CN105859606B - Indole derivatives and its preparation method and application containing piperazinyl - Google Patents

Abstract

The invention belongs to the technical field of medicine, and relates to an indole derivative containing a piperazine group and its medical application. Phenyl indole derivatives include stereoisomers and pharmaceutically acceptable salts of such compounds, and their general structural formula is as follows: Indole derivatives containing piperazine groups and pharmaceutically acceptable acid additions of such compounds The salts 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: bone loss, fractures, osteoporosis, hot flashes, LDL cholesterol Elevated levels, cardiovascular disease, cognitive impairment, degenerative brain diseases, anxiety, depression due to estrogen deficiency, sexual dysfunction, hypertension, retinal degeneration and cancer, especially osteoporosis.

Description

Indole derivatives and its preparation method and application containing piperazinyl

Technical field

The present invention relates to indole derivatives containing piperazinyl and preparation method thereof and its preparation estrogen receptor tune Save the application in the drug of agent.

Background technique

The compound for simulating estrogen-like action has extensive treatment and prevention effect, including: treatment sclerotin is dredged Pine alleviates menopausal symptom, treats acne, treats dysmenorrhea and dysfunctional uterine bleeding, and prostate cancer and prevention are cardiovascular Disease.

Research finds estrogen receptor (ER), and there are two types of types: ER α and ER β.After ligand is in conjunction with the two hypotypes, with not Same tissue specificity plays physiological action.

This field as controversies in hormone replacement in the elderly it is desirable that can produce positive reaction but without adverse side effect or secondary work With reduced compound, and to the estrogen-like action of physical exertion tissue specificity.Phenylindole analog derivative has because of it With space structure as estrogens, analog estrogen plays physiological action in vivo in conjunction with estrogen receptor.

Estrogen is a kind of important hormonal compounds in human body, after women enters menopause, internal estrogen level Thus decline causes the diseases such as osteoporosis, menopausal syndrome, senile dementia and cardiovascular system.For post menopausal Decrease in estrogen takes controversies in hormone replacement in the elderly (est rogen replacement therapy, ERT), can be significant Reduce incidence (Turner RT, the Riggs BL, Spelsberg of postmenopausal osteoporosis fracture and coronary heart disease 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 induce breast cancer and intrauterine Film cancer (Persson I, Weiderpass E, Bergkvist L, et al.Cancer Causes Control, 1999,10 (4):253-260).For the adverse reaction for overcoming estrogen carcinogenesis, people have been developed the property that Estrogen and progestin is used in combination again and have been swashed Plain alternative medicine (hormone replacement therapy, HRT), but long-term HRT treatment can still can increase breast cancer Incidence, even if using progestational hormone, carcinoma of endometrium caused by not capable of overcoming in all cases by estrogen Occur, these adverse reactions limit the prolonged application of HRT.Selective estrogen receptor modulators (selective Estrogen receptor modulators, SERMs) there is estrogen-like action to bone and cardiovascular system, and antithetical phrase Palace and mammary gland show the drug of estrogenic antagonist.But the tamoxifen and Raloxifene clinically used can lead to uterus The adverse reactions such as endometrial carcinomas and hot flash (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)。

Summary of the invention

It is living that technical problem solved by the invention is to provide one kind compound shown in formula I, its pro-drug and drug Property metabolin and above compound stereoisomer and its pharmaceutically acceptable salt, and provide its preparation prevent Application in the drug of disease relevant with treatment estrogen.

Wherein: R is independent to be selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted phenyl；Wherein replace Base is selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 halogenated alkyl.

Preferably, R is independent is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted phenyl；Wherein take Dai Ji is selected from C1-C4 alkyl, halogen, C1-C4 alkoxy, C1-C4 halogenated alkyl.

It is highly preferred that R is independent to be selected from hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclohexyl, 4- chlorodiphenyl first Base, 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- difluorophenyls, 4- methoxyphenyl, 4- trifluoromethyl.

The compound of the present invention can individually give or preferably with pharmaceutically acceptable carrier or diluent, optional basis Conventional pharmaceutical practice is combined with known adjuvant, is given in pharmaceutical composition.Compound is administered orally or through parenteral route Including intravenous, intramuscular, in peritonaeum, subcutaneously, rectum and topic route are given.

In tablet for oral administration, being usually added into the carrier generally used includes lactose and cornstarch, and lubrication Agent such as magnesium stearate.For the oral medicine of capsule form, available diluent includes lactose and dry cornstarch.To root For the oral route use of therapeutic compounds of the invention, selected compound can in the form of such as tablet or capsule, Or it is given as aqueous solution or suspension.For the oral administration of tablet or capsule form, active pharmaceutical ingredient can be with Orally available, nontoxic, pharmaceutically acceptable inert carrier combination, carrier for example has lactose, starch, sucrose, glucose, methyl fibre Dimension element, magnesium stearate, Dicalcium Phosphate, calcium sulfate, mannitol, sorbierite etc.；For the oral administration of liquid form, oral medicine Object ingredient can be with arbitrary orally available, nontoxic, pharmaceutically acceptable inert carrier such as ethyl alcohol, glycerol, the combination such as water.This Outside, suitable adhesive, lubricant, disintegrating agent and colorant can also be added in the mixture.Suitable adhesive includes starch, Gelatin, natural sugar such as glucose or lactose, corn sweetener, natural and synthesis natural gum such as Arabic gum, tragacanth or sea Mosanom, carboxymethyl cellulose, polyethylene glycol, wax etc..Suitable lubricant includes enuatrol, odium stearate, magnesium stearate, benzene Sodium formate, sodium acetate, sodium chloride etc..It, can be by active constituent and emulsifier and suspension group when aqueous suspension is administered orally It closes.Certain sweeteners or corrigent can also be added.To intramuscular, in peritonaeum, for subcutaneous and intravenous use, it is generally prepared as living The sterile solution of property ingredient, the pH of solution should adjusting appropriate and buffering.For intravenous use, solute should be controlled Total concentration is so that preparation remains isotonic.

The compound of the present invention can also in the form of liposome administration system such as small unilamellar vesicles, unilamellar vesicles and The form of multi-layer vesicles is given.Liposome can be formed by various phosphatide such as cholesterol, stearylamine or phosphatidyl choline.

The compound of the present invention can also be given by using monoclonal antibody as independent carrier, wherein compound point Son is coupled.The compound of the present invention can also be coupled with the soluble polymer as targetable drug carriers.This birdss of the same feather flock together Closing object may include polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, poly- hydroxy-ethyl asparagus fern Amide-phenol or the polyethylene glycol oxide-polylysine replaced by palmityl.In addition, the compound of the present invention can be with one kind The biodegradable polymer for realizing medicine controlled releasing is coupled, and the polymer has such as polylactic acid, and polyglycolic acid gathers cream The copolymer of acid and polyglycolic acid, polycaprolactone, polyhydroxybutyrate, polyorthoester class, polyacetals, poly- dihydropyran, paracyanogen The crosslinking of base acrylate and hydrogel or amphiphilic block copolymer.

The compound of the present invention can also be used with the known pharmaceutical agent combinations that can be used to treat or prevent following disease: bone is lost Mistake, osteoporosis, metastatic osteopathy, periodontosis, cartilage degradation, mullerianosis, uterine fibroid disease, hectic fever, LDL gallbladder Sterol levels increase, cardiovascular disease, Cognitive, cerebral degenerative disorders, anxiety, the suppression due to caused by estrogen deficiency It is strongly fragrant, inflammation, inflammatory bowel disease, sex dysfunction, hypertension, retinosis and cancer, especially osteoporosis.It is open at present Compound with to can be used to treat or prevent combining for the medicament for being disclosed disease also within the scope of the invention.Such medicine Agent includes following substance: Organic bisphosphonate；Cathepsin K inhibitor；Estrogen or estrogenic agents；Androgen Receptor modulators；Osteoclast proton atpase inhibitor；HMG-CoA reductase inhibitor；Integrain receptor antagaonists；At Osteoblast anabolic agent such as PTH；Calcitonin；Vitamin D or the novel vitamin D analogues of synthesis；Selective serotonin is again Uptake inhibitor (SSRIS)；Aromatase inhibitor；And its pharmaceutically acceptable salt and mixture.Preferred combination is this hair Bright compound and organic phosphonate.It is the compounds of this invention and histone K inhibitor that another, which is preferably combined,.Another is excellent The combination of choosing is the compounds of this invention and estrogen.It is that the compounds of this invention and androgen receptor are adjusted that another, which is preferably combined, Agent.It is the compounds of this invention and osteoblast anabolic agent that another, which is preferably combined,.

" diphosphonate " includes diphosphonate and its pharmaceutically acceptable salt class and derivative." estrogen " includes but not It is limited to naturally occurring estrogen, the combination estrogen of synthesis, oral contraceptive and sulfated estrogens." estrogen receptor tune Section agent " refers to interference or resists substance of the estrogen in conjunction with receptor, regardless of mechanism." cathepsin K inhibitor " refers to It is the compound that can interfere cysteine proteinase Cathepsin K activities." androgen receptor modifier " refers to interfere Or inhibit compound of the androgen in conjunction with receptor, no matter mechanism, including Finasteride and other 5 alpha-reductases inhibit Agent." osteoclast proton atpase inhibitor " refers to the inhibitor of proton ATP enzyme, can look on the teleblem of osteoclast It arrives, and it has been reported that it has played remarkable effect in the resorption process of bone.This proton pump is illustrated for designing bone The noticeable target of reuptake inhibithors can be potentially served as treating and preventing osteoporosis and relevant metabolism disease Disease." HMG-CoA reductase inhibitor " refers to the inhibitor of 3- hydroxy-3-methyl glutaryl base-CoA reductase.To HMG- There is CoA reductase the compound of inhibitory activity can be readily determined with measuring method known in the art." integrin receptor is short of money Anti-agent " refers to the selective antagonism of energy, inhibits or fights compound of the physiologic ligand in conjunction with 3 integrin of α γ β, can select Selecting property antagonism, inhibits or compound of the confrontation physiologic ligand with 3 integrin of α γ β ining conjunction with, can selectivity antagonism, inhibition or Fight compound of the physiologic ligand with 5 integrin of 3 integrin of α γ β and α γ β ining conjunction with, can selectivity antagonism, inhibition or Fight the active compound of the specific integrin of capillary epithelium cell expression.The effect of antagonism α γ β 3, which is selected from, inhibits bone It reabsorbs, inhibits restenosis, inhibit macular degeneration, inhibit arthritis and inhibit cancer and transforming growth." osteoblast synthesizes generation Thank to agent " refer to construct that the medicament of bone, such as PTH, calcitonin can inhibit the weight of bone by inhibiting the activity of osteoclast It absorbs." vitamin D " includes but is not limited to vitamine D3 and calciferol, they are the hydroxylating biology work of vitamin D Naturally occurring, the biological inactivity precursor of property metabolin." novel vitamin D analogues of synthesis " include acting on similar vitamin D Non-naturally occurring compound.Selective serotonin reuptake inhibitor is sent out by increasing the quantity of serotonin in brain The effect of waving, non-limiting example include Prozac, Paro spit of fland, Sertraline, Citalopram and Fluvoxamine, can be used for treating Disease related with estrogen function." aromatase inhibitor " includes the compound for inhibiting aromatase enzyme, and non-limiting is selected from: Aminoglutethimide, Letrozole, formestane, Exemestane, atamestane, Fadrozole, fluorine sieve azoles, Vorozole.

Term " giving " and its variant (such as " giving " compound) in relation to the compounds of this invention are meant chemical combination The prodrug of object or compound is introduced into animal system in need for the treatment of.When the compound of the present invention or its prodrug with it is one or more When other activating agent (such as bisphosphonate compound etc.) combinations provide, " giving " and its variant can be understood to include together When and be introduced sequentially into compound or its prodrug and other medicaments.Before the present invention includes the compounds of this invention within its scope Medicine.In general, this prodrug is that the functional derivatives of the compounds of this invention are readily converted into required compound in vivo. In this way, in treatment method of the invention, term " giving " will be comprising with specifically disclosed compound or may be not by specific public affairs The compound opened, but it can be after giving patient in being converted into specific compound in vivo, to treat the various diseases. For selecting and preparing the conventional method of suitable prodrug derivant, it is hereby incorporated by reference.The metabolin of these compounds Including the compound of the present invention is introduced the active material generated after biotic environment.

The compound of the present invention is the ligand of estrogen receptor, be can be used to treat or prevent relevant to estrogen function each Kind disease, including: application as claimed in claim 8, which is characterized in that the estrogen-related condition are as follows: bone It loses, fracture, osteoporosis, metastatic osteopathy, cartilage degradation, breast cancer, mullerianosis, hectic fever, hypertrophy of the prostate, Prostate cancer, oophoroma, menopausal syndrome or with the unbalance related bad reproduction of contact environment chemicals or natural hormone. The present invention also includes that can be used for treating the pharmaceutical composition of osteoporosis or other osteopathy, and treatment includes giving therapeutically effective amount The compounds of this invention, the composition contain or not contain pharmaceutically acceptable carrier or diluent.Proper combination of the invention Object includes the aqueous solution containing the compounds of this invention and pharmaceutically acceptable carrier such as salt water, pH on certain level, such as It is 7.4.Solution can be introduced in the blood flow of patient by local bolus injection.

When the compound of the present invention is given in human subjects, daily dose will usually be determined that dosage is general by prescriber According to the age of individual patients, the severity of weight and reaction and patient symptom and change.In an exemplary application, The compound of appropriate amount is given to the mammal for receiving treatment.When for indicated effect, oral dose of the invention It would be about the every kg weight of 0.01mg (mg/kg/ days) to about 100mg/kg/ days daily, preferably 0.01 Dao 10mg/kg/ days, most preferably 0.1 Dao 5.0mg/kg/ days.For oral administration, composition is preferably provided in the form of tablet, and wherein tablet includes The active constituent of 0.01,0.05,0.1,0.5,1.0,2.5,5.0,10.0,15.0,25.0,50.0,100 and 500mg, for adjusting Section is by the dosage for controlling patient symptom.Drug generally comprises about 0.01mg to the active constituent of about 500mg, and preferably from about 1mg is to about 100mg active constituent.For intravenous injection, during constant speed gasing injection, most preferred dosage would be about 0.1 to about 10mg/kg/ point Clock.The compound of the present invention can be given with dosage once a day, or every total daily dose can be divided into twice daily, Three times or four dosage is given.In addition, preferred compounds of the invention can pass through local use in the form of intranasal pharmaceutical Suitable nasal carrier, or by cutaneous routes, given using transdermal skin patches form known to persons of ordinary skill in the art. For the administration carried out in the form of transdermal delivery system, dosage administration will be continuous certainly in entire dosage regimen Rather than it is intermittent.

The compound of the present invention can be used with the pharmaceutical agent combinations of other situations that can be used for treating estrogen-mediated.This group The each ingredient closed can separately or concurrently be given during treatment with different numbers with separated form or single combined form It gives.Therefore the present invention makes sense as comprising all such schemes either simultaneously or alternately treated, and term " giving " also phase That answers is construed in that manner.The combined model of the compounds of this invention and other medicaments that can be used for treating tissue proteases mediate situation Enclose, include in principle with can be used for treat with estrogen function have related disorders any pharmaceutical composition any combination.

Therefore the present invention can also include the use with second of pharmaceutical agent combinations, wherein second of medicament is selected from: You Jishuan Phosphate compounds, cathepsin K inhibitor, estrogen, estrogenic agents, androgen receptor modifier are osteoclastic Cell proton ATPase inhibitors, HMG-CoA reductase inhibitor, integrain receptor antagaonists, osteoblast anabolic Agent, calcitonin, vitamin D, the novel vitamin D analogues of synthesis, selective serotonin reuptake inhibitor, aromatase enzyme inhibit Agent and its pharmaceutically acceptable salt and mixture.

The compound of the present invention can be with other pharmaceutical agent combinations uses that can be used for treating by the situation of estrogen-mediated.It is this Each ingredient of combination can be given respectively during treatment with different numbers or simultaneously with separated form or single combination Form give.Therefore the present invention should be understood comprising all such schemes either simultaneously or alternately treated, and term " is given Give " it should also be construed in that manner.It should be understood that the group of the compounds of this invention and other medicaments that can be used for treating estrogen-mediated situation The range of conjunction include in principle with can be used for treat with estrogen function have related disorders any pharmaceutical composition any combination.

It will be selected according to many factors using the dosage of the compounds of this invention, this includes the type of patient, kind Belong to, the age, weight, gender and medical condition；By the severity for situation of controlling；Administration route；The kidney and liver function of patient；And Specific compound used or its salt.Ordinary skill doctor, animal doctor or clinician, which readily can determine and issue, to be needed to prevent, The effective dose resisted or situation is prevented to develop.

In the method for the invention, the compound being described in detail here can form active constituent, and be according to form of medication Oral tablet, capsule, elixir, syrup etc. and with the suitable pharmaceutical diluent that suitably selects, excipient or carrier (are united herein Referred to as ' carrier ' substance) mixing, and meet conventional pharmacy habit.

The pharmaceutically acceptable salt class of the compounds of this invention includes the conventional non-toxic salts formed by inorganic or organic acid.Often The nontoxic salts of rule include being originated from inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, the salt of nitric acid etc., Yi Jiyou Organic acids such as acetic acid, propionic acid, succinic acid, glycolic, 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, p-aminobenzene sulfonic acid, 2- acetyl oxygen Base-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, the preparation such as trifluoracetic acid Salt.The salt of the compounds of this invention pharmaceutically received can be frequent by the compounds of this invention comprising acid or alkaline part Rule are chemically synthesized.In general, the salt of alkali compounds can be prepared by ion-exchange chromatography, or by free alkali and change Metering or excessive desired salt-forming inorganic or organic acid is learned to be reacted in the various combinations of suitable solvent or solvent To prepare.Similar, the salt of acid compound can be formed by being reacted with suitable inorganic or organic base.

The compound of the present invention can be prepared according to general approach below using suitable substance, and be passed through then Specific embodiment further illustrates.The condition of following preparation step and the various known variants of method can be used for preparing These compounds.All temperature are degree Celsius, unless otherwise specified.

Following process describes the preparation of the several representative embodiments of the present invention.

Wherein: R is independent to be selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, substituted or unsubstituted phenyl；Wherein replace Base is selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 halogenated alkyl.

Preferably, R is independent is selected from hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclohexyl, 4- chlorodiphenyl first Base, 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- difluorophenyls, 4- methoxyphenyl, 4- trifluoromethyl.

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

Specific embodiment

The present invention is described in detail with following examples.It should be noted, however, that following realities that the present invention is not limited to specifically describe Example.

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

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

By 4- benzyloxy-aniline (7.8g, 0.039mol), the bromo- 1- acetone of 1- (4- benzyloxy-phenyl) -2- (10.5g, It 0.033mol) is placed in 500mL round-bottomed flask, ethanol as solvent, is added triethylamine (6.6g, 0.065mol), back flow reaction 5h. Cooled to room temperature filters, obtains Off-white solid 12.3g, 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, 0.028mol), 4- benzyloxy Base aniline (14.0g, 0.070mol) is placed in 500mL flask, and ethylene glycol monoethyl ether makees solvent, back flow reaction 6h.It removes under reduced pressure Solvent, residue add ethyl alcohol to stir, and filter, obtain 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=2.6Hz, 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): the preparation of 1- (4- brombutyl) -5- benzyloxy -2- (4- benzyloxy-phenyl) -3- Methyl-1H-indole

Sodium hydride (1.1g, 0.048mol) is placed in 250mL round-bottomed flask, n,N-Dimethylformamide is added (15mL) stirs 10min under ice bath, is added dropwise dissolved with 5- benzyloxy -2- (4- benzyloxy-phenyl) -3- Methyl-1H-indole The n,N-Dimethylformamide solution of (10.0g, 0.024mol), drop finish, and continue to stir 30min under ice bath.It is added dropwise and contains under equality of temperature There is the n,N-Dimethylformamide solution of Isosorbide-5-Nitrae-dibromobutane (7.7g, 0.036mol), drop finishes, and is warming up to room temperature, reacts 2.5h. Reaction solution is poured into ice water, methylene chloride extracts (3 × 50mL), and saturated sodium-chloride washing, anhydrous sodium sulfate is dry, and decompression is steamed Except solvent, column chromatographs to obtain 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-1 H- Yin The preparation of diindyl

By 1- (4- brombutyl) -5- benzyloxy -2- (4- benzyloxy-phenyl) -3- Methyl-1H-indole (2mmol), 1- methyl Piperazine (2.4mmol), triethylamine (4mmol) are placed in eggplant type bottle, and n-butanol makees solvent, back flow reaction 4h.Evaporating solvent under reduced pressure, Residue is dissolved with methylene chloride, stirs 10min under ice salt bath, is slowly added dropwise Boron tribromide (50mmol), and drop has a large amount of after finishing Solid generates, and filters, and column chromatography obtains yellow solid 0.46g, yield 50.0%.m.p.116-118℃.ESI-MS:m/z 394 ([M+H]⁺)。¹H-NMR(400MHz,DMSO-d₆) δ 9.10 (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-1 H- The preparation of indoles

According to 1 method of embodiment, yellow solid 0.31g, yield 36.7% are obtained.m.p.106-107℃.ESI-MS:m/z 408([M+H]⁺)。¹H-NMR(400MHz,DMSO-d₆) δ 8.53 (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=5.6Hz, 3H).

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

According to 1 method of embodiment, crocus solid 0.32g, yield 41.9% are obtained.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, light yellow solid 0.30g, yield 51.0% are obtained.m.p.193-194℃.ESI-MS: m/z 484([M+H]⁺),506([M+Na]⁺)。¹H-NMR(400MHz,DMSO-d₆)δ9.27(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- first The preparation of base -1H- indoles

According to the method for embodiment 1, yellow solid 0.38g, yield 43.3% are obtained.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 phenyl) - The preparation of 3- Methyl-1H-indole

According to the method for embodiment 1, yellow solid 0.28g, yield 37.2% are obtained.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- first The preparation of base -1H- indoles

According to the method for embodiment 1, yellow solid 0.23g, yield 32.9% are obtained.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- first The preparation of base -1H- indoles

According to the method for embodiment 1, yellow solid 0.28g, yield 43.7% are obtained.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- first The preparation of base -1H- indoles

According to the method for embodiment 1, yellow solid 0.40g, yield 51.4% are obtained.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=7.0Hz, 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 phenyl) - The preparation of 3- Methyl-1H-indole

According to the method for embodiment 1, yellow solid 0.25g, yield 46.2% are obtained.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- first The preparation of base -1H- indoles

According to the method for embodiment 1, yellow solid 0.43g, yield 30.9% are obtained.m.p.126-127℃.ESI-MS:m/z 474([M+H]⁺),512([M+K]⁺)。¹H-NMR(400MHz,DMSO-d₆)δ9.76(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 preparations, " active constituent " refers to 1 compound of formula or its salt or solvate.

Embodiment 12: gelatine capsule

Embodiment 13: tablet

Embodiment 14: tablet

By active component, starch and cellulose are sieved and are sufficiently mixed by 45 mesh U.S., by gained powder and polyethylene pyrrole Pyrrolidone mixing, is then sieved by 14 mesh U.S., and the particle obtained in this way is sieved in 50-60 DEG C of drying and by 18 mesh U.S.. By sodium carboxymethylcellulose, magnesium stearate and talcum first pass through 60 mesh U.S. sieve, are then added into above-mentioned particle, after mixing, It is tabletted on tablet press machine.

Embodiment 15: suspending agent

Drug is sieved by 45 mesh U.S. and is mixed to form homogeneous paste object with sodium carboxymethylcellulose and syrup, by benzene Formic acid solution, corrigent and colorant are diluted with some water, and are added while stirring, sufficient amount water are added then to reach The volume needed.

Embodiment 16: aerosol

Active constituent is mixed with ethyl alcohol, and gained mixture is added into the propellant 22 of part, is cooled to 30 DEG C, And it is transferred in container.Then aequum is added into rustless steel container and sprays dilution agent with residue, then valve is installed Device.

Embodiment 17: suppository

Active component is sieved by 60 mesh U.S. and is suspended in pre-melted saturated fatty acid glyceride class chemical combination In object, then mixture is poured into the 2g chamber suppository mold of standard and is cooled down.

Embodiment 18: injectable formulation

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

Pharmacological effect experiment

Embodiment 19: estrogen receptor Binding experiment

Estrogen receptor ligands combination experimental design is to be detected using scintillation proximity, uses estradiol and recombination table containing tritium The estrogen receptor reached.Full length recombinant mankind ER α and ER β albumen is produced in baculovirus expression system.ER α and ER β are extracted Object is diluted in containing 6mM α-monothioglycerol phosphate buffered saline with 1:400.By the dilution of 200 μ L equal samples by system Standby object is added in the 96 hole each holes of Flashplate plate.Culture plate is covered with Saran Wrap, is incubated overnight in 4 DEG C.Second day Morning, the 20 μ L phosphate buffered saline aliquot for containing 10% bovine serum albumin(BSA) was added into each hole of 96 orifice plate, And make it in 4 DEG C of incubation 2h.Then contained 20mMTris (pH7.2) with 200 μ L, 1mM EDTA, 10% glycerine, 50mM KCl And 6mM α-monothioglycerol buffer washs culture plate.To be tested in the coated culture plate of these receptors, it is added In each hole of 178 μ L same buffers to 96 orifice plates.Then 20 μ L 10nM 3H- estradiol solution are added to the culture plate Each hole in.

The assessment test compound in the concentration range of 0.01nM to 1000nM.Testing Compound Stock solution should be 100% It is prepared as testing the 100X of desired final concentration in test in DMSO.DMSO amount in 96 orifice plate instrument connections is not to be exceeded 1%. Ultimately joining into test is the 2 μ L test compound aliquot being formulated in 100%DMSO.It seals this plate and makes it In equilibrium at room temperature 3h.The tally in the scintillation counter for counting 96 orifice plates equipment.

Sample segment is listed as follows estrogen receptor ER β Binding experiment inhibiting rate:

The compound of embodiment 1-11 is shown to the binding affinity of ER α in IC₅₀Within the scope of=75 to 10000 μM, and To the binding affinity of ER β in IC₅₀In the range of=8.3 to 40 μM.The result obtained in above-mentioned standard pharmacologic test procedure Show that the compound of the present invention belongs to estrogen receptor activity compound, certain compounds have strongly preferential to ER α receptor Affinity.The compounds of this invention to ER α there is the selective affinity higher than ER β to have simultaneously almost quite to two kinds of receptors Affine variation.Therefore, the compounds of this invention has the various work for being at least partially based on its receptor affinity selectional feature Property.In addition, since various novel receptor ligand complexes are different, its interaction between various auxiliary regulatory proteins is also Different, the compounds of this invention would indicate that different adjusting activity according to locating cellular environment.For example, in certain cell classes In type, certain compound can be used as estrogen agonist, and in other tissues, which is antagonist.With above-mentioned work The compound of property is commonly known as SERM (selective estrogen receptor modulators).However, unlike most of estrogen, Many SERM do not cause the increase of uterine wet weight.These compounds have antiestrogenic in uterus, thus in uterus group In knitting can antagonising oestrogen agonist completely nutritional activities.However, these compounds are in bone, cardiovascular and central nervous system Estrogen agonist is used as in system.Since these compounds have above-mentioned tissue selectivity, thus can be used to treat or prevent Caused by due to estrogen deficiency (in certain tissues such as bone and angiocarpy) or estrogen excessive (in uterus or mammary gland) Or associated pathological state or syndrome.Even exceed on above-mentioned cell-specific adjustment effect, chemical combination of the present invention Object is potentially also agonist to certain acceptor type, and is antagonist to another receptor.For example, be antagonist to ER β, It and is agonist to ER α.This Estrogen Receptor Selective Agonist Antagonist activity provides medicine for this series compound Dramatically different estrogenic activity in Neo-Confucianism.

What be can be convenient measures the living features of the compounds of this invention using Standard pharmacological test step.Of the present inventionization It closes object and shows the bioactivity similar with Raloxifene.

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

Making it in conventional H OB culture medium in 96 hole wares on human body osteoclast HOB bed board, (HamShi F12, is supplemented with 28mM HEPES, Ph7.4,10%FCS, 1.1mM CaCl₂, 2mM glutamine and 1% Antibiotic-Antimycotic) in density be 7×10³A cells/well.Next day, cell compound or vehicle treated (0.2%DMSO) are handled 30 minutes, and IL-1 is then added β (1ng/mL) and TNF-α (10ng/mL).Culture continues 18 to 24 hours.Using in commercial ELISA Assay kit measurement culture medium IL-6 and GM-CSF is horizontal.The compounds of this invention shows the inhibiting effect to IL-6 and GM-CSF.

Sample segment activity is listed as follows:

Claims (4)

1. The following compounds, stereoisomers and pharmaceutically acceptable salts thereof: 1-[4-(4-Methylpiperazin-1-yl)butyl]-5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indole; 1-[4-(4-Ethylpiperazin-1-yl)butyl]-5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indole; 1-[4-(Piperazin-1-yl)butyl]-5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indole; 1-{4-[4-(2-Ethylphenyl)piperazin-1-yl]butyl}-5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indole ; 1-{4-[4-(2-Chlorophenyl)piperazin-1-yl]butyl}-5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indole; 1-{4-[4-(2,6-Difluorophenyl)piperazin-1-yl]butyl}-5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H- indole; 1-{4-[4-(3-Chlorophenyl)piperazin-1-yl]butyl}-5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indole; 1-{4-[4-(4-Chlorophenyl)piperazin-1-yl]butyl}-5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indole; 1-{4-[4-(4-Bromophenyl)piperazin-1-yl]butyl}-5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indole; 1-{4-[4-(4-Chlorobenzyl)piperazin-1-yl]butyl}-5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indone Indol; 1-{4-[4-(4-Fluorophenyl)piperazin-1-yl]butyl}-5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indole. 2. A pharmaceutical composition comprising the compound of claim 1, a stereoisomer and a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. 3. Use of the compound of claim 1, a stereoisomer and a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 2 in the preparation of a medicament for the treatment of bone resorption diseases. 4. The use according to claim 3, wherein the bone resorption disease is osteoporosis.