CN103694299A - Steroid androgen receptor inhibitors and preparation method and medical application thereof - Google Patents

Steroid androgen receptor inhibitors and preparation method and medical application thereof Download PDF

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CN103694299A
CN103694299A CN201410012759.1A CN201410012759A CN103694299A CN 103694299 A CN103694299 A CN 103694299A CN 201410012759 A CN201410012759 A CN 201410012759A CN 103694299 A CN103694299 A CN 103694299A
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compound
preparation
pyrimidine
androstene
esi
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向华
劳可静
何聪慧
唐郑普
严明
肖红
尤启冬
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China Pharmaceutical University
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China Pharmaceutical University
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Abstract

The invention relates to the field of medicinal chemistry, and particularly relates to a series of steroid androgen receptor inhibitors and a preparation method and medical application thereof, and particularly relates to an application as a medicine for preventing or treating the androgen receptor-related diseases such as cell proliferation depending on androgen, hirsutism, acne, androgenetic alopecia and the like.

Description

Steroid androgen receptor inhibitor, its preparation method and medicinal use thereof
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to a series of steroid androgen receptor inhibitor, their preparation method and their medicinal use, especially for treating androgen-receptor related diseases, as depend on the purposes of the medicine of androgenic cell proliferation, hirsutism, acne and androgens psilosis etc.
Background technology
Androgen receptor (Androgenic Receptor, AR) belongs to nuclear receptor family, includes four main region: N and holds territory, active transcripting controling area (NTD), DNA calmodulin binding domain CaM (DBD), hinge area and ligand binding domain (LBD).AR mainly for example expresses in prostate gland, suprarenal gland, epididymis, skeletal muscle, liver and central nervous system at male sex hormone target tissue.In prostate gland, suprarenal gland and epididymis, observe higher expression level.AR can activate with the androgenic combination of the endogenous that comprises testosterone and 5 α-dihydrotestosterone (5 α-DHT).
Prostate cancer (Prostate cancer, PCa) is the malignant tumour betiding in male prostate tissue, is the result of the abnormal unordered growth of prostate gland acinous cell.The sickness rate of prostate cancer has obvious geography and racial difference.In the developed countries such as America and Europe and area, it is the modal malignant tumour of the male sex, and its mortality ratio occupies the second of various cancers; In Asia, its sickness rate is lower than western countries, but is in recent years rapid ascendant trend; At present the prostate cancer sickness rate of China rises year by year, and middle and advanced stages that are while finding more.
The generation of PCa, development and male sex hormone are closely related, and endocrine therapy is the primary treatment method of current advanced prostate cancer.Most patients is originally all effective to castration (operation or medicine) or combined androgen blockade treatment, but after the median time of 14～30 months, nearly all patient's pathology all will develop into castration resistivity prostate cancer (CRPC) gradually.The overexpression and the castration opposing that studies show that AR are closely related.Approximately there is 1/3rd CPRC patient to occur the amplification of AR gene order, and then cause that AR expresses increase.And the sudden change that mainly occurs in AR ligand binding domain not only causes the non-AR active substance generation agonisms such as oestrogenic hormon, more seriously cause the androgen receptor inhibitor such as bicalutamide to produce agonist activity, thereby resist.Finally, studies have found that the androgen levels in CPRC patient's prostate gland is still 25% of normal serum androgen levels.This may be due to the increase of the synthetic relevant enzyme expression of male sex hormone in body and then cause the excessive synthetic androgen of endogenous.Therefore, suppressing estrogen receptor activity and suppress that male sex hormone becomes is the important method for the treatment of CPRC.
Summary of the invention
The invention discloses the steroid androgen antagonist compound with general formula one structure.Through pharmacological evaluation, prove that this compounds has good androgen antagonist active.
General formula one:
Figure BSA0000100178930000021
Wherein represent-NH-of X or-NH-CO-or-CH 2-NH-;
R 1represent H or C 1-C 4straight chained alkyl;
R 2represent H or C 1-C 4straight chained alkyl;
Or R 1, R 2be connected to Pyrrolidine base with N;
R 3expression-OEt or-COOEt;
Part of compounds structure of the present invention is as follows:
I：X=-NH-CO-
Figure BSA0000100178930000022
Figure BSA0000100178930000023
II：X=-NH-
Figure BSA0000100178930000024
Figure BSA0000100178930000025
III：X=-CH 2-NH-
Figure BSA0000100178930000031
Figure BSA0000100178930000032
In pharmacological evaluation and embodiment, the code name of compound is equal to the corresponding compound structure of above code name.
The compound of general formula one of the present invention can be prepared by following methods:
I-6A～I-6F
Figure BSA0000100178930000033
Wherein R is substituted-amino described in general formula one;
Reactant and reaction conditions: a) dehydrated alcohol, oxammonium hydrochloride, ammonium acetate, refluxes; B) methyl alcohol, sodium borohydride, Nickel dichloride hexahydrate; C) methylene dichloride, EDCI, HOBt; D) methylene dichloride, metachloroperbenzoic acid, sodium carbonate, O ℃; E) DMF, contains substituent amine described in general formula one, salt of wormwood; F) methyl alcohol, salt of wormwood.
II-6A～II-6F
Figure BSA0000100178930000041
Wherein R is substituted-amino described in general formula one;
Reactant and reaction conditions: g) DMF, salt of wormwood; D) methylene dichloride, metachloroperbenzoic acid, sodium carbonate, 0 ℃; E) DMF, contains substituent amine described in general formula one, salt of wormwood; F) methyl alcohol, salt of wormwood,
III-6A～III-6F
Wherein R is substituted-amino described in general formula one;
Reactant and reaction conditions: h) Nitromethane 99Min., quadrol, reflux water-dividing; I) tetrahydrofuran (THF), Lithium Aluminium Hydride; J) tetrahydrofuran (THF), salt of wormwood, 50 ℃; E) methylene dichloride, metachloroperbenzoic acid, sodium carbonate, 0 ℃; F) DMF, contains substituent amine described in general formula one, salt of wormwood;
The pharmacologically active that is part of compounds of the present invention below detects
Androgen receptor suppresses active testing
This experiment is a kind of test method of carrying out androgen receptor modifier screening active ingredients based on fluorescence polarization technology.This experiment is used fluorescently-labeled testosterone as fluorescence aglucon, with testing compound, being at war with property of androgen receptor is combined.When testing compound and androgen receptor have stronger avidity, most of acceptor is combined with testing compound, and fluorescence aglucon is free small molecules state more, while being stimulated due to polarization light intensity and material, the speed of molecular rotation is inversely proportional to, small-molecule substance rotation is fast, its polarizing fluorescence just a little less than; If when testing compound can not be with receptors bind, most of fluorescence aglucon is combined with androgen receptor, form macromolecular complex, macromolecular substance rotation is slow, and the polarizing fluorescence measuring is just strong.React and detect after 90 minutes, the intensity that detected result is polarizing fluorescence, judges that according to polarization value size the combination of compound and androgen receptor is active.
1 materials and methods
1.1 material
Fluormone?Al?Green(Invitrogen，USA)
Androgen?receptor?LBD?domain(Invitrogen，USA)
AR?Green?Assay?Buffer(Invitrogen，USA)
DTT(Invitrogen，USA)
Positive drug mesterolone (Mesterolone) is for providing standard substance for sample prescription
384 hole black microwell plates (Croning, USA)
Rifle head (Axygen, USA)
1.2 experimental procedure
1.2.1 the preparation of reagent
①Complete?AR?Green?Assay?Buffer
Every 1ml AR Green Assay Buffer adds the DTT of 2 μ L1M to be made into.Now with the current, be no more than one day
②2X?Test?Compound?of?interest
Every kind of accurate weighing of testing compound, adds DMSO solvent to form mother liquor, then uses CompleteAR GReen Assay Buffer preparation testing compound solution to desired concn
③2X?AR-LBD(His-GST)／Fluormone TM?AL?Green?Complex
Use Complete AR Green Assay Buffer preparation 2X AR-LBD and Fluormone tMit is 50nM that AL Green mixed solution makes final AR-LBD concentration, Fluormone tMaL Green concentration is 2nM.
1.2.2 the mensuration of sample
1. every hole adds 20 μ L testing compounds;
2. every hole adds 20 μ L2X AR-LBD (His-GST) and Fluormone maL Green mixing solutions, mixes;
3. control wells is set
1X?Fluormone TM?AL?Green，
IX?AR-LBD(His-GST)／Fluormone TM?AL?Green?Complex
AR?Green?Assay?Buffer?alone
4. lucifuge operation.Room temperature (20-25 ℃) is hatched 4-8h.
5. detect.Excitation wavelength is 485nM, and emission wavelength is 535nM.
1.2.3 testing sample is processed
Testing sample accurate weighing 1mg, adds DMSO solvent to be made into mother liquor, and concentration 10mg/ml is used physiological saline or detect damping fluid to be made into working fluid, and primary dcreening operation concentration is about 0.1mg/ml.
1.2.4 data processing
1. according to formula, calculate the inhibiting rate of each testing compound to androgen receptor
Y=mP 100％+(mP 0％-mP 100％)／1+10 ((LogIC50-x)×Hillslope)
Y=mP，X=Log[inhibitor]，mP 100％=100％inhibiton，and?mP 0％=0％inhibiton
2. use the inclined to one side value of milli and the mapping of logarithm concentration value to ask and calculate IC 50
2 experimental results
Figure BSA0000100178930000061
Figure BSA0000100178930000071
Embodiment (described embodiment is just used for illustrating the present invention, rather than is used for limiting the present invention)
Part of compounds to prepare example as follows:
Hydrogen nuclear magnetic resonance spectrometer is that (TMS is interior mark to BrukerAV500 type, deuterated CDCl 3or deuterated DMSO is solvent); Mass spectrograph is Shimadzu GCMS-QP2010 type mass spectrograph or Mariner mass spectrograph; In experiment, column chromatography all adopts 100-200 order silica gel that Qingdao Marine Chemical Co., Ltd. the produces phase that fixes; Chemical reagent is commercially available chemical pure or analytical pure product, goes out outside specified otherwise, unprocessed direct use.
Embodiment 1
The preparation of 5-androstene-3 β-ol-17-ketoxime-3-acetic ester (I-1)
5.00g (15.2mmol) Dehydroepiandrosterone Acetate is dissolved in 200ml methyl alcohol, adds oxammonium hydrochloride 7.88g (0.113mmol), sodium acetate 9.38g (0.113mmol), back flow reaction 1.5h, TLC demonstration reacts completely.After the most of methyl alcohol of underpressure distillation, pour in 50ml water, have a large amount of solids to separate out, suction filtration obtains white solid 5.18g, yield 99.2%.ESI-MSm／z：346[M+H] +；
Embodiment 2
The preparation of 17-amino-5-androstene-3 β-ol-3-acetic ester (I-2)
0.25g (0.87mmol) intermediate compound I-1 is dissolved in 16ml methyl alcohol, adds 0.35g (17.4mmol) Nickel dichloride hexahydrate, under room temperature, slowly add 0.27 (8.7mmol) NaBH in batches 4, room temperature reaction 1h, TLC demonstration reacts completely, and adds 10ml1NHCl quencher reaction.Under stirring, with strong aqua, adjust PH to 5, have solid to separate out.Add CH 2cl 2extract 3 times, merge organic phase, saturated NaHC0 3wash saturated common salt washing, anhydrous Na S0 4dry, underpressure distillation, to dry, obtains light yellow solid 0.18g, yield 76.72%.ESI-MS?m／z：332[M+H] +
Embodiment 3
The preparation of 17-((2 '-methylthio group-4 '-oxyethyl group) pyrimidine-5 '-methane amide) base-5-androstene-3 β-ol-3-acetic ester (I-3)
1.07g (5mmol) 2-first sulphur-4-oxyethyl group pyrimidine-5-formic acid is dissolved in to 25mlCH 2cl 2in, add 0.75g (5.5mmol) HOBt, 1.05g (5.5mmol) EDCI, stirring at room reaction 0.5h, reaction solution becomes clarification by muddiness.Add 1.39g (4.2mmol) intermediate compound I-2, room temperature reaction spends the night, and TLC shows that reaction finishes.Reaction solution adds 25ml CH 2cl 2after use saturated NaHC0 3wash saturated common salt washing, anhydrous Na S0 three times 4dry, underpressure distillation, to dry, obtains light yellow oil crude product 2.35g.Column chromatography for separation (developping agent sherwood oil: ethyl acetate=4: 1), obtain white sterling 1.869g, yield 84.34%.ESI-MS?m／z：528[M+H] +；
Embodiment 4
The preparation of 17-((2 '-methyl sulfinyl-4 '-oxyethyl group) pyrimidine-5 '-methane amide) base-5-androstene-3 β-ol-3-acetic ester (I-4)
Under ice bath, 1.00g (1.93mmol) intermediate compound I-3 are dissolved in to 15ml CH 2cl 2in, add 0.25g (2.42mmol) Na 2c0 3, m-CPBA0.49g (2.42mmol), 0 ℃ of stirring reaction, reaction solution is muddy gradually, and after 20min, TLC demonstration reacts completely.Add water 50ml to stir 30min, separate organic layer.Water layer adds CH 2cl 2extract 3 times, merge organic phase, saturated common salt washing, anhydrous Na SO 4dry, underpressure distillation, to dry, obtains faint yellow solid 0.84g, yield 78.21%.ESI-MS?m／z：542[M-H] +；
Embodiment 5
The preparation of 17-((2 '-dimethylamino-4 '-oxyethyl group) pyrimidine-5 '-formyl ammonia) base-5-androstene-3 β-ol-3-acetic ester (I-5A)
0.56g (1.03mmol) intermediate compound I-4 are dissolved in 5mlDMF, add dimethylamine hydrochloride 0.22g (2.76mm0l), K 2cO 30.38g (2.76mmol), room temperature reaction spends the night.TLC demonstration reacts completely.Reaction solution is poured elutriation in 25ml water into, and suction filtration obtains white solid 0.43g, yield 80.41%.ESI-MS?m／z：525[M+H] +；
Embodiment 6
The preparation of 17-((2 '-dimethylamino-4 '-oxyethyl group) pyrimidine-5 '-formyl ammonia) base-5-androstene-3 β-ol (I-6A)
0.43g (0.83mmol) I-5A is dissolved in 5ml methyl alcohol, adds 0.12g (0.83mmol) K 2cO 3, stirred overnight at room temperature, TLC demonstration reacts completely.Reaction solution is poured elutriation in 25ml water into, and suction filtration obtains white crude product.Column chromatography for separation (sherwood oil: ethyl acetate=2: 3), obtain white sterling 0.31g, yield 79.11%. 1H?NMR(DMSO-d6，300MHz)δ：8.6(s，1H，pyrimidine-H)，7.4(d，1H，J=8.22Hz,17-NH)，5.2(s，1H，6-H)，4.6(s，1H，3-OH)，3.9(t，2H,J=8.55，-OC H 2CH 3)，3.1(s，6H，-N(CH 3) 2)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；ESI-MS?m／z：483[M+H] +；
Embodiment 7
The preparation of 17-((2 '-methylamino--4 '-oxyethyl group) pyrimidine-5 '-formyl ammonia) base-5-androstene-3 β-ol (I-6B)
Synthesizing of concrete operations reference compound (I-6A), drop into compound (I-4) 0.43g, obtain white sterling 0.27g, yield 74.15%. 1H?NMR(DMSO-d6，300MHz)δ：8.5(s，1H，pyrimidine-H)，7.4(d，1H，J=8.22Hz,17-NH)，5.2(s，1H，6-H)，4.5(s，1H，3-OH)，3.9(t，2H,J=8.55，-OC H 2CH 3)，2.5(s，3H，-NHC H 3)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；ESI-MS?m／z：469[M+H] +；
Embodiment 8
The preparation of 17-((2 '-diethylin-4 '-oxyethyl group) pyrimidine-5 '-formyl ammonia) base-5-androstene-3 β-ol (I-6C)
Synthesizing of concrete operations reference compound (I-6A), drop into compound (I-4) 0.43g, obtain white sterling 0.27g, yield 66.04%. 1H?NMR(DMSO-d6，300MHz)δ：8.6(s，1H，pyrimidine-H)，7.3(d，1H，J=8.22Hz,17-NH)，5.2(s，1H，6-H)，4.5(s，1H，3-OH)，3.9(t，2H,J=8.55，-OC H 2CH 3)，3.6(m，4H，-N(C H 2CH 3) 2)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；ESI-MS?m／z：510[M+H] +；
Embodiment 9
The preparation of 17-((2 '-ethylamino-4 '-oxyethyl group) pyrimidine-5 '-formyl ammonia) base-5-androstene-3 β-ol (I-6D)
Synthesizing of concrete operations reference compound (I-6A), drop into compound (I-4) 0.43g, obtain white sterling 0.25g, yield 65.16%. 1H?NMR(DMSO-d6，300MHz)δ：8.5(s，1H，pyrimidine-H)，7.4(d，1H，J=8.22Hz,17-NH)，5.2(s，1H，6-H)，4.6(s，1H，3-OH)，3.9(t，2H,J=8.55，-OC H 2CH 3)，3.1(t，2H，-NHC H 2CH 3)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；ESI-MS?m／z：483[M+H] +；
Embodiment 10
The preparation of 17-((2 '-(pyrrolidin-1-yl)-4 '-oxyethyl group) pyrimidine-5 '-formyl ammonia) base-5-androstene-3 β-ol (I-6E)
Synthesizing of concrete operations reference compound (I-6A), drop into compound (I-4) 0.43g, obtain white sterling 0.29g, yield 71.42%. 1H?NMR(DMSO-d6，300MHz)δ：8.6(s，1H，pyrimidine-H)，7.3(d，1H，J=8.22Hz,17-NH)，5.2(s，1H，6-H)，4.6(s，1H，3-OH)，3.9(t，2H,J=8.55，-OC H 2CH 3)，3.5(t，3H，C H 2-N-C H 2)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；ESI-MS?m／z：509[M+H] +；
Embodiment 11
The preparation of 17-((2 '-n-butyl amine base-4 '-oxyethyl group) pyrimidine-5 '-formyl ammonia) base-5-androstene-3 β-ol (I-6F)
Synthesizing of concrete operations reference compound (I-6A), drop into compound (I-4) 0.43g, obtain white sterling 0.21g, yield 53.32%. 1H?NMR(DMSO-d6，300MHz)δ：8.6(s，1H，pyrimidine-H)，7.4(d，1H，J=8.22Hz,17-NH)，5.2(s，1H，6-H)，4.5(s，1H，3-OH)，3.5(t，2H,=8.55，-OC H 2CH 3)，3.1(s，3H，-NHC H 2CH 2)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；ESI-MS?m／z：511[M+H] +；
Embodiment 12
The preparation of N-(2 '-methylthio group-5 '-ethoxycarbonyl pyrimidine-4-yl)-17-amino-5-androstene-3 β-ol 3-acetic ester (II-3)
3.00g (9mmol) intermediate compound I-2 are dissolved in 60m1DMF, add 4-chloro-2-methylthiopyrimidine-5-ethyl formate 1.64g (7mmol), 1.24g (9mmol) K 2cO 3, stirring at room reaction 12h, TLC shows that reaction is substantially complete.Reaction solution is poured elutriation in 300ml water into, and suction filtration obtains crude product.Column chromatography purification (sherwood oil: ethyl acetate=6: 1), obtain white sterling 2.80g yield 58.7%.ESI-MS?m／z：528[M+H] +；
Embodiment 13
The preparation of N-(2 '-methylsulfinyl base-5 '-ethoxycarbonyl pyrimidine-4-yl)-17-amino-5-androstene-3 β-ol-3-acetic ester (II-4)
Under ice bath, 2.80g (5.31mmol) intermediate II-3 are dissolved in to 42ml CH 2cl 2in, add Na 2cO 30.70g (6.64mmol), m-CPBA1.14g (6.64mmol), stirring reaction, reaction solution is muddy gradually, and after 20min, TLC demonstration reacts completely.Add water 50ml to stir 30min, separate organic layer.Water layer adds CH 2cl 2extract 3 times, merge organic phase, saturated common salt washing, anhydrous Na SO 4dry, underpressure distillation, to dry, obtains faint yellow solid 2.28g, yield 86.4%.ESI-MSm／z：542[M-H] +；
Embodiment 14
The preparation of N-(2 '-dimethylamino-5 '-ethoxycarbonyl pyrimidine-4-yl)-17-amino-5-androstene-3 β-ol (II-6A)
Synthesizing of concrete operations reference compound (I-6A), drop into compound (II-4) 0.43g, obtain white sterling 0.32g, yield 85.12%. 1H?NMR(CDCl 3，300MHz)δ：8.6(s，1H，pyrimidine-H)，5.3(s，1H，6-H)，4.1～4.3(m，3H，-COOC H 2CH 3，3-H)，3.8(s，1H，-NH)，3.2(s，6H，-N(C H 3) 2)，0.9(s，3H，19-CH 3)，0.8(s，3H，18-CH 3)ppm；ESI-MS?m／z：483[M+H] +；
Embodiment 15
The preparation of N-(2 '-methylamino--5 '-ethoxycarbonyl pyrimidine-4-yl)-17-amino-5-androstene-3 β-ol (II-6B)
Synthesizing of concrete operations reference compound (I-6A), drop into compound (II-4) 0.47g, obtain white sterling 0.27g, yield 73.37%. 1H?NMR(CDCl 3，300MHz)δ：8.5(s，1H，pyrimidine-H)，5.4(s，1H，6-H)，4.1～4.3(m，3H，-COOC H 2CH 3，3-H)，3.0(s，3H，-NHC H 3)，0.9(s，3H，19-CH 3)，0.8(s，3H，18-CH 3)ppm；ESI-MS?m／z：469[M+H] +；
Embodiment 16
The preparation of N-(2 '-diethylin-5 '-ethoxycarbonyl pyrimidine-4-yl)-17-amino-5-androstene-3 β-ol (II-6C)
Synthesizing of concrete operations reference compound (I-6A), drop into compound (II-4) 0.47g, obtain white sterling 0.29g, yield 72.94%. 1H?NMR(CDCl 3，300MHz)δ：8.5(s，1H，pyrimidine-H)，5.4(s，1H，6-H)，4.2～4.3(m，3H，-COOC H 2CH 3，3-H)，3.8(s，1H，-NH)，3.0(t，4H，-N(C H 2CH 3) 2)，0.9(s，3H，19-CH 3)，0.8(s，3H，18-CH 3)ppm；ESI-MS?m／z：511[M+H] +；
Embodiment 17
The preparation of N-(2 '-ethylamino-5 '-ethoxycarbonyl pyrimidine-4-yl)-17-amino-5-androstene-3 β-ol (II-6D)
Synthesizing of concrete operations reference compound (I-6A), drop into compound (II-4) 0.5g, obtain white sterling 0.31g, yield 68.62%. 1H?NMR(CDCl 3，300MHz)δ：8.5(s，1H，pyrimidine-H)，5.4(s，1H，6-H)，4.2～4.3(m，3H，-COOC H 2CH 3，3-H)，3.8(s，1H，-NH)，3.4(t，2H，-NHC H 2CH 3)，0.9(s，3H，19-CH 3)，0.8(s，3H，18-CH 3)ppm；ESI-MS?m／z：483[M+H] +；
Embodiment 18
The preparation of N-(2 '-(pyrrolidin-1-yl)-5 '-ethoxycarbonyl pyrimidine-4-yl)-17-amino-5-androstene-3 β-ol (II-6E)
Synthesizing of concrete operations reference compound (I-6A), drop into compound (II-4) 0.5g, obtain white sterling 0.30g, yield 62.94%. 1H?NMR(CDCl 3，300MHz)δ：8.6(s，1H，pyrimidine-H)，5.4(s，1H，6-H)，4.2～4.3(m，3H，-COOC H 2CH 3，3-H)，3.5(m，2H，-C H 2NHC H 2)，0.9(s，3H，19-CH 3)，0.8(s，3H，18-CH 3)ppm；ESI-MS?m／z：509[M+H] +；
Embodiment 19
The preparation of N-(2 '-n-butyl amine base-5 '-ethoxycarbonyl pyrimidine-4-yl)-17-amino-5-androstene-3 β-ol (II-6F)
Synthesizing of concrete operations reference compound (I-6A), drop into compound (II-4) 0.5g, obtain white sterling 0.29g, yield 62.57%. 1H?NMR(CDCl 3，300MHz)δ：8.5(s，1H，pyrimidine-H)，5.4(s，1H，6-H)，4.2～4.3(m，3H，-COOC H 2CH3，3-H)，3.5(t，2H，-NHC H 2CH 3)，0.9(s，3H，19-CH 3)，0.8(s，3H，18-CH 3)ppm；ESI-MS?m／z：511[M+H] +；
Embodiment 20
The preparation of 17-Nitromethylene-5-androstene-3 β-ol-3-acetic ester (III-1)
5.00g (15.21mmol) Dehydroepiandrosterone Acetate is dissolved in 75ml Nitromethane 99Min., adds anhydrous ethylenediamine 0.9ml (15.21mmol), reflux water-dividing, after 10h, TLC shows that reaction is substantially complete.Reaction solution is poured in 50ml water, adds CH 2cl 2extract 3 times, merge organic phase, 1NHC1 washes, saturated common salt washing, anhydrous Na SO 4dry, underpressure distillation, to dry, obtains red crude product.Column chromatography purification (sherwood oil: ethyl acetate=10: 1), obtain white sterling 2.43g, yield 43.09%.ESI-MS?m／z：374[M+H] +；
Embodiment 21
The preparation of 17-amine methyl-5-androstene-3 β-ol (III-2)
Dry instrument, is dissolved in 2.43g (6.5lmmol) III-1 in the anhydrous THF of 90mL, under ice bath, drips LiALH 4be dissolved in the solution of the anhydrous THF of 10ml, react 25min at 0 ℃, TLC shows and reacts completely.Add water quencher reaction, suction filtration, filtrate decompression is distilled to dry, obtains white solid 1.93g, yield 97.97%.MS(ESI)：304[M+H] +；
Embodiment 22
The preparation of N-(2 '-methylthio group-5 '-ethoxycarbonyl pyrimidine-4-yl)-17-aminomethyl-5-androstene-3 β-ol (III-3)
1.93g (6.38mmol) intermediate III-2 are dissolved in 30mlDMF, add 4-chloro-2-methylthiopyrimidine-5-ethyl formate 1.77g (7.66mmol), triethylamine lml (7.66mmol), 50 ℃ of stirring reactions spend the night, and TLC shows that reaction is substantially complete.Underpressure distillation reaction solution, to dry, adds water 50ml, with 1NHCl, adjusts PH to 5, adds CH 2cl 2extract saturated common salt washing, anhydrous Na SO 3 times 4dry, underpressure distillation, to dry, obtains crude product.Column chromatography purification (sherwood oil: ethyl acetate=5: 1), obtain white sterling 1.76g, yield 55.47%.MS(ESI)：500[M+H] +；
Embodiment 23
The preparation of N-(2 '-methylsulfinyl-5 '-ethoxycarbonyl pyrimidine-4-yl)-17-amine methyl-5-androstene-3 β-ol (III-4)
Under ice bath, 1.76g (3.54mmol) III-2 is dissolved in to 35ml CH 2cl 2in, add Na 2c0 30.56g (5.31mmol), m-CPBA1.21g (5.31mmol), 0 ℃ of stirring reaction, reaction solution is muddy gradually, and after 20min, TLC demonstration reacts completely.Add water 40ml to stir 30min, separate organic layer.Water layer adds CH 2cl 2extract 3 times, merge organic phase, saturated common salt washing, anhydrous Na SO4 is dry, and underpressure distillation, to dry, obtains faint yellow solid 1.58g, yield 86.65%.ESI-MS?m／z：514[M-H] +；
Embodiment 24
The preparation of N-(2 '-dimethylin-5 '-ethoxycarbonyl pyrimidine-4-yl)-17-amine methyl-5-androstene-3 β-ol (III-5A)
150mg (0.35mmol) intermediate III-4 are dissolved in 2mlDMF, add dimethylamine hydrochloride 73mg (0.92mmol), 130mg (0.92mmol) K 2cO 3, room temperature reaction spends the night.TLC demonstration reacts completely.Reaction solution is poured elutriation in 10ml water into, and suction filtration obtains white solid.Column chromatography purification (sherwood oil: ethyl acetate=2.5: 1) obtain sterling 140.4mg, yield 72.12%. 1HNMR(DMSO-d6，300MHz)δ：8.6(s，1H，pyrimidine-H)，5.3(s，1H，6-H)，4.3(t，2H，-OC H 2CH 3)，3.6(t，2H，-C H 2NH-)，3.2(s，6H，-N(CH 3) 2)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；ESI-MS?m／z：497[M+H] +；
Embodiment 25
The preparation of N-(2 '-methylamino-5 '-ethoxycarbonyl pyrimidine-4-yl)-17-amine methyl-5-androstene-3 β-ol (III-5B)
Synthesizing of concrete operations reference compound (III-5A), drop into compound (III-4) 0.35g, obtain white sterling 0.22g, yield 67.84%. 1H?NMR(CDCl 3，300MHz)δ：8.6(s，1H，pyrimidine-H)，5.3(s，1H，6-H)，4.3(t，2H，-OC H 2CH 3)，3.7(t，2H，-C H 2NH-)，3.0(s，6H，-NHCH 3)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；ESI-MS?m／z：497[M+H] +；
Embodiment 26
The preparation of N-(2 '-methylamino-5 '-ethoxycarbonyl pyrimidine-4-yl)-17-amine methyl-5-androstene-3 β-ol (III-5B)
Synthesizing of concrete operations reference compound (III-5A), drop into compound (III-4) 0.35g, obtain white sterling 0.18g, yield 55.01%. 1H?NMR(CDCl 3，300MHz)δ：8.6(s，1H，pyrimidine-H)，5.3(s，1H，6-H)，4.3(t，2H，-OC H 2CH 3)，3.7(t，2H，-C H 2NH-)，3.0(s，6H，-NHCH 3)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；ESI-MS?m／z：497[M+H] +；
Embodiment 27
The preparation of N-(2 '-diethylin-5 '-ethoxycarbonyl pyrimidine-4-yl)-17-amine methyl-5-androstene-3 β-ol (III-5C)
Synthesizing of concrete operations reference compound (III-5A), drop into compound (III-4) 0.35g, obtain white sterling 0.16g, yield 45.90%. 1H?NMR(CDCl 3，300MHz)δ：8.6(s，1H，pyrimidine-H)，5.3(s，1H，6-H)，4.3(t，2H，-OC H 2CH 3)，3.7(t，2H，-C H 2NH-)，3.4(t，4H，-N(C H 2CH 3) 2)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；ESI-MS?m／z：525[M+H] +；
Embodiment 28
The preparation of N-(2 '-ethylamino--5 '-ethoxycarbonyl pyrimidine-4-yl)-17-amine methyl-5-androstene-3 β-ol (III-5D)
Synthesizing of concrete operations reference compound (III-5A), drop into compound (III-4) 0.35g, obtain white sterling 0.15g, yield 44.97%. 1H?NMR(CDCl 3，300MHz)δ：8.6(s，1H，pyrimidine-H)，5.3(s，1H，6-H)，4.3(t，2H，-OC H 2CH 3)，3.7(t，2H，-C H 2NH-)，3.5(t，2H，-NHC H 2CH 3)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；ESI-MS?m／z：497[M+H] +；
Embodiment 29
The preparation of N-(2 '-(pyrrolidin-1-yl)-5 '-ethoxycarbonyl pyrimidine-4-yl)-17-amine methyl-5-androstene-3 β-ol (III-5E)
Synthesizing of concrete operations reference compound (III-5A), drop into compound (III-4) 0.35g, obtain white sterling 0.19g, yield 54.90%. 1H?NMR(CDCl 3，300MHz)δ：8.6(s，1H，pyrimidine-H)，5.3(s，1H，6-H)，4.3(t，2H，-OC H 2CH 3)，3.7(t，2H，-C H 2NH-)，3.4(t，4H，-C H 2NHC H 2)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；ESI-MS?m／z：523[M+H] +；
Embodiment 30
The preparation of N-(2 '-n-butylamine-based-5 '-ethoxycarbonyl pyrimidine-4-yl)-17-amine methyl-5-androstene-3 β-ol (III-5F)
Synthesizing of concrete operations reference compound (III-5A), drop into compound (III-4) 0.35g, obtain white sterling 0.21g, yield 61.21%. 1H?NMR(CDCl 3，300MHz)δ：8.6(s，1H，pyrimidine-H)，5.3(s，1H，6-H)，4.3(t，2H，-OC H 2CH 3)，3.7(t，2H，-C H 2NH-)，3.6(t，2H，-NHCH 2CH 2)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；ESI-MS?m／z：525[M+H] +。

Claims (6)

1. the compound of following general formula or its pharmaceutically acceptable steric isomer:
Figure FSA0000100178920000011
Wherein represent-NH-of X or-NH-CO-or-CH 2-NH-;
R 1represent H or C 1-C 4straight chained alkyl;
R 2represent H or C 1-C 4straight chained alkyl;
Or R 1, R 2be connected to Pyrrolidine base with N;
R 3expression-OEt or-COOEt.
2. the compound in claim 1 or its pharmacy acceptable salt, wherein represent-CH of X 2-NH-.
3. the compound in claim 2 or its pharmacy acceptable salt, wherein R 1represent H or ethyl; R2 represents H, ethyl or normal-butyl; Or R1, R2 are connected to Pyrrolidine base.
4. a pharmaceutical composition, wherein contains compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of any one in claims 1 to 3.
In claims 1 to 3 arbitrary compound or its pharmacy acceptable salt for the preparation of the purposes of medicine of prevention or treatment androgen-receptor related diseases.
6. described in claim 5, androgen-receptor related diseases is any in following disease: benign prostatic hyperplasia, prostate cancer, hirsutism, acne, androgens psilosis.
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CN104356192A (en) * 2014-11-18 2015-02-18 中国药科大学 Novel steroid androgen receptor inhibitors, and preparation method and medicinal application thereof
CN114933628A (en) * 2022-06-15 2022-08-23 昆明理工大学 Steroid compound targeting P53 mutant, preparation method thereof and application thereof in treating tumors
WO2022199289A1 (en) * 2021-03-22 2022-09-29 中国药科大学 Novel androgen receptor degrader, preparation method, and medical use

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CN1357003A (en) * 1999-04-30 2002-07-03 亚其发展公司 Steroid derivatives
CN1784236A (en) * 2003-05-07 2006-06-07 麦克公司 Androgen receptor modulators and methods of use thereof
CN101155823A (en) * 2005-03-02 2008-04-02 马里兰州立大学 Novel c-17-heteroaryl steroidal cyp17 inhibitors/antiandrogens: synthesis, in vitro biological activities, pharmacokinetics and antitumor activity

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Publication number Priority date Publication date Assignee Title
CN104262442A (en) * 2014-10-10 2015-01-07 湖南科瑞生物科技有限公司 Preparation method for progestin
CN104356192A (en) * 2014-11-18 2015-02-18 中国药科大学 Novel steroid androgen receptor inhibitors, and preparation method and medicinal application thereof
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CN114933628A (en) * 2022-06-15 2022-08-23 昆明理工大学 Steroid compound targeting P53 mutant, preparation method thereof and application thereof in treating tumors
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