KR20170052873A - Novel bis(4-hydroxy) benzophenone oxime ether derivatives, preparation method thereof and composition for preventing or treating ER-related diseases comprising the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel bis (4-hydroxy) benzophenone oxime ether derivative compound, a process for preparing the same, and a composition for preventing or treating an estrogen receptor-related disease comprising the same as an active ingredient. Roxy) benzophenone oxime ether derivative compound is excellent in the effect of inhibiting cancer cells of breast cancer and cervix cancer by binding to an estrogen receptor and thus can be usefully used as a pharmaceutical composition or a health food composition capable of preventing or treating an estrogen receptor-related disease.

Description

TECHNICAL FIELD The present invention relates to a novel bis (4-hydroxy) benzophenone oxime ether derivative compound, a process for preparing the same, and a composition for preventing or treating an estrogen receptor-related disease, and composition for preventing or treating ER-related diseases comprising the same as an active ingredient}

The present invention relates to a novel bis (4-hydroxy) benzophenone oxime ether derivative compound, a process for preparing the same, and a composition for preventing or treating estrogen receptor-related diseases containing the same as an active ingredient.

The estrogen receptor ("ER") is a ligand-activated transcriptional regulatory protein that mediates the induction of a variety of biological effects through interactions with endogenous estrogens. Endogenous estrogens include 17 [beta] -estradiol (E2) and estrone. ER was found to have two isoforms, ER-alpha and ER-beta.

Estrogen and estrogen receptors are implicated in a number of diseases or conditions, such as breast, ovarian, colon, prostate, endometrial, uterine, and other diseases or conditions.

Compounds that bind to estrogen receptors are potentially useful in the treatment of a wide range of disease states. These include estrogen agonists for the treatment of estrogen deficiency (for example, osteoporosis in postmenopausal women, myocardial disease and neurodegenerative diseases) and estrogen antagonists for the treatment of breast and uterine cancer, . Also, some types of ligands exhibit mixed efficacy / antagonism (i.e., they are estrogen agonists, estrogen antagonists, or partial estrogen antagonists when bound to estrogen receptors of other tissues) loss, and at the same time reduce the risk of breast cancer.

The estrogen or estrogen receptor agonist, which has been used to treat estrogen receptor-related diseases, has a problem in that it can cause breast cancer and thus has inconvenience to use with other anticancer drugs such as tamoxifen. Therefore, there is a need to develop a new therapeutic agent for breast cancer cells that can induce an effective pharmacological effect on diseases caused by estrogen receptor deficiency without inducing breast cancer.

With respect to compounds having conventional estrogen receptor modulating activity, WO 2005/018636 discloses certain indole derivatives which are estradiol derivatives having estrogen receptor modulating activity, wherein the indoles are all oximes.

However, there is still a need for estrogen-like compounds that can exhibit the same positive response as estrogen replacement therapy without negative side effects and that have a specific effect on the different tissues of the body.

U.S. Pat. No. 4,954,523

Accordingly, the inventors of the present invention have found that a novel bis (4-hydroxy) benzophenone oxime ether derivative compound can easily bind to an estrogen receptor and exhibits excellent anticancer activity in breast cancer and cervical cancer cell lines, which are estrogen receptor-related diseases, Receptor-related diseases, and completed the present invention.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating an estrogen receptor-related disease, which comprises a novel bis (4-hydroxy) benzophenone oxime ether derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient .

It is also an object of the present invention to provide a health functional food for inhibiting estrogen receptor-related diseases comprising a novel bis (4-hydroxy) benzophenone oxime ether derivative compound as an active ingredient.

In order to achieve the above object,

A novel bis (4-hydroxy) benzophenone oxime ether derivative compound, an isomer thereof and a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, the novel bis (4-hydroxy) benzophenone oxime ether derivative compound is

1) bis (4-hydroxyphenyl) methanone oxime;

2) bis (4-hydroxyphenyl) methanone O-propyloxime;

3) bis (4-hydroxyphenyl) methanone O-butyloxime;

4) bis (4-hydroxyphenyl) methanone O-but-3-en-1-yloxime;

5) bis (4-hydroxyphenyl) methanone O-pentyloxime;

6) bis (4-hydroxyphenyl) methanone O-pent-4-en-1-yl oxime;

7) bis (4-hydroxyphenyl) methanone O-hept-6-en-1-yl oxime;

8) bis (4-hydroxyphenyl) methanone O-isobutyloxime;

9) bis (4-hydroxyphenyl) methanone O-isopentyl oxime;

10) bis (4-hydroxyphenyl) methanone O- (3-methylbut-2-en-1-yl) oxime;

11) bis (4-hydroxyphenyl) methanone O-cyclohexylmethyloxime;

12) bis (4-hydroxyphenyl) methanone O- (2-hydroxyethyl) oxime;

13) bis (4-hydroxyphenyl) methanone O- (2-methoxyethyl) oxime; And

14) 2- (bis (4-hydroxyphenyl) methylene) aminooxyacetic acid.

The present invention also provides a process for preparing the novel bis (4-hydroxy) benzophenone oxime ether derivative compound.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating an estrogen receptor-related disease comprising the novel bis (4-hydroxy) benzophenone oxime ether derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment of the present invention, the estrogen receptor related disease is selected from the group consisting of bone loss, fracture, osteoporosis, degenerative arthritis, endometriosis, uterine leiomyoma, transient fever, elevated levels of LDL cholesterol, cardiovascular disease, cognitive dysfunction, Anxiety, depression, menopause, menopausal depression, postpartum depression, premenstrual syndrome, manic depression, dementia, obsessive-compulsive disorder, attention deficit disorder (ADHD) , Alzheimer's disease, Huntington's disease, Lou Gehrig's disease, spinal cord injury, stroke, autoimmune disease, inflammation, inflammation Hypertension, retinopathy, breast cancer, uterine cancer, ovarian cancer, and prostate cancer. ≪ RTI ID = 0.0 >

In one embodiment of the present invention, the estrogen receptor-related disease can be selected from the group consisting of menopausal, breast, ovarian, and uterine cancer.

The present invention also provides a health functional food for inhibiting an estrogen receptor-related disease comprising the novel bis (4-hydroxy) benzophenone oxime ether derivative compound as an active ingredient.

The novel bis (4-hydroxy) benzophenone oxime ether derivative compound of the present invention acts as an agonist on the estrogen receptor and has excellent inhibitory effect on estrogen receptor-related diseases such as breast cancer and uterine cancer. Therefore, And can be usefully used as a pharmaceutical composition or a health food composition capable of preventing or treating a related disease.

1 is a graph showing the estrogenic activity of a novel bis (4-hydroxy) benzophenone oxime ether derivative compound according to an embodiment of the present invention.
2 is a graph showing the effect of a novel bis (4-hydroxy) benzophenone oxime ether derivative compound according to an embodiment of the present invention on the survival ability of a breast cancer cell line (MCF7).
3 is a graph showing changes in estrogen receptor mediated transcriptional activity depending on the dose of the novel bis (4-hydroxy) benzophenone oxime ether derivative compound (12c) according to an embodiment of the present invention.
4 is a graph showing changes in estrogen receptor mediated transcriptional activity depending on the dose of the novel bis (4-hydroxy) benzophenone oxime ether derivative compound (12e) according to one embodiment of the present invention.
5 is a graph showing changes in estrogen receptor mediated transcriptional activity depending on the dose of the novel bis (4-hydroxy) benzophenone oxime ether derivative compound (12h) according to an embodiment of the present invention.
6 is a graph showing the inhibition of proliferation (A) of breast cancer cell line (MCF7) and (B) cervical cancer cell line (Ishikawa) by the novel bis (4-hydroxy) benzophenone oxime ether derivative compound (12i) according to an embodiment of the present invention .
Figure 7 shows a molecular docking model for the estrogen receptor-alpha (ERa) of the novel bis (4-hydroxy) benzophenone oxime ether derivative compound (12c) according to one embodiment of the present invention.

The present invention provides a novel bis (4-hydroxy) benzophenone oxime ether derivative compound having a structure represented by the following formula (1), an isomer thereof, and a pharmaceutically acceptable salt thereof.

≪ Formula 1 >

(Wherein, R is H; unsubstituted or OH, C _{1 -6} alkoxy group, a cycloalkyl C _{1 -6} alkyl group or a carboxy group-substituted C _1-6 straight or branched alkyl; C _{1 -6} straight or branched alkenyl; Beach and is selected from the group consisting of allyl-substituted ring with one or more C _{1 -6} straight or branched chain alkyl)

Preferably, R is H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isobutyl, isopentyl, butenyl, Is selected from the group consisting of methyl, cyclohexylmethyl, and dimethylallyl.

Preferably, in the present invention, the compound is

1) bis (4-hydroxyphenyl) methanone oxime;

2) bis (4-hydroxyphenyl) methanone O-propyloxime;

3) bis (4-hydroxyphenyl) methanone O-butyloxime;

4) bis (4-hydroxyphenyl) methanone O-but-3-en-1-yloxime;

5) bis (4-hydroxyphenyl) methanone O-pentyloxime;

6) bis (4-hydroxyphenyl) methanone O-pent-4-en-1-yl oxime;

7) bis (4-hydroxyphenyl) methanone O-hept-6-en-1-yl oxime;

8) bis (4-hydroxyphenyl) methanone O-isobutyloxime;

9) bis (4-hydroxyphenyl) methanone O-isopentyl oxime;

10) bis (4-hydroxyphenyl) methanone O- (3-methylbut-2-en-1-yl) oxime;

11) bis (4-hydroxyphenyl) methanone O-cyclohexylmethyloxime;

12) bis (4-hydroxyphenyl) methanone O- (2-hydroxyethyl) oxime;

13) bis (4-hydroxyphenyl) methanone O- (2-methoxyethyl) oxime; And

14) 2- (bis (4-hydroxyphenyl) methylene) aminooxyacetic acid.

The compounds of the present invention may be prepared by pharmaceutically acceptable salts and solvates according to methods conventional in the art.

As salts, acid addition salts formed by pharmaceutically acceptable free acids are useful. The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The molar amount of the compound and the acid or alcohol in the moles (e.g., glycol monomethyl ether) may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered by suction.

As the organic acid, an organic acid and an inorganic acid can be used. As the inorganic acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. Examples of the organic acid include methanesulfonic acid, p- toluenesulfonic acid, acetic acid, trifluoroacetic acid, But are not limited to, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, , Vanillic acid, and hydroiodic acid.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-soluble compound salt, and evaporating and drying the filtrate. In this case, as a metal salt, it is particularly preferable to produce sodium, potassium or calcium salt, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

Pharmaceutically acceptable salts of the compounds of the present invention include, unless otherwise indicated, salts of acidic or basic groups that may be present in the compounds. For example, pharmaceutically acceptable salts include the sodium, calcium, and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, (Mesylate) and p-toluenesulfonate (tosylate) salts, which can be prepared by a process or process known to those skilled in the art, such as, for example, sodium phosphate, acetate succinate citrate, tartrate, lactate, mandelate methanesulfonate .

The present invention also provides a process for preparing the novel bis (4-hydroxy) benzophenone oxime ether derivative of the formula (1).

The process for the preparation of the compounds of the present invention, as shown in Scheme 1,

Condensing the bis (4-hydroxy) benzophenone compound of formula (2) with an alkoxyamine salt in the presence of an organic solvent to produce a compound of formula (1).

<Reaction Scheme 1>

(In the above Reaction Scheme 1, R is the same as defined in Formula 1)

In the production method according to the present invention, ethanol, dichloromethane, pyridine, etc. may be used as the organic solvent, and the reaction may be carried out at room temperature for 2 to 24 hours.

The product can be purified through additional steps such as washing, concentration, extraction with ethyl acetate, drying and column chromatography, and its structural and physicochemical properties can be analyzed by IR, NMR, melting point (mp)

Furthermore, the present invention relates to a pharmaceutical composition for preventing or treating estrogen receptor-related diseases comprising the novel bis (4-hydroxy) benzophenone oxime ether derivative compound of the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient to provide.

The present inventors have found that the compound of the present invention obtained by the above-mentioned method binds to an estrogen receptor and effectively inhibits cancer cells in diseases related to estrogen receptors such as breast cancer and cervical cancer, and thus is useful as a composition for preventing or treating estrogen receptor- And it is suitable for use.

In the present invention, the term "estrogen receptor-related disease" refers to a disease associated with estrogen receptor activity and includes bone loss, fracture, osteoporosis, degenerative arthritis, endometriosis, uterine leiomyoma, Anxiety, depression, menopause, menopausal depression, postpartum depression, postpartum depression, hypertension, hypertension, diabetes mellitus, hyperlipidemia, hypercholesterolemia, Alzheimer's disease, Huntington's disease, Parkinson's disease, Parkinson's disease, Parkinson's disease, Parkinson's disease, Parkinson's disease, Parkinson's disease, Parkinson's disease, Parkinson's disease, Alzheimer's disease, spinal cord injury, stroke, autoimmune disease, inflammation, inflammatory growth disease, irritable bowel syndrome, insensitivity, hypertension, Sex, breast cancer, uterine cancer, ovarian cancer, and prostate cancer.

Therefore, the composition according to the present invention can be used as a pharmaceutical composition capable of preventing or treating an estrogen receptor-related disease.

Refers to reversing, alleviating, inhibiting, or preventing the disease or disorder to which the term applies, or one or more symptoms of the disease or disorder, unless stated otherwise , And the term " treatment " as used herein refers to an act of treating. Therapeutic or therapeutic treatment of an estrogen receptor related disorder in a mammal therefore may include one or more of the following:

(1) inhibiting the growth of estrogen receptor-related diseases, i.e., inhibiting its development,

(2) preventing the spread of estrogen receptor-related diseases, i.e., preventing metastasis,

(3) alleviate estrogen receptor-related diseases.

(4) preventing recurrence of estrogen receptor related diseases, and

(5) palliating the symptoms of estrogen receptor related diseases.

The composition for preventing or treating an estrogen receptor-related disease according to the present invention comprises a pharmaceutically effective amount of a compound represented by formula (I) or a salt thereof alone or in combination with one or more pharmaceutically acceptable carriers, excipients or diluents . A pharmaceutically effective amount as used herein refers to an amount sufficient to prevent, ameliorate, and treat symptoms of an estrogen receptor-related disease.

The pharmaceutically effective amount of the novel bis (4-hydroxy) benzophenone oxime ether derivative compound or its salt according to the present invention is 0.5 to 100 mg / day / kg body weight, preferably 0.5 to 5 mg / day / kg body weight. However, the pharmacologically effective amount may be appropriately changed depending on the degree of symptoms of the estrogen receptor-related diseases, the age, body weight, health condition, sex, administration route and treatment period of the patient.

The term "pharmaceutically acceptable" as used herein refers to a composition that is physiologically acceptable and does not normally cause an allergic reaction such as gastrointestinal disorder, dizziness, or the like when administered to a human. Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Further, it may further include a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent.

In addition, the compositions of the present invention may be formulated using methods known in the art so as to provide rapid, sustained or delayed release of the active ingredient after administration to the mammal. The formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatine capsules, sterile injectable solutions, sterile powders.

In addition, the composition for preventing or treating an estrogen receptor-related disease according to the present invention may be administered through various routes including oral, transdermal, subcutaneous, intravenous, or muscular, and the dose of the active ingredient may vary depending on administration route, The composition for prevention or treatment of an estrogen receptor-related disease according to the present invention can be appropriately selected according to various factors such as sex, weight and severity of a patient, and the composition for preventing or treating an estrogen receptor- It may be administered in combination with a known compound.

Accordingly, the present invention can provide a medicament for the prevention or treatment of an estrogen receptor-related disease comprising a composition containing a novel bis (4-hydroxy) benzophenone oxime ether derivative compound or a salt thereof as an active ingredient, Can provide a composition for treating estrogen receptor-related diseases, which comprises a novel bis (4-hydroxy) benzophenone oxime ether derivative compound or a salt thereof as an active ingredient.

On the other hand, the present invention can provide a food composition capable of improving or preventing symptoms of an estrogen receptor-related disease containing a novel bis (4-hydroxy) benzophenone oxime ether derivative compound or its salt as an active ingredient, The composition for food according to the present invention can be easily utilized as a food which is effective for improving or preventing the symptoms of estrogen receptor-related diseases, for example, as a raw material, additives, food additives, functional foods or beverages of foods.

In the present invention, the term "food" means a natural product or a processed product containing one or more nutrients, preferably a state of being able to be eaten directly through a certain degree of processing, Which includes food, food additives, functional foods and beverages.

Foods to which the food composition according to the present invention can be added include, for example, various foods, beverages, gums, tea, vitamin complexes, and functional foods. In addition, in the present invention, the food may contain special nutritional foods (e.g., crude oil, spirit, infant food, etc.), meat products, fish products, tofu, jelly, noodles (Such as soy sauce, soybean paste, kochujang, mixed potatoes), sauces, confectionery (eg, snacks), candies, chocolate, gums, ice cream, milk products (eg, fermented milk, cheese, But are not limited to, pickled foods (various kinds of kimchi, pickles, etc.), beverages (e.g., fruit drinks, vegetable beverages, beverages, fermented beverages and the like) and natural seasonings (e.g. The food, beverage or food additive may be prepared by a conventional production method.

The above-mentioned "functional food" refers to a food group which is imparted with added value to function and express the function of the food by physical, biochemical or biotechnological techniques, or to control the bio-defense rhythm of the food composition, Refers to a food prepared by processing a body so as to sufficiently express the body's control function on the body, such as recovery, and the like. Specifically, it may be a health functional food. The functional food may include a food-acceptable food-aid additive, and may further comprise suitable carriers, excipients and diluents conventionally used in the production of functional foods.

In the present invention, the term "beverage" means a general term for drinking or enjoying a taste, and includes a functional beverage. The beverage is not particularly limited as long as it contains a composition for improving or preventing symptoms of the immunological disease as an essential ingredient at the indicated ratio, and may contain various flavors or natural carbohydrates as an additional ingredient can do.

Further, in addition to the above-described foods, the food containing the composition for food for improving or preventing symptoms of estrogen receptor-related diseases of the present invention may contain various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors , Coloring agents and fillers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, , And these components can be used independently or in combination.

In the food containing the food composition of the present invention, the amount of the composition according to the present invention may be 0.001% by weight to 90% by weight, preferably 0.1% by weight to 40% by weight, And may be contained in a ratio of 0.001 g to 2 g, preferably 0.01 g to 0.1 g, based on 100 ml in the case of beverage. However, in the case of long-term intake for health and hygiene purposes or for health control purposes May be less than the above range, and since the active ingredient has no problem in terms of safety, it can be used in an amount of more than the above range, so it is not limited to the above range.

Hereinafter, the present invention will be described in more detail with reference to Examples. It will be apparent to those skilled in the art that these embodiments are merely illustrative of the present invention and that the scope of the present invention is not limited to these embodiments.

< Reference example >

Reagents and Materials

Without specific mention, all reactions were carried out in an oven dried glassware under an argon atmosphere. All reagents, including starting materials and solvents, were purchased from Aldrich Chemical Co. Or TCI and used without further purification. Chromatography, including silica gel chromatography and thin layer chromatography (TLC), was performed using Merck silica gel 60, 230400 mesh and Merck silica gel 60 F ₂₅₄ plates. TLC plates were visualized using a combination of UV, p -anisaldehyde, ninhydrin, and potassium permanganate (KMnO ₄ ) staining. NMR spectra were recorded on a Bruker 400 (400 MHz for 1H; 100 MHz for 13C) spectrometer. ¹ H and ¹³ C NMR chemical shifts were reported in ppm relative to TMS (tetramethylsilane) with the residual solvent peak used as internal reference material. The signals are m (multiplet), s (singular), d (doublet), t (triplet), q (quadruplet), bs Doublet), dt (doublet of triplets), or dq (quadruplet of doublets); Coupling constants were reported in hertz (Hz). Low resolution mass spectra were obtained on an AccuTOF single-reflection time-of-flight mass spectrometer (JEOL Ltd., Tokyo, Japan) or VG Trio-2 GCMS.

< Example >

&Lt; Example 1 >

Bis (4-hydroxyphenyl) methanone Oxime  (12a)

Hydroxylamine HCl (69 mg, 0.99 mmol) was added at room temperature to a solution of bis (4-hydroxy) benzophenone (100 mg, 0.46 mmol) in EtOH (2 mL). Stirred until all starting material was consumed the reaction mixture on TLC and was quenched with H ₂ O. The resulting mixture was diluted with EtOA and the organic phase was washed with H ₂ O and brine, dried over MgSO ₄ and concentrated in vacuo. Silica gel flash column chromatography over (EtOAc: hexane = 1: 5 to 1: 3) to give the residue of Compound 12a as a colorless liquid was obtained 90 mg (84%) ^{by: 1 H-NMR (400 MHz} , CDCl 3 ) δ 7.30 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 6.85 (2H, d, J = 8.6 Hz), 6.76 (2H, d, J = 8.6 Hz), 3.49 (2H, s), 0.92 (1H, s); ¹³ C-NMR (MeOD, 125 MHz) ? 158.4, 157.8, 157.3, 131.2, 131.2, 129.4, 129.4, 128.9, 124.7, 114.7, 114.7, 114.4, 114.4; HR-MS (FAB) calculated for LR-MS (FAB) m / z (M + H ⁺ ) 230; (M + H ⁺ ) 230.0817; Experiment 230.0823.

< Example  2>

Bis (4-hydroxyphenyl) methanone O -profile Oxime  (12b)

Compound 12b was prepared using the same method as for the synthesis of compound 12a. ^{(Yield: 58%): 1 H-} NMR (400 MHz, CDCl 3) δ 7.34 (2H, d, J = 8.6 Hz), 7.29 (2H, d, J = 8.6 Hz), 6.83 (2H, d, J = 8.6 Hz), 6.75 (2H, d, J = 8.6 Hz), 4.12 (2H, t, J = 6.7 Hz), 7.72 (2H, m), 0.93 (3H, t, J = 7.5 Hz); ¹³ C-NMR (MeOD, 125 MHz) ? 158.6, 157.9, 157.0, 131.2, 131.2, 129.5, 129.5, 128.6, 124.8, 114.7, 114.7, 114.3, 114.3, 75.4, 22.3, 9.7; HR-MS (FAB) calculated for LR-MS (FAB) m / z (M + H ⁺ ) 272; (M + H ⁺ ) 272.1287; Experiment 272.1283.

< Example  3>

Bis (4-hydroxyphenyl) methanone O - Butyl Oxime  (12c)

Compound 12c was prepared using the same method as for the synthesis of compound 12a. ^{(Yield: 48%): 1 H-} NMR (400 MHz, CDCl 3) δ 7.29 (2H, d, J = 8.6 Hz), 7.26 (2H, d, J = 8.6 Hz), 6.79 (2H, d, J = 8.6 Hz), 6.69 (2H, d, J = 8.6 Hz), 6.12 (2H, s), 4.16 (2H, t, J = 6.7 Hz), 1.63-1.69 (2H, m), 1.34-1.38 , &lt; / RTI &gt; m), 0.90 (3H, t, J = 7.4 Hz); ¹³ C-NMR (MeOD, 125 MHz) ? 158.6, 157.9, 157.0, 131.2, 131.2, 129.5, 129.5, 128.6, 124.8, 114.7, 114.7, 114.3, 114.3, 73.6, 31.2, 19.1, 13.1; HR-MS (FAB) calculated for LR-MS (FAB) m / z (M + H ⁺ ) 286; (M + H ⁺ ) 286.1443; Experiment 286.1443.

< Example  4>

Bis (4-hydroxyphenyl) methanone O - Boot -3-en-1-yl Oxime  (12d)

Compound 12d was prepared using the same method as for the synthesis of compound 12a. ^{(Yield: 70%): 1 H-} NMR (400 MHz, CDCl 3) δ 7.29 (2H, d, J = 8.6 Hz), 7.26 (2H, d, J = 8.6 Hz), 6.79 (2H, d, J = 8.6 Hz), 6.70 (2H , d, J = 8.6 Hz), 6.29 (2H, s,), 5.80 (1H, m), 5.03 (2H, d, J = 10.2 Hz), 4.20 (2H, t, J = 6.7 Hz), 2.45 (2H, m, J = 6.6 Hz); ¹³ C-NMR (MeOD, 125 MHz) ? 158.6, 157.9, 157.2, 135.2, 131.3, 131.3, 129.6, 129.6, 128.5, 124.7, 115.7, 114.8, 114.8, 114.2, 114.2, 73.1, 33.7; HR-MS (FAB) calculated for LR-MS (FAB) m / z (M + H @ ⁺ ) 284; (M + H @ ⁺ ) 284.1287; Experimental value 284.1296.

< Example  5>

Bis (4-hydroxyphenyl) methanone O - Pentyl Oxime  (12e)

Compound 12e was prepared using the same method as for the synthesis of compound 12a. ^{(Yield: 72%): 1 H-} NMR (400 MHz, CDCl 3) δ 7.30 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz), 6.80 (2H, d, J = 8.6 Hz), 6.70 (2H, d, J = 8.6 Hz), 5.95 (2H, s), 4.16 (2H, t, J = 6.8 Hz), 1.66-1.70 (2H, m), 1.30-1.52 , &lt; / RTI &gt; m), 1.24-1.26 (2H, m), 0.87 (3H, t, J = 6.8 Hz); _{^{13 C-NMR (CDCl 3,}} 125MHz) δ 157.1, 156.4, 131.8, 130.2, 129.5, 125.7, 115.5, 115.5, 115.1, 115.1, 74.7, 29.0, 28.3, 28.3, 22.7, 22.7, 14.3,14.3; HR-MS (FAB) 300.1600 calculated for LR-MS (FAB) m / z (M + H ⁺ ) 300; (M + H ⁺ ); Experimental value 300.1599.

< Example  6>

Bis (4-hydroxyphenyl) methanone O - Pent -4-en-1-yl Oxime  (12f)

Compound 12f was prepared using the same method as for the synthesis of compound 12a. ^{(Yield: 78%): 1 H-} NMR (400 MHz, CDCl 3) δ 7.29 (2H, d, J = 8.6 Hz), 7.25 (2H, d, J = 8.6 Hz), 6.79 (2H, d, J = 8.6 Hz), 6.68 (2H , d, J = 8.6 Hz), 6.29 (2H, s), 5.78 (1H, m), 4.92-5.01 (2H, m), 4.17 (2H, t, J = 6.7 Hz ), 2.06-2.09 (2H, m), 1.75-1.79 (2H, m); _{^{13 C-NMR (CDCl 3,}} 125MHz) δ 157.1, 156.4, 138.4, 131.8, 131.8, 130.1, 130.1, 129.5, 125.7, 115.5, 115.5, 115.2, 115.2, 73.9, 30.4, 30.4, 28.5, 28.5; HR-MS (FAB) 298.1443 calculated for LR-MS (FAB) m / z (M + H ⁺ ) 298; (M + H ⁺ ); Experiment 298.1439.

< Example  7>

Bis (4-hydroxyphenyl) methanone O - Hept -6-en-1-yl Oxime  (12g)

12 g of the compound was prepared using the same method as the synthesis of compound 12a. ^{(Yield: 60%): 1 H-} NMR (400 MHz, CDCl 3) δ 7.31 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz), 6.83 (2H, d, J = 8.6 Hz), 6.76 (2H, d, J = 8.6 Hz), 4.94 (2H, t, J = 9.1 Hz), 4.12-4.16 (2H, m), 3.30 , m), 1.66-1.72 (2H, m), 1.34-1.42 (2H, m), 1.27 (1H, m); ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 157.1, 156.4, 139.1, 131.8, 131.8, 130.4, 130.4, 129.5, 125.7, 115.5, 115.5, 115.1, 115.1, 114.6, 114.6, 74.6, 33.9, 29.1, 28.8, 25.6 ; HR-MS (FAB) 326.1756 calculated for LR-MS (FAB) m / z (M + H ⁺ ) 326; (M + H ⁺ ); Experiment 326.1754.

< Example  8>

Bis (4-hydroxyphenyl) methanone O - Isobutyl Oxime  (12h)

Compound 12h was prepared using the same method as for the synthesis of compound 12a. ^{(Yield: 99%): 1 H-} NMR (400 MHz, CDCl 3) δ 7.31 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz), 6.38 (2H, d, J = 8.6 Hz), 6.77 (2H , d, J = 8.6 Hz), 3.91 (2H, d, J = 6.8 Hz), 3.42 (2H, s), 2.05 (1H, s), 0.91 (6H, d, J = 6.7 Hz); ¹³ C-NMR (MeOD, 125 MHz) ? 158.6, 157.9, 157.0, 131.2, 131.2, 129.5, 129.5, 128.5, 124.8. 114.8, 114.8, 114.4, 114.4, 80.5, 28.1, 18.5, 18.5; HR-MS (FAB) calculated for LR-MS (FAB) m / z (M + H ⁺ ) 286; (M + H ⁺ ) 286.1443; Experiment 286.1435.

< Example  9>

Bis (4-hydroxyphenyl) methanone O - Isopentyl Oxime  (12i)

Compound 12i was prepared using the same method as for the synthesis of compound 12a. ^{(Yield: 53%): 1 H-} NMR (400 MHz, CDCl 3) δ 7.30 (2H, d, J = 8.6 Hz), 7.26 (2H, d, J = 8.6 Hz), 6.80 (2H, d, J = 8.6 Hz), 6.70 (2H, d, J = 8.6 Hz), 4.19 (2H, t, J = 6.9 Hz), 1.64 (1H, m), 1.56-1.60 , J = 7.1 Hz), 0.89 (6H, d, J = 6.5 Hz); ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 156.9, 156.2, 131.7, 131.7, 130.0, 130.0, 129.8, 125.9, 115.4, 115.4, 115.0, 115.0, 73.3, 38.1, 25.4, 22.9, 22.9, 22.9; HR-MS (FAB) 300.1600 calculated for LR-MS (FAB) m / z (M + H ⁺ ) 300; (M + H ⁺ ); Experimental value 300.1605.

< Example  10>

Bis (4-hydroxyphenyl) methanone O - (3- Methyl boot 2-en-1-yl) Oxime  (12j)

Compound 12j was prepared using the same method as for the synthesis of compound 12a. ^{(Yield: 63%): 1 H-} NMR (400 MHz, CDCl 3) δ 7.31 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz), 6.83 (2H, d, J (2H, d, J = 6.4 Hz), 6.77 (2H, d, J = 8.6 Hz), 5.44 1.70 (3 H, s); ¹³ C-NMR (MeOD, 125 MHz) ? 158.6, 157.9, 157.2, 137.2, 131.3, 131.3, 129.5, 129.5, 128.6, 124.7, 120.5, 114.7, 114.7, 114.4, 114.4, 70.4, 24.8, 17.1; HR-MS (FAB) 298.1443 calculated for LR-MS (FAB) m / z (M + H ⁺ ) 298; (M + H ⁺ ); Experiment 298.1453.

< Example  11>

Bis (4-hydroxyphenyl) methanone O - Cyclohexylmethyl Oxime  (12k)

Compound 12k was prepared using the same method as for the synthesis of compound 12a. ^{(Yield: 87%): 1 H-} NMR (400 MHz, CDCl 3) δ 7.31 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz), 6.84 (2H, d, J (2H, m, J = 8.6 Hz), 6.78 (2H, d, J = 8.6 Hz), 3.94 (2H, d, J = 5.9 Hz), 1.65-1.76 (2H, m); ¹³ C-NMR (MeOD, 125 MHz) ? 158.6, 157.9, 156.9, 131.2, 131.2, 129.5, 129.5, 128.5, 124.8, 114.7, 114.7, 114.3, 114.3, 79.5, 37.7, 29.8, 29.8, 26.5, 25.8, 25.8; HR-MS (FAB) 326.1756 calculated for LR-MS (FAB) m / z (M + H ⁺ ) 326; (M + H ⁺ ); Experiment 326.1754.

< Example  12>

Bis (4-hydroxyphenyl) methanone O -(2- Hydroxyethyl ) Oxime  (12l)

Compound 12l was prepared using the same method as for the synthesis of compound 12a. ^{(Yield: 87%): 1 H-} NMR (400MHz, CDCl 3) δ 7.28 (2H, d, J = 8.6 Hz), 7.26 (2H, d, J = 8.6 Hz), 6.84 (2H, d, J = 8.6 Hz), 6.76 (2H, d, J = 8.6 Hz), 4.23 (2H, t, J = 4.5 Hz), 3.87-3.89 (2H, m), 3.48 (2H, s), 1.26 (1H, t, J = 7.0); ¹³ C-NMR (MeOD, 125 MHz) ? 158.7, 158.0, 157.4, 131.4, 131.4, 129.6, 129.6, 128.5, 124.6, 114.8, 114.8, 114.4, 114.4, 75.1, 60.5; HR-MS (FAB) 274.1079 calculated for LR-MS (FAB) m / z (M + H @ ⁺ ) 274; (M + H @ ⁺ ); Experiment 274.1079.

< Example  13>

Bis (4-hydroxyphenyl) methanone O -(2- Methoxyethyl ) Oxime  (12m)

Compound 12m was prepared using the same method as for the synthesis of compound 12a. ^{(Yield: 95%): 1 H-} NMR (400 MHz, CDCl 3) δ 7.30 (2H, d, J = 8.6 Hz), 7.26 (2H, d, J = 8.6 Hz), 6.80 (2H, d, J = 8.6 Hz), 6.76 (2H, d, J = 8.6 Hz), 4.29 (2H, t, J = 4.7 Hz), 3.71 (2H, t, J = 4.7 Hz), 3.78 (3H, s); ¹³ C-NMR (MeOD, 125 MHz) ? 158.7, 158.0, 157.6, 132.4, 131.4, 131.4, 129.7, 129.7, 128.3, 124.6, 114.8, 114.8, 114.4, 114.4, 73.0, 70.9; LR-MS (FAB) m / z (M + H ⁺ ) 288; HR-MS calculated for (M + H ⁺ ) 288.1236; Experiment 288.1237.

< Example  14>

2-( Bis (4-hydroxyphenyl) methylene ) Aminooxyacetic acid  (12n)

Compound 12n was prepared using the same method as for the synthesis of compound 12a. ^{(Yield: 95%): 1 H-} NMR (400 MHz, CDCl 3) δ 7.36 (2H, d, J = 8.6 Hz), 7.30 (2H, d, J = 8.6 Hz), 6.85 (2H, d, J = 8.6 Hz), 6.76 (2H, d, J = 8.6 Hz), 4.67 (2H, s), 4.13 (2H, s), 1.26 (1H, s); ¹³ C-NMR (MeOD, 125 MHz) ? 158.9, 158.4, 158.1, 131.4, 131.4, 129.8, 129.8, 128.3, 128.0, 124.4, 114.8, 114.8, 114.3, 114.3, 70.2; LR-MS (FAB) m / z (M + H ⁺ ) 288; HR-MS calculated for (M + H ⁺ ) 288.0872; Experiment 288.0880.

< Comparative Example >

&Lt; Comparative Example 1 &

(E) -1- (4- Hydroxyphenyl ) Ethanone O - Butyl Oxime  (14a)

Hydroxylamine HCl (33 mg, 0.26 mmol) was added at room temperature to a solution of 4-hydroxyacetophenone (30 mg, 0.22 mmol) in EtOH (1 mL). Stirred until all starting material was consumed the reaction mixture on TLC and was quenched with H ₂ O. The resulting mixture was diluted with EtOA and the organic phase was washed with H ₂ O and brine, dried over MgSO ₄ and concentrated in vacuo. Silica gel flash column chromatography over (EtOAc: hexane = 1: 6 to 1: 5) to give the residue of Compound 14a as a colorless liquid 36 mg (79%) was obtained ^{by: 1 H-NMR (400 MHz} , CDCl 3 ) δ 7.46 (2H, d, J = 8.7 Hz), 6.71 (2H, d, J = 8.7 Hz), 6.52 (1H, s), 4.17 (2H, t, J = 6.6 Hz), 2.20 (3H, s ), 1.64-1.71 (2H, m), 1.38-1.44 (2H, m), 0.94 (3H, t, J = 7.4 Hz); HR-MS (FAB) 208.1338 calculated for LR-MS (FAB) m / z (M + H ⁺ ) 208; (M + H ⁺ ); Experiment 208.1346.

< Comparative Example  2>

(E) -1- (4- Hydroxyphenyl ) Ethanone O - Isopentyl Oxime  (14b)

Compound 14b was prepared using the same method as for the synthesis of 14a. ^{(Yield: 53%): 1 H-} NMR (400MHz, CDCl 3) δ 7.48 (2H, d, J = 8.7 Hz), 6.73 (2H, d, J = 8.7 Hz), 6.18 (1H, s), 4.20 (2H, t, J = 6.8 Hz), 2.20 (3H, s), 1.76 (1H, m), 1.60-1.65 (2H, m), 0.93 (6H, d, J = 6.4 Hz); LR-MS (FAB) m / z (M + H @ ⁺ ) 222; HR-MS (FAB) calcd 222.1494; Experiment 222.1495.

<Experimental Example 1>

Evaluation of estrogenic activity by ERE-luciferase assay

The present inventors conducted the following experiment to analyze the estrogenic effect of the compounds of the present invention prepared in the above Examples.

MCF7 cells, a breast cancer cell line, were co-infected with the estrogen responsive element (ERE) -Luc and the thymidine kinase-Renilla (pRL-TK) expression plasmid and incubated with 10% CS-FBS (charcoal-stripped FBS) Phenol-redfree RPMI for 1 day. Cells were treated with the compounds of Examples and Comparative Examples for 24 hours and analyzed by double-luciferase assay (Promega, Madison, Wis.) And the results are shown in FIG.

As shown in Fig. 1, most of the synthesized compounds exhibited remarkable estrogenic activity similar to bisphenol A (4), which is known to be one of the powerful ERa agonists at 10 [mu] M. In particular, the compound xy having 4-6 carbon chains had a relatively superior ER action activity than other analogues. Compound 13, which did not have a second phenolic group, exhibited lower activity than the other analogs. From this it can be seen that additional phenol is essential for making the hydrogen bond of the compound and the hER LBD for strong binding.

<Experimental Example 2>

Evaluation of cytotoxicity of compounds by MTT

Cytotoxicity of the compounds of the present invention on MCF7 and MDA-MB-231 breast cancer cell lines and Ishikawa cervical cancer cell lines was determined by measuring the cytotoxicity of MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide ] Cell viability assay. Cells in 96-well plates were treated for 48 hours with increasing concentrations of the compounds prepared in the Examples and Comparative Examples. After replacement with 20 μl of MTT (5 mg / ml) in fresh media, cells were incubated for an additional 4 hours and lysed with 200 μl of DMSO. The absorbance of the melt was measured at 570 nm using a microplate reader. To observe apoptotic cell death by the compound, cells were seeded onto a coverslip and treated with 17 [beta] -estradiol (E2) or compound for an additional 24 hours. Cells were fixed with 4% paraformaldehyde-PBS and washed with PBS. After permeation to 0.1% Triton-X-100, cells were stained with DAPI solution for 5 minutes and observed under a fluorescence microscope.

As shown in Fig. 2, compounds 12c, 12e and 12h according to the present invention showed intermediate cytotoxicity against carcinoma cells.

To further analyze the efficacy of the compounds as ER agonists, the EC ₅₀ values of 12c, 12e and 12h were measured and the results are shown in Figures 3 to 5. [

As shown in FIGS. 3-5, the EC ₅₀ values for compounds 12c, 12e and 12h from the ER activity assay were 0.075 μM, 0.046 μM and 0.077 μM, respectively, indicating significant efficacy for ER activation.

In addition, as shown in FIG. 6, in the case of the compound 12i, even at a low concentration of 10 μM, the proliferation of MCF7 cells and uterine cancer cells was clearly inhibited, but the same concentration of 17β-estradiol (E2) It did not affect.

Therefore, the novel bis (4-hydroxy) benzophenone oxime ether derivative compound according to the present invention exhibits strong estrogenic activity and exhibits cytotoxicity against carcinomas such as breast cancer and uterine cancer associated with the activity of estrogen receptor, Which is effective for the treatment of diseases.

<Experimental Example 3>

Docking analysis using molecular modeling

To investigate the binding mode of the bis (4-hydroxy) benzophenone analog identified as a novel ER agonist, docking analysis of compound 12c and the hER LBD active site was performed using the Autodock 4.2 program (Molecular Graphic Laboratory).

The AutoDock program was chosen because it uses genetic algorithms and uses the Lamarckian version of the genetic algorithm to form known or predicted binding site types within the ligand where molecules after in situ optimization The variation of the steric configuration employed by the system is used as a subsequent form of offspring. After docking experiments, water was removed from the 3D X-ray coordinates, while the tool from the AutoDock suite was used to position the Gasteiger charge on the X-ray structure with the active site of p38 MAPK and compound 12c. For the ligand docking experiments, the p38 MAPK domain center grid box and the 0.37 gap defined as 11.466, -18.150, -32.019 points were selected. The docking parameters are considered as a distribution size of up to 150, a number of occurrences of up to 27000, and an estimate of up to 25000000, while the docking performance is set to 50 and the root-mean-squared tolerance for grouping of each docking run Was limited to 1.

As shown in Fig. 7, the compound 12c of the present invention was well fitted to the active site. The measured free bond energy was -8.19 kcal / mol. The two phenolic moieties in the analog of the invention interact with hER LBD via hydrogen bonding with Glu353 and His 524 while the n-butyl group occupies the lipophilic pocket surrounded by Thr 347, Leu 346, Leu 384 and Trp 383 Thus forming a vandalus interaction. Thus, it is believed that the binding mode of the compounds of the present invention is consistent with bisphenol A (4).

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (8)

A novel bis (4-hydroxy) benzophenone oxime ether derivative compound having a structure represented by the following formula (1), an isomer thereof and a pharmaceutically acceptable salt thereof;
&Lt; Formula 1 >

Wherein R is H; Unsubstituted or OH, C _{1 -6} alkoxy group, a cycloalkyl C _{1 -6} alkyl group or a carboxy group-substituted C _1-6 alkyl; C _{1 -6} straight or branched alkenyl; And it is selected from the group consisting of unsubstituted or one or more C _{1 -6} straight or branched alkyl substituted with an allyl. The method according to claim 1,
Wherein R is selected from H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isobutyl, isopentyl, butenyl, perenyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, carboxymethyl, cyclohexyl Methyl, and dimethylallyl, an isomer thereof, and a pharmaceutically acceptable salt thereof. The method according to claim 1,
The novel bis (4-hydroxy) benzophenone oxime ether derivative compound
1) bis (4-hydroxyphenyl) methanone oxime;
2) bis (4-hydroxyphenyl) methanone O-propyloxime;
3) bis (4-hydroxyphenyl) methanone O-butyloxime;
4) bis (4-hydroxyphenyl) methanone O-but-3-en-1-yloxime;
5) bis (4-hydroxyphenyl) methanone O-pentyloxime;
6) bis (4-hydroxyphenyl) methanone O-pent-4-en-1-yl oxime;
7) bis (4-hydroxyphenyl) methanone O-hept-6-en-1-yl oxime;
8) bis (4-hydroxyphenyl) methanone O-isobutyloxime;
9) bis (4-hydroxyphenyl) methanone O-isopentyl oxime;
10) bis (4-hydroxyphenyl) methanone O- (3-methylbut-2-en-1-yl) oxime;
11) bis (4-hydroxyphenyl) methanone O-cyclohexylmethyloxime;
12) bis (4-hydroxyphenyl) methanone O- (2-hydroxyethyl) oxime;
13) bis (4-hydroxyphenyl) methanone O- (2-methoxyethyl) oxime; And
14) A compound, an isomer thereof and a pharmaceutically acceptable salt thereof, which is 2- (bis (4-hydroxyphenyl) methylene) aminooxyacetic acid. (4-hydroxy) benzophenone oxime of claim 1, which comprises condensing a bis (4-hydroxy) benzophenone compound of formula (2) with an alkoxyamine salt in the presence of an organic solvent to produce a compound of formula Method of preparing ether derivative compound:
<Reaction Scheme 1>

In the above Reaction Scheme 1, R is the same as defined in Formula 1 above. 5. The method of claim 4,
The organic solvent is selected from the group consisting of ethanol, dichloromethane and pyridine, and the reaction is carried out at room temperature for 2-24 hours. The preparation of the novel bis (4-hydroxy) benzophenone oxime ether derivative Way. A pharmaceutical composition for preventing or treating an estrogen receptor-related disease comprising the novel bis (4-hydroxy) benzophenone oxime ether derivative compound of claim 1 and a pharmaceutically acceptable salt thereof as an active ingredient. The method according to claim 6,
The estrogen receptor-related diseases include but are not limited to bone loss, fracture, osteoporosis, degenerative arthritis, endometriosis, uterine myoma, transient hot sensation, elevated levels of LDL cholesterol, cardiovascular disease, cognitive dysfunction, Depression, postmenopausal depression, premenstrual syndrome, manic depression, dementia, obsessive-compulsive disorder, attention deficit disorder, attention deficit hyperactivity disorder, sleep disorder , Irritable bowel syndrome, irritable bowel syndrome, irritable bowel syndrome, irritable bowel syndrome, irritable bowel syndrome, irritable bowel syndrome, irritable bowel syndrome, irritable bowel syndrome, irritable bowel syndrome, Hypertension, retinal degeneration, breast cancer, uterine cancer, ovarian cancer, and prostate cancer. A pharmaceutical composition for preventing or treating ring. A health functional food for inhibiting an estrogen receptor-related disease comprising the novel bis (4-hydroxy) benzophenone oxime ether derivative compound of claim 1.

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