant reaction mixture under reduced pressure, and purifying the obtained residue Wherein R < 1 >

[Formula 1]

In one embodiment of the present invention, R ₁ in the general formula (1) is hydrogen or CH ₃ , R ₂ is hydrogen or CH ₂ CN, and R ₃ is CCCH ₂ OH, but is not limited thereto.

The invention is a) the quercetin N, N - after adding potassium carbonate dissolved in a solution in dimethylformamide (N, N -Dimethylformamide) was added benzyl bromide mideueul, Purification of the residue obtained by concentration under reduced pressure and the reaction mixture of methane / Tris (benzyloxy) -2- (3,4-bis (benzyloxy) phenyl) -4H-chromen-4-one obtained by recrystallization from ethyl acetate was dissolved in anhydrous pyridine, After adding glycol and potassium hydroxide, the reaction mixture was extracted with dichloromethane and the organic layer was concentrated under reduced pressure to give 2- (benzyloxy) -1- (2,4-bis (benzyloxy) -6-hydroxyphenyl ) Ethanone;

b) dissolving the 2- (benzyloxy) -1- (2,4-bis (benzyloxy) -6-hydroxyphenyl) ethanone in methanol and tetrahydrofuran, adding palladium / charcoal, The mixture was stirred in the presence of hydrogen to dissolve 2-hydroxy-1- (2,4,6-trihydroxyphenyl) ethanone in dichloromethane and then pyridinium-para-toluenesulfonic acid and 3,4-dihydro- 2H-pyran was added and the stirred reaction mixture was concentrated under reduced pressure to obtain 2- (tetrahydropyranyl) -1- (2,4-bis (tetrahydropyranyl) -6-hydroxyphenyl) ethanone;

c) reacting the 2- (tetrahydropyranyl) -1- (2,4-bis (tetrahydropyranyl) -6-hydroxyphenyl) ethanone compound with an aromatic carboxylic acid in N, N -dimethylformamide After the reaction mixture was dissolved, a mixture of 4-dimethylaminopyridine (DMAP) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) was added to the reaction mixture and the reaction mixture was concentrated under reduced pressure. Was dissolved in toluene, potassium carbonate and tetrabutylammonium bromide were added to the mixture, and the mixture was stirred under reduced pressure to form 3,5 ', 7'-tri (tetrahydropyranyl) -flavonoid derivative And

d) The above 3,5 ', 7'-tri (tetrahydropyranyl) -flavonoid derivative is dissolved in methanol, para-toluenesulfonic acid is added and the reaction mixture is concentrated under reduced pressure to obtain a residue Which comprises dissolving tetrahydropyranylated compound in anhydrous tetrahydrofuran, adding lithium aluminum hydride, and stirring the compound of formula

[Formula 1]

In one embodiment of the invention, and in the formula 1 R ₁ is hydrogen or CH _3, R ₂ is hydrogen or CH ₂ CN, R ₃ shall one preferred that the hydrogen not limited to this.

Hereinafter, the present invention will be described.

Substances exhibiting selective Janus kinase 3 (JAK3) inhibitory activity are highly likely to be developed as effective and safe immunosuppressants. However, JAK3 inhibitors currently under development, including CP-690,550, have the problem of being able to induce inflammatory anemia upon long-term administration due to lack of selectivity for kinases belonging to the same JAK family, particularly JAK2. As a result of efforts to discover inhibitors having selectivity, the inventors have discovered a substance having JAK3 inhibition ability which is much higher than JAK2 among the flavonoid derivatives and completed the invention.

Hereinafter, the present invention will be described in detail.

In the present invention, an inhibitor which is selective for JAK3 than JAK2 was developed.

First, CP-690,550, which is well-known as a JAK3 inhibitor, was analyzed by three-dimensional crystal structure combined with JAK3. As a result, JAK3 inhibitory activity by CP-690,550 was found to be located on both hydrogen bonds and hydrogen bonds with the enzyme hinge motif (Leu905, Glu903) It was predicted that the hydrophobic interaction of the two substituents, namely the CH2CN and Me functional groups and the enzymatic period of action, would play a very important role [Fig. 1].

Therefore, in the present invention, a flavonoid [Hou DX; Kumamoto, T. Antioxid. Redox Signal 2010, 13, 691] A novel flavonoid derivative was prepared by introducing two substituents of CP-690,550, that is, CH2CN and Me functional groups, into the precursor structure [Fig. 2] [Figure 3] By verifying the inhibition of JAK2 and JAK3 [Fig. 4], a novel use as a selective JAK3 inhibitor was found and the invention was completed. The flavonoid derivatives were synthesized by a general flavonoid synthesis method (Fig. 3). In detail, the compound 1 obtained from quercetin, which is commercially available at the outset [Hauteville, M .; Chadenson, M .; Chopin, J. Bull. Chim. Soc. Fr. 1979, 11, 125], compound 2 can be synthesized by removing a benzylic group by hydrogenolysis and introducing a new THP group into the compound. A benzoic acid having various substituents at the R ₁ , R ₂ , and R ₃ positions of the aromatic ring is subjected to EDC coupling with Compound 2 to obtain a condensed ester, which is then cyclized in the presence of TBAB to obtain a main intermediate 3 having a flavonoid mother nucleus . From this, to obtain the final products 4a-4c, the THP scavenger is first removed under acidic conditions and finally the Br group is reduced to LAH. On the other hand, the other end products 4d to 4f can be obtained directly by removing the THP scavenger from 3d to 3f, respectively.

JAK2 and JAK3 inhibitory activity by the synthesized flavonoid derivatives was verified by Upstate's KinaseProfiler (TM) Assay Protocol. As a result, selective JAK3 inhibitory activity was confirmed in two derivatives (4b and 4e) having CH3 and CH2CN functional groups at the R1 and R2 positions of the flavonoid derivatives (Fig. 4). These two flavonoid derivatives inhibited the kinase activity of JAK3 by 63% and 56%, respectively, at a concentration of 10 μM, and did not inhibit the activity of JAK2 at all.

As described above, in the present invention, it was confirmed that the flavonoid derivatives introduced with appropriate substituents did not inhibit the kinase activity of JAK2, but could have a selective inhibitory activity against JAK3. Through this, it was confirmed that the existing JAK3 inhibitor immunosuppressive agent And it can be used as a safe immunosuppressive agent that does not cause problems such as malignant anemia which has been pointed out as a side effect of the present invention.

Figure 1 illustrates the coupling of the known JAK3 inhibitors CP-690,550 and JAK3.
Figure 2 illustrates the anticipation of the manner in which the flavonoid derivative is coupled to JAK3.
3 illustrates the synthesis of compounds represented by Formula 1.
FIG. 4 is a table showing JAK2 and JAK3 inhibitory activities by the compounds represented by the formula (1).

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as limited by these examples.

Example 1. Synthesis of 2- ( benzyloxy ) -1- (2,4- bis ( benzyloxy ) -6 -hydroxyphenyl ) ethanone ( 1 )

Quercetin (10 g, 33.1 mmol) of N, N - dimethylformamide (N, N -Dimethylformamide) add potassium carbonate (45.7 g, 331 mmol) was dissolved in a solution (150 mL) benzyl bromide (39.3 mL, 331 mmol) was added thereto, followed by reflux stirring at 80 占 폚 for 3 days. After the reaction mixture was cooled to room temperature, potassium carbonate was filtered through filter paper and concentrated under reduced pressure. The resulting residue was recrystallized from dichloromethane / ethyl acetate. (25.2 g, 29.9 mmol) was added to anhydrous pyridine (80 mL) at room temperature to give the title compound Diethylene glycol (40 mL) and 18 N potassium hydroxide (40 mL) were added thereto, followed by reflux stirring at 120 ° C for 12 hours. The reaction mixture is cooled to room temperature, neutralized with a 2 N aqueous hydrochloric acid solution, and extracted three times with dichloromethane (100 mL). The organic layer was washed with magnesium sulfate to remove water, concentrated under reduced pressure and purified by silica gel column chromatography (16: 1: 1 = hexane: dichloromethane: ethyl acetate) to obtain Compound 1 as a yellow solid (4.0 g , 8.8 mmol, 29% ^{yield): 1 H NMR (500 MHz} , CDCl 3) δ 13.74 (s, 1H), 7.21-7.39 (m, 15H), 6.18 (s, 1H), 6.06 (s, 1H), 5.05 (s, 2H), 4.98 (s, 2H), 4.56 (s, 2H), 4.52 (s, 2H).

Example 2. Synthesis of 2- ( tetrahydropyranyl ) -1- (2,4- bis ( tetrahydropyranyl ) -6 -hydroxyphenyl ) ethanone ( 2 )

2- (benzyloxy) -1- (2,4-bis (benzyloxy) -6-hydroxyphenyl) -ethanone (1) (4 g, 8.8 mmol) in methanol (10 mL), tetrahydrofuran (20 mL) followed by addition of palladium / charcoal (0.4 g, 0.88 mmol). The mixture is stirred in the presence of hydrogen for 6 hours. 2-hydroxy-1- (2,4,6-trihydroxyphenyl) ethanone (1.5 g, 8.1 mmol) obtained by filtering the reaction mixture with diatomaceous earth using acetone and concentrating under reduced pressure was dissolved in dichloromethane pyridinium-para-toluenesulfonic acid (0.6 g, 2.4 mmol) and 3,4-dihydro-2H-pyran (2.3 mL, 25.1 mmol) were added thereto and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on a silica gel column (8: 1 = hexane: acetic acid ethyl ester) to give pale yellow oil-like Compound 2 . (1.6 g, 3.6 mmol, 40 % ^{yield): 1 H NMR (400 MHz} , CDCl 3) δ 6.22 (dd, J = 2.1, 6.6 Hz, 2H), 5.41 (t, J = 3.3 Hz, 3H), 4.54 (s, 2H), 3.82-3.94 (m, 3H), 3.57-3.61 (m, 3H), 1.83-2.01 (m, 9H), 1.50-1.69 (m, 9H).

Example  3. 3,5 ', 7'-tri ( Tetrahydropyranyl ) -Flavonoid derivatives ( 3 ):

Compound 2 (0.25 g, 0.6 mmol) and aromatic carboxylic acid (0.6 mmol) were dissolved in N, N -dimethylformamide (3 mL), followed by 4-dimethylaminopyridine (DMAP) (0.15 g, Ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) (0.28 g, 1.8 mmol). The mixture is stirred for 4 h at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on a silica gel column (5: 1 = hexane: acetic acid ethyl ester) to obtain 0.5 mmol of the compound in toluene (5 mL). Potassium carbonate (0.2 g, 1.5 mmol) and tetrabutylammonium bromide (0.16 g, 0.5 mmol) were added to the mixture, and the mixture was refluxed and stirred at 90 占 폚 for 4 hours. After the reaction mixture was cooled to room temperature, potassium carbonate was filtered through filter paper and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (4: 1 = hexane: acetone) to obtain Compound 3 in the form of yellow powder It can be obtained: 3a (0.2 g, 0.4 mmol , 67% ^{yield) 1 H NMR (400 MHz,} Acetone- d 6) δ 7.44 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 1.9 Hz, 1H), 7.08 (dd, J = 1.9, 8.4 Hz, 1H), 6.45 (d, J = 2.2 Hz, 1H), 6.40 (d, J = 2.2 Hz, 1H), 4.92 (brt, J = 3.4 Hz, 1H), 4.20 (s, 2H), 3.88-3.98 (m, 1H), 3.56-3.61 (m, 1H), 1.82-2.05 (m, 3H), 1.52-1.72 (m, 3H); 3b (0.1 g, 0.2 mmol, 33% ^{yield) 1 H NMR (400 MHz,} Acetone- d 6) δ 7.36 (d, J = 8.4 Hz, 2H), 6.45 (d, J = 2.2 Hz, 1H), 6.40 (d, J = 2.2 Hz, 1H), 4.90 (brt, J = 3.4 Hz, 1H), 4.18 (s, 2H), 3.86-3.96 2.03 (m, 3H), 1.50 - 1.71 (m, 3H), 2.43 (s, 3H); 3c (0.2 g, 0.4 mmol, 70% ^{yield) 1 H NMR (400 MHz,} Acetone- d 6) δ 7.39 (d, J = 8.4 Hz, 1H), 7.25 (br, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.44 ( d, J = 2.1 Hz, 1H), 6.40 (d, J = 2.1 Hz, 1H), 4.92 (t, J = 3.4 Hz, 1H), 3.88-3.98 (m, 1H) , 3.56-3.61 (m, 1H), 1.82-2.05 (m, 3H), 1.52-1.72 (m, 3H), 2.40 (s, 3H); 3d (0.1 g, 0.2 mmol, 34% ^{yield) 1 H NMR (400 MHz,} Acetone- d 6) δ 7.81 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 1.9 Hz, 1H), 7.06 (dd, J = 1.9, 8.4 Hz, 1H), 6.45 (d, J = 2.2 Hz, 1H), 6.40 (d, J = 2.2 Hz, 1H), 4.92 (t, J = 3.4 Hz, 1H), 4.20 (s, 2H), 3.84-3.94 (m, 1H), 4.12 (s, 2H), 3.56-3.60 (m, 1H), 1.82-2.03 (m, 3H), 1.52-1.72 (m, 3H); 3e (0.05 g, 0.1 mmol, 15% ^{yield) 1 H NMR (400 MHz,} Acetone- d 6) δ 7.60 (d, J = 8.4 Hz, 2H), 6.45 (d, J = 2.2 Hz, 1H), 6.40 (d, J = 2.1 Hz, 1H), 4.90 (brt, J = 3.4 Hz, 1H), 4.20 (s, 2H), 4.12 (s, 2H), 3.86-3.96 m, 1H), 1.80-2.03 (m, 3H), 1.50-1.71 (m, 3H), 2.48 (s, 3H); 3f (0.2 g, 0.4 mmol, 70% ^{yield) 1 H NMR (400 MHz,} Acetone- d 6) δ 7.81 (d, J = 8.4 Hz, 1H), 7.27 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.44 ( d, J = 2.1 Hz, 1H), 6.40 (d, J = 2.1 Hz, 1H), 4.92 (brt, J = 3.4 Hz, 1H), 4.13 (s, 2H), 3.86 3,96 (m, 1H), 3.54-3.60 (m, 1H), 1.80-2.03 (m, 3H), 1.50-1.72 (m, 3H), 2.42 (s, 3H).

Example  4. Flavonoid derivatives ( 4 ):

Compound 3 (0.1 mmol) was dissolved in methanol (5 mL), para-toluenesulfonic acid (0.2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (2: 1 = hexane: acetone) to obtain a yellow powdery flavonoid derivative ( 4d to 4f ): 4d (0.07 g, 0.2 mmol, 95% ^{yield) 1 H NMR (400 MHz,} Acetone- d 6) δ 7.81 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 1.9 Hz, 1H), 7.06 (dd, J = (D, J = 2.1 Hz, 1H), 6.40 (d, J = 2.1 Hz, 1H), 6.40 (d, J = 2.2 Hz, 1H), 4.20 (s, 2H), 4.12 4e (0.06 g, 0.16 mmol, 80% ^{yield) 1 H NMR (400 MHz,} Acetone- d 6) δ 7.60 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 2.1 Hz, 1H), 6.47 (d, J = 2.1 Hz, 1 H), 4.20 (s, 2H), 4.12 (s, 2H), 2.46 (s, 3H); 4f (0.06 g, 0.18 mmol, 90% ^{yield) 1 H NMR (400 MHz,} Acetone- d 6) δ 7.81 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.12 (dd, J = 2.0, 8.4 Hz), 6.65 (d, J = 2.1 Hz, 1H), 6.42 (d, J = 2.1 Hz, 1H), 4.12 (s, 2H), 2.42 (s, 3H).

(0.1 mmol) of the compounds 3a to 3c which had been subjected to tetrahydropyranylation by tetrahydrofuranylation were dissolved in anhydrous tetrahydrofuran (5 mL), and lithium aluminum hydride (0.1 mmol) was added at 0 ° C Lt; / RTI > and stirred for 1 hour. The reaction mixture is neutralized with aqueous 1 N hydrochloric acid at 0 < 0 > C and extracted three times with ethyl acetate (30 mL). The organic layer was dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (2: 1 = hexane: acetone) to obtain yellow powdery flavonoid derivatives ( 4a to 4c ): 4a (0.02 g, 0.05 mmol, 50% ^{yield) 1 H NMR (400 MHz,} Acetone- d 6) δ 12.7 (s, OH), 7.18-7.30 (m, 4H), 6.44 (d, J = 2.1 Hz, 1H), 6.40 (d, J = 2.1 Hz, 1 H), 4.20 (s, 2 H); 4b (0.02 g, 0.06 mmol, 60% ^{yield) 1 H NMR (400 MHz,} Acetone- d 6) δ 12.7 (s, OH), 7.32-7.38 (m, 3H), 6.86 (d, J = 1.9 Hz, 1H), 6.78 (d, J = 1.9 Hz, 1 H), 4.18 (s, 2H), 2.48 (s, 3H); 4c (0.03 g, 0.08 mmol, 80% ^{yield) 1 H NMR (400 MHz,} Acetone- d 6) δ 12.8 (s, OH), 7.21-7.36 (m, 3H), 7.05 (br, 1H), 6.43 ( d, J = 2.1Hz, 1H), 6.40 (d, J = 2.1Hz, 1H), 2.48 (s, 3H).

While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

Claims (11)

Compounds of the formula < RTI ID = 0.0 > 1 < / RTI > and pharmaceutically acceptable salts thereof:
[Chemical Formula 1]

In Formula 1, R ₁ and R ₂ are a substituent selected from the group consisting of hydrogen, CH ₃ , and CH ₂ CN and are present in the ortho-position, and in Formula 1, R ₃ is hydrogen or CCCH ₂ OH substituent And are present in the para-position. The compound of claim 1, wherein in Formula 1, R ₁ and R ₂ are CH ₃ , and CH ₂ CN, respectively, and are in the ortho-position, and in Formula 1, R ₃ is hydrogen or CCCH _2. And pharmaceutically acceptable salts thereof, wherein the compound is an OH substituent and is present in the para- position. The compound and pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound selectively inhibits activity of Janus kinase 3. The compound and a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound has an immunosuppressive effect. A composition comprising the compound of Formula 1 as an active ingredient:
[Chemical Formula 1]

In Formula 1, R ₁ and R ₂ are a substituent selected from the group consisting of hydrogen, CH ₃ , and CH ₂ CN and are present in the ortho-position, and in Formula 1, R ₃ is hydrogen or CCCH ₂ OH substituent And are present in the para-position. The compound of claim 5, wherein in Formula 1, R ₁ and R ₂ are each CH ₃ , and CH ₂ CN, and are in the ortho-position, and in Formula 1, R ₃ is hydrogen or CCCH _2. And is an OH substituent and is present in the para- position. 7. The composition of claim 5 or 6, wherein said composition selectively inhibits Janus kinase 3 activity. A pharmaceutical composition for immunosuppression comprising as an active ingredient a compound of the following formula 1 and a pharmaceutically acceptable carrier:
[Chemical Formula 1]

In Formula 1, R ₁ and R ₂ are a substituent selected from the group consisting of hydrogen, CH ₃ , and CH ₂ CN and are present in the ortho-position, and in Formula 1, R ₃ is hydrogen or CCCH ₂ OH substituent And are present in the para-position. The compound of claim 8, wherein in Formula 1, R ₁ and R ₂ are CH ₃ and CH ₂ CN, respectively, and are in the ortho-position, and in Formula 1, R ₃ is hydrogen or CCCH _2. Pharmaceutical composition, characterized in that it is an OH substituent and is present in the para- position. a) the quercetin N, N - dimethyl formamide (N, N -Dimethylformamide) solution was added potassium carbonate was added benzyl bromide mideueul, the reaction mixture was concentrated under reduced pressure and the residue dichloromethane / acetic acid ethyl ester obtained in the dissolved in Tris (benzyloxy) -2- (3,4-bis (benzyloxy) phenyl) -4H-chromen-4-one obtained by recrystallization was dissolved in anhydrous pyridine, and diethylene glycol and potassium hydroxide The resulting reaction mixture was extracted with dichloromethane and the organic layer was concentrated under reduced pressure to give 2- (benzyloxy) -1- (2,4-bis (benzyloxy) -6-hydroxyphenyl) ;
b) dissolving the 2- (benzyloxy) -1- (2,4-bis (benzyloxy) -6-hydroxyphenyl) ethanone in methanol and tetrahydrofuran, adding palladium / charcoal, The mixture was stirred in the presence of hydrogen to dissolve 2-hydroxy-1- (2,4,6-trihydroxyphenyl) ethanone in dichloromethane and then pyridinium-para-toluenesulfonic acid and 3,4-dihydro- 2H-pyran was added and the stirred reaction mixture was concentrated under reduced pressure to obtain 2- (tetrahydropyranyl) -1- (2,4-bis (tetrahydropyranyl) -6-hydroxyphenyl) ethanone;
c) reacting the 2- (tetrahydropyranyl) -1- (2,4-bis (tetrahydropyranyl) -6-hydroxyphenyl) ethanone compound with an aromatic carboxylic acid in N, N -dimethylformamide After the reaction mixture was dissolved, a mixture of 4-dimethylaminopyridine (DMAP) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) was added to the reaction mixture and the reaction mixture was concentrated under reduced pressure. Was dissolved in toluene, potassium carbonate and tetrabutylammonium bromide were added to the mixture, and the mixture was stirred under reduced pressure to form 3,5 ', 7'-tri (tetrahydropyranyl) -flavonoid derivative step;
And
d) dissolving the above 3,5 ', 7'-tri (tetrahydropyranyl) -flavonoid derivative in methanol, adding para-toluenesulfonic acid and stirring the resultant reaction mixture under reduced pressure, and purifying the obtained residue Lt; RTI ID = 0.0 > (I) < / RTI >
[Chemical Formula 1]

In the above formula (1), R ₁ is hydrogen or CH ₃ , R ₂ is hydrogen or CH ₂ CN, and R ₃ is CCCH ₂ OH. a) the quercetin N, N - dimethyl formamide (N, N -Dimethylformamide) solution was added potassium carbonate was added benzyl bromide mideueul, the reaction mixture was concentrated under reduced pressure and the residue dichloromethane / acetic acid ethyl ester obtained in the dissolved in Tris (benzyloxy) -2- (3,4-bis (benzyloxy) phenyl) -4H-chromen-4-one obtained by recrystallization was dissolved in anhydrous pyridine, and diethylene glycol and potassium hydroxide The resulting reaction mixture was extracted with dichloromethane and the organic layer was concentrated under reduced pressure to give 2- (benzyloxy) -1- (2,4-bis (benzyloxy) -6-hydroxyphenyl) ;
b) dissolving the 2- (benzyloxy) -1- (2,4-bis (benzyloxy) -6-hydroxyphenyl) ethanone in methanol and tetrahydrofuran, adding palladium / charcoal, The mixture was stirred in the presence of hydrogen to dissolve 2-hydroxy-1- (2,4,6-trihydroxyphenyl) ethanone in dichloromethane and then pyridinium-para-toluenesulfonic acid and 3,4-dihydro- 2H-pyran was added and the stirred reaction mixture was concentrated under reduced pressure to obtain 2- (tetrahydropyranyl) -1- (2,4-bis (tetrahydropyranyl) -6-hydroxyphenyl) ethanone;
c) reacting the 2- (tetrahydropyranyl) -1- (2,4-bis (tetrahydropyranyl) -6-hydroxyphenyl) ethanone compound with an aromatic carboxylic acid in N, N -dimethylformamide After the reaction mixture was dissolved, a mixture of 4-dimethylaminopyridine (DMAP) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) was added to the reaction mixture and the reaction mixture was concentrated under reduced pressure. Was dissolved in toluene, potassium carbonate and tetrabutylammonium bromide were added to the mixture, and the mixture was stirred under reduced pressure to form 3,5 ', 7'-tri (tetrahydropyranyl) -flavonoid derivative step;
And
d) The 3,5 ', 7'-tri (tetrahydropyranyl) -flavonoid derivative was dissolved in methanol, and then para-toluene sulfonic acid was added and the stirred reaction mixture was concentrated under reduced pressure to purify the residue obtained. Dissolving the tetrahydropyranylated compound in anhydrous tetrahydrofuran, and then adding a lithium aluminum hydride and stirring the method of preparing a compound of formula (1).
[Chemical Formula 1]

In Formula 1, R ₁ is hydrogen or CH ₃ , R ₂ is hydrogen, or CH ₂ CN, R ₃ is hydrogen.

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