CN106866773A - One group of preparation method and application with active anticancer pyrazolyl steroid derivative - Google Patents
One group of preparation method and application with active anticancer pyrazolyl steroid derivative Download PDFInfo
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Abstract
The invention discloses the preparation method and application that a group has active anticancer pyrazolyl steroid derivative; belong to technical field of medicine synthesis; first by different pregnenolone 1; 5; phenylhydrazone 2 and 8 is generated under 16 diene progesterone and the catalysis of phenylhydrazine acetic acid; then there is ring closure reaction under the catalysis of POCl3 and obtain the compound 3 and 9 with pyrazole ring, then hydrolysis obtains the compound 4 and 10 of deformylase, to 6 under the reduction of sodium borohydride.There is amination reduction reaction and obtain 5a e and 11a e in intermediate product 4 and 10 with amine under the catalysis of sodium triacetoxy borohydride.Route of the invention is novel and high being easily isolated of yield is the optimal route for preparing such compound.
Description
Technical field
The invention belongs to technical field of medicine synthesis, it is related to one group of preparation with active anticancer pyrazolyl steroid derivative
Method and application.
Background technology
Cancer is the biggest threat of human health all the time, although present prevention and treatment means has developed still
The annual patient for dying from cancer is still increasing.The need for the treatment method of existing medicine can not meet treatment for diseases, urgently
Need to filter out new anticarcinogen to tackle changeable illness.Toxicity based on steroidal drug is low, and utilization rate is high, is difficult to produce
The advantages of raw drug resistance, increasing steroidal drug is developed.
The content of the invention
It is an object of the invention to provide the preparation method and application that a group has active anticancer pyrazolyl steroid derivative.
Its concrete technical scheme is：
One group has active anticancer pyrazolyl steroid derivative, and chemical structural formula is：
A kind of preparation method with active anticancer pyrazolyl steroid derivative of the present invention, comprises the following steps：
(1) 6.32g pregnenolones are dissolved in the 250mL eggplant type flasks of 150mL glacial acetic acid, stirring is treated completely molten
Solution, is then dividedly in some parts phenylhydrazine, and stirring ultrasound is measured in slowly instill under 3.46mL triethylamine normal temperature reaction system to dissolving,
Dripped after half an hour and finished, stirring at normal temperature 6h solids to be had are separated out, suction filtration, and are washed with glacial acetic acid, dry to obtain the He of target compound 2
87.8g, this product can be directly used for next step reaction without separating；
(2) visemier reagents are prepared first：Abundant dry round-bottomed flask is taken, the dried DMF of 20mL are inwardly added
Solution, lower inside slowly dropwise addition POCl3 solution 4.65mL, the 50mmol of stirring, drips after half an hour and finishes, and whole period temperature need to
It is maintained at 0 DEG C.It is stand-by that mixed liquor continues stirring reaction 20min.Substrate steroidal phenylhydrazone 10mmol is dissolved in 30mL dry DMFs
In, at 0 DEG C, this slowly being instilled in prepared visemier reagents, this process needs 30min, drop to continue to stir 24h after finishing,
Detection reaction is to complete.Now reaction system is poured into the sodium bicarbonate solution of saturation, stirred to there is solid to separate out, suction filtration is obtained
Crude product to target product is then dissolved in being extracted three times in dichloromethane, and gained organic phase merges drying, filtering, post point, stone
Oily ether: ethyl acetate=4: 1, obtain the sterling 3g of target compound 3 and 9；
(3) pyrazolyl pregnene alcohol 5mmol is taken, is dissolved in the mixed solution of 20mL tetrahydrofurans and 20mL methyl alcohol, Ran Houjia
Enter potassium carbonate 5.5mmol, 759mg, ultrasonic agitation is heated to reflux 2h to being completely dissolved, detection reaction to complete, and then with rotating
Evaporimeter removes solvent, and profit is extracted with ethyl acetate three times, merges organic phase, and post gets target compound 4 and 10
4.8mmol；
(4) remove that formylated pyrazolyl pregnene alcohol 0.5mmol is dissolved in 10mL tetrahydrofurans and the mixing of 10mL methyl alcohol is molten
In liquid, sodium borohydride 38mg, 1mmol are then dividedly in some parts, after room temperature reaction 1h, detection reaction is finished and is quenched with glacial acetic acid, so
After be extracted with ethyl acetate three times, merge organic, Xiang Zhufen, petroleum ether: ethyl acetate=1: 1, obtain target product
60.48mmol；
(5) take 25mL dries round-bottomed flask, goes formylated pyrazolyl pregnene alcohol to be dissolved in 1, the 2- bis- of water removal 1mmol
In chloroethanes 15mL, stirring is lower to add anil 1.1mmol, is then dividedly in some parts Sodium triacetoxyborohydride, and normal temperature is stirred
8h, detection reaction are mixed, question response adds the sodium bicarbonate solution of saturation to be quenched, then extracted three times with dichloromethane afterwards completely,
Merge organic phase, post divides, dichloromethane: methyl alcohol=10: 1, obtain amination reduzate 5a-e and 11a-e 0.75mmol.
It is of the present invention to prepare treatment human lung adenocarcinoma, cervix cancer, people with active anticancer pyrazolyl steroid derivative
Application during breast cancer medicines.
Compared with prior art, beneficial effects of the present invention are：
1 three kinds of pyrazolyl steroid derivatives of the invention are brand-new compounds, and its preparation method is also to synthesize such
Successful Application first in compound.
(A549 (human lung adenocarcinoma cell), (cervix cancer is thin for Hela to three kinds of tumour cells for 2 three kinds of derivatives of the invention
Born of the same parents be), MCF7 (human breast cancer cell)) and 293T cells propagation all have good inhibitory activity, its IG50Between
Between 0.53uM-7.51uM.
3 routes of the invention are novel and high being easily isolated of yield is the optimal route for preparing such compound.
Brief description of the drawings
Fig. 1 is the syntheti c route a of pyrazolyl steroid derivative, wherein, (a) Phenylhydrazine, AcOH, rt；(b)
POCl3, DMF, 0 DEG C；(c)K2CO3, THF/H2O, rt；(d)R-NH2, DCE, NaBH (AcO)3, rt；(e) MeOH/THF, NaBH4,
rt；
Fig. 2 is the syntheti c route b of pyrazolyl steroid derivative, wherein, (f) Phenylhydrazine, AcOH, rt；(g)
POCl3, DMF, 0 DEG C~40 DEG C；(h)K2CO3, THF/H2O, rt；(i)R-NH2, DCE, NaBH (AcO)3, rt.
Specific embodiment
Technical scheme is described in more detail with specific embodiment below in conjunction with the accompanying drawings.
First phenylhydrazone 2 and 8 will be generated under the catalysis of the diene progesterone of different pregnenolone 1,5,16- and phenylhydrazine acetic acid, then three
There is ring closure reaction under the catalysis of chlorethoxyfos and obtain the compound 3 and 9 with pyrazole ring, then hydrolysis obtains deformylase
Compound 4 and 10, to 6 under the reduction of sodium borohydride.Intermediate product 4 and 10 under the catalysis of sodium triacetoxy borohydride and
Amine generation amination reduction reaction obtains 5a-e and 11a-e, 5a-e and 11a-e is specifically shown in Table 1.
Table 1
Embodiment 1
Chemical synthesis prepares the pyrazolyl steroid derivative of formula (I)
(1) 6.32g (20mmol) pregnenolone is dissolved in the 250mL eggplant type flasks of 150mL glacial acetic acid, stirring is treated
It is completely dissolved, is then dividedly in some parts phenylhydrazine (22mmol), stirring ultrasound measures 3.46mL (25mmol) triethylamine normal temperature to dissolving
Under slowly instill reaction system, dripped after half an hour and finish, stirring at normal temperature 6h solids to be had are separated out, suction filtration, and are washed with glacial acetic acid
Wash, dry to obtain the about 7.8g of target compound 2 and 8, this product can be directly used for next step reaction without separating.
(2) visemier reagents are prepared first：Abundant dry round-bottomed flask is taken, the dried DMF of 20mL are inwardly added
Solution, lower inside slowly dropwise addition POCl3 solution (4.65mL, 50mmol) of stirring, drips after half an hour and finishes, whole period temperature
0 DEG C need to be maintained at.It is stand-by that mixed liquor continues stirring reaction 20min.Substrate steroidal phenylhydrazone (10mmol) is dissolved in 30mL anhydrous
In DMF, at 0 DEG C, this is slowly instilled in prepared visemier reagents, this process needs 30min, drop to continue to stir after finishing
24h, detection reaction is to complete.Now reaction system is poured into the sodium bicarbonate solution of saturation, stirred to there is solid to separate out, taken out
The crude product that filter obtains target product is then dissolved in being extracted three times in dichloromethane, and gained organic phase merges drying, filtering, post point
(petroleum ether: ethyl acetate=4: 1) obtains the sterling about 3g of target compound 3 and 9.
(3) pyrazolyl pregnene alcohol 5mmol is taken, is dissolved in the mixed solution of 20mL tetrahydrofurans and 20mL methyl alcohol, Ran Houjia
Enter potassium carbonate (5.5mmol, 759mg), ultrasonic agitation is to being completely dissolved.Be heated to reflux 2h, detection reaction to complete, and then with revolving
Turn evaporimeter and remove solvent, profit is extracted with ethyl acetate three times, merge organic phase, post gets target compound 4 and 10 about
4.8mmol。
(4) remove that formylated pyrazolyl pregnene alcohol 0.5mmol is dissolved in 10mL tetrahydrofurans and the mixing of 10mL methyl alcohol is molten
In liquid, sodium borohydride (38mg, 1mmol) is then dividedly in some parts, after room temperature reaction 1h, detection reaction is finished and is quenched with glacial acetic acid,
Then it is extracted with ethyl acetate three times, merges organic, (petroleum ether: ethyl acetate=1: 1) obtains target product 6 about to Xiang Zhufen
0.48mmol。
(5) take 25mL dries round-bottomed flask, goes formylated pyrazolyl pregnene alcohol to be dissolved in 1, the 2- bis- of water removal 1mmol
In chloroethanes 15mL, stirring is lower to add anil 1.1mmol, is then dividedly in some parts Sodium triacetoxyborohydride, and normal temperature is stirred
8h, detection reaction are mixed, question response adds the sodium bicarbonate solution of saturation to be quenched, then extracted three times with dichloromethane afterwards completely,
Merge organic phase, (dichloromethane: methyl alcohol=10: 1) obtains amination reduzate 5a-e and 11a-e about 0.75mmol to post point.
Embodiment 2
The Structural Identification of chemical combination, synthesized three compounds its structure passes through1H-NMR、13C-NMR, high resolution mass spectrum
(HRMS) confirm.
1H-NMR、13C-NMR and HRMS data are as follows：
17β-(1-phenyl-4-((methylamino)methyl)-3-pyrazolyl)androst-3β-ol(5a)
5a, white solid, Yield：204-206 DEG C of 88%, mp；1H-NMR(CDCl3&CD3OD, 500MHz)：δ
(ppm) 8.09 (s, 1H), 7.67 (d, 2H, J=8.5Hz), 7.43 (t, 2H, J=7.0Hz), 7.26 (t, 1H, J=7.5Hz),
3.90-3.80 (m, 2H), 3.58-3.53 (m, 1H), 2.74 (t, 1H, J=9.5Hz), 2.53 (s, 3H, CH3), 2.47-2.40
(m, 1H), 2.01-1.93 (m, 1H), 1.78-1.70 (m, 4H), 1.56-1.54 (m, 3H), 1.40-1.10 (m, 12H), 1.00-
0.93 (m, 2H), 0.81 (s, 3H, CH3), 0.73-0.67 (m, 1H), 0.64 (s, 3H, CH3)；13C-NMR(CDCl3&CD3OD,
125MHz)：δ (ppm) 152.48,140.02,129.29,129.29,127.45,126.18,118.91,118.91,115.61,
70.81,56.33,54.53,48.39,44.91,44.79,44.33,38.56,37.74,37.02,35.99,35.53,
33.17,32.07,31.04,28.65,26.66,24.43,21.07 (CH3), 13.33 (CH3), 12.22 (CH3)；HRMS(ESI)
m/z calcd for C30H44N3O+(M+H)+462.34789, found 462.34738.
17β-(1-phenyl-4-((ethylamino)methyl)-3-pyrazolyl)androst-3β-ol(5b)
5b, white solid, Yield：246-248 DEG C of 80%, mp；1H-NMR (DMSO-d, 500MHz)：δ(ppm)
8.66 (s, 1H), 7.72-7.70 (m, 2H), 7.50 (t, 2H, J=7.0,8.5Hz), 7.30 (t, 1H, J=7.5Hz), 4.43
(s, br, 1H), 4.01-3.92 (m, 2H), 2.98 (dq, 2H, J=2.0,7.5Hz), 2.92 (t, 1H, J=9.5Hz), 2.40-
2.33 (m, 1H), 1.96-1.91 (m, 1H), 1.70-1.60 (m, 4H), 1.53-1.41 (m, 3H), 1.37-1.06 (m, 12H),
1.24 (t, 3H, J=7.5Hz), 0.96-0.88 (m, 2H), 0.74 (s, 3H, CH3), 0.71-0.65 (m, 1H), 0.55 (s, 3H,
CH3)；13C-NMR (DMSO-d, 125MHz)：δ (ppm) 152.71,139.98,130.13,130.13,129.58,126.65,
118.52,118.52,114.09,69.79,56.18,54.58,47.58,44.98,44.67,42.06,40.32,38.67,
37.95,37.21,36.08,35.69,32.32,31.86,28.88,26.62,24.57,21.16,13.85 (CH3), 12.65
(CH3), 11.57 (CH3)；HRMS(ESI)m/z calcd for C31H46N3O+(M+H)+476.36354, found
476.36313.
17β-(1-phenyl-4-((propylamino)methyl)-3-pyrazolyl)androst-3β-ol(5c)
5c, light brown solid, Yield：160-162 DEG C of 76%, mp；1H-NMR (DMSO-d, 500MHz)：δ
(ppm) 8.28 (s, 1H), 7.74-7.73 (m, 2H), 7.45 (t, 2H, J=7.5,8.0Hz), 7.30 (t, 1H, J=7.5Hz),
3.90 (s, br, 1H), 3.63-3.61 (m, 2H), 3.38-3.32 (m, 1H), 2.81 (t, 1H, J=10.0Hz), 2.56 (t, 2H,
J=7.5Hz), 2.37-2.30 (m, 1H), 1.68-1.58 (m, 4H), 1.55-1.32 (m, 5H), 1.28-1.04 (m, 10H),
0.94-0.90 (m, 2H), 0.87 (t, 3H, J=7.5Hz), 0.74 (s, 3H, CH3), 0.70-0.65 (m, 1H), 0.58 (s, 3H,
CH3)；13C-NMR (DMSO-d, 125MHz)：δ (ppm) 151.54,139.74,129.32,129.32,126.64,125.25,
120.35,117.52,117.52,69.23,55.67,53.94,50.41,47.59,44.37,44.07,42.47,38.10,
37.83,36.61,35.50,35.10,31.70,31.29,28.32,26.23,24.05,21.87,21.45,13.34 (CH3),
12.06(CH3), 11.62 (CH3)；HRMS(ESI)m/z calcd for C32H48N3O+(M+H)+490.37919, found
490.37924.
17β-(1-phenyl-4-((isopropylamino)methyl)-3-pyrazolyl)androst-3β-ol
(5d)
5d, white solid, Yield：216-218 DEG C of 83%, mp；1H-NMR(CDCl3&CD3OD, 500MHz)：δ
(ppm) 7.94 (s, 1H), 7.67-7.65 (m, 2H), 7.41 (t, 2H, J=7.0,8.5Hz), 7.23 (t, 1H, J=7.5Hz),
3.70 (m, 2H), 3.57-3.53 (m, 1H), 2.92-2.97 (m, 1H), 2.72 (t, 1H, J=10.0Hz), 2.47-2.39 (m,
1H), 2.00-1.94 (m, 1H), 1.80-1.69 (m, 4H), 1.60-1.54 (m, 3H), 1.45-1.32 (m, 3H), 1.35-1.28
(m, 6H), 1.15 (d, 6H, J=6.5Hz, 2CH3), 1.12-0.86 (m, 4H), 0.81 (s, 3H, CH3), 0.74-0.69 (m,
1H), 0.66 (s, 3H, CH3)；13C-NMR(CDCl3&CD3OD, 125MHz)：δ (ppm) 152.13,140.34,129.29,
129.29,126.40,125.83,119.70,118.84,118.84,70.99,56.42,54.59,48.66,44.99,
44.80,40.62,38.74,37.92,37.10,36.06,35.61,32.15,31.21,29.69,28.74,26.83,
24.54,22.12 (CH3), 21.99 (CH3), 21.16,13.49 (CH3), 12.33 (CH3)；HRMS(ESI)m/z calcd for
C32H48N3O+(M+H)+490.37919, found 490.37918.
17β-(1-phenyl-4-((butylamino)methyl)-3-pyrazolyl)androst-3β-ol(5e)
5e, white solid, Yield：138-140 DEG C of 83%, mp；1H-NMR(DMSO-d&CDCl3, 500MHz)：δ
(ppm) 8.35 (s, 1H), 7.73 (d, 2H, J=8.0Hz), 7.46 (t, 2H, J=7.5,8.5Hz), 7.24 (t, 1H, J=
7.5Hz), 3.73 (m, 2H), 3.37-3.33 (m, 1H), 2.84 (t, 1H, J=9.5Hz), 2.70 (t, 2H, J=7.5Hz),
2.38-2.32 (m, 1H), 1.69-1.62 (m, 4H), 1.51-1.47 (m, 4H), 1.34-1.11 (m, 12H), 1.08-0.88 (m,
6H), 0.88 (t, 3H, J=7.5Hz), 0.75 (s, 3H, CH3), 0.70-0.66 (m, 1H), 0.58 (s, 3H, CH3)；13C-NMR
(DMSO-d&CDCl3, 125MHz)：δ (ppm) 151.78,139.71,129.40,129.40,127.30,125.52,118.38,
117.72,117.72,69.30,55.74,54.04,47.71,47.48,44.45,44.14,41.98,38.13,37.77,
36.69,35.56,35.16,31.77,31.32,29.94,28.38,26.24,24.08,21.17,20.65,13.73 (CH3),
13.36(CH3), 12.12 (CH3)；HRMS(ESI)m/z calcd for C33H50N3O+(M+H)+504.39484, found
504.39404.
17 β-(1-phenyl-4- ((methylamino) methyl) -3-pyrazolyl) androst-5,16-
dienes-3β-ol(11a)
11a, white solid, Yield：108-110 DEG C of 80%, mp；1H-NMR(CDCl3&CD3OD, 500MHz)：δ
(ppm) 8.23 (s, 1H), 7.74-7.72 (m, 2H), 7.45 (t, 2H, J=7.5Hz, 8.5Hz), 7.28 (t, 1H, J=
7.5Hz), 5.93-5.92 (m, 1H), 5.40-5.39 (m, 1H), 4.00 (m, 2H), 3.52-3.46 (m, 1H), 3.36 (s, 1H),
2.58 (s, 3H), 2.41-2.25 (m, 4H), 2.17-2.06 (m, 1H), 1.88-1.75 (m, 3H), 1.72-1.64 (m, 2H),
1.58-1.26 (m, 5H), 1.15-0.87 (m, 9H), 1.15 (s, 3H, CH3), 1.08 (s, 3H, CH3)；13C-NMR(CDCl3&
CD3OD, 125MHz)：δ (ppm) 148.34,147.13,141.57,139.99,129.87,129.59,129.59,127.72,
126.56,121.39,118.72,118.72,114.74,71.49,57.02,50.88,48.56,43.84,42.12,37.41,
36.96,35.47,33.04,32.59,31.82,31.41,30.67,21.15 (CH3), 19.43 (CH3), 16.35 (CH3)；
HRMS(ESI)m/z calcd for C30H40N3O+(M+H)+458.31659, found 458.31656.
17 β-(1-phenyl-4- ((ethylamino) methyl) -3-pyrazolyl) androst-5,16-dienes-
3β-ol(11b)
11b, white solid, Yield：106-108 DEG C of 79%, mp；1H-NMR(CDCl3&CD3OD, 500MHz)：δ
(ppm) 7.86 (s, 1H), 7.62-7.60 (m, 2H), 7.36-7.32 (m, 2H), 7.16 (t, 1H, J=7.5Hz), 5.84 (s,
1H), 5.30 (s, 1H), 3.73-3.67 (m, 3H), 3.42-3.38 (m, 1H), 2.67-2.62 (m, 2H), 2.43-2.40 (m,
2H), 2.27-2.14 (m, 3H), 2.05-1.97 (m, 2H), 1.79-1.67 (m, 3H), 1.63-1.58 (m, 3H), 1.47-1.34
(m, 3H), 1.12-0.80 (m, 11H), 1.07 (t, 3H, CH3, J=7.5Hz), 1.04 (s, 3H, CH3), 1.00 (s, 3H,
CH3)；13C-NMR(CDCl3&CD3OD, 125MHz)：δ (ppm) 147.78,147.67,141.51,140.22,129.43,
129.43,128.95,126.11,125.97,121.38,120.18,118.46,118.46,71.43,56.95,50.84,
48.40,43.86,43.51,42.09,37.36,36.90,35.59,32.45,31.79,31.37,30.63,21.14,19.38
(CH3), 16.29 (CH3), 14.56 (CH3)；HRMS(ESI)m/z calcd for C31H42N3O+(M+H)+472.33224,
found 472.33211.
177- (1-phenyl-4- ((propylamino) methyl) -3-pyrazolyl) androst-5,16-
diennes-3β-ol(11c)
11c, white solid, Yield：130-132 DEG C of 62%, mp；1H-NMR(CDCl3&CD3OD, 500MHz)：δ
(ppm) 8.06 (s, 1H), 7.72-7.70 (m, 2H), 7.43 (t, 2H, J=7.5Hz, 8.5Hz), 7.25 (t, 1H, J=
7.5Hz), 5.93-5.92 (m, 1H), 5.39 (d, 1H, J=5.0Hz), 3.90-3.83 (m, 2H), 3.52-3.47 (m, 2H),
2.69 (t, 2H, J=7.5Hz), 2.48-2.46 (m, 1H), 2.34-2.22 (m, 3H), 2.15-2.06 (m, 2H), 1.87-1.75
(m, 3H), 1.68-1.40 (m, 9H), 1.14-1.04 (m, 8H), 1.14 (s, 3H, CH3), 1.08 (s, 3H, CH3), 0.95 (t,
3H, J=7.5Hz)；13C-NMR(CDCl3&CD3OD, 125MHz)：δ (ppm) 147.96,147.51,141.51,140.13,
129.46,129.46,129.23,127.70,126.12,121.39,118.53,118.53,118.33,71.49,56.98,
50.84,50.47,48.43,43.35,42.14,37.35,36.90,35.53,32.49,31.79,31.43,30.62,
21.92,21.12,19.41 (CH3), 16.33 (CH3), 11.59 (CH3)；HRMS(ESI)m/z calcd for C32H44N3O+(M
+H)+486.34789, found 486.34793.
17 β-(1-phenyl-4- ((isopropylamino) methyl) -3-pyrazolyl) androst-5,16-
dienes-3β-ol(11d)
77d, white solid, Yield：202-204 DEG C of 73%, mp；1H-NMR(CDCl3&CD3OD, 500MHz)：δ
(ppm) 8.57 (s, 1H), 7.76-7.74 (m, 2H), 7.43 (t, 2H, J=7.5Hz, 8.5Hz), 7.27 (t, 1H, J=
7.5Hz), 5.89-5.88 (m, 1H), 5.39 (d, 1H, J=5.0Hz), 4.13-4.06 (m, 2H), 3.52-3.46 (m, 1H),
3.36 (s, 1H), 3.27-3.22 (m, 1H), 2.36-2.25 (m, 4H), 2.17-2.05 (m, 2H), 1.86-1.75 (m, 3H),
1.71-1.62 (m, 3H), 1.56-1.49 (m, 3H), 1.37 (d, 3H, J=6.5Hz), 1.34 (d, 3H, J=6.5Hz), 1.15-
1.03 (m, 8H), 1.15 (s, 3H, CH3), 1.07 (s, 3H, CH3)；13C-NMR(CDCl3&CD3OD, 125MHz)：δ(ppm)
147.96,146.53,141.06,139.38,129.72,129.07,129.07,128.19,126.14,120.87,118.30,
118.30,112.51,71.04,56.64,50.36,48.60,48.05,41.67,38.41,36.90,36.45,34.82,
32.10,31.31,30.96,30.15,20.60,19.25,18.96 (CH3), 18.83 (CH3), 15.91 (CH3)；HRMS(ESI)
m/z calcd for C32H44N3O+(M+H)+486.34789, found 486.34750.
177- (1-phenyl-4- ((butylamino) methyl) -3-pyrazolyl) androst-5,16-dienes-
3β-ol(11e)
11e, glasslike solid, Yield：100-102 DEG C of 89%, mp；1H-NMR(CDCl3&CD3OD,
500MHz)：δ (ppm) 7.95 (s, 1H), 7.71-7.69 (m, 2H), 7.43 (t, 2H, J=7.5Hz, 8.5Hz), 7.24 (t, 1H,
J=7.5Hz), 5.93-5.94 (m, 1H), 5.40 (d, 1H, J=5.0Hz), 3.82-3.74 (m, 2H), 3.50-3.48 (m,
1H), 3.37 (s, 1H), 2.67 (t, 2H, 7.5Hz), 2.51-2.49 (m, 1H), 2.35-2.26 (m, 3H), 2.14-2.07 (m,
2H), 1.89-1.80 (m, 3H), 1.72-1.67 (m, 3H), 1.52-1.26 (m, 8H), 1.15-1.05 (m, 8H), 1.14 (s,
3H, CH3), 1.05 (s, 3H, CH3), 0.94 (t, 3H, J=7.5Hz)；13C-NMR(CDCl3&CD3OD, 125MHz)：δ(ppm)
147.82,147.70,141.50,140.23,129.44,129.44,128.96,126.19,125.97,121.41,120.11,
118.48,118.48,71.49,56.97,50.85,49.07,48.40,44.08,42.11,37.35,36.90,35.59,
32.46,31.80,31.60,31.40,30.63,21.14,20.52,19.40 (CH3), 16.32 (CH3), 13.95 (CH3)；
HRMS(ESI)m/z calcd for C33H46N3O+(M+H)+500.36354, found 500.36353.
Embodiment 3
The anti-tumour cell proliferative activity of the pyrazolyl steroid derivative of formula (I) of the present invention
The pyrazolyl steroid derivative of formula (I) of the present invention is determined to A549 (human lung adenocarcinoma cell), Hela using RSB methods
(cervical cancer cell system), MCF7 (human liver cancer cell), four kinds of proliferation inhibition activities of cell of 293T cell lines.
Specific method：Precise testing compound 1-3mg, with DMSO as solvent, it is 10mMol/L's to be configured to concentration
Solution, at room temperature stand half an hour preserve stand-by after sample is completely dissolved.Take the A549 in exponential phase, Hela,
293T, MCF7 cell, clean and are made cell suspension after being digested with pancreatin, and cell count is simultaneously diluted to debita spissitudo, by cell
Suspension is uniformly added in 96 orifice plates, per hole 100ul, three repetitions of every group of setting, while setting negative control and positive control
Hole.Good testing compound is added in 96 orifice plates to take a certain amount of configured in advance, compound from 50uM, 3 times of gradient dilutions,
Totally 9 gradients, the cell that then will be handled well is placed in 5% gas concentration lwevel, 72h is cultivated in 37 DEG C of incubators.Incubation time
Later, terminate culture, remove supernatant, each hole adds cold 10%TCA100ul, and 2h is fixed under the conditions of 4 DEG C, uses secondary steaming
Distilled water is rinsed 5 times repeatedly, and about half an hour is dried in 50 DEG C of baking ovens.After after its drying, the SRB solution of glacial acetic acid preparation is added
100ul, 5 dyestuffs to remove non-specific binding are rinsed after room temperature dyeing half an hour with 1% glacial acetic acid, and this step needs operation
It is rapid preventing the dyestuff decomposition for having been combined with protein-specific.50 DEG C of oven for drying half an hour, plus 150ul Tris solution
Dissolving is patted and mixed, and ELIASA A540nm mensuration absorbances calculate its inhibiting rate, its IC is calculated with EXCEl50, the results are shown in Table 2.
The part of compounds antiproliferation IC of table 250(μmol/L)
The result of table 2 illustrates pyrazolyl steroid derivative to A549 (human lung adenocarcinoma cell), Hela (cervical cancer cells
System), MCF7 (human breast cancer cell), four kinds of tumour cells of 293T cells have good cytotoxicity.
The above, preferably specific embodiment only of the invention, protection scope of the present invention not limited to this are any ripe
Those skilled in the art are known in the technical scope of present disclosure, the letter of the technical scheme that can be become apparent to
Altered or equivalence replacement are each fallen within protection scope of the present invention.
Claims (3)
1. one group has active anticancer pyrazolyl steroid derivative, it is characterised in that chemical structural formula is：
2. there is the preparation method of active anticancer pyrazolyl steroid derivative described in a kind of claim 1, it is characterised in that including
Following steps：
(1) 6.32g pregnenolones are dissolved in the 250mL eggplant type flasks of 150mL glacial acetic acid, stir and wait to be completely dissolved, so
After be dividedly in some parts phenylhydrazine, stirring ultrasound is measured in slowly instill under 3.46mL triethylamine normal temperature reaction system, half an hour to dissolving
Drip afterwards and finish, stirring at normal temperature 6h solids to be had are separated out, suction filtration, and are washed with glacial acetic acid, dry to obtain each 7.8g of target compound 2 and 8,
This product is directly used in next step reaction without separating；
(2) visemier reagents are prepared first：Abundant dry round-bottomed flask is taken, the dried DMF solutions of 20mL are inwardly added,
Lower inside slowly dropwise addition POCl3 solution 4.65mL, the 50mmol of stirring, drips after half an hour and finishes, and whole period temperature need to be maintained at
0℃；It is stand-by that mixed liquor continues stirring reaction 20min；Substrate steroidal phenylhydrazone 10mmol is dissolved in 30mL dry DMFs, 0 DEG C
Under, this slowly being instilled in prepared visemier reagents, this process needs 30min, drop to continue to stir 24h after finishing, and detection is anti-
Should be to complete；Now reaction system is poured into the sodium bicarbonate solution of saturation, stirred to there is solid to separate out, suction filtration obtains target
The crude product of product is then dissolved in being extracted three times in dichloromethane, and gained organic phase merges drying, filtering, post point, petroleum ether：Second
Acetoacetic ester=4:1, obtain the sterling 3g of target compound 3 and 9；
(3) pyrazolyl pregnene alcohol 5mmol is taken, is dissolved in the mixed solution of 20mL tetrahydrofurans and 20mL methyl alcohol, be subsequently adding carbon
Sour potassium 5.5mmol, 759mg, ultrasonic agitation are heated to reflux 2h to being completely dissolved, and detection reaction uses rotary evaporation to complete
Instrument removes solvent, and profit is extracted with ethyl acetate three times, merges organic phase, and post gets the 4.8mmol of target compound 4 and 10；
(4) formylated pyrazolyl pregnene alcohol 0.5mmol is removed to be dissolved in the mixed solution of 10mL tetrahydrofurans and 10mL methyl alcohol,
Then sodium borohydride 38mg, 1mmol are dividedly in some parts, after room temperature reaction 1h, detection reaction is finished and is quenched with glacial acetic acid, then uses second
Acetoacetic ester is extracted three times, merges organic, Xiang Zhufen, petroleum ether：Ethyl acetate=1:1, obtain the 0.48mmol of target product 6；
(5) take 25mL dries round-bottomed flask, goes formylated pyrazolyl pregnene alcohol to be dissolved in the chloroethenes of 1,2- bis- of water removal 1mmol
In alkane 15mL, stirring is lower to add anil 1.1mmol, is then dividedly in some parts Sodium triacetoxyborohydride, stirring at normal temperature 8h,
Detection reaction, question response adds the sodium bicarbonate solution of saturation to be quenched afterwards completely, is then extracted three times with dichloromethane, is associated with
Machine phase, post point, dichloromethane：Methyl alcohol=10:1, obtain amination reduzate 5a-e and 11a-e 0.75mmol.
3. there is active anticancer pyrazolyl steroid derivative to prepare treatment human lung adenocarcinoma, cervix cancer, people described in claim 1
Application during breast cancer medicines.
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