CN105859606A - Piperazinyl-containing indole derivatives, and preparation method and application thereof - Google Patents

Abstract

The invention belongs to the technical field of medicine, and relates to piperazinyl-containing indole derivatives and medical application thereof. The phenyl indole derivatives comprise stereomers and pharmaceutically applicable salts of the compounds, and the structural general formula is disclosed in the specification. The piperazinyl-containing indole derivatives and pharmaceutically applicable acid-added salts of the compounds can be mixed with the existing drug or independently used as an estrogen receptor regulator for treating or preventing various estrogen-function-related diseases, such as bone loss, fracture, osteoporosis, hectic fever, LDL cholesterol level increase, cardiovascular diseases, cognitive impairment, brain degeneration diseases, anxiety, depression caused by deficiency of estrogen, sexual disorder, hypertension, retinosis and cancer, and especially osteoporosis.

Description

Indole derivatives containing piperazinyl and its preparation method and application

Technical field

The present invention relates to indole derivatives containing piperazinyl and preparation method thereof, and it female swashs preparing Application in the medicine of element receptor modulators.

Background technology

The compound of simulation estrogen-like effects has treatment and preventive effect widely, including: Treatment osteoporosis, alleviates menopausal symptom, treats acne, treatment dysmenorrhea and dysfunction temper Palace is hemorrhage, carcinoma of prostate and prevention cardiovascular disease.

Research finds that estrogen receptor (ER) has a two types: ER α and ER β.Part with this two After individual hypotype combines, play physiological action with different tissue specificities.

This area is it is desirable that can produce positive reaction but without bad pair as controversies in hormone replacement in the elderly The compound that effect or side effect reduce, and estrogen-like effects tissue-specific to physical exertion. Phenylindole analog derivative because of its have with estrogens as space structure, estrogen can be simulated, Be combined with estrogen receptor in vivo, play physiological action.

Estrogen is the hormonal compounds that in human body, a class is important, after women enters menopause, internal Decrease in estrogen, thus causes osteoporosis, climacteric syndrome, senile dementia and the heart The diseases such as vascular system.Decline for postmenopausal estrogen level, take controversies in hormone replacement in the elderly (est Rogen replacement therapy, ERT), it is possible to significantly reduce postmenopausal osteoporosis fracture and The incidence rate of coronary heart disease (Turner RT, Riggs BL, Spelsberg TC.Endocr Rev, 1994,15 (3):275-300；Mora S,Kershner DW,Vigilance CP,et al.Curr Treat Options Cardiovasc Med,2001,3(1):67-79).But, ERT may induction breast carcinoma and intrauterine Film cancer (Persson I, Weiderpass E, Bergkvist L, et al.Cancer Causes Control, 1999,10(4):253-260).For overcoming the untoward reaction of estrogen carcinogenesis, people developed again female, The gonadal hormone alternative medicine (hormone replacement therapy, HRT) that progestin combinations uses, But long-term HRT treatment still may increase the incidence rate of breast carcinoma, even if using progestogen, not exists All can overcome the generation of the carcinoma of endometrium caused by estrogen in the case of all of, these are bad instead The prolonged application of HRT should be limited.Selective estrogen receptor modulators (selective estrogen Receptor modulators, SERMs) skeleton and cardiovascular system are had estrogen-like effects, and Uterus and mammary gland are shown the medicine of estrogenic antagonist.But the tamoxifen used clinically The untoward reaction such as carcinoma of endometrium and hot flush (Fisher B, Costantino can be caused with raloxifene 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)。

Summary of the invention

Technical problem solved by the invention is to provide a kind of compound shown in formula I, its precursor medicine Thing and pharmaceutical active metabolite, and the stereoisomer of above-claimed cpd and pharmaceutically acceptable Salt, and provide it in preparation prevention and the application in the medicine of the treatment relevant disease of estrogen.

Wherein: R independence selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxyl, replace or do not take The phenyl in generation；Wherein substituent group is selected from C1-C6 alkyl, halogen, C1-C6 alkoxyl, C1-C6 Haloalkyl.

Preferably, R independence selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxyl, replace or not Substituted phenyl；Wherein substituent group is selected from C1-C4 alkyl, halogen, C1-C4 alkoxyl, C1-C4 Haloalkyl.

It is highly preferred that R independence selected from hydrogen, methyl, ethyl, propyl group, isopropyl, the tert-butyl group, Cyclohexyl, 4-chlorobenzhydryl, phenyl or substituted-phenyl；Wherein substituted-phenyl is selected from 4-methylbenzene Base, 4-ethylphenyl, 2-chlorphenyl, 3-chlorphenyl, 4-chlorphenyl, 4-bromophenyl, 4-fluorophenyl, 2,6-difluorophenyls, 4-methoxyphenyl, 4-trifluoromethyl.

The compound of the present invention can individually give or preferably with pharmaceutically acceptable carrier or dilution Agent, optionally combines with known adjuvant according to conventional pharmaceutical practice, gives in pharmaceutical composition. Compound is administered orally or includes intravenous through parenteral route, intramuscular, and intraperitoneal is subcutaneous, Rectum and topic route give.

In tablet for oral administration, it is usually added into the carrier generally used and includes that lactose and Semen Maydis form sediment Powder, and lubricant such as magnesium stearate.For the oral medicine of capsule form, available diluent Including lactose and dry corn starch.The oral route of the therapeutic compound according to the present invention is made For with, selected compound can be with the form of such as tablet or capsule, or as aqueous solution or mixed Suspension and be given.For the oral administration of tablet or capsule form, active pharmaceutical ingredient can be with Orally available, nontoxic, pharmaceutically acceptable inert carrier combines, and carrier such as has a lactose, starch, Sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, Sorbitol etc.；For the oral administration of liquid form, oral drug components can be with the best to eat Clothes, nontoxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water etc. combines.Additionally, Also can add suitable binding agent, lubricant, disintegrating agent and coloring agent in the mixture.Suitable Binding agent includes starch, gelatin, natural sugar such as glucose or lactose, corn sweetener, natural and The natural gum such as arabic gum of synthesis, tragakanta or sodium alginate, carboxymethyl cellulose, poly-second two Alcohol, wax etc..Suitable lubricant includes enuatrol, sodium stearate, magnesium stearate, sodium benzoate, Sodium acetate, sodium chloride etc..When aqueous suspension orally uses, can be by active component and emulsifying agent Combine with suspensoid.Also some sweeting agent or correctives can be added.To intramuscular, intraperitoneal, subcutaneous For using with intravenous, being generally prepared as the sterile solution of active component, the pH of solution should fit When regulation and buffering.For intravenous uses, it should control the total concentration of solute so that preparation Maintain isotonic.

The compound of the present invention can also with the form of liposome administration system such as small unilamellar vesicles, The form of unilamellar vesicles and multilamellar vesicle gives.Liposome can by various phospholipid such as cholesterol, Stearylamine or phosphatidylcholine are formed.

The compound of the present invention can also give as independent carrier by using monoclonal antibody, Wherein compound molecule is coupled.The compound of the present invention can also carry with as drug target The soluble polymer coupling of body.This base polymer can include polyvinylpyrrolidone, pyrans copolymerization Thing, poly-hydroxypropyhnethacrylamide-phenol, poly-hydroxy-ethyl aspartarnide-phenol or by Petiolus Trachycarpi Substituted polyethylene glycol oxide-the polylysine of acyl group.Additionally, the compound of the present invention can with a class The biodegradable polymer coupling for realizing medicine controlled releasing, described polymer has such as polylactic acid, The copolymer of polyglycolic acid, polylactic acid and polyglycolic acid, polycaprolactone, poly butyric, poly-former Esters of gallic acid, polyacetals, poly-dihydropyran, polybutylcyanoacrylate and the crosslinking of hydrogel or two Property block copolymer.

The compound of the present invention also can be with the known medicament group that can be used for treating or prevent following disease Close and use: bone loss, osteoporosis, metastatic bone lesions, periodontal disease, cartilage degradation, intrauterine Film dystopy, uterine fibroid disease, hectic fever, LDL-C level raises, cardiovascular disease, Cognitive, cerebral degenerative disorders, anxiety, the depression caused by estrogen deficiency, scorching Disease, inflammatory bowel, sexual dysfunction, hypertension, retinal degeneration and cancer, especially bone Matter is loosened.Presently disclosed compound with can be used for treatment or prevention is disclosed the medicament of disease Combine also within the scope of the invention.Such medicament includes following material: Organic bisphosphonate；Group Knit cathepsin K inhibitor；Estrogen or estrogenic agents；Androgen receptor modifier； Osteoclast proton atpase inhibitor；HMG-CoA reductase inhibitor；Integrin receptor Antagonist；Osteoblast anabolic agent such as PTH；Calcitonin；Vitamin D or the dimension of synthesis Raw element D analog；Selective serotonin reuptake inhibitor (SSRIS)；Aromatase inhibitor； And pharmaceutically acceptable salt and mixture.Preferably combination is the compounds of this invention and organic phosphine Hydrochlorate.Another preferably combines is the compounds of this invention and histone K inhibitor.Another Preferably combination is the compounds of this invention and estrogen.Another preferably combines is chemical combination of the present invention Thing and androgen receptor modifier.Another preferably combines is the compounds of this invention and osteoblast Anabolic agent.

" diphosphonate " includes diphosphonate and pharmaceutically acceptable salt class thereof and derivant." female sharp Element " include but not limited to naturally occurring estrogen, the combination estrogen of synthesis, oral contraceptive and Sulfated estrogens." estrogenic agents " refers to interference or resists what estrogen was combined with receptor Material, regardless of mechanism." cathepsin K inhibitor " refers to disturb cysteine egg The compound of white enzyme Cathepsin K activities." androgen receptor modifier " refer to disturb or The suppression compound that is combined with receptor of androgen, no matter mechanism, including finasteride and other 5 alpha reductase inhibitors." osteoclast proton atpase inhibitor " refers to proton ATP enzyme Inhibitor, it can find on the teleblem of osteoclast, and it has been reported that its inhaling again at bone Remarkable effect has been played during receipts.This proton pump illustrates for designing bone resorption inhibitor Noticeable target, it can be potentially served as treating and preventing osteoporosis and relevant metabolism Disease." HMG-CoA reductase inhibitor " refers to 3-hydroxy-3-methyl glutaryl base-CoA also The inhibitor of protoenzyme.The compound to HMG-CoA reductase with inhibitory activity can use this area Known algoscopy is readily determined." integrain receptor antagaonists " refers to energy selectivity antagonism, The compound that suppression or antagonism physiologic ligand are combined with α γ β 3 integrin, energy selectivity antagonism, The compound that suppression or antagonism physiologic ligand are combined with α γ β 3 integrin, energy selectivity antagonism, The compound that suppression or antagonism physiologic ligand are combined with α γ β 3 integrin and α γ β 5 integrin, Can selectivity antagonism, suppress or resist the activity of specific integrin of capillary epithelium cell expression Compound.The effect of antagonism α γ β 3, selected from suppression bone resorption, suppresses restenosis, suppresses macula lutea Degeneration, suppression arthritis and suppression cancer and transforming growth." osteoblast anabolic agent " refers to Being the medicament that can build bone, such as PTH, calcitonin can be pressed down by the activity of suppression osteoclast The heavily absorption of bone processed." vitamin D " including, but not limited to vitamin D3 and vitamin D2, they It is hydroxylating biologic activity metabolite naturally occurring of vitamin D, biological inactivity precursor. " novel vitamin D analogues of synthesis " includes the compound acting on the non-naturally-occurring of similar vitamin D. Selective serotonin reuptake inhibitor plays work by increasing the quantity of 5-hydroxy tryptamine in brain With, its limiting examples includes fluoxetine, Paro spit of fland, Sertraline, citalopram and fluorine volt sand Bright, can be used for treating the disease relevant with estrogen function." aromatase inhibitor " includes suppression The compound of aromatase, being selected from of its indefiniteness: aminoglutethimide, letrozole, formestane, depend on Xi Meitan, atamestane, fadrozole, fluorine sieve azoles, vorozole.

Term about the compounds of this invention " gives " and the meaning of variant (such as " giving " compound) Think of is to be introduced in the animal system needing treatment by the prodrug of compound or compound.When the present invention's Compound or its prodrug combine with one or more other activating agents (such as bisphosphonate compound etc.) During offer, " giving " and variant thereof can be understood to include simultaneously and be introduced sequentially into compound or Its prodrug and other medicament.Present invention resides in the prodrug of the compounds of this invention in the range of it. Generally, this prodrug is by the functional derivatives of the compounds of this invention, and it is readily converted in vivo Required compound.So, in the Therapeutic Method of the present invention, term " gives " to comprise apparatus Compound disclosed in body or the compound that may be specifically disclosed, but it can be after giving patient It is specific compound in conversion in the body, with the various diseases described in treatment.For selecting and preparing The conventional method of suitable prodrug derivant, is hereby incorporated by reference.The metabolism of these compounds The active substance that thing produces after including the compound of the present invention is introduced biotic environment.

The compound of the present invention is the part of estrogen receptor, can be used for treatment or prevention and estrogen The various diseases that function is relevant, including: apply as claimed in claim 8, it is characterised in that Described estrogen-related condition is: bone loss, fracture, osteoporosis, and metastatic bone lesions is soft Bone deterioration, breast carcinoma, endometriosis, hectic fever, prostate hyperplasia, carcinoma of prostate, ovarian cancer, Menopausal syndrome or relevant bad reproduction unbalance with contact environment chemicals or natural hormone.This Bright also comprising can be used for treating osteoporosis or the pharmaceutical composition of other osteopathia, and treatment includes giving The compounds of this invention of therapeutically effective amount, said composition contains or not contain pharmaceutically acceptable load Body or diluent.The proper combination thing of the present invention includes containing the compounds of this invention and pharmaceutically can connect The aqueous solution of stand under load body such as saline, pH on certain level, for example, 7.4.Solution can lead to Cross local bolus injection and be introduced in the blood flow of patient.

When the compound of the present invention is given in human subjects, daily dose will be the most true by prescriber Fixed, dosage is typically based on the serious journey of the age of individual patients, body weight and reaction and patients symptomatic Spend and change.In an exemplary application, the compound of Sq is connect the subject food in one's mouth Breast animal.When for indicated effect, it is every that the oral dose of the present invention would be about 0.01mg Kg body weight every day (mg/kg/ days) Dao about 100mg/kg/ days, preferably 0.01 arrives 10mg/kg/ days, Preferably 0.1 arrives 5.0mg/kg/ days.For oral disposition is administered, compositions is preferably with the form quilt of tablet Thering is provided, wherein tablet comprises 0.01, and 0.05,0.1,0.5,1.0,2.5,5.0,10.0,15.0, The active component of 25.0,50.0,100 and 500mg, for regulation by the dosage controlling patients symptomatic. Medicine generally comprises the about 0.01mg active component to about 500mg, preferably from about 1mg to about 100 Mg active component.For intravenous injection, during constant speed gasing injection, most preferred dosage would be about 0.1 By about 10mg/kg/ minute.The compound of the present invention can give with dosage once a day, or Being every TDD can be divided into every day twice, the dosage of three times or four times gives.Additionally, this The preferred compound of invention can use suitable intranasal to carry with the form of intranasal pharmaceutical by local Body, or by cutaneous routes, use transdermal skin patches form known to persons of ordinary skill in the art and Give.For the administration carried out with the form of transdermal delivery system, dosed administration is given whole Regimen will be continuous rather than interruption certainly.

The pharmaceutical agent combinations that the compound of the present invention can be used for treating the situation of estrogen-mediated with other Use.Each composition of this combination can during treating with different number of times separately or concurrently with point The form opened or the form of single combination give.Therefore the present invention make sense for comprise all so While or the scheme of alternating treatment, and term " gives " to be construed in that manner the most accordingly.The present invention The scope that compound can be used for treating the combination of the medicament of cathepsin mediated conditions with other, former Include there be any pharmaceutical composition any of related disorders with being used for treating with estrogen function on then Combination.

Therefore the present invention can also include and the use of the second pharmaceutical agent combinations, wherein the second medicament It is selected from: organic Diphosphonate compound, cathepsin K inhibitor, estrogen, estrogen is subject to Body regulator, androgen receptor modifier, osteoclast proton atpase inhibitor, HMG-CoA Reductase inhibitor, integrain receptor antagaonists, osteoblast anabolic agent, calcitonin, Vitamin D, the novel vitamin D analogues of synthesis, selective serotonin reuptake inhibitor, virtue Fragrant enzyme inhibitor, and pharmaceutically acceptable salt and mixture.

The compound of the present invention can be used for treating by the medicament group of the situation of estrogen-mediated with other Close and use.Each composition of this combination can give respectively with different number of times during treating or Give with the form of separate form or single combination simultaneously.Therefore the present invention should be understood to comprise All such schemes either simultaneously or alternately treated, and term " gives " also should be construed in that manner.Should This understanding, the combination that the compounds of this invention can be used for treating the medicament of estrogen-mediated situation with other Scope include in principle and treatment can be used for have any drug regimen of related disorders with estrogen function The combination in any of thing.

The dosage using the compounds of this invention will select according to many factors, and this includes suffering from The type of person, kind, age, body weight, sex and medical condition；By the order of severity controlling situation； Route of administration；The kidney of patient and liver function；And specific compound used or its salt.Common skill Art doctor, veterinary or clinicist can readily determine and open needs prevention, resists or stops shape Effective dose of condition development.

In the method for the invention, the compound being described in detail here can form active component, and root According to form of medication i.e. oral tablet, capsule, elixir, syrup etc. and suitable with suitably select Pharmaceutical diluent, excipient or carrier (being herein collectively referred to as ' carrier ' material) mixing, and meet routine Pharmacy is accustomed to.

The pharmaceutically acceptable salt class of the compounds of this invention include by inorganic or organic acid formed normal Rule nontoxic salts.Conventional nontoxic salts includes being derived from mineral acid such as hydrochloric acid, hydrobromic acid, sulphuric acid, ammonia Base sulfonic acid, phosphoric acid, the salt of nitric acid etc., and by organic acids such as acetic acid, propanoic acid, succinic acid, Glycolic, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, double hydroxyl naphthalenes Acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, to amino Benzenesulfonic acid, 2-acetoxy-benzoic, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane two Sulfonic acid, oxalic acid, isethionic acid, salt prepared by trifluoracetic acid etc..The pharmacy of the compounds of this invention The salt of upper acceptance can be by comprising the compounds of this invention of acidity or basic moiety through conventional chemistry side Method synthesizes.Generally, the salt of alkali compounds can be prepared by ion exchange chromatography, maybe will trip From alkali and stoichiometry or the desired salt-forming inorganic of excess or organic acid at suitable solvent or molten The various combinations of agent carry out reacting preparing.Be similar to, the salt of acid compound can by with Suitable inorganic or organic base carries out reacting being formed.

The compound of the present invention can use suitable material to prepare according to following general approach, and And further illustrated by specific embodiment subsequently.The condition of following preparation process and side The various known variant of method can be used for preparing these compounds.All of temperature is degree Celsius, Unless otherwise.

Following flow process describes the preparation of the several representative embodiment of the present invention.

Wherein: R independence selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxyl, replace or do not take The phenyl in generation；Wherein substituent group is selected from C1-C6 alkyl, halogen, C1-C6 alkoxyl, C1-C6 Haloalkyl.

Preferably, R independence selected from hydrogen, methyl, ethyl, propyl group, isopropyl, the tert-butyl group, ring Hexyl, 4-chlorobenzhydryl, phenyl or substituted-phenyl；Wherein substituted-phenyl is selected from 4-aminomethyl phenyl, 4-ethylphenyl, 2-chlorphenyl, 3-chlorphenyl, 4-chlorphenyl, 4-bromophenyl, 4-fluorophenyl, 2,6- Difluorophenyl, 4-methoxyphenyl, 4-trifluoromethyl.

Compounds process for production thereof of the present invention is simple, stable yield, and the compound of preparation can be preferably Prevention and the treatment relevant disease of estrogen.

Detailed description of the invention

The present invention is described in detail with following example.It should be noted, however, that the invention is not restricted to the following reality specifically described Example.

Embodiment 1:1-[4-(4-methylpiperazine-1-yl) butyl]-5-hydroxyl-2-(4-hydroxy phenyl)-3-methyl isophthalic acid H- The preparation of indole

Step A): the preparation of 1-(4-benzyloxy-phenyl)-2-(4-benzyloxy-phenyl amino)-1-acetone

By 4-benzyloxy-aniline (7.8g, 0.039mol), 1-(4-benzyloxy-phenyl)-2-bromo-1-acetone (10.5g, 0.033mol) is placed in 500mL round-bottomed flask, ethanol as solvent, adds triethylamine (6.6 G, 0.065mol), back flow reaction 5h.Naturally cool to room temperature, sucking filtration, obtain Off-white solid 12.3 G, yield 85.3%.m.p.125-126℃.ESI-MS:m/z 438([M+H]⁺)。

Step B): the preparation of 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-Methyl-1H-indole

By 1-(4-benzyloxy-phenyl)-2-(4-benzyloxy-phenyl amino)-1-acetone (12.3g, 0.028 Mol), 4-benzyloxy-aniline (14.0g, 0.070mol) be placed in 500mL flask, ethylene glycol list second Ether makees solvent, back flow reaction 6h.Removing solvent under reduced pressure, residue adds ethanol stirring, sucking filtration, obtains Brown solid 9.5g, yield 80.5%.m.p.151-152℃.ESI-MS:m/z 420([M+H]⁺)。¹H-NMR(400MHz,CDCl₃) δ 7.89 (s, 1H), 7.45 (m, 14H), 7.28 (d, J=2.6 Hz, 1H), 7.11 (d, J=8.4Hz, 2H), 6.97 (dd, J₁=8.5Hz, J₂=1.5Hz, 1H), 5.18 (s,2H),5.15(s,2H),2.43(s,3H)。

Step C): 1-(4-brombutyl)-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-Methyl-1H-indole Preparation

Sodium hydride (1.1g, 0.048mol) is placed in 250mL round-bottomed flask, adds N, N-diformazan Base Methanamide (15mL), stirs 10min under ice bath, dropping is dissolved with 5-benzyloxy-2-(4-benzyloxy benzene Base) the DMF solution of-3-Methyl-1H-indole (10.0g, 0.024mol), drip and finish, Stirring 30min is continued under ice bath.Under equality of temperature, dropping is containing 1,4-dibromobutane (7.7g, 0.036mol) DMF solution, drip and finish, be warming up to room temperature, react 2.5h.Reactant liquor is fallen Enter in frozen water, dichloromethane extraction (3 × 50mL), saturated sodium-chloride washs, and anhydrous sodium sulfate is dried, Removing solvent under reduced pressure, column chromatography obtains light yellow solid 8.0g.Yield 60.6%.m.p.89-90℃. ESI-MS:m/z 554([M+H]⁺),576([M+Na]⁺)。¹H-NMR(400MHz,DMSO-d₆) δ 7.42 (m, 14H), 7.17 (d, J=8.7Hz, 1H), 7.10 (d, J=2.3Hz, 1H), 6.88 (dd, J₁=8.8Hz, J₂=2.4Hz, 1H), 5.17 (s, 2H), 5.13 (s, 2H), 4.04 (t, J=6.5Hz, 2H), 3.31 (t, J=6.0Hz, 2H), 2.10 (s, 3H), 1.54 (m, 4H).

Step D): 1-[4-(4-methylpiperazine-1-yl) butyl]-5-hydroxyl-2-(4-hydroxy phenyl)-3-methyl The preparation of-1H-indole

By 1-(4-brombutyl)-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-Methyl-1H-indole (2 Mmol), 1-methyl piperazine (2.4mmol), triethylamine (4mmol) is placed in eggplant type bottle, and n-butyl alcohol is made Solvent, back flow reaction 4h.Removing solvent under reduced pressure, residue dichloromethane dissolves, under cryosel bath Stirring 10min, is slowly added dropwise Boron tribromide (50mmol), drips and has a large amount of solid to produce after finishing, takes out Filter, column chromatography, obtain yellow solid 0.46g, yield 50.0%.m.p.116-118℃.ESI-MS: m/z 394([M+H]⁺)。¹H-NMR(400MHz,DMSO-d₆)δ9.10(s,1H),7.97(s, 1H), 7.20 (d, J=8.4Hz, 1H), 7.17 (d, J=8.6Hz, 2H), 6.89 (d, J=8.5Hz, 2H), 6.77 (d, J=2.2Hz, 1H), 6.64 (dd, J₁=8.7Hz, J₂=2.2Hz, 1H), 4.22 (t, J=6.6Hz, 2H), 3.95 (m, 2H), 3.64 (m, 2H), 3.41 (m, 2H), 2.97 (m, 2H), 2.33 (s, 3H), 2.18 (t, J=7.4Hz, 2H), 2.04 (s, 3H), 1.06 (t, J=7.0Hz, 2H), 0.91 (t, J=7.4Hz, 2H).

Embodiment 2:1-[4-(4-ethyl piperazidine-1-base) butyl]-5-hydroxyl-2-(4-hydroxy phenyl)-3-methyl isophthalic acid H- The preparation of indole

According to embodiment 1 method, obtain yellow solid 0.31g, yield 36.7%.m.p.106-107℃. ESI-MS:m/z 408([M+H]⁺)。¹H-NMR(400MHz,DMSO-d₆)δ8.53(s,1H), 7.96 (s, 1H), 7.23 (d, J=8.7Hz, 1H), 7.17 (d, J=8.6Hz, 2H), 6.89 (d, J= 8.5Hz, 2H), 6.77 (d, J=2.2Hz, 1H), 6.64 (dd, J=8.4,1.9Hz, 1H), 4.22 (t, J =6.6Hz, 2H), 3.95 (t, J=7.1Hz, 2H), 3.62 (m, 2H), 3.47 (m, 2H), 2.98 (m, 2H), 2.67 (m, 2H), 2.18 (m, 2H), 2.04 (s, 3H), 1.62 (m, 4H), 1.06 (t, J=5.6 Hz,3H)。

Embodiment 3:1-[4-(piperazine-1-base) butyl]-5-hydroxyl-2-(4-hydroxy phenyl)-3-Methyl-1H-indole Preparation

According to embodiment 1 method, obtain crocus solid 0.32g, yield 41.9%.m.p. 155-156℃。ESI-MS:m/z 380([M+H]⁺)。¹H-NMR(400MHz,DMSO-d₆)δ 9.78 (s, 1H), 8.52 (s, 1H), 7.23 (d, J=8.7Hz, 1H), 7.17 (d, J=8.6Hz, 2H), 6.89 (d, J=8.5Hz, 2H), 6.77 (d, J=2.2Hz, 1H), 6.64 (dd, J₁=8.7Hz, J₂ =2.2Hz, 1H), 4.22 (t, J=6.6Hz, 2H), 3.95 (m, 2H), 3.64 (m, 2H), 3.47 (m, 2H), 2.98 (m, 2H), 2.39 (s, 1H), 2.18 (t, J=7.1Hz, 2H), 2.04 (s, 3H), 1.07 (m, 4H)。

Embodiment 4:1-{4-[4-(2-ethylphenyl) piperazine-1-base] butyl }-5-hydroxyl-2-(4-hydroxy phenyl)-3- The preparation of Methyl-1H-indole

According to the method for embodiment 1, obtain light yellow solid 0.30g, yield 51.0%.m.p. 193-194℃。ESI-MS:m/z 484([M+H]⁺),506([M+Na]⁺)。¹H-NMR(400MHz, DMSO-d₆) δ 9.27 (s, 1H), 8.69 (s, 1H), δ 7.49 (d, J=5.2Hz, 1H), 7.26 (d, J= 8.8Hz, 1H), 7.19 (d, J=8.3Hz, 2H), 7.15 (d, J=6.9Hz, 1H), 7.05 (d, J= 7.0Hz, 1H), 7.02 (d, J=8.5Hz, 1H), 6.90 (d, J=8.5Hz, 2H), 6.78 (d, J= 2.2Hz,1H),6.64(dd,J₁=8.6Hz, J₂=2.4Hz, 1H), 4.22 (t, J=6.5Hz, 2H), 3.51(t,2H),3.42(m,2H),2.74(m,2H),2.67(m,2H),2.61(m,2H),2.14(m, 2H), 2.05 (s, 3H), 1.64 (t, J=5.3Hz, 3H), 1.16 (m, 4H).

Embodiment 5:1-{4-[4-(2-chlorphenyl) piperazine-1-base] butyl }-5-hydroxyl-2-(4-hydroxy phenyl)-3- The preparation of Methyl-1H-indole

According to the method for embodiment 1, obtain yellow solid 0.38g, yield 43.3%.m.p. 142-143℃。ESI-MS:m/z 490([M+H]⁺)。¹H-NMR(400MHz,DMSO-d₆)δ 9.78 (s, 1H), 8.71 (s, 1H), 7.24 (d, J=8.8Hz, 1H), 7.20 (d, J=7.5Hz, 2H), 7.18 (d, J=8.2Hz, 1H), 6.91 (d, J=3.1Hz, 2H), 6.89 (d, J=2.9Hz, 1H), 6.87 (d, J=8.4Hz, 1H), 6.78 (d, J=2.3Hz, 1H), 6.76 (d, J=8.8Hz, 2H), 6.63(dd,J₁=8.7Hz, J₂=2.2Hz, 1H), 3.96 (t, J=6.6Hz, 2H), 3.09 (s, 8H), 2.11 (t, J=7.0Hz, 2H), 2.05 (s, 3H), 1.23 (m, 4H).

Embodiment 6:1-{4-[4-(2,6-difluorophenyl) piperazine-1-base] butyl }-5-hydroxyl-2-(4-hydroxy benzenes Base) preparation of-3-Methyl-1H-indole

According to the method for embodiment 1, obtain yellow solid 0.28g, yield 37.2%.m.p. 129-130℃。ESI-MS:m/z 492([M+H]⁺)。¹H-NMR(400MHz,DMSO-d₆)δ 9.00 (s, 1H), 8.36 (s, 1H), 7.24 (d, J=8.7Hz, 1H), 7.21 (d, J=9.0Hz, 2H), 7.17 (d, J=8.4Hz, 1H), 6.91 (d, J=6.0Hz, 2H), 6.89 (d, J=5.4Hz, 2H), 6.78 (d, J=2.2Hz, 1H), 6.63 (dd, J₁=8.7Hz, J₂=2.3Hz, 1H), 3.96 (t, J= 7.2Hz,2H),3.04(m,4H),2.32(m,4H),2.12(m,2H),2.05(s,3H),1.06(m, 2H),0.85(m,2H)。

Embodiment 7:1-{4-[4-(3-chlorphenyl) piperazine-1-base] butyl }-5-hydroxyl-2-(4-hydroxy phenyl)-3- The preparation of Methyl-1H-indole

According to the method for embodiment 1, obtain yellow solid 0.23g, yield 32.9%.m.p. 170-173℃。ESI-MS:m/z 490([M+H]⁺)。¹H-NMR(400MHz,DMSO-d₆)δ 9.80 (s, 1H), 8.71 (s, 1H), 7.42 (d, J=8.5Hz, 1H), 7.37 (d, J=7.4Hz, 1H), 7.33 (d, J=8.4Hz, 1H), 7.27 (d, J=7.6Hz, 1H), 7.21 (d, J=8.5Hz, 1H), 7.15 (d, J=8.5Hz, 2H), 6.87 (d, J=8.4Hz, 2H), 6.76 (d, J=2.0Hz, 1H), 6.62(dd,J₁=8.6Hz, J₂=2.0Hz, 1H), 3.91 (t, J=7.3Hz, 2H), 2.98 (m, 4H), 2.20(m,4H),2.06(m,2H),2.03(s,3H),1.44(m,2H),1.14(m,2H)。

Embodiment 8:1-{4-[4-(4-chlorphenyl) piperazine-1-base] butyl }-5-hydroxyl-2-(4-hydroxy phenyl)-3- The preparation of Methyl-1H-indole

According to the method for embodiment 1, obtain yellow solid 0.28g, yield 43.7%.m.p. 213-214℃。ESI-MS:m/z 490([M+H]⁺)。¹H-NMR(400MHz,DMSO-d₆)δ 9.14 (s, 1H), 8.33 (s, 1H), 7.24 (d, J=8.7Hz, 1H), 7.21 (d, J=9.0Hz, 2H), 7.17 (d, J=8.4Hz, 2H), 6.91 (d, J=6.0Hz, 2H), 6.89 (d, J=8.4Hz, 2H), 6.78 (d, J=2.2Hz, 1H), 6.63 (dd, J₁=8.7Hz, J₂=2.3Hz, 1H), 3.96 (t, J= 7.0Hz, 2H), 3.04 (m, 4H), 2.32 (m, 4H), 2.11 (t, J=7.0Hz, 2H), 2.05 (s, 3H), 1.46(m,4H)。

Embodiment 9:1-{4-[4-(4-bromophenyl) piperazine-1-base] butyl }-5-hydroxyl-2-(4-hydroxy phenyl)-3- The preparation of Methyl-1H-indole

According to the method for embodiment 1, obtain yellow solid 0.40g, yield 51.4%.m.p. 161-162℃。ESI-MS:m/z 534([M+H]⁺)。¹H-NMR(400MHz,DMSO-d₆)δ 9.78 (s, 1H), 8.69 (s, 1H), 7.24 (d, J=8.8Hz, 1H), 7.20 (d, J=7.5Hz, 2H), 7.18 (d, J=8.2Hz, 2H), 6.90 (d, J=8.4Hz, 2H), 6.87 (d, J=8.4Hz, 2H), 6.78 (d, J=2.3Hz, 1H), 6.63 (dd, J₁=8.7, J₂=2.2Hz, 1H), 3.96 (t, J=7.0 Hz, 2H), 3.09 (m, 4H), 2.32 (m, 4H), 2.11 (t, J=7.0Hz, 2H), 2.05 (s, 3H), 1.22(m,4H)。

Implement: 10:1-{4-[4-(4-chlorobenzhydryl) piperazine-1-base] butyl-5-hydroxyl-2-(4-hydroxy benzenes Base) preparation of-3-Methyl-1H-indole

According to the method for embodiment 1, obtain yellow solid 0.25g, yield 46.2%.m.p. 141-143℃。ESI-MS:m/z 580([M+H]⁺)。¹H-NMR(400MHz,DMSO-d₆)δ 9.78 (s, 1H), 8.70 (s, 1H), 7.42 (d, J=8.5Hz, 1H), 7.29 (m, 9H), 7.15 (d, J= 8.5Hz, 2H), 6.87 (d, J=8.4Hz, 2H), 6.76 (d, J=2.0Hz, 1H), 6.62 (dd, J₁ =8.6Hz, J₂=2.0Hz, 1H), 4.26 (s, 1H), 3.91 (t, J=7.3Hz, 2H), 3.43 (m, 2H), 2.20(m,8H),2.03(s,3H),1.43(m,2H),1.13(m,2H)。

Embodiment 11:1-{4-[4-(4-fluorophenyl) piperazine-1-base] butyl }-5-hydroxyl-2-(4-hydroxy phenyl)-3- The preparation of Methyl-1H-indole

According to the method for embodiment 1, obtain yellow solid 0.43g, yield 30.9%.m.p. 126-127℃。ESI-MS:m/z 474([M+H]⁺),512([M+K]⁺)。¹H-NMR(400MHz, DMSO-d₆) δ 9.76 (s, 1H), 8.70 (s, 1H), 7.25 (d, J=8.8Hz, 1H), 7.21 (d, J= 7.5Hz, 2H), 7.18 (d, J=8.2Hz, 2H), 6.90 (d, J=8.4Hz, 2H), 6.87 (d, J= 8.4Hz, 2H), 6.78 (d, J=2.3Hz, 1H), 6.64 (dd, J₁=8.7Hz, J₂=2.2Hz, 1H), 3.96 (t, J=7.0Hz, 2H), 3.08 (m, 4H), 2.33 (m, 4H), 2.10 (t, J=7.0Hz, 2H), 2.05(s,3H),1.23(m,4H)。

Pharmaceutical composition

In following preparation, " active component " refers to formula 1 compound, or its salt or solvate.

Embodiment 12: gelatine capsule

Embodiment 13: tablet

Embodiment 14: tablet

Active component, starch and cellulose are sieved and are sufficiently mixed by 45 mesh U.S., by gained powder End mixes with polyvinylpyrrolidone, is then sieved by 14 mesh U.S., is existed by the granule so obtained 50-60 DEG C is dried and is sieved by 18 mesh U.S..By sodium carboxymethyl cellulose, magnesium stearate and Talcum, First pass through 60 mesh U.S. sieves, be subsequently adding to above-mentioned granule, after mixing, tablet machine is suppressed Piece agent.

Embodiment 15: suspending agent

Medicine is sieved by 45 mesh U.S. and mixes with sodium carboxymethyl cellulose and syrup to be formed uniformly Pastel, dilutes benzoic acid solution, correctives, and coloring agent with some water, and while stirring Add, be subsequently adding q.s water to reach required volume.

Embodiment 16: aerosol

Active component is mixed with ethanol, and gained mixture is added to the propellant 22 of part, It is cooled to 30 DEG C, and is transferred in container.Then aequum added to rustless steel container and use Residue propellant dilution, then installs valving.

Embodiment 17: suppository

Active component is sieved by 60 mesh U.S. and to be suspended in the satisfied fatty acid melted in advance sweet In grease compounds, then mixture it is poured in the 2g chamber suppository mold of standard and cools down.

Embodiment 18: injectable formulation

By above solution intravenous injection to patient, about 1mL is per minute for speed.

Pharmacological effect is tested

Embodiment 19: estrogen receptor Binding experiment

Estrogen receptor ligands binding tests is designed as using scintillation proximity detection, uses and contains the female of tritium Glycol and recombinant expressed estrogen receptor.Total length recombined human is produced in baculovirus expression system Class ER α and ER β albumen.ER α and ER β extract are at the phosphorus containing 6mM α-MTG Acid buffering saline dilutes with 1:400.The dilution receptor prepared product of 200 μ L equal samples is added 96 In each hole of Flashplate plate, hole.Cover culture plate with Saran Wrap, be incubated overnight in 4 DEG C. The phosphate-buffered saline aliquot that 20 μ L contain the next morning 10% bovine serum albumin adds To each hole of this 96 orifice plate, and make it at 4 DEG C of incubation 2h.Then 20mM is contained with 200 μ L Tris (pH7.2), 1mM EDTA, 10% glycerol, 50mM KCl and 6mM α-MTG Buffer solution culture plate.For testing in the coated culture plate of these receptors, add 178 μ L same buffer are in each hole of 96 orifice plates.Then by 20 μ L 10nM 3H-estradiol Solution adds to each hole of this culture plate.

Assessment test compound in the concentration range of 0.01nM to 1000nM.Test compound storage Liquid should be prepared as the 100X of the desired final concentration of test in test in 100%DMSO.In 96 holes DMSO amount in board test hole is not to be exceeded 1%.Ultimately join to test in for being formulated in 2 μ L in 100%DMSO test compound aliquot.Seal this plate and make it put down in room temperature Weighing apparatus 3h.Counting chamber in the scintillation counter for counting 96 orifice plate equipment.

Estrogen receptor ER β Binding experiment suppression ratio is listed as follows by sample segment:

The compound of embodiment 1-11 shows the binding affinity to ER α at IC₅₀=75 to In the range of 10000 μMs, and to the binding affinity of ER β at IC₅₀In the range of=8.3 to 40 μMs. The result obtained in above-mentioned standard pharmacologic testing procedure shows, the compound of the present invention belongs to female and swashs Element acceptor active compound, some compound has strong selective affinity to ER α receptor.This Invention compound has to two kinds of receptors from having the selective affinity higher than ER β to ER α simultaneously The most suitable affinity variation.Therefore, the compounds of this invention has and various is at least partially based on it The activity of receptor affinity selectional feature.Further, since various novel receptor ligand complexes are different, Therefore the interaction between it and various auxiliary regulation albumen also differs, the compounds of this invention Different regulation activity is would indicate that according to residing cellular environment.Such as, in some cell type, Certain compound can be as estrogen agonist, and in other tissue, this compound is but antagonist. The compound with above-mentioned activity is commonly called SERM (selective estrogen receptor modulators).So And, unlike most of estrogen, a lot of SERM do not cause the increase of uterine wet weight.This A little compounds have antiestrogenic in uterus, thus can antagonism completely in uterine cancer cell The nutritional activities of estrogen agonist.But, these compounds are at bone, cardiovascular and nervus centralis As estrogen agonist in system.Owing to these compounds have above-mentioned tissue selectivity, because of And can be used for treatment or prevention due to estrogen deficiency (in some organizes such as bone and cardiovascular) or That estrogen excess (in uterus or mammary gland) causes or associated pathological state or syndrome. Even beyond on above-mentioned cell-specific regulation effect, the compounds of this invention the most potential to certain Acceptor type is agonist, and is antagonist to another kind of receptor.Such as, it is antagonism to ER β Agent, and be agonist to ER α.This Estrogen Receptor Selective Agonist Antagonist activity is this A series of compounds provide the most dramatically different estrogen activity.

Standard pharmacological test step can be utilized easily to record the living features of the compounds of this invention. Compound of the present invention all shows the biological activity similar with raloxifene.

Embodiment 16: the effect that IL-6 and GM-CSF in HOB cell is produced

Human body osteoclast HOB bed board make in 96 hole wares it at conventional H OB culture medium (Ham Family name F12, is supplemented with 28mM HEPES, Ph7.4,10%FCS, 1.1mM CaCl₂, 2mM paddy Amide and 1% Antibiotic-Antimycotic) in density be 7 × 10³Individual cells/well.Next day, cell is used Compound or vehicle treated (0.2%DMSO) process 30 minutes, be subsequently added IL-1 β (1ng/mL) and TNF-α(10ng/mL).Cultivate and continue 18 to 24 hours.Commercial ELISA Assay kit is utilized to measure IL-6 and GM-CSF level in culture medium.The compounds of this invention demonstrates IL-6 and GM-CSF Inhibitory action.

Sample segment activity is listed as follows:

Claims (11)

1. standing of the compound shown in Formulas I, its prodrug and pharmaceutical active metabolite, and above-claimed cpd Body isomer and pharmaceutically acceptable salt thereof:

Wherein: R independence selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxyl, replace or unsubstituted Phenyl；Wherein substituent group is selected from C1-C6 alkyl, halogen, C1-C6 alkoxyl, C1-C6 halo Alkyl.

2. compound as claimed in claim 1, its prodrug and pharmaceutical active metabolite, and above-mentioned chemical combination The stereoisomer of thing and pharmaceutically acceptable salt thereof:

Wherein: R independence selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxyl, replace or unsubstituted Phenyl；Wherein substituent group is selected from C1-C4 alkyl, halogen, C1-C4 alkoxyl, C1-C4 halo Alkyl.

3. compound as claimed in claim 1 or 2, its prodrug and pharmaceutical active metabolite, and above-mentioned The stereoisomer of compound and pharmaceutically acceptable salt thereof:

Wherein, R independence selected from hydrogen, methyl, ethyl, propyl group, isopropyl, the tert-butyl group, hexamethylene Base, 4-chlorobenzhydryl, phenyl or substituted-phenyl；Wherein substituted-phenyl is selected from 4-aminomethyl phenyl, 4- Ethylphenyl, 2-chlorphenyl, 3-chlorphenyl, 4-chlorphenyl, 4-bromophenyl, 4-fluorophenyl, 2,6- Difluorophenyl, 4-methoxyphenyl, 4-trifluoromethyl.

4. the compound as described in claim 1-3 any one, its prodrug and pharmaceutical active metabolite, And the stereoisomer of above-claimed cpd and pharmaceutically acceptable salt thereof: it is selected from,

1-[4-(4-methylpiperazine-1-yl) butyl]-5-hydroxyl-2-(4-hydroxy phenyl)-3-Methyl-1H-indole；

1-[4-(4-ethyl piperazidine-1-base) butyl]-5-hydroxyl-2-(4-hydroxy phenyl)-3-Methyl-1H-indole；

1-[4-(piperazine-1-base) butyl]-5-hydroxyl-2-(4-hydroxy phenyl)-3-Methyl-1H-indole；

1-{4-[4-(2-ethylphenyl) piperazine-1-base] butyl }-5-hydroxyl-2-(4-hydroxy phenyl)-3-Methyl-1H-indole；

1-{4-[4-(2-chlorphenyl) piperazine-1-base] butyl }-5-hydroxyl-2-(4-hydroxy phenyl)-3-Methyl-1H-indole；

1-{4-[4-(2,6-difluorophenyl) piperazine-1-base] butyl }-5-hydroxyl-2-(4-hydroxy phenyl)-3-Methyl-1H-indole；

1-{4-[4-(3-chlorphenyl) piperazine-1-base] butyl }-5-hydroxyl-2-(4-hydroxy phenyl)-3-Methyl-1H-indole；

1-{4-[4-(4-chlorphenyl) piperazine-1-base] butyl }-5-hydroxyl-2-(4-hydroxy phenyl)-3-Methyl-1H-indole；

1-{4-[4-(4-bromophenyl) piperazine-1-base] butyl }-5-hydroxyl-2-(4-hydroxy phenyl)-3-Methyl-1H-indole；

1-{4-[4-(4-chlorobenzhydryl) piperazine-1-base] butyl }-5-hydroxyl-2-(4-hydroxy phenyl)-3-Methyl-1H-indole；

1-{4-[4-(4-fluorophenyl) piperazine-1-base] butyl }-5-hydroxyl-2-(4-hydroxy phenyl)-3-Methyl-1H-indole.

5. a pharmaceutical composition, comprises the compound described in claim 1-4 any one, its prodrug And pharmaceutical active metabolite, and the stereoisomer of above-claimed cpd and pharmaceutically acceptable salt thereof and medicine Acceptable carrier or diluent on.

6. the compound of formula I described in claim 1-4 any one, its prodrug and pharmaceutical active metabolite, And the stereoisomer of above-claimed cpd and pharmaceutically acceptable salt thereof or the medicine described in claim 5 Compositions application in preparation treatment bone resorption disease medicament.

Application the most according to claim 6, it is characterised in that: described bone resorption disease is osteoporosis

Disease.

8. the compound of formula I described in claim 1-4 any one, its prodrug and pharmaceutical active metabolite, And the stereoisomer of above-claimed cpd and pharmaceutically acceptable salt thereof or the combination described in claim 5 Thing is the application in regulator gene expression in expressing estrogen receptor cell.

Application the most according to claim 8, it is characterised in that: described estrogen receptor is estrogen receptor alpha Or erss；Described cell is skeleton, bladder, uterus, ovary, prostate, testis, epididymis, Gastrointestinal tract, kidney, mammary gland, eye, heart, blood vessel wall, immune system, lung, hypophysis cerebri, Hippocampus or under The cell of thalamus.

10. the compound of formula I described in claim 1-4 any one, its prodrug and pharmaceutical active metabolite, And the stereoisomer of above-claimed cpd and pharmaceutically acceptable salt thereof or the medicine described in claim 5 Compositions application in the medicine of preparation treatment or prevention estrogen-related condition.

Application described in 11. claim 10, it is characterised in that described estrogen-related condition is: bone loss, Fracture, osteoporosis, metastatic bone lesions, cartilage degradation, breast carcinoma, endometriosis, hectic fever, front Row gland is loose, carcinoma of prostate, ovarian cancer, menopausal syndrome or unbalance with contact environment chemicals or natural hormone Relevant bad reproduction.