CN103554210A - Sterides 5 alpha-reductase inhibitor, as well as preparation method and medical application thereof - Google Patents

Sterides 5 alpha-reductase inhibitor, as well as preparation method and medical application thereof Download PDF

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CN103554210A
CN103554210A CN201310516044.5A CN201310516044A CN103554210A CN 103554210 A CN103554210 A CN 103554210A CN 201310516044 A CN201310516044 A CN 201310516044A CN 103554210 A CN103554210 A CN 103554210A
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reductase inhibitor
pharmaceutically acceptable
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sterides
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向华
宁珊珊
刘元元
孙洁
寻国良
严明
张陆勇
廖清江
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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 in particular relates to a sterides 5 alpha-reductase inhibitor shown in a general formula (1), as well as a preparation method of the sterides 5 alpha-reductase inhibitor and a medical application of the sterides 5 alpha-reductase inhibitor. The compounds can be used for treating various human endocrine diseases such as benign prostatic hyperplasia, prostate cancer, baldness, black heads, female polytrichia and the like mainly caused by dihydrotestosterone.

Description

Steroid 5α-reductase inhibitor, its preparation method and medicinal use thereof
Technical field
The present invention relates to a series of steroid 5α-reductase of pharmaceutical chemistry and organic chemistry filed inhibitor.These compounds can be used for the treatment of mainly by dihydrotestosterone (Dihydrotestosterone, DHT) the multiple mankind's endocrinopathy causing, as benign prostatic hyperplasia (Benign prostate hyperplasia, BPH), prostate cancer, alopecia, acne, female hirsutism.
Background technology
5α-reductase is a polypeptide being comprised of 254 amino acid, is to rely in the membrane bound enzyme ， male sex hormone sensitive organization of NADPH cofactor to have distribution.It is existing that oneself finds that 5α-reductase has two kinds of hypotypes, i.e. α I, two kinds of isozyme of α II, and they are encoded by different genes respectively.α I type is common in the tissues such as liver, kidney, brain, lung, skin; α II type is be distributed in prostate gland, seminal vesicle, epididymis more.Current research shows, in human prostate tissue, α I type and α II type enzyme have expression, and the two has played keying action in testosterone being converted into active stronger dihydrotestosterone (DHT).
The formation of dihydrotestosterone (DHT) is relevant with a lot of mankind's endocrinopathys, as benign prostatic hyperplasia (BPH), prostate cancer, alopecia, acne, female hirsutism.The sickness rate of BPH in elderly men is very high, and nearly 30%, 80 years old of 50 years old above sickness rate is above up to 80%.People expectation is by the research to 5α-reductase inhibitor, realizes the new breakthrough for the treatment of BPH and other and 5α-reductase relative disease.
Classical steroid 5α-reductase inhibitor is divided into 3-olefin(e) acid class, azepine class steroidal and progestational hormone three classes.Finasteride (Finasteride, trade(brand)name: Proscar, proscar) is the 5α-reductase inhibitor of first listing, belongs to 4-azepine class steroidal compounds, in 1988, through FDA approval, is used for the treatment of BPH.At present, existing multiple 5α-reductase inhibitor enters clinical study or has gone on the market.Epristeride (Epristeride) is that the states such as a kind of 3-olefin(e) acid class 5α-reductase inhibitor ，Qi U.S., Britain, Italy, Japan, Spain all enter the clinical study of three phases.Domesticly by China Medicine University, the cooperation of organic Suo, Yangzhou, Shanghai pharmaceutical factory, tackled key problems, by the research requirement of a kind new medicine by new drug reviewing, the listing of going into operation in 1998.
The present invention is on the basis of the classical architecture based on steroid 5α-reductase inhibitor, the mechanism of action and great many of experiments, 3-olefin(e) acid class 5α-reductase inhibitor is carried out to structure of modification and optimization, design the steroid 5α-reductase inhibitor of a collection of novel structure, and by pharmacological evaluation, proved that some of them compound has good 5α-reductase and suppresses active.
Summary of the invention
The invention discloses a series of steroid 5α-reductase inhibitor compound and pharmacy acceptable salts thereof that meet general formula one.Through pharmacological evaluation, prove that this compounds has good 5α-reductase and suppresses active.
General formula one:
Figure BSA0000096768410000021
The transformation of this formula based on to 3-olefin(e) acid class 5α-reductase inhibitor.
Wherein work as R 1during for COOH, R 2for phenyl, 2-cyano-phenyl, 2,5-bis-trifluoromethyls, 3,5-bis-trifluoromethyls, 2-methyl-4-carboxyl phenyl, 4-p-methoxy-phenyl, the chloro-3-trifluoromethyl of 4-, 3-trifluoromethyl, 2-p-methoxy-phenyl, 2,5-dimethyl benzene methyl;
Work as R 1for
Figure BSA0000096768410000022
r 2for the tertiary butyl.
The invention further relates to the compound of general formula one and the medicinal compositions that pharmaceutically acceptable carrier forms.
Pharmacological evaluation demonstration, this serial invention compound has 5α-reductase restraining effect in various degree, and it is active suitable with epristeride, even stronger that part of compounds suppresses.
V～VI compounds that general formula one of the present invention to general formula three comprises can be prepared by following method:
V～VI: androstane-3,5-diene-3-carboxylic acid-17 β-amides and androstane-3,5-diene-3-tetrafluoro azoles-17 β-amides synthetic
Figure BSA0000096768410000023
R is wherein the substituted-amino in above-claimed cpd;
Reaction conditions and reagent: a) phosphorus tribromide, acetic acid; B) oxalyl chloride, above-mentioned substitutional amine-group, pyridine; C) cuprous cyanide, DMF; D) 20% aqueous sodium hydroxide solution, ethanol; E) sodiumazide, ammonium chloride.
The structure of part of compounds of the present invention is as follows:
Figure BSA0000096768410000024
Figure BSA0000096768410000025
In pharmacological evaluation and embodiment, the code name of compound is equal to the corresponding compound structure of above code name.
Part pharmacology test and the result of part of compounds of the present invention below:
1. experiment material
Testosterone T (Shanghai Jiu Bang Chemical Co., Ltd. product, lot number: 0602801) with dehydrated alcohol (AR) dissolved dilution to 20 μ mol/L;
Reducibility coenzyme NADPH (the biological company limited of Nanjing great order product, lot number: 621706) be assigned to 6mmol/L with Tris damping fluid;
Enzyme reaction buffer solution (buffer): Tris-HCl (10mmol/L) EDTA (1.5mmol/L) MgCl 2(5mmol/L) beta-mercaptoethanol (15mmol/L) [enzyme reaction buffer solution compound method: Tris1211.4mg, EDTA-Na 218mg, MgCl 26H 2o1024mg, beta-mercaptoethanol 40mg, NaCl2.92g, sucrose 45g, adds tri-distilled water to 1000ml (adjusting pH to 7.0 with hydrochloric acid)].
Contrast medicine epristeride is synthesized by this laboratory.
Given the test agent is by being all mixed with 1 * 10 with DMSO -2the mother liquor of mol/L, uses phosphoric acid buffer (PBS) to be diluted to desired concn as required.
2. laboratory apparatus
Organize decollator (T25, ultra-turrax, Germany); 752 ultraviolet spectrophotometers (Mode752c, Shanghai San analytical instrument factory); Sovell high speed low temperature centrifugal machine (Mode ST21, U.S. Suo Fu company); The Beckman refrigerated centrifuge that exceeds the speed limit; Vortex mixer (MVS-1, Beijing North Deco is learned equipment company limited); Digital display thermostat water bath (HH-4, Changzhou Guohua Electric Appliance Co., Ltd.); Electronic balance (BS210S, Beijing Sai Duolisi company limited).
3. test method
3.1. the preparation of steroidal 5α-reductase
Get 3 female sd inbred rats (body weight 300g left and right), fasting is got liver after one night, intravenous infusion also immerses in PBS liquid, every part of 1g left and right after cleaning shreds (3mm size) on ice platform, adds the PBS liquid of 10 times of volumes, in ice bath, use ULTRA-TURRAX refiner with 12,000g/min homogenate three times, each 5 seconds, 30 seconds, interval.In operating process, should keep low temperature, agents useful for same and articles for use also must low temperature.By supercentrifuge 10 for homogenate, 000g * 30min is centrifugal, gets supernatant liquor (carefully), obtains PMS.By ultracentrifuge 100 for PMS, 000g * 1h is centrifugal, outwells supernatant, precipitation is resuspended in to PBS and (containing 30% glycerine, 1:3v/v), obtains microsome suspension liquid.Be placed in-80 ℃ of Refrigerator stores standby, so can preserve one month.
3.2. the mensuration of enzymic activity
5α-reductase catalysis testosterone changes the participation that needs coenzyme NADP 11 in dihydrotestosterone process into.Reduced-NADP H has characteristic absorbance at 340nm place, carrying out NADPH and will change oxidized form NADP into along with reaction +, the characteristic absorbance at its 340nm wavelength place disappears.According to NADPH in reaction process, in the characteristic absorbance at 340nm wavelength place, change, can screen the inhibitor of 5α-reductase.
The mensuration of blank: in reaction tubes, add Buffer1.660ml, testosterone 100 μ l, PBS200 μ l, NADPH20 μ l, finally adds 20 μ l enzymes, after mixing, measures A 340nmvalue, hatches for 37 ℃, after reaction 6min, measures A 340nmvalue.Deduction NADPH blank decline background values, measures blank drop-out value (Δ A o).When experiment starts and finish, each is in triplicate.
The mensuration of inhibitor: in reaction tubes, add Buffer1.660ml, testosterone 100 μ l, (final concentration is 10 to inhibitor -6mol/L, if inhibiting rate > 50%, dilution downwards) 200 μ l, NADPH20 μ l, finally adds 20 μ l enzymes, after mixing, measures A 340nmvalue, hatches for 37 ℃, after reaction 10min, measures A 340nmvalue.Deduction NADPH blank decline background values, measures inhibitor drop-out value (Δ An).With the positive medicine of epristeride, calculate the inhibiting rate of enzyme.
Calculation formula: I (%)=(Δ A o-Δ An)/Δ A o* 100%
Result judgement, if 10 -6the inhibiting rate > 50% of given the test agent under mol/L concentration, can think that given the test agent has stronger 5α-reductase and suppresses active, can carry out next step screening, given the test agent concentration dilution is 10 times, again suppress active mensuration, the rest may be inferred.
3.3. data statistics
Result demonstration, each test-compound all has 5α-reductase in various degree to suppress active.
Figure BSA0000096768410000041
3.4. structure activity relationship analysis
This series has been carried out active testing to 11 compounds, all demonstrates certain inhibition active, and it is active that V1, V7, V8, V9, V10 show the inhibition stronger than epristeride.The ortho position of test result explanation benzamide has electron withdrawing group replacement that activity is improved and had very great help.The activity of VI1 is very general.Inferring may be because the excessive combination having affected with 5α-reductase of steric hindrance of tetrazole have caused active decline.Further research is also underway.
3.5 conclusion
Pharmacological evaluation demonstration, the compounds of this invention can obviously suppress the external activity of 5α-reductase, and part of compounds suppresses activity and is better than positive control epristeride.This compound can be used for treating the diseases such as BPH, prostate cancer.
The invention further relates to the compound of general formula one and the medicinal compositions that pharmaceutically acceptable carrier forms.
The compounds of this invention can be made preparation for administration separately or with one or more pharmaceutically acceptable carrier combinations.Can use oral dosage form administration, as conventional tablet and capsule, slow releasing tablet and capsule, controlled release tablet and capsule, dripping pill, dispersible powder, granule etc.; Also can be prepared into injection formulations.In these medicinal preparationss, can contain for example activeconstituents of 0.05% to 90% weight with carrier combinations, the more common approximately activeconstituents of weight between 15% to 60%.The compounds of this invention dosage can be 0.001～100mg/kg/ days, also can depart from this dosage range according to the difference of the difference of disease degree or formulation.
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:
XT4 type micro melting point apparatus for fusing point; Hydrogen nuclear magnetic resonance spectrometer is Bruker AV500 type (TMS is interior mark); Mass spectrograph is Shimadzu GCMS-QP2010 type mass spectrograph or Mariner mass spectrograph; Infrared spectrometer is Nicolet Impact410 type (KBr compressing tablet); Elemental analyser is ElementarVario EL III.
Embodiment 1
Bromo-17 β-carboxylate methyl ester-androstane-3 of 3-, the preparation of 5 diene (179)
162 (10g, 0.032mol) are dissolved in 52mL Glacial acetic acid, and stirring at room is dissolved, and drips PBr 3(4.6mL, 0.048mol), reaction 30min, separates out solid.Suction filtration, Glacial acetic acid washing leaching cake, infrared lamp is dry, obtains white solid 179 (7.8g, 65%).m.p.：228-230℃； 1H?NMR(CDCl 3，300MHz)δ：6.3(s，1H，C 4-H)，5.4(s，1H，C 6-H)，1.0(s，3H，19-CH 3)，0.77(s，3H，18-CH 3)ppm；ESI-MS?m/z：378[M-H] -.
Embodiment 2
3-bromo-N-[2,5-bis-(trifluoromethyl) phenyl] androstane-3,5-diene-17 β-methane amides (180-1) synthetic
By bromo-17 β-carboxylate methyl ester-androstane-3 of 3-, 5 diene (6.0g, 15.87mmol) be dissolved in 120mL toluene, under ice bath, add anhydrous pyridine (2.1mL) and oxalyl chloride (2.4mL), under ice bath, stir 1h, at room temperature stir again 1h, add 2,5-bis-(trifluoromethyl) aniline (10.0mL), reaction 2h, concentrate and remove most of solvent, add 40mL CH 2cl 2, 10%H 2sO 4, H 2o respectively washes 3 times, anhydrous Na 2sO 4dry, the dense yellow solid 180-1 (20%) that does to obtain.EI-MS?m/z：590(M +).
Embodiment 3
3-cyano group-N-[2,5-bis-(trifluoromethyl) phenyl] androstane-3,5-diene-17 β-methane amides (181-1) synthetic
180-1 (0.8g, 1.35mmol) is dissolved in 15mL DMF, adds cuprous cyanide (0.24g, 2.7mmol), be warming up to 180 ℃ of reaction 12h.Cooling, suction filtration, collects filtrate, pours in 60mL water, stirs, standing, suction filtration, and infrared lamp is dry, obtains deep yellow solid 181-1 (0.45g, 62%).ESI-MS?m/z：559[M+Na] +.
Embodiment 4
17 β-{ N-[2,5-bis-(trifluoromethyl) phenyl] carbamyl } androstane-3,5-diene-3-carboxylic acid (V1) synthetic
181-1 (0.45g, 0.84mmol) is dissolved in 10mL ethanol, adds 20%NaOH solution 0.17mL, be warming up to back flow reaction 6h.Cooling, decompression is revolved and is desolventized ethanol, and product is dissolved in 10mL water, and 2N hydrochloric acid conditioning solution pH value is 2, separate out solid, suction filtration, infrared lamp is dry, obtains yellow solid, column chromatography, launches with petrol ether/ethyl acetate=2:1, obtains yellow solid V1 (0.2g, 43%).m.p.：280-284℃； 1H?NMR(DMSO，300MHz)δ：12.0(s，1H，COOH)，9.4(s，1H，NH)，8.0～7.7(m，3H，Ar-H)，6.8(s，1H，C 4-H)，5.9(s，1H，C 6-H)，0.9(s，3H，19-CH 3)，0.8(s，3H，18-CH 3)ppm；IR(KBr)v：3434，2930，1725，1384，1097cm -1；ESI-MS?m/z：554[M-H] -；Anal.calcd?for?C 29H 31F 6NO 3：C62.70，H5.62，N2.52；Found：C62.84，H5.384，N2.318.
Embodiment 5
17 β-{ N-[3,5-bis-(trifluoromethyl) phenyl] carbamyl } androstane-3,5-diene-3-carboxylic acid (V2) synthetic
Concrete operations, with embodiment 4, obtain yellow solid V2 (23%).m.p.：140-142℃； 1H?NMR(DMSO，300MHz)δ：10.2(s，1H，COOH)，8.4(s，1H，NH)，7.73～7.68(m，2H，Ar-H)，7.3(s，1H，Ar-H)，6.8(s，1H，C 4-H)，5.7(s，1H，C 6-H)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；IR(KBr)v：3357，2941，1670，1436，1134cm -1；ESI-MS?m/z：554[M-H] -；Anal.calcd?for?C 29H 31F 6NO 3：C62.70，H5.62，N2.52；Found：C62.95，H5.298，N2.309.
Embodiment 6
17 β-[N-(2-methyl-4-carboxyl phenyl) carbamyl] androstane-3,5-diene-3-carboxylic acid (V3) synthetic
Concrete operations, with embodiment 4, obtain yellow solid V3 (35%).m.p.：294-296℃； 1HNMR(DMSO，300MHz)δ：9.0(s，1H，NH)，7.8～7.6(m，3H，Ar-H)，6.9(s，1H，C 4-H)，5.9(s，1H，C 6-H)，2.3(s，3H，Ar-H)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；IR(KBr)v：3439，2967，2200，1681，1292cm -1；?ESI-MS?m/z：476[M-H] -；Anal.calcd?for?C 29H 35NO 5：C72.93，H7.39，N2.93；Found：C73.27，H7.71.N2.54.
Embodiment 7
17 β-[N-(4-p-methoxy-phenyl) carbamyl] androstane-3,5-diene-3-carboxylic acid (V4) synthetic
Concrete operations, with embodiment 4, obtain yellow solid V4 (24%).m.p.：194-196℃； 1H?NMR(DMSO，300MHz)δ：9.4(s，1H，NH)，7.5(d，2H，J＝8.67Hz，2’，6’-H)，6.9(d，2H，J＝8.7Hz，3’，5’-H)，6.7(s，1H，C 4-H)，5.7(s，1H，C 6-H)，3.7(s，3H，O-CH 3)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；IR(KBr)v：3414，2940，1661，1511，1234cm -1；ESI-MS?m/z：450[M+H] +；Anal.calcd?for?C 28H 35NO 4：C74.80，H7.85，N3.12；Found：C74.55，H8.117，N2.755.
Embodiment 8
17 β-[N-(the chloro-3-trifluoromethyl of 4-) carbamyl] androstane-3,5-diene-3-carboxylic acid (V5) synthetic
Concrete operations, with embodiment 4, obtain yellow solid V5 (13%).m.p.：158-164℃； 1H?NMR(DMSO，300MHz)δ：10.0(s，1H，COOH)，8.2(s，1H，NH)，7.9(d，1H，J＝8.7Hz，2’-H)，7.7(d，1H，J＝8.67Hz，5’-H)，7.3(m，1H，6’-H)，6.7(s，1H，C 4-H)，5.7(s，1H，C 6-H)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；IR(KBr)v：3339，2940，1659，1413，1173cm -1；ESI-MS?m/z：523[M+H] +；Anal.calcd?forC 28H 31ClF 3NO 3：C64.43，H5.99，N2.68；Found：C64.55，H5.776，N2.556.
Embodiment 9
17 β-[N-(3-trifluoromethyl) carbamyl] androstane-3,5-diene-3-carboxylic acid (V6) synthetic
Concrete operations, with embodiment 4, obtain yellow solid V6 (17%).m.p.：140-142℃； 1HNMR(DMSO，300MHz)δ：9.9(s，1H，NH)，8.1(s，1H，2’-H)，7.8(d，1H，J＝8.01Hz，6’-H)，7.5～7.3(m，2H，4’，5’-H)，6.7(s，1H，C 4-H)，5.7(s，1H，C 6-H)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)PPm；IR(KBr)v：3342，2937，1661，1333，698cm -1；ESI-MS?m/z：488[M+H] +；Anal.calcd?for?C 28H 32F 3NO 3：C68.98，H6.62，N2.87；Found：C68.56，H7.173，N2.952.
Embodiment 10
17 β-(N-phenyl amino formyl) androstane-3,5-diene-3-carboxylic acid (V7) synthetic
Concrete operations, with embodiment 4, obtain yellow solid V7 (24%).m.p.：138-140℃； 1HNMR(DMSO，300MHz)δ：9.5(s，1H，NH)，7.6(d，2H，J＝7.89Hz，2’，6’-H)，7.3(t，2H，J＝7.53Hz，3’，5’-H)，7.0(t，1H，J＝7.26Hz，4’-H)，6.7(s，1H，C 4-H)，5.7(s，1H，C 6-H)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；IR(KBr)v：3474，2936，1661，1439，753cm -1；ESI-MS?m/z：420[M+H] +；Anal.calcd?forC 27H 33NO 3：C77.29，H7.93，N3.34；Found：C77.20，H7.66，N3.74.
Embodiment 11
17 β-[N-(2-cyano-phenyl) carbamyl] androstane-3,5-diene-3-carboxylic acid (V8) synthetic
Concrete operations, with embodiment 4, obtain yellow solid V8 (15%).m.p.：175-180℃； 1HNMR(DMSO，300MHz)δ：12.1(s，1H，COOH)，11.9(s，1H，NH)，8.1(d，1H，J＝7.4Hz，6’-H)，7.8(m，1H，5’-H)，7.6(d，1H，J＝7.52Hz，3’-H)，7.4(m，1H，4’-H)，6.9(s，1H，C 4-H)，5.9(s，1H，C 6-H)，0.85(s，3H，19-CH 3)，0.6(s，3H，18-CH 3)ppm；IR(KBr)v：3457，2938，1672，1610，774cm -1；ESI-MS?m/z：443[M-H] -；Anal.calcd?for?C 28H 32N 2O 3·1/4CH 3OH：C74.97，H7.35，N6.19；Found：C75.06，H7.831，N5.986.
Embodiment 12
17 β-[N-(2,5-3,5-dimethylphenyl) carbamyl] androstane-3,5-diene-3-carboxylic acid (V9) synthetic
Concrete operations, with embodiment 4, obtain yellow solid V9 (28%).m.p.：200-205℃； 1HNMR(DMSO，300MHz)δ：12.1(s，1H，COOH)，8.9(s，1H，NH)，7.15(s，1H，6’-H)，7.08(d，1H，J＝7.68Hz，3’-H)，6.94(s，1H，C 4-H)，6.9(d，1H，J＝7.53Hz，4’-H)，5.85(s，1H，C 6-H)，2.3(s，3H，Ar-CH 3)，2.2(s，3H，Ar-CH 3)，0.9(s，3H，19-CH 3)，0.8(s，3H，18-CH 3)ppm；IR(KBr)v：2963，2360，1669，1284，804cm -1；ESI-MS?m/z：446[M-H] -；Anal.calcd?for?C 29H 37NO 3：C77.82，H8.33，N3.13；Found：C77.71，H7.895，N3.056.
Embodiment 13
17 β-[N-(2-p-methoxy-phenyl) carbamyl] androstane-3,5-diene-3-carboxylic acid (V10) synthetic
Concrete operations reference compound V1's is synthetic, obtains yellow solid V10 (26%).m.p.：232-235℃； 1H?NMR(DMSO，300MHz)δ：12.1(s，1H，COOH)，8.4(s，1H，NH)，7.9(d，1H，J＝8.07Hz，6’-H)，7.1～6.9(m，3H，3’，4’，5’-H)，6.9(s，1H，C 4-H)，5.9(s，1H，C 6-H)，3.8(s，3H，O-CH 3)，0.9(s，3H，19-CH 3)，0.7(s，3H，18-CH 3)ppm；IR(KBr)v：3425，2946，1673，1483，741cm -1；ESI-MS?m/z：448[M-H] -；Anal.calcd?for?C 28H 35NO 4·1/2H 2O：C74.06，H7.88，N3.08；Found：C73.68，H8.135，N2.738.
Embodiment 14
Bromo-17 β of 3--(tertiary butyl carbamyl)-androstane-3, the preparation of 5 diene (182)
163-1 (1.5g, 4.0mmol) is dissolved in 8mLHOAc, drips PBr 3(0.39mL), in 10min, add, reaction 30min, separates out orange solid 182 (1.47g, 85%).M.p.182～184 ℃ (document [3]m.p.184～186 ℃).
Embodiment 15
3-itrile group-17 β-(tertiary butyl carbamyl)-androstane-3, the preparation of 5 diene (183)
182 (2.15g, 4.96mmol) are dissolved in 55mL DMF, add CuCN (0.90g), be heated to 140 ℃, reaction 6h, cooling, be poured in 500mL trash ice water, filter, dry, add 10mL hot acetone, filter, concentrate and remove half volume, put refrigerator standing, separate out faint yellow solid 183 (1.52g, 81%).M.p.193～195 ℃. (document [4]m.p.195～197 ℃).
Embodiment 16
2-(5-1H-tetrazole)-17 β-(N-tertiary butyl carbamyl)-androstane-3, the preparation of 5 diene (VI1)
183 (0.7g, 1.84mmol) are dissolved in 15mL DMF, add NH 4cl (0.19g), NaN 3(0.38g), be heated to 150 ℃, reaction 48h, cooling, add 10%H 2sO 4solution 1mL, stirs 1h, is poured in 200mL trash ice water, filters, and obtains khaki color solid VI1 (0.26g, 29%). 1H?NMR(CDCl 3，300MHz)δ：7.06(s，1H，4-H)，5.79(s，1H，6-H)，5.23(s，1H，N-H)，1.38(s，9H，tBu)，0.99(s，3H，19-CH 3)，0.74(s，3H，18-CH 3)；IR(KBr)v：3442，1647，1606，1547，1385，1227cm -1；ESI-MS?m/z：422.3[M-H] -。

Claims (6)

1.符合通式一的化合物及其药学上可接受的盐：1. Compounds meeting the general formula 1 and pharmaceutically acceptable salts thereof: 通式一：General formula one:
Figure FSA0000096768400000011
Figure FSA0000096768400000011
 其中当R1为COOH时，R2为苯基、2-氰基苯基、2，5-二三氟甲基苯基、3，5-二三氟甲基苯基、2-甲基-4-羧基苯基、4-甲氧基苯基、4-氯-3-三氟甲基苯基、3-三氟甲基苯基、2-甲氧基苯基、2，5-二甲基苯甲基；Wherein when R 1 is COOH, R 2 is phenyl, 2-cyanophenyl, 2,5-ditrifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 2-methyl- 4-carboxyphenyl, 4-methoxyphenyl, 4-chloro-3-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-methoxyphenyl, 2,5-dimethyl phenylbenzyl; 当R1为R2为叔丁基。When R1 is R 2 is t-butyl. 2.权利要求1中的化合物及其药学上可接受的盐，其特征在于R1为COOH，R2为苯基、2-氰基苯基、2，5-二三氟甲基苯基、4-甲氧基苯基、2，5-二甲基苯甲基。2. the compound in claim 1 and pharmaceutically acceptable salt thereof are characterized in that R 1 is COOH, R 2 is phenyl, 2-cyanophenyl, 2,5-two trifluoromethylphenyl, 4-methoxyphenyl, 2,5-dimethylbenzyl. 3.权利要求2中的化合物及其药学上可接受的盐，其特征在于R1为COOH且R2为2，5-二三氟甲基苯基。3. Compounds and pharmaceutically acceptable salts thereof in claim 2, characterized in that R 1 is COOH and R 2 is 2,5-bistrifluoromethylphenyl. 4.权利要求1至3中的化合物的合成方法：4. the synthetic method of the compound in the claim 1 to 3:
Figure FSA0000096768400000013
Figure FSA0000096768400000013
 其中的R为权利要求1所述化合物中的取代氨基；Wherein R is the substituted amino group in the compound described in claim 1; 反应条件及试剂：a)三溴化磷，醋酸；b)草酰氯，上述取代胺类，吡啶；c)氰化亚铜，DMF；d)20％的氢氧化钠水溶液，乙醇；e)叠氮化钠，氯化铵。Reaction conditions and reagents: a) phosphorus tribromide, acetic acid; b) oxalyl chloride, the above-mentioned substituted amines, pyridine; c) cuprous cyanide, DMF; d) 20% aqueous sodium hydroxide solution, ethanol; Sodium Nitride, Ammonium Chloride. 5.5α-还原酶抑制剂的药物组合物，其中含有权利要求1至3的任一项化合物或其药学上可接受的盐及药学上可接受的载体。5.5 A pharmaceutical composition of an α-reductase inhibitor, which contains any one of the compounds of claims 1 to 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 6.权利要求1至3任一项化合物或其药学上可接受的盐用于制备作为5α-还原酶抑制剂的药物的用途。6. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament as a 5α-reductase inhibitor.
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CN112494488A (en) * 2020-06-17 2021-03-16 中国药科大学 Application of rebamipide in preventing alopecia and growing hair
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