CN110041271A - Estrogen modulators and its composition obtained - Google Patents
Estrogen modulators and its composition obtained Download PDFInfo
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- CN110041271A CN110041271A CN201910366388.XA CN201910366388A CN110041271A CN 110041271 A CN110041271 A CN 110041271A CN 201910366388 A CN201910366388 A CN 201910366388A CN 110041271 A CN110041271 A CN 110041271A
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- A—HUMAN NECESSITIES
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- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
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- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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Abstract
The present invention relates to hormone receptor modulator technical fields, in particular disclose a kind of estrogenic agents and its composition obtained.The structural formula of compound of the estrogenic agents is as follows:Estrogenic agents of the present invention can raise the function of ERR α and PGC-1 α, it is effectively applied to alleviate insulin resistance or restores insulin sensitivity, improve the glucose balance of diabetic, and is effectively reduced the blood sugar concentration and glycated hemoglobin level of glycosylation of diabetic.
Description
Technical field
The present invention relates to hormone receptor modulator technical field, a kind of estrogen modulators and its obtained are in particular disclosed
Composition.
Background technique
Currently, living standards of the people are continuously improved, but consequent is various metabolism with the development of economy and society
Property disease is such as: diabetes, hypertension, hyperlipidemia disease incidence persistently increase, these metabolic diseases cause patient's human body simultaneously
Organ, multiple positions do not accommodate lesion, seriously affect the health and quality of life of people, also give various countries' health system
Band brings heavy burden.
Diabetes can be divided into two kinds of type-1 diabetes mellitus (insulin-dependent) and type-2 diabetes mellitus (non-insulin-dependent).
But they all have in fasting or duration promotes blood sugar concentration in the state of feeding glucose (when glucose resists test)
Characteristic.Insulin is that a kind of effectively adjust carries out glucose and rouge in the insulin sensitive tissues such as muscle, liver and adipose tissue
The hormone of matter metabolism.Not normal energy metabolism regulation in muscle, liver and adipose tissue etc. is type-2 diabetes mellitus glucose concentration
One of not normal most important reason.And many type-2 diabetes mellitus patient simultaneous hyperinsulinemias.Insulin resistance is
The important pathogenesis of type-2 diabetes mellitus.
Skeletal muscle and liver are the important insulin effect organs for maintaining euglycemia balance.Correlative study table
Bright, mitochondrial function is not normal closely related with insulin resistance in skeletal muscle.In the skeletal muscle of type-2 diabetes mellitus patient, line grain
Body oxidative phosphorylation gene (OXPHOS) function is obviously lowered.Mitochondria gene (OXPHOS) then mainly passed through
Peroxisome grows 1 α (peroxisome proliferat and-activated of peroxisome proliferator-activated receptor gamma co-activation factor PGC
The α of recept and γ coactivat and -1, (PGC-1 α)) transcriptional control.The reduction of PGC-1 alpha levels theoretically should can
To cause the downward of OXPHOS gene expression, the oxidation of fatty acid is reduced, and then causes the accumulation of lipid in skeletal muscle, is finally lured
Send out insulin resistance and type-2 diabetes mellitus.In fact, PGC-1 α imbalance is the common phenomenon of potential diabetic.This is into one
It is a major incentive of onset diabetes that step, which illustrates that PGC-1 alpha levels reduce,.
Estrogen-related receptor (Estrogen-Related Recept and s, ERRs) is a kind of and estrogen receptor alpha
(Estrogen Recept and α) closely related nuclear hormone receptor.ERRs is living the factor (co-activat and) with it altogether
In conjunction with when do not need participation with any inside and outside source ligand, it is considered to be constitute the orphan nuclear hormone receptor of activation
(constitutively active and phan nuclear h and mone recept and s).Studies have shown that ERRs
Comprising 3 kinds of different hypotypes, ERR α, ERR β and ERR γ.ERR β is mainly related to organismal development, its expression is after birth
By stringent control, only there is a small amount of expression in liver, stomach, skeletal muscle, heart and kidney.The expression of ERR γ then concentrates on spinal cord
And central nervous system.ERR α is then mainly distributed on the active organizer of the metabolism such as skeletal muscle, heart, kidney, liver and adipose tissue
In official.
Mitochondria is that the metabolisms such as glucose, fat generate step the most key in ATP energy process
Suddenly.PGC-1 is an important regulatory factor of OXPHOS, thin to heat generation, muscle in the tissue such as skeletal muscle and brown fat
The processes such as the biosynthesis of born of the same parents' Mitochondria and respiration and skeletal muscle fibre type change play important adjustment effect.This
Outside, PGC-1 also controls the expression that can encode the gene of a variety of gluconeogenesis enzymes.Studies have shown that the reduction of PGC-1 level can be with shadow
The metabolism for ringing the energy matters such as glucose and fat utilizes, and causes accumulation of lipid and blood glucose surplus in skeletal muscle, final to induce
Insulin resistance and type-2 diabetes mellitus.
ERR α is the direct downstream target gene of PGC-1 α.PGC-1 α is mainly by the direct interaction with ERR α, effectively
Regulate and control Mitochondria (OXPHOS) and the isogenic transcription of fatty acid oxidase OXPHOS process to be adjusted.
Studies have shown that PGC-1 α can promote ERR alpha expression under outer signals such as fasting, physical training or the stimulation of cold, and
By and ERR α combination, induction ERR α combined with the gene promoter particular combination site of its own, further promote ERR
The transcription of α.The interaction of PGC-1 α and ERR α can also promote ERR α and the other specific knots of downstream gene promoter of PGC-1 α
Coincidence point combines, and promotes these downstream functional gene (such as phosphoenolpyruvate ester carboxykinases
(phosphoenolpyruvate carboxykinase (PEPCK)), medium chain acyl dehydrogenase (medium chain
Acyl dehydrogenase (MCAD)) and (the pyruvate dehydrogenase kinase 4 of pyruvic dehydrogenase kinase 4
(PDK4)) genes such as) transcription, and then Mitochondria (OXPHOS) and fatty acid oxidation are effectively adjusted
Control promotes the metabolism of fatty acid and glucose to utilize.Therefore ERR α and PGC-1 α are selectively adjusted by small molecule compound
Function effectively improve the function of Mitochondria gene (OXPHOS) in particular with ERR α small molecule agonist
Can, promote the oxidation of fatty acid or reduce the utilization of glucose, can be used as treatment diabetes and relevant obesity, hyperglycemia
Disease, hypoglycemia tolerance, insulin resistance, obesity, lipid disorders, blood-lipid imbalance, hyperlipidemia, high triglyceride, high cholesterol
Mass formed by blood stasis, Gao Mizhi protein level is low, and low compact substance protein level is excessively high, atherosclerosis and its secondary disease, hemadostewnosis, abdomen
Portion's obesity, metabolic syndrome, fatty liver is with the available strategy of equal metabolic diseases.Further, since ERR α small molecule agonist can
Effectively to improve the expression of PGC-1 α gene, enhance cell to the sensibility of insulin, therefore, they can also be with other pancreases
Island element sensitizer or insulin secretion stimulators class administered in combination improve clinical effectiveness.
It finds after study, the reduction of estrogen level is its main inducing that osteoporosis occurs after postmenopausal women.It grinds
Study carefully and show that the high expression of ERR in osteoblast can promote the formation of bone tubercle, and utilizes the table of anti-sense reduction ERR α
Up to the reduction for then causing bone tubercle to be formed.With this, the small molecule of estrogen-related receptor (ERR α, ERR β and ERR γ etc.) is exciting
Agent is also possible to the regeneration for sclerotin.Conversely, for the too fast relevant disease of bone tissue growth, then be also possible to using female
Hormone cognate receptor ((treat by the micromolecular inhibitor of ERR α, ERR β and ERR γ etc..Although estrogen-related receptor ((ERR
α, ERR β and ERR γ etc.) it is classified as orphan nuclear hormone receptor, and continue to keep greater activity, recently research have indicated that, phenolic group acyl group
Hydrazone micromolecular compound effectively in conjunction with the end the C- ligand binding domain of ERR β and ERR γ and can raise its function.And it is right
In the ERR α that can improve insulin sensitivity by enhancing the function of PGC1, therefore exploitation small molecule estrogen is adjusted
Agent, the treatment to diabetes and relevant to diabetes B hyperlipidemia, hypercholesterolemia, hypertriglyceridemia are improved
Effect has a very important significance.
Summary of the invention
In order to overcome shortcoming and defect existing in the prior art, the purpose of the present invention is to provide can be effectively exciting female
The compound of hormone cognate receptor, the compound can effectively excitement be such as ERR α, the estrogen-related receptors such as beta, gamma, and is used in and controls
Treat metabolic disease such as diabetes and hyperlipidemia relevant to diabetes B, hypercholesterolemia, hypertriglyceridemia etc.
Disease or symptom.
The purpose of the invention is achieved by the following technical solution: a kind of estrogen modulators, and the structural formula of compound is as follows:
Wherein, the R1 is selected from
1) H；
2) C1-C6 alkyl；
3) aryl；
4) halogen；
5) C1-C5 contains fluoroalkyl；
Wherein, the R2 is selected from
1) H；
2) C1-C4 alkyl；
3) aryl；
4) C1-C6 contains fluoroalkyl；
Wherein, the R3 is selected from
1) H；
2) C1-C6 alkyl；
3) C3-C6 naphthenic base；
4) C1-C5 contains fluoroalkyl；
5) halogen
Wherein, the R2 is selected from
1) H；
2) C1-C6 alkyl；
3) aryl；
4) C1-C5 contains fluoroalkyl；
Further, in the estrogen-related receptor modulator compound, R1 is methyl, and R2 is phenyl, and R3 is methyl, R4
For H.
Further, in the estrogen-related receptor modulator compound, R1 is methyl, and R2 is-(4- bromophenyl),
R3 is methyl, R4 H.
Further, in the estrogen-related receptor modulator compound, R1 H, R2 are-(4- fluorophenyl), R3
It is methyl for Cl, R4.
Further, in the estrogen-related receptor modulator compound, R1 H, R2 are-CH2CF3, and R3 is first
Base, R4 are isopropyl.
Further, the estrogen-related receptor modulator compound, it is characterised in that: R1 is hydroxyl, R2 is-
CH2CF3, R3 H, R4 are isobutyl group.
The present invention also provides a kind of composition, the composition includes a effective amount of above-mentioned estrogen-related receptor modulator
Compound and pharmaceutically acceptable carrier or excipient.
Beneficial effects of the present invention: the present invention provides it is a kind of can effectively exciting estrogen-related receptor compound,
The compound can effectively excitement be such as ERR α, the estrogen-related receptors such as beta, gamma, and is used in treatment metabolic disease such as diabetes
And diseases or the symptom such as hyperlipidemia relevant to diabetes B, hypercholesterolemia, hypertriglyceridemia.In the present invention
The function of ERR α and PGC-1 α can be raised by stating compound, be effectively applied to alleviate insulin resistance or restored insulin
Sensibility improves the glucose balance of diabetic, and can be effectively reduced patient blood glucose's concentration and diabetes serum
Marker glycated hemoglobin level of glycosylation.
The present invention is using a effective amount of above-mentioned estrogen-related receptor modulator compound and pharmaceutically acceptable
Composition made from carrier or excipient treats metabolic disease such as diabetes and hyperlipidemia relevant to diabetes B, height
The diseases such as cholesterolemia, hypertriglyceridemia or symptom improve the therapeutic effect to above-mentioned disease.
Detailed description of the invention
Fig. 1 is influence schematic diagram of the compound D1 to estrogen-related receptor active alpha；
Fig. 2 is compound D1 to estrogen-related receptor activity α/β/γ influence schematic diagram；
Fig. 3 is the schematic diagram of influence of the compound D1 to estrogen-related receptor active alpha；
Fig. 4 is the schematic diagram that compound D1 influences ERR α driving PGC1 α promoter reporter gene expression；
Fig. 5 is the schematic diagram of influence of the compound D2 to glucose absorption；
Fig. 6 is the schematic diagram of the compound D2 and compound D1 influence resistance to glucose；
Fig. 7 is the schematic diagram of the influence of compound D2 and compound D1 to animal's liver weight.
Specific embodiment
For the ease of the understanding of those skilled in the art, the present invention is made further below with reference to examples and drawings
Bright, the content that embodiment refers to not is limitation of the invention.
Embodiment 1
A kind of estrogen modulators, the structural formula of compound are as follows:
Wherein, R1 is methyl, and R2 is phenyl, and R3 is methyl, R4 H.
The compound is denoted as compound D1, the preparation method of the compound D1 the following steps are included:
(1) 10mmol 2- amino-4-methoxyl benzoic acid is dissolved in 10mL pyridine at a temperature of 20-25 DEG C, benzene is slowly added dropwise
Reaction mixture is poured into 50 grams after stirring 5h at a temperature of 20-25 DEG C by formyl chloride (1.7g, 6mmol are dissolved in 5mL pyridine)
It in ice water, adopts and is extracted with ethyl acetate, through column chromatographic purifying (petroleum ether: ethyl acetate=6:1), it is (white that 2.14 grams of product is made
Color solid, 76.7%).
(2) by step (1) obtain compound 0.253g (1.0mmol) is mixed with 0.675g methylamine hydrochloride (10mmol)
In 10 mLDMF, it is heated to reflux 5h.Reaction mixture is poured into 50mL ice water.Ethyl acetate extracts, through column chromatographic purifying
(petroleum ether: ethyl acetate=2:1) obtains 0.16 gram of product (white solid, 50.2%).
1HNMR (400MHz, CDCl3), δ 8.25 (d, J=8.8Hz, 1H), 7.58~7.25 (m, 5H)；7.14 (d, J=
2.4 Hz, 1H), 7.8, (dd, J=2.4,8.8Hz, 1H), 3.94 (s, 3H), 3.48 (s, 3H)；MS (ESI), m/z:268 (M
+).
Embodiment 2
A kind of estrogen modulators, the structural formula of compound are as follows:
Wherein, R1 is methyl, and R2 is-(4- bromophenyl), and R3 is methyl, R4 H.
The compound is denoted as compound D2, the preparation method reference compound D1 of the compound D2.
lHNMR (400 MHz, CDCl3), δ 8.19 (d, J=8.8 Hz, 1H), 7.59~7.56 (m, 2
H);7.26~7.19 (m, 2H), 7 10 (d, J=2.0 Hz, 1H), 7.06 (dd, J=2.0,8.8 Hz,
1H), 3.89 (s, 3 H), 3.46 (s, 3H);
MS(ESI), m/z: 290 (M+H) +.
Embodiment 3
A kind of estrogen modulators, the structural formula of compound are as follows:
Wherein, R1 H, R2 are-(4- fluorophenyl), and R3 Cl, R4 are methyl.
The compound is denoted as compound D3, the preparation method reference compound D1 of the compound D3.
1HNMR (400 MHz, CDCl3, δ 8 .2 1 (d, J=8.6 Hz, lH), 7.60 (Hz of d, J=6.8,
2 H);7.45 (d, J=6.8Hz, 2 H), 7.11~7.07 (m, 2 H), 3.91 (s, 3 H), 3.48 (s,
3H);MS(ESI), m/z: 340(M) +.
Embodiment 4
A kind of estrogen modulators, the structural formula of compound are as follows:
Wherein, R1 H, R2 are-(4- fluorophenyl), and R3 Cl, R4 are methyl.
The compound is denoted as compound D4, the preparation method reference compound D4 of the compound D2.
IHNMR (400 MHz, CDCl3), 8 8.23 (d, J=8.8 Hz, 1H), 7.54~7.49 (m, 2
H);7.36~7.21 (m, 2H), 7.12~7.08 (m, 2H), 3.91 (8,3 H), 3.48 (8,3H);
MS (ESI, m/z:290 (M)+
Embodiment 5
The present embodiment can effectively enhance ERR α in HeLa cell using compound obtained by embodiment 1-4 etc. and be regulated and controled
Reporter gene expression, illustrate that compound according to the present invention can the effective function of excitement ERR α.
In order to detect the compound to the adjusting activity of ERR and other nuclear hormone receptors, inventor utilizes to be contained simultaneously
The expression vector of these receptors of suitable reporter gene transiently transfects HeLa cell.Used method and suitable report
Accusing gene is known to this field skilled work personnel.Other known carrier also can operate with detection method of the invention.
Firstly, by the ligand binding domain sequence and yeast GAL4DNA binding domain of mankind ERR α, ERR β or Muridae ERR γ
(amino acid 1-147accession X85976) fusion, forms and contains ERR α, ERR β, the GAL4 of ERR γ receptor ligand binding domain
Fusion.Thus construct selective GAL-hERR α, GAL-L-hERR β and Gal-mERR γ expression vector.PGAL is only
Control containing yeast GAL4 DNA binding domain without ERR α, ERR β or ERR γ.And CMV-PGC-1 α then contains and expresses
The PGC-1 α coded sequence as derived from PGC-1 α (accession NM.sub.--008904).
HeLa cell in logarithmic growth phase is passed in 96 porocyte culture plates with 104/ hole, overnight incubation is long
For transfecting when expiring to 80~90%.2000 reagent (0.5ul/ of lipoFectamine is diluted with optimization culture liquid MEM
100ul) and Plasmid DNA.Plasmid concentration is respectively as follows: pCMV-Gal4 hERR-LBD or pCMV-Gal4 after the dilution of optimization culture liquid
The hole hERR-LBD, 25ng/；The hole pFR-Luci, 50ng/；The hole pFRTlaczeo plasmid, 50ng/.lipoFectamine
After 2000 dilutions 5 minutes, by after dilution liposome and Plasmid DNA mix in equal volume, in being placed at room temperature for 20min.It rapidly will be thin
Born of the same parents change liquid at containing 10%C harcoal-Strip fetal calf serum without phenol red DMEM100ul.Add liposome/DNA mixing
Object gos deep into pipette tips under liquid level, is added dropwise, and jiggles mixing.
Compound is dissolved in DMSO, after 6 h of cell transient transfection plasmid, is separately added into the compound of various concentration
(DK-3), DMSO is control.It is put in 5%CO2 incubator and continues to cultivate 24 h, later according to Promega company Steady-
Glo kit specification utilizes VERITASTM Microplate
Luminometer (Turner Biosystems) measures the fluorescent value of cell, and fluorescent value reacts ERR activity, and with-Gal
It is corrected as internal standard.It takes 20 μ l cell lysates to be placed in 96 orifice plates, is added: 100 × Mg solution 1.5 μ l, 1 × ONPG
Solution 33 μ l, 0.1mol/L sodium phosphate (pH7.5) 95.5 μ l.50 μ l, 0.1mol/L are added to there is yellow in 37 DEG C of warm bath
Na2CO3 terminates reaction and reads OD405.
Compound D1 etc. dose-dependently enhances GAL-hERR in the presence of CMV-PGC-1 to reporter gene UASgx4-
The control of TK-Luc.The EC50 of the compound is about 0.5 nM (referring to Fig. 1-3), is followed successively by control group from left to right in Fig. 2
With compound D1 group.In addition, compound D1 can also dose-dependently reverse ERR alpha specific inhibitor XCT-790 to ERR
The known activity of α.
Embodiment 6
The present embodiment is for confirming that compound according to the present invention (such as compound D1) can effectively enhance in HeLa cell
The expression for the reporter gene that PGC1 α promoter is regulated and controled.
Using the α of pGL3-PGC1 derived from pGL3 promoter-promoter (Promega) and ERR alpha expression carrier to HeLa into
Row transiently transfects, while determining transfection efficiency using Renilla pRL-CMV luciferase carrier as control vector.Human full-length
ERR α sequence is cloned into pCMV expression vector.It is related to drawing according to the sequence at PGC1 alpha transcriptional initiation site upstream 2.6kb
Object, and PGC1 α promoter is obtained by the method for PCR using mankind gDNA as template.
DMEM culture of the Hela cell containing 10% fetal calf serum for activity analysis is based on 37 DEG C, trains in 5%CO2
It supports.The day before transfection, by cell inoculation to 50-80% convergence degree, DMEM-FBS culture.In this experiment inventor using
The rotaring transfecting mode of liposome.PGL3-PGC1 α Luciferase Expression Vectors and pCMV carrier or pCMV-hERR α carrier be used to turn
Contaminate cell.At DMEM-FBS culture medium of the cell of transfection carrier containing 0.01% DMSO or various concentration DK compound
Reason is for 24 hours.
It can be observed that ERR α driving PGC1 α promoter reporter gene is in compound agent in compound D1 compound processing group
Amount dependent expression increases and (refers to Fig. 4).
Embodiment 7
The present embodiment is for confirming that compound according to the present invention (such as compound D1 compound) can effectively activate L6
Myocyte absorbs glucose in a manner of insulin-dependent.
Mouse sarcoblast L6 cultivates 6 days induction myotubes with differential medium (DMEM+2%FBS) and is formed.Contain 0.01%
The culture medium (control) of DMSO or medium treatment myotube containing positive reference compound Rosiglitazone or compound D2.48h
Afterwards, every hole is washed three times with the PBS of 1ml pre-temperature.The pre-temperature FCB buffer of 250 μ l insulin containing 100nM is added in every hole,
37 DEG C are incubated for 20 minutes.The PBS of 8.2ml is mixed with the glucose of 1.0ml 11mM and 0.83ml 3H-2- deoxidation-glucose
2DOG mixture is formed, every hole is added 25 μ l and is incubated for 10 minutes.Reaction is terminated by the way that the PGS of ice bath is added, and with ice bath PBS
It washes four times.Every hole face is added in the solution of dry flashing again and is transferred to measurement (FCB buffer=Kreb ' s Ringer in test tube
125mM containing Hepes NaCl, 5mM KCl, 1.8mM CaCl2,2.6mM MgSO4 and 25mM Hepes add 2mM glucose and
0.3%BSA.).
Experiments have shown that insulin can induce intake of the myotube to radiolabeled glucose.Antidiabetic medicine
Rosiglitazone can effectively enhance intake of the muscle cell to glucose.Compound (compound according to the present invention
D2) can effectively enhance muscle cell to absorb the insulin-dependent of glucose.Its activity (please quite join with positive control
See Fig. 5, Cong Zuozhi is by being followed successively by negative control, positive control, compound D2).
Embodiment 8
The present embodiment is for confirming that compound according to the present invention (compound D1 compound) can effectively improve high in fat feed
Support tolerance of the inducing mouse to glucose.
The C57BL/J6 male mice of 50 days sizes uses normal diet (chow diet) or 60% card containing lard respectively
High-fat diet in road 70 weeks.30 animals are divided into 6 groups (every group 5), respectively with the method for feeding is added, take drugs tax to animal
Shape agent (blank control), 10mg/kg/day rosiglitazone (positive control), 0.5mg/kg/day compound D1,5 mg/
Kg/day compound D1,0.5mg/kg/day compound D1 and 5mg/kg/day compound D2, successive administration 2 weeks.Then
Animal oral glucose is given, blood sample is extracted in 0,15,30,60 and 120 after taking glucose minute respectively.Utilize monitor
(Accu-chek Advantage, Roche) measures blood glucose level；It is respectively the mapping of longitudinal and transverse coordinate with blood glucose level and time,
Calculate the area under the curve (AUC) of different animals group.
Studies have shown that, compound D2 and chemical combination similar with positive control test (rosiglitazone, 10mg/kg/day)
Object D1 can be in the area under the curve (AUC) of the low oral glucose tolerance test of dose degradation of 0.5 or 5mg/kg/day, explanation
ERR agonist (compound D1 and compound D2 etc.) test in animal body in improve glucose-tolerant (Fig. 6 is referred to, from a left side
To by being followed successively by chow diet, high fat diet, positive control, 0.5mg D1,5mg D1,0.5mg D2,5mg D2).
Embodiment 9
The present embodiment is for confirming that compound according to the present invention can effectively improve the rouge of high fat diet inducing mouse
Fat liver symptom.
The C57BL/J6 male mice of 50 days sizes with normal diet (chow diet) or contains lard respectively
60% calorie of High-fat diet 70 weeks.30 animals are divided into 6 groups (every group 5), respectively with the method for feeding is added, and take respectively
Drug excipient (blank control), 10mg/kg/day rosiglitazone
(positive control), 0.5mg/kg/day compound D1,5mg/kg/day compound D1,0.5mg/kg/day compound D1,
And 5mg/kg/day compound D2, successive administration 15 days.Then the weight of animals, liver are weighed and counted, and to dynamic
Object liver specimens carry out pathological section, micro- sem observation.
Compared to positive control test (rosiglitazone, 10mg/kg/day), compound D2 and compound D1 can be with
Do not increase animal's liver weight under the dosage of 0.5 or 5mg/kg/day and (refers to Fig. 7, Cong Zuozhi is by being followed successively by high-fat feeding
Material, positive control, 0.5mg D1,5mg D1,0.5mg D2,5mg D2).
The present invention also provides a kind of composition, comprising a effective amount of estrogen modulators and pharmaceutically acceptable load
Body or excipient.Estrogen modulators stem cell of the invention can be administered individually or in the form of pharmaceutical composition.Its preparation
Form depends on selected administration route, can be manufactured according to common sense well known in the art.
The above is only a preferred embodiment of the present invention, for those of ordinary skill in the art, according to the present invention
Thought, there will be changes in the specific implementation manner and application range, and the content of the present specification should not be construed as to the present invention
Limitation.
Claims (6)
1. a kind of estrogen modulators, it is characterised in that: the structural formula of compound of the estrogen modulators is as follows:
Wherein, the R1 is selected from
H；
C1-C6 alkyl；
Aryl；
Halogen；
C1-C5 contains fluoroalkyl；
Wherein, the R2 is selected from
H；
C1-C4 alkyl；
Aryl；
C1-C6 contains fluoroalkyl；
Wherein, the R3 is selected from
H；
C1-C6 alkyl；
C3-C6 naphthenic base；
C1-C5 contains fluoroalkyl；
Halogen
Wherein, the R2 is selected from
H；
C1-C6 alkyl；
Aryl；
C1-C5 contains fluoroalkyl.
2. estrogen modulators according to claim 1, it is characterised in that: R1 is methyl, and R2 is phenyl, and R3 is methyl,
R4 is H.
3. estrogen modulators according to claim 1, it is characterised in that: R1 is methyl, and R2 is-(4- bromophenyl), R3
For methyl, R4 H.
4. according to estrogen modulators described in claim 1, it is characterised in that: R1 H, R2 are-(4- fluorophenyl), R3 Cl,
R4 is methyl.
5. according to estrogen modulators described in claim 1, it is characterised in that: R1 H, R2 are-CH2CF3, R3 is methyl, and R4 is
Isopropyl.
6. a kind of composition, it is characterised in that: the composition includes the arbitrarily described estrogen tune of a effective amount of claim 1-5
Save agent and pharmaceutically acceptable carrier or excipient.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910366388.XA CN110041271A (en) | 2019-05-05 | 2019-05-05 | Estrogen modulators and its composition obtained |
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