CN110272465A - Abiraterone derivative, preparation method and application - Google Patents
Abiraterone derivative, preparation method and application Download PDFInfo
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- CN110272465A CN110272465A CN201910636068.1A CN201910636068A CN110272465A CN 110272465 A CN110272465 A CN 110272465A CN 201910636068 A CN201910636068 A CN 201910636068A CN 110272465 A CN110272465 A CN 110272465A
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- abiraterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
Abstract
The present invention provides a kind of abiraterone derivatives as shown in formula (i) or formula (ii), present invention also provides the preparation methods of one kind abiraterone derivative as shown in formula (I), present invention also provides the preparation methods of one kind abiraterone derivative as shown in formula (II), and present invention also provides application of the abiraterone derivative in preparation treatment prostate cancer drug.Due to introducing specifically containing cl radical in abiraterone derivative provided by the present application, so that abiraterone derivative can significantly inhibit prostate gland cancer cell proliferation, and there is stronger inhibitory activity to prostate gland cancer cell.
Description
Technical field
The present invention relates to pharmaceutical technology field more particularly to abiraterone derivatives, preparation method and application.
Background technique
Abiraterone (Abiraterone), -3 β -ol of chemical name 17- (3- pyridyl group) androstane -5,16- diene, molecule
Formula is C24H31NO, specifically as shown in formula (I).
The mechanism of action that abiraterone is applied to prostate cancer is: the growth of prostate gland cancer cell needs androgen mostly
Supply, CYP17 are the rate-limiting enzyme in the biosynthetic process of male sex hormone, and abiraterone reaches anti-by the inhibition to CYP17
The effect of prostate cancer.Abiraterone, which is clinically primarily adapted for use in, is combined the receiving for the treatment of the past containing Docetaxel with prednisone
Treat transfer castration refractory prostate cancer patient.In addition, to improve its body absorption, abiraterone uses its pro-drug Ah ratio
Special dragon acetic acid esters form as shown in formula (II) oral administration, releases abiraterone in vivo and generates drug effect.Although Ah's bit
Dragon has biggish clinical value, but abiraterone clinical therapeutic efficacy is still limited, inhibits prostate gland cancer cell activity not
Height clinically still needs new therapeutic agent.
Summary of the invention
Present invention solves the technical problem that being to provide a kind of abiraterone derivative and its application, the abiraterone are derivative
Object has stronger inhibitory activity to prostate gland cancer cell.
In view of this, this application provides a kind of abiraterone derivative as shown in formula (i) or formula (ii),
Present invention also provides the preparation methods of the abiraterone derivative as shown in formula (I), comprising:
Abiraterone and solid phosgene are reacted in a solvent, obtain intermediate product；
By the intermediate product and bischloroethylamines hydrochloric acid reactant salt, the abiraterone derivative as shown in formula (I) is obtained；
Present invention also provides the preparation methods of the abiraterone derivative as shown in formula (II), comprising:
Abiraterone and dichloroacetyl chloride are reacted in a solvent, obtain the abiraterone derivative as shown in formula (II)；
Present invention also provides application of the abiraterone derivative in preparation treatment prostate cancer drug, Ah's bits
Imperial derivative is selected from one or both of abiraterone derivative as shown in formula (I) and formula (II)；
Present invention also provides a kind of preparation, including abiraterone derivative and pharmaceutically acceptable auxiliary material, Ah
Bit dragon derivative is selected from one or both of abiraterone derivative shown in formula (I) and formula (II)；
Preferably, the dosage form of the preparation is oral preparation, injection, suppository or inhalant.
Preferably, the dosage form of the preparation be tablet, capsule, granule, pill, liquid preparation, soft extract, suspending agent,
Dispersing agent, syrup, gelling agent or aerosol.
Preferably, the dosage of the abiraterone derivative is 0.5~250mg.
This application provides a kind of abiraterone derivative such as (I) or formula (II) shown in, due to introducing in the derivative
Specifically contain cl radical, so that abiraterone derivative can significantly inhibit prostate gland cancer cell proliferation, and thin to prostate cancer
Born of the same parents have stronger inhibitory activity.
Detailed description of the invention
Fig. 1 is a series of anti-prostate cancer cell activity experimental result of compounds and combinations thereof in embodiment 4.
Specific embodiment
For a further understanding of the present invention, the preferred embodiment of the invention is described below with reference to embodiment, still
It should be appreciated that these descriptions are only further explanation the features and advantages of the present invention, rather than to the claims in the present invention
Limitation.
In view of the problem that abiraterone in the prior art inhibits prostate gland cancer cell activity not high, this application provides one kind
Prostate gland cancer cell proliferation can be effectively suppressed in abiraterone derivative, the derivative, and has to prostate gland cancer cell stronger
Inhibitory activity, specifically, the embodiment of the invention discloses a kind of abiraterone derivative as shown in formula (i) or formula (ii),
Above two abiraterone derivative provided by the present application introduce respectively it is above two specifically containing cl radical, by
This makes abiraterone derivative more excellent to the inhibitory effect of prostate gland cancer cell.
Present invention also provides the preparation methods of the abiraterone derivative as shown in formula (I), comprising:
Abiraterone and solid phosgene are reacted in a solvent, obtain intermediate product；
By the intermediate product and bischloroethylamines hydrochloric acid reactant salt, the abiraterone derivative as shown in formula (I) is obtained；
During above-mentioned preparation abiraterone derivative as shown in formula (I), first by abiraterone and solid light
Gas initial reaction under alkaline condition in a solvent, obtains intermediate, the solvent is methylene chloride, and alkali is triethylamine；To above-mentioned
Fully reacting and then addition bischloroethylamines hydrochloride, obtain the abiraterone derivative as shown in formula (I) after reaction.?
In above-mentioned reaction process, the molar ratio of the abiraterone and the solid phosgene is 1:(1~2.5)；The intermediate and institute
The molar ratio for stating bischloroethylamines hydrochloride is 1:(1~2).
Present invention also provides the preparation methods of the abiraterone derivative as shown in formula (II), comprising:
It will be reacted under abiraterone and dichloroacetyl chloride in a solvent alkaline condition, obtain Ah's bit as shown in formula (II)
Imperial derivative；
In above-mentioned preparation process, the solvent is methylene chloride, and the alkali that the alkaline condition uses is triethylamine.It is described
The time of reaction is 5~6h.
Present invention also provides application of the abiraterone derivative in preparation treatment prostate cancer drug, Ah's bits
Imperial derivative is selected from one or both of abiraterone derivative shown in formula (I) and formula (II)；
Further, present invention also provides a kind of preparations comprising abiraterone derivative and pharmaceutically acceptable
Auxiliary material, the abiraterone derivative are selected from one or both of abiraterone derivative shown in formula (I) and formula (II)；
In above-mentioned preparation, the abiraterone derivative can individually use above two abiraterone derivative,
It can be using the above two derivative of simultaneous selection as the component of preparation.The auxiliary material is auxiliary material well known to those skilled in the art,
This application is not particularly limited.
The dosage form of above-mentioned preparation is oral preparation, injection, suppository or inhalant, more specifically, the dosage form of the preparation
For tablet, capsule, granule, pill, liquid preparation, soft extract, suspending agent, dispersing agent, syrup, gelling agent or aerosol.
In above-mentioned preparation, the dosage of the abiraterone derivative is 0.5~250mg.
For a further understanding of the present invention, below with reference to embodiment to abiraterone derivative provided by the invention, its system
Preparation Method is described in detail with application, and protection scope of the present invention is not limited by the following examples.
The preparation of 1 abiraterone derivative 1 of embodiment
40 milliliters of DCM are added in 1 gram of abiraterone (commercially available, HPLC purity 98%), 0.8 gram of triethylamine, are cooled to 0-5
Degree is slowly added to 1.5 grams of solid phosgene, stirs 1-2 hours, and TLC confirms raw material fully reacting；Add bischloroethylamines hydrochloride
It 0.5 gram, stirs 4-5 hours, TLC monitoring confirmation raw material fully reacting sequentially adds 50 milliliters of water, DCM, stirs 2min, point
Liquid is added 50 milliliters of sodium bicarbonate aqueous solution washing organic phases, organic phase, 10-20 milliliters of ethyl acetate is concentrated, stirred crystallization obtains
To 0.7 gram of white solid.
1HNMR (400MHz, CDCl3): δ 8.62 (d, J=2.1Hz, 1H), 8.45 (dd, J=4.8,1.5Hz, 1H),
7.64 (dt, J=7.9,2.0Hz, 1H), 7.21 (dd, J=7.9,4.8Hz, 1H), 5.99 (dd, J=3.4,1.8Hz, 1H),
5.41-5.37 (m, 1H), 4.5 (m, 1H), 3.6-3.7 (m, 8H), 2.36-2.20 (m, 3H), 2.12-2.00 (m, 3H), 1.89-
1.81 (m, 2H), 1.80-1.43 (m, 7H), 1.15-1.10 (m, 2H), 1.07 (s, 3H), 1.05 (s, 3H)；
ESI-MS m/z:517.15[M+H]+。
The preparation of 2 abiraterone derivative 2 of embodiment
40 milliliters of DCM are added in 1 gram of abiraterone, 0.8 gram of triethylamine is added, is cooled to 0-5 degree, two chloroethenes are slowly added dropwise
It 0.5 gram of acyl chlorides, is stirred 5-6 hours after dripping off, 50 milliliters of water is added, stir 2min, 50 milliliters of organic phase sodium bicarbonate solution are washed
Wash once, organic phase is concentrated after dry, residue ethyl acetate: petroleum ether=1:1 eluant, eluent must be produced by silica gel column chromatography
0.5 gram of product.
1HNMR (400MHz, CDCl3): δ 8.62 (d, J=2.1Hz, 1H), 8.45 (dd, J=4.8,1.5Hz, 1H),
7.64 (dt, J=7.9,2.0Hz, 1H), 7.21 (dd, J=7.9,4.8Hz, 1H), 6.2 (m, 1H) 5.99 (dd, J=3.4,
1.8Hz, 1H), 5.41-5.37 (m, 1H), 4.6 (m, 1H), 2.36-2.20 (m, 3H), 2.12-2.00 (m, 3H), 1.89-1.81
(m, 2H), 1.80-1.43 (m, 7H), 1.15-1.10 (m, 2H), 1.07 (s, 3H), 1.05 (s, 3H)；
ESI-MS m/z:460.44[M+H]+。
Embodiment 3 tests the inhibitory activity of prostate gland cancer cell
Prostate cancer 22Rv1 cell is added in flat 96 porocyte culture plates, volume is according to 5000 cells/wells
After 100 μ l, adherent growth 12h, test compound, 200 μ l of final volume is added；Compound is tested since highest 100uM concentration,
2 times of concentration gradients dilute, totally 6 concentration；After cultivating 48h, 10 μ l CCK-8 are added, after being incubated for 4h, are detected using microplate reader
450nm absorption value.Cell survival rate %=(OD450Administration group-OD450Culture medium)/(OD450Non- dosing group-OD450Culture medium)*100.It uses
GraphpadPrism5.0 calculates compound IC50 value, and the results are shown in Table 1:
The different compounds of table 1 inhibit prostate gland cancer cell test result tables of data
| Untested compound | IC50(μM) |
| Abiraterone | >50 |
| Abiraterone derivative 1 | 5.5 |
| Abiraterone derivative 2 | 16 |
From table 1 it follows that abiraterone derivative 1 and 2 of the invention all has significant cell with respect to abiraterone
Inhibitory activity.
A series of anti-prostate cancer cell activity of the compounds of embodiment 4 and combinations thereof is tested
Prostate cancer 22Rv1 cell is added in flat 96 porocyte culture plates, volume is according to 5000 cells/wells
After 100 μ l, adherent growth 12h, test compound is added, final volume is 200 μ l；Experimental group be " derivative 1 ", " derivative 2 ",
Control group is " abiraterone ", " mustine hydrochlcride ", " dichloroacetic acid ", " abiraterone+mustine hydrochlcride ", "+two chloroethene of abiraterone
Acid "；Compound is arranged four 100,50,25,12.5 μM of concentration, " abiraterone+mustine hydrochlcride " and "+two chloroethene of abiraterone
The combination drug concentration of two control groups of acid " is identical, is added according to the concentration of 1:1；After cultivating 48h, 10 μ l CCK- are added in every hole
8, after being incubated for 4h, 450nm absorption value is detected using microplate reader.Cell survival rate %=(OD450Administration group-OD450Culture medium)/
(OD450Non-administered group-OD450Culture medium)*100.Dunnett ' t is carried out using SPSS14.0 to examine, as a result as shown in Fig. 1, * P <
0.05 indicates significant statistical difference.
As shown in Figure 1, derivative 1 and derivative 2 when concentration is greater than 12.5 μM can effectively killing prostate cancer 22Rv1 it is thin
Born of the same parents.With under molar concentration, 1 fragmentation effect of derivative is better than derivative 2, and abiraterone, mustine hydrochlcride, dichloroacetic acid etc. pair
22Rv1 cell is without obvious cytotoxicity, and mustine hydrochlcride, dichloroacetic acid and abiraterone are without synergistic effect.
The above description of the embodiment is only used to help understand the method for the present invention and its core ideas.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out
Some improvements and modifications, these improvements and modifications also fall within the scope of protection of the claims of the present invention.
The foregoing description of the disclosed embodiments enables those skilled in the art to implement or use the present invention.
Various modifications to these embodiments will be readily apparent to those skilled in the art, as defined herein
General Principle can be realized in other embodiments without departing from the spirit or scope of the present invention.Therefore, of the invention
It is not intended to be limited to the embodiments shown herein, and is to fit to and the principles and novel features disclosed herein phase one
The widest scope of cause.
Claims (8)
1. a kind of abiraterone derivative as shown in formula (i) or formula (ii),
2. the preparation method of the abiraterone derivative as shown in formula (I), comprising:
Abiraterone and solid phosgene are reacted in a solvent, obtain intermediate product；
By the intermediate product and bischloroethylamines hydrochloric acid reactant salt, the abiraterone derivative as shown in formula (I) is obtained；
3. the preparation method of the abiraterone derivative as shown in formula (II), comprising:
Abiraterone and dichloroacetyl chloride are reacted in a solvent, obtain the abiraterone derivative as shown in formula (II)；
4. application of the abiraterone derivative in preparation treatment prostate cancer drug, the abiraterone derivative are selected from such as formula
(I) and one or both of abiraterone derivative shown in formula (II)；
5. a kind of preparation, including abiraterone derivative and pharmaceutically acceptable auxiliary material, the abiraterone derivative are selected from
One or both of abiraterone derivative shown in formula (I) and formula (II)；
6. preparation according to claim 5, which is characterized in that the dosage form of the preparation is oral preparation, injection, suppository
Or inhalant.
7. preparation according to claim 5, which is characterized in that the dosage form of the preparation is tablet, capsule, granule, ball
Agent, liquid preparation, soft extract, suspending agent, dispersing agent, syrup, gelling agent or aerosol.
8. preparation according to claim 5, which is characterized in that the dosage of the abiraterone derivative be 0.5~
250mg。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112979744A (en) * | 2021-02-18 | 2021-06-18 | 齐齐哈尔医学院 | Diosgenin mosaic nitrogen mustard derivative with anti-tumor activity and preparation method and application thereof |
| CN114560903A (en) * | 2022-03-09 | 2022-05-31 | 绍兴市上虞区武汉理工大学高等研究院 | Simple preparation method of abiraterone derivative and cytotoxicity evaluation of abiraterone derivative |
| WO2023020135A1 (en) * | 2021-08-18 | 2023-02-23 | 广东中科药物研究有限公司 | Abiraterone derivative and preparation and application thereof |
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Cited By (3)
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| WO2023020135A1 (en) * | 2021-08-18 | 2023-02-23 | 广东中科药物研究有限公司 | Abiraterone derivative and preparation and application thereof |
| CN114560903A (en) * | 2022-03-09 | 2022-05-31 | 绍兴市上虞区武汉理工大学高等研究院 | Simple preparation method of abiraterone derivative and cytotoxicity evaluation of abiraterone derivative |
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Application publication date: 20190924 |