CN105237474B - The preparation and its application of the sweet-smelling formacyl quinolinones compound of 6 hydroxyl 7 - Google Patents

Abstract

The invention belongs to the technical field of medicine, and relates to 6-hydroxy-7-aroyl quinolinone compounds and applications thereof. 6-Hydroxy-7-aroyl quinolinone compounds include stereoisomers and pharmaceutically applicable salts of 6-hydroxy-7-aryl formyl quinolinone compounds, and their general structural formula is as follows: 6-hydroxy-7-aroyl quinolinone compounds and the pharmaceutically applicable acid addition salts of such compounds can be combined with existing drugs or used alone as estrogen receptor modulators for the treatment or prevention of Various diseases related to estrogen function, such as: osteoporosis, cancer, especially breast cancer, ovarian cancer, osteosarcoma and endometrial cancer.

Description

Preparation and Application of 6-Hydroxy-7-Aroylquinolinones

technical field

The present invention relates to 6-hydroxyl-7-aryl formyl quinolinone compound, its pharmaceutical application as estrogen receptor modulator, and its preparation method.

Background technique

Compounds that mimic estrogen-like effects have a wide range of therapeutic and prophylactic applications, including: relief of menopausal symptoms, treatment of acne, treatment of dysmenorrhea and dysfunctional uterine bleeding, osteoporosis, prostate cancer and prevention of cardiovascular disease.

Studies have found that there are two types of estrogen receptors: ERα and ERβ. After the ligand binds to these two isoforms, it exerts physiological effects with different tissue specificities.

What is needed in the art is a compound that can produce a positive response like estrogen replacement therapy but without adverse side effects or with reduced side effects, and exert tissue-specific estrogen-like effects on the body. Since quinolinone derivatives have a similar spatial structure to estrogen, they can mimic estrogen and bind to estrogen receptors in vivo to exert physiological effects.

The compounds of the present invention are ligands of estrogen receptors and can be used for the treatment or prevention of various diseases related to estrogen function, including: osteoporosis, cancer, especially breast cancer, ovarian cancer, osteosarcoma and intrauterine membrane cancer.

Estrogen is an important class of hormone compounds in the human body. When women enter menopause, the level of estrogen in the body decreases, which leads to menopausal syndrome, osteoporosis, Alzheimer's disease and cardiovascular system diseases. For postmenopausal estrogen levels decline, estrogen replacement therapy (est rogen replacement therapy, ERT) can significantly reduce the incidence of postmenopausal osteoporotic fractures and coronary heart disease (Turner RT, Riggs BL, Spelsberg TC.EndocrRev, 1994, 15(3):275-300; Mora S, Kershner DW, Vigilance CP, et al. Curr Treat Options Cardiovasc Med, 2001, 3(1):67-79). However, ERT may induce breast cancer and endometrial cancer (Persson I, Weiderpass E, Bergkvist L, et al. Cancer Causes Control, 1999, 10(4):253-260). In order to overcome the adverse reactions of estrogen-induced carcinogenesis, people have developed sex hormone replacement therapy (hormone replacement therapy, HRT), which is combined with estrogen and progesterone, but long-term HRT treatment may still increase the incidence of breast cancer, even if progesterone is used , not in all cases can overcome the occurrence of endometrial cancer caused by estrogen, these adverse reactions limit the long-term application of HRT. Selective estrogen receptor modulators (selective estrogen receptor modulators, SERMs) have estrogen-like effects on the bone and cardiovascular system, but exhibit anti-estrogenic effects on the uterus and breast. But clinically used tamoxifen and raloxifene can cause adverse reactions such as endometrial cancer and hot flashes (Fisher B, Costantino JP, Wickerham DL, et al.J Nati Cancer Inst, 1998,90:1371- 1388; Walsh BW, Kuller LH, Wild RA, et al. J Am Med Assoc, 1998, 279:1445-1451).

Contents of the invention

The technical problem solved by the present invention is to provide a compound as shown in formula I, its prodrug and drug active metabolite, as well as the stereoisomer and pharmaceutically acceptable salt thereof, and provide its Application in the preparation of medicines for preventing and treating estrogen-related diseases.

Wherein X can be selected from O; R ₁ R ₂ is independently selected from hydrogen, C ₁ -C ₄ alkyl, benzyl, C ₁ -C ₄ alkyl substituted benzyl, C ₁ -C ₄ alkoxy substituted Benzyl, hydroxy and halogen substituted benzyl, phenyl, C ₁ -C ₄ alkyl substituted phenyl, C ₁ -C ₄ alkoxy substituted phenyl, hydroxy and halogen substituted phenyl, or R ₁ R ₂ forms 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 4-phenyl-1-piperazinyl, 4-(4-methylphenyl)- 1-piperazinyl, 4-(4-fluorophenyl)-1-piperazinyl, 4-(4-chlorophenyl)-1-piperazinyl, 4-(4-bromophenyl)-1- Piperazinyl, 4-(4-methoxyphenyl)-1-piperazinyl, 4-(4-trifluoromethylphenyl)-1-piperazinyl or 4-benzhydryl-1- piperazinyl.

Preferably, R ₁ R ₂ together with their attached nitrogen atoms form dimethylamino, diethylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 4-phenyl-1- Piperazinyl, 4-(4-methylphenyl)-1-piperazinyl, 4-(4-fluorophenyl)-1-piperazinyl, 4-(4-chlorophenyl)-1-piperazinyl Azinyl, 4-(4-bromophenyl)-1-piperazinyl, 4-(4-methoxyphenyl)-1-piperazinyl, 4-(4-trifluoromethylphenyl)- 1-piperazinyl or 4-benzhydryl-1-piperazinyl.

The present invention also provides a pharmaceutical composition of the compound of formula I and a pharmaceutically acceptable carrier. The present invention is also contemplated to include pharmaceutical compositions comprising a pharmaceutically acceptable carrier and any compound specifically disclosed in this application. The invention also relates to methods of preparing the compositions of the invention. The present invention also relates to processes that can be used to prepare the compounds and pharmaceutical compositions of the present invention.

The compounds of the present invention can be administered alone or preferably in pharmaceutical compositions in combination with pharmaceutically acceptable carriers or diluents, optionally in combination with known adjuvants according to conventional pharmaceutical practices. The compounds are administered orally or parenterally including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes.

In tablets for oral administration, commonly used carriers including lactose and corn starch, as well as lubricating agents such as magnesium stearate are usually added. For oral medication in a capsule form, acceptable diluents include lactose and dried cornstarch. For oral route use of therapeutic compounds according to the invention, the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. For oral administration in tablet or capsule form, the active pharmaceutical ingredient can be combined with an orally acceptable, nontoxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, hard Magnesium fatty acid, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.; for oral administration in liquid form, oral pharmaceutical ingredients can be mixed with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol , glycerin, water and other combinations. In addition, suitable binders, lubricants, disintegrants and colorants may be added to the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol , wax, etc. Suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. When the aqueous suspension is used orally, the active ingredient may be combined with emulsifying and suspending agents. Certain sweetening or flavoring agents may also be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are generally prepared, the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to maintain the formulation isotonic.

The compounds of the invention can also be administered in the form of liposomal delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of the invention can also be administered through the use of monoclonal antibodies as separate carriers to which the compound molecules are conjugated. The compounds of the present invention can also be coupled with soluble polymers as desired drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl . In addition, the compounds of the present invention can be coupled with a class of biodegradable polymers for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly Cross-linked or amphiphilic block copolymers of caprolactone, polyhydroxybutyrate, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.

The compounds of the present invention may also be used in combination with known agents useful in the treatment or prevention of osteoporosis, cancer, especially breast cancer, ovarian cancer, osteosarcoma and endometrial cancer. Combinations of the presently disclosed compounds with agents useful in the treatment or prophylaxis of the diseases disclosed herein are also within the scope of the invention. Compounds of the Invention and Estrogens.

"Estrogen" includes, but is not limited to, naturally occurring estrogens, synthetic conjugated estrogens, oral contraceptives, and sulfated estrogens. "Estrogen receptor modulator" means a substance that interferes with or counteracts the binding of estrogen to the receptor, regardless of the mechanism. Selective serotonin reuptake inhibitors work by increasing the amount of serotonin in the brain, non-limiting examples of which include fluoxetine, parotine, sertraline, citalopram, and fluvoxamine, also It can be used to treat diseases related to estrogen function. "Aromatase inhibitors" include compounds that inhibit aromatase, non-limitingly selected from the group consisting of: aminoglutethimide, letrozole, formestane, exemestane, atamestane, fadrozole, flurazole , vorozole.

The term "administering" and variants thereof (eg "administering" a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of an animal in need of treatment. When a compound of the present invention, or a prodrug thereof, is provided in combination with one or more other active agents (e.g., bisphosphonate compounds, etc.), "administration" and variations thereof are understood to include simultaneous and sequential introduction of the compounds or Prodrugs thereof and other agents. The present invention includes within its scope prodrugs of the compounds of the invention. Typically, such prodrugs are functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound. Thus, in the method of treatment of the present invention, the term "administration" shall include the use of a specifically disclosed compound or a compound which may not be specifically disclosed, but which is converted in vivo to a specific compound after administration to a patient, to treat said various diseases. Routine methods for selecting and preparing suitable prodrug derivatives are incorporated herein by reference. Metabolites of these compounds include active substances produced upon introduction of the compounds of the present invention into the biological environment.

When the compounds of this invention are administered to human subjects, the daily dosage will generally be determined by the prescribing physician and will generally vary according to the age, weight and response of the individual patient and the severity of the patient's symptoms. In one exemplary application, an appropriate amount of the compound is administered to a mammal receiving treatment. When used for the indicated effects, the oral dosage of the present invention will be about 0.01 mg per kg body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, most preferably 0.1 to 5.0mg/kg/day. For oral administration, the composition is preferably presented in the form of a tablet comprising 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 mg of the active ingredient , used to adjust the dosage for the symptoms of the treated patients. The medicament generally contains from about 0.01 mg to about 500 mg of active ingredient, preferably from about 1 mg to about 100 mg of active ingredient. For intravenous injection, the most preferred dosage will be from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. The compounds of the present invention may be administered in a once daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. In addition, preferred compounds of the present invention may be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes using transdermal patches known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

The compounds of the invention can be used in combination with other agents useful in the treatment of estrogen-mediated conditions. The individual components of the combination can be administered separately or simultaneously at different times during the treatment period, either in separate form or in a single combination. The present invention is therefore to be understood as encompassing all such regimens of simultaneous or alternate treatment, and the term "administering" is to be construed accordingly. The scope of combinations of the compounds of the invention with other agents useful in the treatment of cathepsin-mediated conditions includes in principle any combination with any pharmaceutical composition useful in the treatment of diseases related to estrogen function.

The present invention therefore also includes use in combination with a second agent selected from the group consisting of estrogens, estrogen receptor modulators, selective serotonin reuptake inhibitors, aromatase inhibitors, and Pharmaceutically acceptable salts and mixtures.

The compounds of the invention can be used in combination with other agents useful in the treatment of estrogen-mediated conditions. Each component of the combination can be administered separately at different times during the treatment period or simultaneously in separate form or in a single combination. The invention is therefore to be understood to encompass all such regimens of simultaneous or alternating treatment and the term "administration" is to be construed accordingly. It should be understood that the scope of combinations of the compounds of the present invention with other agents useful in the treatment of estrogen-mediated conditions includes in principle any combination with any pharmaceutical composition useful in the treatment of diseases related to estrogen function.

Dosage regimens for the compounds of this invention will be selected based on a variety of factors, including the type, species, age, weight, sex and medical condition of the patient; severity of the condition being treated; route of administration; renal and hepatic function of the patient ; and the specific compound or salt thereof used. A physician, veterinarian or clinician of ordinary skill can readily determine and prescribe an effective amount of the drug needed to prevent, combat or arrest the development of the condition.

In the method of the present invention, the compound described in detail herein can form the active ingredient, and according to the form of administration, i.e. oral tablet, capsule, elixir, syrup, etc., is mixed with an appropriate pharmaceutical diluent, excipient or carrier (collectively referred to herein as 'carrier' substances), and conform to conventional pharmaceutical practice.

Pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts formed with inorganic or organic acids. Conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and those derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, Lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy -Salts prepared from benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc. Pharmaceutically acceptable salts of the compounds of the invention can be synthesized from compounds of the invention which contain acidic or basic moieties by conventional chemical methods. In general, salts of basic compounds can be prepared by ion exchange chromatography or by reacting the free base with stoichiometric or excess amounts of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents . Similarly, salts of acidic compounds may be formed by reaction with a suitable inorganic or organic base.

Compounds of the present invention can be prepared according to the following general schemes using appropriate materials and are further illustrated by the specific examples that follow. Various known variations of the conditions and methods of the following preparative steps can also be used to prepare these compounds. All temperatures are in degrees Celsius unless otherwise indicated. The following schemes describe the preparation of several representative examples of the invention.

Wherein X can be selected from H ₂ or O; R ₁ R ₂ is independently selected from hydrogen, C ₁ -C ₄ alkyl, benzyl, C ₁ -C ₄ alkyl substituted benzyl, C ₁ -C ₄ alkoxy Benzyl substituted with radical, benzyl substituted with hydroxy and halogen, phenyl, phenyl substituted with C ₁ -C ₄ alkyl, phenyl substituted with C ₁ -C ₄ alkoxy, phenyl substituted with hydroxy and halogen, Or R ₁ R ₂ together with their connected nitrogen atoms form 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 4-phenyl-1-piperazinyl, 4-(4-methylbenzene Base)-1-piperazinyl, 4-(4-fluorophenyl)-1-piperazinyl, 4-(4-chlorophenyl)-1-piperazinyl, 4-(4-bromophenyl) -1-piperazinyl, 4-(4-methoxyphenyl)-1-piperazinyl, 4-(4-trifluoromethylphenyl)-1-piperazinyl or 4-benzhydryl -1-piperazinyl.

R ₁ R ₂ together with their attached nitrogen atoms form dimethylamino, diethylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 4-phenyl-1-piperazinyl , 4-(4-methylphenyl)-1-piperazinyl, 4-(4-fluorophenyl)-1-piperazinyl, 4-(4-chlorophenyl)-1-piperazinyl, 4-(4-bromophenyl)-1-piperazinyl, 4-(4-methoxyphenyl)-1-piperazinyl, 4-(4-trifluoromethylphenyl)-1-piperazinyl azinyl or 4-benzhydryl-1-piperazinyl.

The preparation method of the compound of the invention is simple, the yield is stable, and the prepared compound can better prevent and treat estrogen-related diseases.

detailed description

The present invention is described in detail with the following examples. However, it should be understood that the present invention is not limited to the examples specifically described below.

Example 1: 6-Hydroxy-7-[4-(2-oxo-2-diethylaminoethoxy)benzoyl]-3,4-dihydro-1H-quinolin-2-one preparation

Add 3.26g (0.02mol) of 6-hydroxyquinolinone, 150mL of dichloromethane, and 2.24g (0.024mol) of triethylamine into a 250mL round bottom flask, and stir evenly at room temperature. Add dropwise a dichloromethane solution containing p-methoxybenzoyl chloride (p-methoxybenzoyl chloride 3.74g, 0.022mol; dichloromethane 40mL) with stirring, dropwise into the reaction solution at a constant speed, and complete the dropwise addition within 20 minutes. Stir at room temperature for 5 h, monitor by TLC until the reaction is complete, slowly pour the reaction solution into 50 mL of 1 mol·L-1 hydrochloric acid, filter with suction, wash the filter cake with 30 mL of water x 3 times, and dry. Transfer the filtrate to a separatory funnel, separate the organic layer, wash with 100 mL of water × 2, dry with anhydrous MgSO ₄ , filter to remove the desiccant, evaporate the filtrate to remove the organic solvent under reduced pressure, and obtain a white solid with a yield of 5.86 g and a yield of 98.7 %. mp 257-259°C; ESI-MS: m/z 297.1 ([M+H] ⁺ ).

In a 100mL round bottom flask, add 2.98g (0.012mol) of 6-(4-methoxybenzoyloxy)-3,4-dihydro-1H-quinolin-2-one, anhydrous trichloride Aluminum (4.4g, 0.034mol) was installed with an air condenser and a spherical drying tube filled with anhydrous CaCl ₂ , reacted in an oil bath at 180°C for 6h, monitored by TLC until the reaction was complete, and cooled to room temperature. Add appropriate amount of ice water and 1mol·L-1 hydrochloric acid solution to adjust the pH to 2-3, soak overnight, beat, filter and wash the product until neutral to obtain a light yellow solid with a yield of 2.91g and a yield of 97.7%. mp281-283℃; ¹ H-NMR (600MHz, DMSO-d6) δ (ppm) 10.38 (s, 1H), 10.15 (s, 1H), 9.90 (s, 1H), 7.61 (d, J = 6.0Hz, 2H), 6.87-6.79(m, 4H), 2.88(t, J=12.0Hz, 2H), 2.43(t, J=12.0Hz, 2H); ESI-MS: m/z 283.1([M+H] ⁺ ).

6-Hydroxy-7-(4-hydroxybenzoyl)-3,4-dihydro-1H-quinolin-2-one (3mmol), N,N-diethyl-2-chloroacetamide (3.5 mmol), potassium carbonate (6.2g, 45mmol) and potassium iodide (0.1g, 0.6mmol) and 30mL of acetone were added to a round bottom flask, heated to reflux for 12h, and monitored by TLC until the reaction was complete. Suction filtration and column chromatography [V (petroleum ether): V (ethyl acetate) = 1:3] separated to obtain 0.39 g of a yellow solid with a yield of 33.23%. ¹ H-NMR (600MHz, DMSO-d6) δ (ppm) 10.19 (s, 1H), 9.95 (s, 1H), 7.68 (d, J = 9.0Hz, 2H), 7.00 (d, J = 9.0Hz, 2H),6.88(s,1H),6.81(s,1H),4.92(s,2H),3.30(m,4H),2.88(t,J=15.0Hz,2H),2.43(t,J=15.0 Hz, 2H), 1.17 (t, J = 13.8Hz, 3H), 1.04 (t, J = 14.4Hz, 3H); MS (m/z): 397.2 ([M+H] ⁺ ).

Example 2: 6-Hydroxy-7-{4-[2-oxo-2-(1-piperidinyl)ethoxy]benzoyl}-3,4-dihydro-1H-quinoline-2 - Preparation of ketones

According to the method of Example 1, a bright yellow solid 0.43 g, yield 35.22%. ¹ H-NMR (600MHz, DMSO-d6) δ (ppm) 10.20 (s, 1H), 9.92 (s, 1H), 7.67 (d, J = 8.4Hz, 2H), 7.01 (d, J = 8.4Hz, 2H), 6.89(s, 1H), 6.81(s, 1H), 4.93(s, 2H), 3.40(d, J=19.2Hz, 4H), 2.88(t, J=15.0Hz, 2H), 2.43( t,J=15.0Hz,2H),1.60(d,J=4.8Hz,2H),1.54(s,2H),1.44(s,2H); MS(m/z):409.2([M+H] ⁺ ).

Example 3: Preparation of 6-hydroxyl-7-[2-oxo-(4-morpholinoethoxy)benzoyl]-3,4-dihydro-1H-quinolin-2-one

According to the method of Example 1, a bright yellow solid 0.19 g, yield 15.67%. ¹ H-NMR (600MHz, DMSO-d6) δ (ppm) 10.20 (s, 1H), 9.92 (s, 1H), 7.67 (d, J = 8.4Hz, 2H), 7.03 (d, J = 9.0Hz, 2H), 6.89(s, 1H), 6.81(s, 1H), 4.98(s, 2H), 3.60(d, J=28.8Hz, 4H), 3.46(s, 4H), 2.89(t, J=15.0 Hz, 2H), 2.43 (t, J = 15.0 Hz, 2H); MS (m/z): 411.2 ([M+H] ⁺ ).

Example 4: Preparation of 6-hydroxy-7-{4-[2-(1-piperidinyl)ethoxy]benzoyl}-3,4-dihydro-1H-quinolin-2-one

According to the method of Example 1, from 6-hydroxy-7-(4-hydroxybenzoyl)-3,4-dihydro-1H-quinolin-2-one, 4-(2-chloroethyl) piperidine salt acid salt to obtain 0.45 g of a bright yellow solid with a yield of 38.07%. ¹ H-NMR (600MHz, DMSO-d6) δ (ppm) 10.13 (s, 1H), 9.91 (s, 1H), 7.68 (d, J = 7.8Hz, 4H), 7.31 (t, J = 15Hz, 4H ), 7.20(t, J=15Hz, 2H), 6.99(d, J=8.4Hz, 2H), 4.16(t, J=15.0Hz, 2H), 2.88(t, J=15Hz, 2H), 2.67( t,J=11.4Hz,2H),2.43(t,J=14.4Hz,6H),1.49(m,4H),1.38(d,J=4.8Hz,2H); MS(m/z):395.2( [M+H] ⁺ ).

Example 5: Preparation of 6-hydroxyl-7-[2-(4-morpholinoethoxy)benzoyl]-3,4-dihydro-1H-quinolin-2-one

According to the method of Example 1, from 6-hydroxyl-7-(4-hydroxybenzoyl)-3,4-dihydro-1H-quinolin-2-one, 4-(2-chloroethyl)morpholine salt acid salt to obtain 0.30 g of a bright yellow solid with a yield of 25.41%. ¹ H-NMR (600MHz, DMSO-d6) δ (ppm) 10.12 (s, 1H), 9.91 (s, 1H), 7.68 (d, J = 9.0Hz, 2H), 7.07 (d, J = 8.4Hz, 2H), 6.86(s, 1H), 6.80(s, 1H), 4.19(s, 2H), 3.58(t, J=8.4Hz, 4H), 2.88(t, J=15Hz, 2H), 2.72(s , 2H), 2.48-2.42 (m, 5H), 2.19 (s, 1H); MS (m/z): 397.2 ([M+H] ⁺ ).

Example 6: 6-Hydroxy-7-{4-[2-oxo-2-(4-benzhydryl-1-piperazinyl)ethoxy]benzoyl}-3,4-dihydro - Preparation of 1H-quinolin-2-one

According to the method of Example 1, from 6-hydroxyl-7-(4-hydroxybenzoyl)-3,4-dihydro-1H-quinolin-2-one, 4-benzhydryl-1-chloroacetylpiper oxazine to obtain 0.58 g of a bright yellow solid with a yield of 33.67%. ¹ H-NMR (600MHz, DMSO-d6) δ (ppm) 10.13 (s, 1H), 9.91 (s, 1H), 7.66 (d, J = 7.8Hz, 2H), 7.44 (d, J = 7.8Hz, 4H), 7.31(t, J=15Hz, 4H), 7.20(t, J=15Hz, 2H), 6.99(d, J=8.4Hz, 2H), 6.88(s, 1H), 6.81(s, 1H) ,4.93(s,2H),4.36(s,1H),3.48(t,J=8.4Hz,4H),2.88(t,J=15Hz,2H),2.43(t,J=9Hz,2H),2.32 (d, J = 29.4 Hz, 4H); MS (m/z): 576.2 ([M+H] ⁺ ).

Example 7: 6-hydroxy-7-{4-[2-oxo-2-(benzylamino)ethoxy]benzoyl}-3,4-dihydro-1H-quinoline-2- Preparation of ketones

According to the method of Example 1, from 6-hydroxy-7-(4-hydroxybenzoyl)-3,4-dihydro-1H-quinolin-2-one, N-benzyl-2-chloroacetamide, to obtain Bright yellow solid 0.28g, yield 21.69%. ¹ H-NMR (600MHz, DMSO-d6) δ (ppm) 10.14 (s, 1H), 9.92 (s, 1H), 8.72 (t, J = 18Hz, 1H), 7.70 (d, J = 13.8Hz, 2H ),7.27(m,5H),7.10(d,J=13.2Hz,2H),6.88(s,1H),6.81(s,1H),4.67(s,2H),4.36(d,J=9.6Hz , 2H), 2.89 (t, J=22.8Hz, 2H), 2.43 (t, J=22.2Hz, 2H); MS (m/z): 431.2 ([M+H] ⁺ ).

Example 8: 6-Hydroxy-7-{4-[2-oxo-2-(4-methylphenylamino)ethoxy]benzoyl}-3,4-dihydro-1H-quinone Preparation of lin-2-ones

According to the method of Example 1, from 6-hydroxy-7-(4-hydroxybenzoyl)-3,4-dihydro-1H-quinolin-2-one, N-(4-methylphenyl)-2 - Chloroacetamide to obtain 0.39 g of bright yellow solid, yield 30.51%. ¹ H-NMR (600MHz, DMSO-d6) δ (ppm) 10.17 (s, 1H), 10.07 (s, 1H), 9.91 (s, 1H), 7.47 (s, 1H), 7.41 (d, J = 12Hz ,1H),7.20(t,J=23.4Hz,1H),7.11(d,J=13.2Hz,2H),6.91-6.85(m,2H),6.81(s,1H),4.81(s,2H) , 2.88 (t, J=22.2Hz, 2H), 2.43 (t, J=22.2Hz, 2H), 2.28 (s, 3H); MS (m/z): 431.2 ([M+H] ⁺ ).

Example 9: 6-Hydroxy-7-[4-(2-oxo-2-dimethylaminoethoxy)benzoyl]-3,4-dihydro-1H-quinolin-2-one preparation

According to the method of Example 1, from 6-hydroxy-7-(4-hydroxybenzoyl)-3,4-dihydro-1H-quinolin-2-one, N,N-dimethyl-2-chloroethyl amide to obtain 0.39 g of a bright yellow solid with a yield of 30.51%. ¹ H-NMR (600MHz, DMSO-d6) δ (ppm) 10.19 (s, 1H), 9.95 (s, 1H), 7.68 (d, J = 9.0Hz, 2H), 7.00 (d, J = 9.0Hz, 2H),6.88(s,1H),6.81(s,1H),4.92(s,2H),3.30(m,4H),2.98(s,6H); MS(m/z):367.2([M+ H] ⁺ ).

Example 10: 6-Hydroxy-7-{4-[2-oxo-2-(4-phenyl-1-piperazinyl)ethoxy]benzoyl}-3,4-dihydro-1H - Preparation of quinolin-2-ones

According to the method of Example 1, from 6-hydroxyl-7-(4-hydroxybenzoyl)-3,4-dihydro-1H-quinolin-2-one, 4-phenyl-1-chloroacetylpiperazine, 0.55 g of a bright yellow solid was obtained with a yield of 31.64%. ¹ H-NMR (600MHz, DMSO-d6) δ (ppm) 10.13 (s, 1H), 9.91 (s, 1H), 7.66 (d, J = 7.8Hz, 2H), 7.44 (d, J = 7.8Hz, 4H), 6.99(d, J=8.4Hz, 2H), 6.81(s, 1H), 4.93(s, 2H), 4.36(s, 1H), 3.48(t, J=8.4Hz, 4H), 2.88( t, J = 15Hz, 2H), 2.43 (t, J = 9Hz, 2H), 2.32 (d, J = 29.4Hz, 4H); MS (m/z): 486.2 ([M+H] ⁺ ).

Example 10 6-Hydroxy-7-{4-[2-oxo-4-(4-methylphenyl)-1-piperazinyl]ethoxy}benzoyl}-3,4-dihydro - Preparation of 1H-quinolin-2-one

According to the method of Example 1, from 6-hydroxy-7-(4-hydroxybenzoyl)-3,4-dihydro-1H-quinolin-2-one, 4-(4-methylphenyl)-1 - Chloroacetylpiperazine to obtain 0.50 g of a bright yellow solid with a yield of 30.67%. ¹ H-NMR (600MHz, DMSO-d6) δ (ppm) 10.13 (s, 1H), 9.91 (s, 1H), 7.66 (d, J = 7.8Hz, 2H), 7.44 (d, J = 7.8Hz, 4H), 6.99(d, J=8.4Hz, 2H), 6.81(s, 1H), 4.93(s, 2H), 4.36(s, 1H), 3.48(t, J=8.4Hz, 4H), 2.88( t,J=15Hz,2H),2.43(t,J=9Hz,2H),2.32(d,J=29.4Hz,4H)2.28(s,3H); MS(m/z):500.2([M+ H] ⁺ ).

Example 11: 6-Hydroxy-7-{4-[2-oxo-4-(4-fluorophenyl)-1-piperazinyl]ethoxy}benzoyl}-3,4-dihydro - Preparation of 1H-quinolin-2-one

According to the method of Example 1, from 6-hydroxy-7-(4-hydroxybenzoyl)-3,4-dihydro-1H-quinolin-2-one, 4-(4-fluorophenyl)-1- Chloroacetylpiperazine gave 0.48 g of a bright yellow solid with a yield of 29.07%. ¹ H-NMR (600MHz, DMSO-d6) δ (ppm) 10.13 (s, 1H), 9.91 (s, 1H), 7.66 (d, J = 7.8Hz, 2H), 7.44 (d, J = 7.8Hz, 4H), 6.99(d, J=8.4Hz, 2H), 4.93(s, 2H), 4.36(s, 1H), 3.48(t, J=8.4Hz, 4H), 2.88(t, J=15Hz, 2H ), 2.43 (t, J=9Hz, 2H), 2.32 (d, J=29.4Hz, 4H); MS (m/z): 504.2 ([M+H] ⁺ ).

Example 12: 6-Hydroxy-7-{4-[2-oxo-4-(4-chlorophenyl)-1-piperazinyl]ethoxy}benzoyl}-3,4-dihydro - Preparation of 1H-quinolin-2-one

According to the method of Example 1, from 6-hydroxy-7-(4-hydroxybenzoyl)-3,4-dihydro-1H-quinolin-2-one, 4-(4-chlorophenyl)-1- Chloroacetylpiperazine gave 0.58 g of a bright yellow solid with a yield of 29.12%. ¹ H-NMR (600MHz, DMSO-d6) δ (ppm) 10.05 (s, 1H), 9.93 (s, 1H), 7.66 (d, J = 7.8Hz, 2H), 7.44 (d, J = 7.8Hz, 4H), 6.99(d, J=8.4Hz, 2H), 3.56(t, J=8.4Hz, 4H), 3.48(t, J=8.4Hz, 4H), 2.88(t, J=15Hz, 2H), 2.43 (t, J = 9 Hz, 2H), 2.32 (d, J = 29.4 Hz, 4H); MS (m/z): 520.2 ([M+H] ⁺ ).

Example 13: 6-Hydroxy-7-{4-[2-oxo-4-(4-bromophenyl)-1-piperazinyl]ethoxy}benzoyl}-3,4-dihydro - Preparation of 1H-quinolin-2-one

According to the method of Example 1, from 6-hydroxy-7-(4-hydroxybenzoyl)-3,4-dihydro-1H-quinolin-2-one, 4-(4-bromophenyl)-1- Chloroacetylpiperazine gave 0.58 g of a bright yellow solid with a yield of 29.12%. ¹ H-NMR (600MHz, DMSO-d6) δ (ppm) 10.05 (s, 1H), 9.93 (s, 1H), 7.66 (d, J = 7.8Hz, 2H), 7.44 (d, J = 7.8Hz, 4H), 6.99(d, J=8.4Hz, 2H), 3.56(t, J=8.4Hz, 4H), 3.48(t, J=8.4Hz, 4H), 2.88(t, J=15Hz, 2H), 2.43 (t, J = 9 Hz, 2H), 2.32 (d, J = 29.4 Hz, 4H); MS (m/z): 564.1 ([M+H] ⁺ ).

Example 14: 6-Hydroxy-7-{4-[2-oxo-4-(4-methoxyphenyl)-1-piperazinyl]ethoxy}benzoyl}-3,4- Preparation of Dihydro-1H-quinolin-2-one

According to the method of Example 1, from 6-hydroxy-7-(4-hydroxybenzoyl)-3,4-dihydro-1H-quinolin-2-one, 4-(4-methoxyphenyl)- 1-Chloroacetylpiperazine, 0.68 g of a bright yellow solid was obtained, and the yield was 32.87%. ¹ H-NMR (600MHz, DMSO-d6) δ (ppm) 10.13 (s, 1H), 9.91 (s, 1H), 7.66 (d, J = 7.8Hz, 2H), 7.54 (d, J = 7.8Hz, 4H), 6.99(d, J=8.4Hz, 2H), 6.81(s, 1H), 4.93(s, 2H), 4.36(s, 1H), 3.48(t, J=8.4Hz, 4H), 2.88( t,J=15Hz,2H),2.43(t,J=9Hz,2H),2.32(d,J=29.4Hz,4H)1.98(s,3H); MS(m/z):500.2([M+ H] ⁺ ).

Example 15: 6-Hydroxy-7-{4-[2-oxo-4-(4-trifluoromethylphenyl)-1-piperazinyl]ethoxy}benzoyl}-3,4 -The preparation of dihydro-1H-quinolin-2-one is according to the method of Example 1, from 6-hydroxyl-7-(4-hydroxybenzoyl)-3,4-dihydro-1H-quinoline-2- The ketone, 4-(4-trifluoromethylphenyl)-1-chloroacetylpiperazine, gave 0.38 g of a bright yellow solid with a yield of 12.25%. ¹ H-NMR (600MHz, DMSO-d6) δ (ppm) 10.13 (s, 1H), 9.91 (s, 1H), 7.66 (d, J = 7.8Hz, 2H), 7.74 (d, J = 7.8Hz, 4H), 6.99(d, J=8.4Hz, 2H), 6.81(s, 1H), 4.93(s, 2H), 4.36(s, 1H), 3.48(t, J=8.4Hz, 4H), 2.88( t, J = 15Hz, 2H), 2.43 (t, J = 9Hz, 2H), 2.32 (d, J = 29.4Hz, 4H); MS (m/z): 554.2 ([M+H] ⁺ ).

pharmaceutical composition

In the following formulations, "active ingredient" refers to the compound of formula 1, or a salt or solvate thereof.

Example 16: Gelatin Capsules

Example 17: Tablets

Example 18: Tablets

Pass the active ingredient, starch and cellulose through a 45-mesh U.S. sieve and mix thoroughly. The resulting powder is mixed with polyvinylpyrrolidone and then passed through a 14-mesh U.S. sieve. The granules thus obtained are dried at 50-60° C. and passed through a 18-mesh U.S. screen. The sodium carboxymethylcellulose, magnesium stearate and talc, first passed through a 60 mesh U.S. sieve, are then added to the above granules, mixed and compressed on a tablet machine to form tablets.

Embodiment 19: Suspending agent

Pass the drug through a 45 mesh U.S. sieve and mix with sodium carboxymethylcellulose and syrup to form a homogeneous paste. Dilute the benzoic acid solution, flavor, and color with some water and add with stirring, then add Sufficient water to achieve desired volume.

Example 20: Aerosol

The active ingredient is mixed with ethanol, and the resulting mixture is added to a portion of the propellant 22, cooled to 30°C, and transferred to a container. The required amount is then added to the stainless steel container and diluted with the remainder of the propellant before installing the valve assembly.

Embodiment 21: suppositories

The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in pre-melted saturated fatty acid glycerides. The mixture is then poured into standard 2g cavity suppository molds and allowed to cool.

Example 22: Injectable Formulations

The above solution was injected intravenously at a rate of about 1 mL per minute.

Pharmacological efficacy experiment

Example 23: Estrogen receptor binding experiment

The estrogen receptor ligand binding assay was designed using a scintillation proximity assay using tritiated estradiol and recombinantly expressed estrogen receptor. Full-length recombinant human ER-α and ER-β proteins were produced in a baculovirus expression system. ER-α and ER-β extracts were diluted 1:400 in phosphate buffered saline containing 6 mM α-monothioglycerol. A 200 [mu]L aliquot of the diluted receptor preparation was added to each well of a 96-well Flashplate. Plates were covered with Saran Wrap and incubated overnight at 4°C.

The next morning a 20 μL aliquot of phosphate buffered saline containing 10% bovine serum albumin was added to each well of the 96-well plate and allowed to incubate at 4°C for 2h. The plate was then washed with 200 μL of a buffer containing 20 mM Tris (pH 7.2), 1 mM EDTA, 10% glycerol, 50 mM KCl and 6 mM α-monothioglycerol. For testing in these receptor-coated plates, 178 [mu]L of the same buffer was added to each well of a 96-well plate. Then 20 μL of 10 nM 3H-estradiol solution was added to each well of the culture plate.

Test compounds were evaluated over a concentration range of 0.01 nM to 1000 nM. Test compound stocks should be prepared in 100% DMSO at 100X the final concentration expected to be tested in the assay. The amount of DMSO in the test wells of the 96-well plate should not exceed 1%. Final additions to the assay were 2 [mu]L aliquots of test compounds in 100% DMSO. The plate was sealed and allowed to equilibrate at room temperature for 3h. Plates were counted in a scintillation counter equipped for counting 96-well plates.

The inhibition rate of estrogen receptor binding experiment of some samples is listed as follows (n=3):

The compounds of Examples 1-15 exhibited binding affinities for ERα in the range of IC ₅₀ =75 to 10000 nm, and binding affinities for ERβ in the range of IC ₅₀ =5 to 250 nm.

The results obtained in the standard pharmacological testing procedures described above indicate that the compounds of the present invention are estrogenic compounds and that certain compounds have a strong preferential affinity for the ERa receptor. The compounds of the invention range from having a preferential affinity for ERα over ERβ to having almost equivalent affinity for both receptors. Thus, the compounds of the present invention possess a variety of activities based at least in part on their receptor affinity selectivity profile. In addition, since various new receptor ligand complexes are different, the interaction between it and various co-regulatory proteins is also different, and the compound of the present invention will show different regulatory activities according to the cell environment. For example, a compound may act as an estrogen agonist in some cell types, but in other tissues it may be an antagonist. Compounds having the above activities are generally referred to as SERMs (Selective Estrogen Receptor Modulators). However, unlike most estrogens, many SERMs do not cause an increase in uterine wet weight. These compounds have antiestrogenic activity in the uterus and thus completely antagonize the nutritional activity of estrogen agonists in uterine tissue. However, these compounds act as estrogen agonists in the bone, cardiovascular and central nervous system. Because these compounds have the above-mentioned tissue selectivity, they can be used for the treatment or prevention of estrogen deficiency (in certain tissues such as bone and cardiovascular) or estrogen excess (in the uterus or breast) caused by or associated with it. Pathological state or syndrome.

Even beyond the cell-specific modulation described above, the compounds of the present invention are potentially agonists for one receptor type and antagonists for another receptor type. For example, it is an antagonist for ERβ and an agonist for ERα. This estrogen receptor selective agonist antagonist activity provides this series of compounds with pharmacologically distinct estrogenic activity.

The activity profile of the compounds of the invention can be readily determined using standard pharmacological assay procedures. Several representative test steps are briefly outlined below. The compounds of the present invention all exhibit biological activities similar to raloxifene.

Example 24: Rat Uterotrophic/Anti-Uterotrophic Test Procedures

The estrogenic and antiestrogenic properties of the compounds can be measured in the uterine nutrition test (4 days) of juvenile rats. Immature rats (Sprague-Dawley rats) (female, 18 days old) were divided into six groups for testing. These animals were checked for antiestrogens by daily ip injections of 10 μg compound, 100 μg compound, (100 μg compound and 1 μg 17β estradiol), and 1 μg 17β estradiol, using 50% DMSO/50% saline as injection vehicle. The animals were sacrificed by _CO2 asphyxiation on the fourth day, the uteri were removed, excess fat was stripped, all fluid was removed, wet weight was measured, a portion of the corner was removed for histological analysis, and the remainder was used to isolate intact RNA to evaluate complement Component 3 Gene Expression.

The list of uterine weight gain of some samples is as follows (n=3):

Embodiment 25: MCF-7/ERE anti-proliferation test procedure

Stock solutions (typically 0.1 M) of test compounds were prepared in DMSO and then diluted 10-100 times in DMSO to bring working solutions to 1-10 mM. DMSO stock solutions were stored at 4°C (0.1M) or -20°C (<0.1M). MCF-7 cells were transduced twice a week with growth medium (D-MEM/F-12 medium). Cells were maintained in 37°C vented flasks in a 5% _CO2 /95% humidified air incubator. One day before treatment, cells were plated in 96-well titer plates with growth medium at 25,000/well and incubated overnight at 37°C.

The cells were infected with 50 μL/well of 1/10 diluted adenovirus 5-ERE-tk-luciferase in the test medium (D-MEM/F-12 medium without phenolsulfonphthalein) for 2 hours at 37°C. Wells were then washed once with 150 μλ assay medium. Finally, cells were treated in replicates at 37°C for 24 h, 8 wells/well with 150 μλ/well vehicle (≤0.1% v/v DMSO) or treated with compound diluted ≥1000-fold in assay medium.

Initial screening of test compounds was performed at a single dose of 1 μM, either alone (agonist mode) or in combination with 0.1 nM 17β estradiol (EC80: antagonist mode). Each 96-well titer plate also included a vehicle control (0.1% v/v DMSO) and an agonist control (0.1 or 1 nM 17[beta] estradiol). Dose response experiments are performed with logarithmic increases of active compound from 10 ⁻¹⁴ to 10 ⁻⁵ M in agonist and/or antagonist mode. Based on these dose-response curves, _EC50 and _IC50 values are mentioned, respectively. The last titration well of each treatment group contained 5 μL of 3×10 ^-5 M ICC-182780 (10 ^-6 M final concentration) as an ER antagonist control.

After treatment, cells were lysed with 25 μL/well of IX Cell Culture Lysis Reagent (Promega Corporation) for 15 minutes on a shaker. Cell lysates (20 μL) were transferred to 96-well luminometer plates and luciferase activity was measured in a MicroLumat LB 96P luminometer (EG&G Berthold) using 100 μL/well of luciferase substrate (Promega Corporation). A 1 s background measurement was performed on each well prior to substrate injection. After substrate injection, luciferase activity was measured within 10 s after a delay of 1 s. These data from the photometer were analyzed with JMF software (SAS Institute); this program subtracted background readings from luciferase activity in each well and then calculated the mean and standard deviation for each treatment.

The luciferase data above were log-transformed, using the Huber M-estimator to downweight transformed results that were far from the center. JMP software was used to analyze the transformed and weighted data for one-way ANOVA (D test). Compound-treated groups were compared to vehicle control results in agonist mode, or positive agonist control results (0.1 nM 17[beta]-estradiol) in antagonist mode. For the initial single-dose experiments, if the compound-treated group results were significantly different (p<0.05) from the corresponding control group, the results were expressed as a percentage relative to the 17[beta]-estradiol control group. Additionally, _EC50 and/or _IC50 values are determined from nonlinear dose-response curves using JMP software.

Part of the sample MCF-7 anti-proliferation test list is as follows (n=3):

Example 26: Effect on proliferation of breast cancer cells

The ability of the compounds of the invention to treat and inhibit various malignancies or hyperproliferative diseases can be evaluated by standard pharmacological assay procedures readily available in the literature.

Ovariectomized athymic nu/nu (nude) mice. One day prior to tumor cell injection, animals were implanted with controlled release pellets containing 0.36-1.7 mg β-estradiol (60 or 90 day release) or placebo. Using a 10-scale precision rotor, the pellets are introduced subcutaneously into the inner glyph area. Next, 1×10 ⁷ MCF-7 cells or 1×10 ⁷ BG-1 cells were subcutaneously injected into mouse mammary gland tissue. Cells were mixed with an equal volume of matrigel, a basement membrane matrix preparation, to enhance tumor establishment. Test compounds can be evaluated by dosing one day after tumor cell implantation (suppressive regimen) or after the tumor has reached a certain volume (therapeutic regimen). Compounds in 1% Tween-80 vehicle in saline were administered daily ip or orally. Tumor volumes were assessed every 3 or 7 days.

Some sample activities are listed as follows (n=3):

Example 27: Effects on IL-6 and GM-CSF Production in HOB Cells

Human osteoclast HOB was plated in a 96-well dish in regular HOB medium (Ham's F12, supplemented with 28mM HEPES, Ph7.4, 10% FCS, 1.1mM CaCl ₂ , 2mM glutamine and 1% antibiotic- antifungal agent) at a density of 7×10 ³ cells/well. The next day, cells were treated with compound or vehicle treatment (0.2% DMSO) for 30 minutes, followed by the addition of IL-1β (1 ng/mL) and TNF-α (10 ng/mL). The cultivation lasts for 18 to 24 hours. The levels of IL-6 and GM-CSF in the culture medium were measured using commercially available ELISA kits. The compounds of the present invention exhibit inhibitory effects on IL-6 and GM-CSF.

Some sample activities are listed as follows (n=3):

Example 28: Effect on proliferation of ovarian cancer cell SKOV3

Digest the cells in the logarithmic growth phase with trypsin, add 6×10 ³ cells/well to a 96-well culture plate, and culture in a 37°C, 5% CO ₂ incubator, and wait for most of the cells to adhere to the wall on the second day Afterwards, it was placed in a 4°C incubator for 1 hour to promote the synchronized growth of cells. Aspirate the supernatant, add RPMI1640 culture medium containing 10% newborn calf serum (FCS), 200 μL/well, and divide into groups according to the experimental design. The compound injection prepared by sterile normal saline was added to 96 wells, and 200 μL was added to each well, so that the drug concentrations in each well were 1 mg/mL, 2 mg/mL and 5 mg/mL, and 0 mg/mL was used as the negative control group. After continuing to culture for 24, 48, and 72 hours, add 20 μL of MTT solution (concentration: 5 mg/mL) to each well, gently shake the culture plate, put it back into the incubator and incubate for another 4 hours, then suck up the supernatant, and put it in each well. Add 200 μL of dimethyl sulfoxide to medium, shake on a shaker for 5-10 minutes, measure the absorbance value (A=580) at a wavelength of 580 nm in each well with an enzyme-labeled photometer, and the value of A=580 is proportional to the number of viable cells.

Some sample activities are listed as follows (n=3):

Claims (12)

1. the quinolinones compound or its pharmaceutically acceptable salt of a kind of logical formula (I),

Wherein X is O；

R₁、R₂Independently selected from hydrogen, C_l-C₄Alkyl, benzyl, C_l-C₄Alkyl-substituted benzyl, C_l-C₄The benzyl of alkoxy substitution, Hydroxyl and benzyl, phenyl, the C of halogen substitution_l-C₄Alkyl-substituted phenyl, C_l-C₄Phenyl, hydroxyl and the halogen of alkoxy substitution Substituted phenyl or R₁、R₂1- pyrrolidinyls, 1- piperidyls, 4- morpholinyls, 4- benzene are constituted together with the nitrogen-atoms that they are connected Base -1- piperazinyls, 4- (4- aminomethyl phenyls) -1- piperazinyls, 4- (4- fluorophenyls) -1- piperazinyls, 4- (4- chlorphenyls) -1- piperazines Base, 4- (4- bromophenyls) -1- piperazinyls, 4- (4- methoxyphenyls) -1- piperazinyls, 4- (4- trifluoromethyls) -1- piperazines Base or 4- benzhydryl -1- piperazinyls.

2. quinolinones compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein,

R₁、R₂Dimethylamino, diethylin, 1- pyrrolidinyls, 1- piperidyls, 4- are constituted together with the nitrogen-atoms that they are connected Quinoline base, 4- phenyl-peiperazinyls, 4- (4- aminomethyl phenyls) -1- piperazinyls, 4- (4- fluorophenyls) -1- piperazinyls, 4- (4- chlorobenzenes Base) -1- piperazinyls, 4- (4- bromophenyls) -1- piperazinyls, 4- (4- methoxyphenyls) -1- piperazinyls, 4- (4- trifluoromethylbenzenes Base) -1- piperazinyls or 4- benzhydryl -1- piperazinyls.

3. following compound or its pharmaceutically acceptable salt, are selected from：

6- hydroxyls -7- [4- (2- oxo -2- diethylin ethyoxyl) benzoyl] -3,4- dihydro -1H- quinoline-2-ones；

6- hydroxyls -7- { 4- [2- oxos -2- (1- piperidyls) ethyoxyl] benzoyl } -3,4- dihydro -1H- quinoline-2-ones；

6- hydroxyls -7- [2- oxos-(4- morpholines base oxethyl) benzoyl] -3,4- dihydro -1H- quinoline-2-ones；

6- hydroxyls -7- { 4- [2- (1- piperidyls) ethyoxyl] benzoyl } -3,4- dihydro -1H- quinoline-2-ones；

6- hydroxyls -7- [2- (4- morpholines base oxethyl) benzoyl] -3,4- dihydro -1H- quinoline-2-ones；

6- hydroxyls -7- { 4- [2- oxos -2- (4- benzhydryl -1- piperazinyls) ethyoxyl] benzoyl } -3,4- dihydros -1H- Quinoline-2-one；

6- hydroxyls -7- { 4- [2- oxos -2- (benzene methanamine base) ethyoxyl] benzoyl } -3,4- dihydro -1H- quinoline-2-ones；

6- hydroxyls -7- { 4- [2- oxos -2- (4- aminomethyl phenyls amido) ethyoxyl] benzoyl } -3,4- dihydro -1H- quinoline - 2- ketone；

6- hydroxyls -7- [4- (2- oxo -2- dimethylamino ethoxies) benzoyl] -3,4- dihydro -1H- quinoline-2-ones；

6- hydroxyls -7- { 4- [2- oxos -4- (4- aminomethyl phenyls) -1- piperazinyls] ethyoxyl } benzoyl } -3,4- dihydros -1H- Quinoline-2-one；

6- hydroxyls -7- { 4- [2- oxos -4- (4- fluorophenyls) -1- piperazinyls] ethyoxyl } benzoyl } -3,4- dihydro -1H- quinolines Quinoline -2- ketone；

6- hydroxyls -7- { 4- [2- oxos -4- (4- chlorphenyls) -1- piperazinyls] ethyoxyl } benzoyl } -3,4- dihydro -1H- quinolines Quinoline -2- ketone；

6- hydroxyls -7- { 4- [2- oxos -4- (4- bromophenyls) -1- piperazinyls] ethyoxyl } benzoyl } -3,4- dihydro -1H- quinolines Quinoline -2- ketone；

6- hydroxyls -7- { 4- [2- oxos -4- (4- methoxyphenyls) -1- piperazinyls] ethyoxyl } benzoyl } -3,4- dihydros - 1H- quinoline-2-ones；

6- hydroxyls -7- { 4- [2- oxos -4- (4- trifluoromethyls) -1- piperazinyls] ethyoxyl } benzoyl } -3,4- two Hydrogen -1H- quinoline-2-ones.

4. a kind of Pharmaceutical composition, said composition contains the compound or pharmaceutically acceptable described in claim 1 or 2 or 3 Salt, and its pharmaceutically acceptable carrier or diluent.

5. the compound or pharmaceutically acceptable salt described in claim 1,2 or 3 are preparing prevention and treatment estrogen correlation Application in the medicine of disease.

6. application of the Pharmaceutical composition in the medicine for preparing prevention and treatment estrogen relative diseases described in claim 4.

7. application as claimed in claim 5, it is characterised in that described estrogen relative diseases are osteoporosis or cancer.

8. application as claimed in claim 6, it is characterised in that described estrogen relative diseases are osteoporosis or cancer.

9. application as claimed in claim 7, it is characterised in that described cancer is breast cancer, oophoroma, osteosarcoma or uterus Endometrial carcinomas.

10. application as claimed in claim 8, it is characterised in that described cancer is breast cancer, oophoroma, osteosarcoma or son Endometrial carcinoma.

11. the application according to claim 5,7 or 9, it is characterised in that：With described in the claim 1 or 2 or 3 of effective dose Compound or pharmaceutically acceptable salt contact ERs, suppress ERs.

12. the application according to any one of claim 6,8,10, it is characterised in that：With claim 4 institute of effective dose The Pharmaceutical composition contact ERs stated, suppresses ERs.