CN111450103A - Application of composition containing cyclopentanoperhydrophenanthrene derivative in preparation of anti-tumor medicine - Google Patents

Application of composition containing cyclopentanoperhydrophenanthrene derivative in preparation of anti-tumor medicine Download PDF

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CN111450103A
CN111450103A CN202010373777.8A CN202010373777A CN111450103A CN 111450103 A CN111450103 A CN 111450103A CN 202010373777 A CN202010373777 A CN 202010373777A CN 111450103 A CN111450103 A CN 111450103A
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向飞
吴洁
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    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
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    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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Abstract

The invention provides application of a composition containing a first cyclopentanoperhydrophenanthrene derivative and a second cyclopentanoperhydrophenanthrene derivative which are different from each other in preparation of an anti-tumor medicament, wherein the specific definition of the cyclopentanoperhydrophenanthrene derivative is shown in an instruction book, and the tumor is preferably selected from one of prostate cancer, gastric cancer and esophagus cancer. The composition has obviously better inhibiting effect on the proliferation of various tumor cells than the in vivo active ingredient compound II of the compound I on the market.

Description

Application of composition containing cyclopentanoperhydrophenanthrene derivative in preparation of anti-tumor medicine
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of a composition containing cyclopentanoperhydrophenanthrene derivatives in preparation of antitumor medicines.
Background
The results of Yun-Kai Shi et al have confirmed (Eur JMed chem.2018Feb 10; 145:11-22.) that the in vivo active form of Compound I, Compound II, is an IC of castration-resistant prostate cancer cell line PC-3 and castration-sensitive prostate cancer cell line L NCaP50About 2080. mu.g/L and 1150. mu.g/L, respectively, while Yun-Kai Shi et al in the same study also disclosed the antiproliferative activity of Compound II on human esophageal carcinoma cells EC-109 and human gastric carcinoma cells MGC-803, as well as its IC50Are respectively about>11200. mu.g/L and 2530. mu.g/L, it appears that the antitumor activity of compound II is to be further improved.
Figure BDA0002479122010000011
Disclosure of Invention
The invention aims to provide application of a composition containing cyclopentanoperhydrophenanthrene derivatives in preparing anti-tumor medicaments, wherein the inhibition effect of the composition on the related cancer cell proliferation is obviously better than that of a compound II.
In order to achieve the above objects, the present invention provides, in one aspect, a use of a composition comprising a first cyclopenta-polyhydrophenanthrene derivative and a second cyclopenta-polyhydrophenanthrene derivative, which are different from each other and selected from compounds 1 to 39 shown below, for the preparation of a medicament for anti-tumor:
compound 1: (3S,8R,9S,10R,13S,14S) -17-acetyl-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 2: (3S,8R,9S,10R,13S,14S) -3-hydroxy-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-17-yl trifluoromethanesulfonate,
compound 3: (3S,8R,9S,10R,13S,14S) -17- (1- (hydroxyimino) ethyl) -10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 4: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (((trifluoromethyl) sulfonyl) oxy) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 5: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (2- (((trifluoromethyl) sulfonyl) oxy) acetyl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 6: (3S,8R,9S,10R,13S,14S) -3- (((3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-3-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl) oxy) -10, 13-dimethyl-1, 2,3,4,7,8,9,10,11,12,13,14,15, 16-decatetrahydro-17H-cyclopenta [ a ] phenanthren-17-one,
compound 7: 3- ((3S,8R,9S,10R,13S,14S) -3-hydroxy-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-17-yl) pyridine 1-oxide,
compound 8: (3S,6aS,6bS,9aS,11aS,11bR) -9a,11 b-dimethyl-9- (pyridin-3-yl) -1,2,3,4,5a,6,6a,6b,7,9a,10,11,11a,11 b-decahydrocyclopentano [1,2] phenanthro [8a,9-b ] oxiran-3-ol,
compound 9: (3S,6aS,6bS,9aS,11aS,11bR) -9a,11 b-dimethyl-9- (pyridin-3-yl) -1,2,3,4,5a,6,6a,6b,7,9a,10,11,11a,11 b-decatetrahydrocyclopenta [1,2] phenanthro [8a,9-b ] oxiran-3-yl acetate,
compound 10: (3R,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-3-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 11: 3- ((8R,9S,10R,13S,14S) -10, 13-dimethyl-2, 7,8,9,10,11,12,13,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-17-yl) pyridine,
compound 12: (4S,6aR,6bS,8aS,8bR,9aR,10aS,10bR) -6a,8 a-dimethyl-8 b- (pyridin-3-yl) -3,4,5,6,6a,6b,7,8,8a,8b,9a,10,10a,10 b-tetradecahydro-1H-naphtho [2',1':4,5] indeno [1,2-b ] oxiran-4-yl acetate,
compound 13: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-7-oxo-17- (pyridin-3-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 14: 1- ((8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-3-yl) -2,7,8,9,10,11,12,13,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl) ethan-1-one,
compound 15: 3- ((3S,8R,9S,10R,13S,14S) -3- ((1-chloro-2-methylpropan-2-yl) oxy) -10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-17-yl) pyridine,
compound 16: 3- ((3S,8R,9S,10R,13S,14S) -3-ethoxy-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-17-yl) pyridine,
compound 17: 3- ((3S,8R,9S,10R,13S,14S) -3-isopropoxy-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-17-yl) pyridine,
compound 18: 3- ((8R,9S,10R,13S,14S) -3-chloro-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-17-yl) pyridine,
compound 19: (5S,8R,9S,10S,13S,14S) -10, 13-dimethyl-17- (pyridin-3-yl) -1,2,4,5,6,7,8,9,10,11,12,13,14, 15-tetradecahydro-3H-cyclopenta [ a ] phenanthren-3-one,
compound 20: 3- ((3S,8R,9S,10R,13S,14S) -3- (4-chlorobutoxy) -10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-17-yl) pyridine,
compound 21: 4- (((3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-3-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl) oxy) -4-oxobutanoic acid,
compound 22: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17-oxo-2, 3,4,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 23: (3S,3' S,8R,8' R,9S,9' S,10R,10' R,13S,13' S,14S,14' S) -3,3' -oxybis (10, 13-dimethyl-1, 2,3,4,7,8,9,10,11,12,13,14,15, 16-decatetrahydro-17H-cyclopenta [ a ] phenanthren-17-one),
compound 24: (3S,8R,9S,10R,13S,14S) -17-ethyl-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 25: (3S,8R,9S,10R,13S,14S) -17-iodo-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-ol,
compound 26: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-3-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-ylsulfonic acid sodium salt,
compound 27: (3S,8R,9S,10R,13S,14S) -3-hydroxy-10, 13-dimethyl-1, 2,3,4,7,8,9,10,11,12,13,14,15, 16-decatetrahydro-17H-cyclopenta [ a ] phenanthren-17-one,
compound 28: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-3-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-ylmethylsulfonate,
compound 29: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-2-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 30: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-2-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-ol,
compound 31: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-4-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-ol,
compound 32: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-4-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 33: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (1-oxopyridin-3-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-ylsulfonic acid sodium salt,
compound 34: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17-oxo-2, 3,4,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H-cyclopenta [ a ] phenanthren-3-ylsulfonate,
compound 35: (3S,8R,9S,10S,13S,14S) -10, 13-dimethyl-17- (pyridin-3-yl) -2,3,4,5,6,7,8,9,10,11,12,13,14, 15-tetradecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 36: 3- ((3S,8R,9S,10R,13S,14S) -3-acetoxy-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-17-yl) pyridine 1-oxide,
compound 37: (4S,6aR,6bS,8aS,8bS,9aS,10aS,10bR) -6a,8 a-dimethyl-8 b- (pyridin-3-yl) -3,4,5,6,6a,6b,7,8,8a,8b,9a,10,10a,10 b-tetradecahydro-1H-naphtho [2',1':4,5] indeno [1,2-b ] oxiran-4-yl acetate,
compound 38:
Figure BDA0002479122010000041
compound 39:
Figure BDA0002479122010000042
preferably, the mass ratio of the first cyclopentanoperhydrophenanthrene derivative to the second cyclopentanoperhydrophenanthrene derivative is 0.01: 1-100: 1.
In another preferred aspect, the tumor of the present invention is one selected from the group consisting of prostate cancer, gastric cancer and esophageal cancer.
Further preferably, the tumor of the present invention is prostate cancer.
Most preferably, the prostate cancer of the present invention is one selected from the group consisting of castration resistant prostate cancer and castration sensitive prostate cancer.
In another aspect, the composition of the present invention preferably further comprises pharmaceutically acceptable excipients.
Further preferably, the pharmaceutically acceptable auxiliary materials of the present invention are one or more selected from lactose, microcrystalline cellulose, crospovidone, starch, hypromellose, aerosil and magnesium stearate.
On the other hand, the medicament can be prepared into oral solid preparations. More preferably, the oral solid preparation is one selected from the group consisting of a capsule, a tablet and a granule.
The results of in vitro experiments show that the compositions of the invention have antiproliferative activity (in terms of IC) on PC-3 cells, L NCaP cells, EC-109 cells, MGC-803 cells50(mu g/L) are remarkably superior to the compound II, the results of animal experiments show that when the dosage is only 1/20 of the compound I, the inhibition effect of the preferred combination of the invention on the proliferation of the prostate cancer of rats is not statistically significant different from that of the compound I, and the promotion effect on the apoptosis of the prostate cancer is superior to that of the compound I.
Detailed Description
The following description of the embodiments is only intended to aid in the understanding of the method of the invention and its core ideas. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention. The following description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.
Test example 1 inhibitory Effect of the composition on the proliferation of various cancer cells
The method of Yun-Kai Shi et al (Eur J Med chem.2018Feb 10; 145:11-22.) was adopted to examine the IC (integrated Circuit) of a mixture (marked as MIX (X-Y), X, Y is selected from 1-39, and X ≠ Y) obtained by mixing a compound X and a compound Y at a specific mass ratio (R) on various tumor cells50The results are shown in tables 1 to 4, as values (in. mu.g/L, based on the total mass of the mixture).
TABLE 1 inhibition of PC-3 cell proliferation by MIX (X-Y)
Figure BDA0002479122010000051
Figure BDA0002479122010000061
Figure BDA0002479122010000071
TABLE 2 inhibition of proliferation of L NCaP cells by MIX (X-Y)
Figure BDA0002479122010000072
Figure BDA0002479122010000081
TABLE 3 inhibition of EC-109 cell proliferation by MIX (X-Y)
Figure BDA0002479122010000082
Figure BDA0002479122010000091
TABLE 4 inhibitory Effect of MIX (X-Y) on MGC-803 cell proliferation
Figure BDA0002479122010000092
Figure BDA0002479122010000101
As a control, the inhibitory effects of compound I and compound II on the proliferation of the above-mentioned tumor cells were measured in the same manner as in the present invention, and the IC50 values (μ g/L) are shown in Table 5.
TABLE 5 inhibitory Effect of Compound I and Compound II on the proliferation of respective tumor cells
Figure BDA0002479122010000102
Test example 2 Effect of composition on prostate cancer progression in rats
By using
Figure BDA0002479122010000114
The procedure disclosed by BF et al (Horm cancer.2018 Jun; 9(3):175-The effects of the drugs on the proliferation of prostate cancer cells (Ki67 positive rate) and the apoptosis index (TUNE L positive rate) in rats were specifically measured, and the results are shown in tables 6 and 7.
TABLE 6 Effect of drugs on prostate cancer cell proliferation
Figure BDA0002479122010000111
TABLE 7 Effect of drugs on apoptosis of prostate cancer cells
Figure BDA0002479122010000112
As can be seen from tables 6 and 7, even though the doses of MIX (18-11) (R ═ 1) and MIX (16-10) (R ═ 0.01) were only 1/20 of compound i, the Ki67 positivity rates of both were not statistically significant different from that of compound i, while the TUNE L positivity rate was significantly higher than that of compound i.
EXAMPLE 1 oral solid preparation of composition containing Cyclopentahydrophenanthrene derivative and method for preparing the same
Prescription
Figure BDA0002479122010000113
Figure BDA0002479122010000121
Figure BDA0002479122010000131
Figure BDA0002479122010000141
Preparation method
The prescription dose of MIX (X-Y) and auxiliary materials are sieved by a 100-mesh sieve. Mixing MIX (X-Y), lactose, microcrystalline cellulose, polyvinylpolypyrrolidone and starch; taking the hydroxypropyl methylcellulose with the prescription amount, preparing a solution with the concentration of 10% based on the hydroxypropyl methylcellulose, adjusting the pH to 3.0-4.0 by using lactic acid, adding the solution into the mixed material to prepare a soft material, granulating by using a 16-mesh sieve, and drying for 3-4 h at 80 ℃. Granulating with 16 mesh sieve, adding prescription amount of silica gel micropowder and magnesium stearate, mixing, and encapsulating to obtain capsule with weight of 500 mg;
the prescription dose of MIX (X-Y) and auxiliary materials are sieved by a 100-mesh sieve. Mixing MIX (X-Y), lactose, microcrystalline cellulose, polyvinylpolypyrrolidone and starch; taking the hydroxypropyl methylcellulose with the prescription amount, preparing a solution with the concentration of 10% based on the hydroxypropyl methylcellulose, adjusting the pH to 3.0-4.0 by using lactic acid, adding the solution into the mixed material to prepare a soft material, granulating by using a 16-mesh sieve, and drying for 3-4 h at 80 ℃. Sieving with 16 mesh sieve, adding silica gel micropowder and magnesium stearate, mixing, and packaging to obtain granule with weight of 5g per bag.
The prescription dose of MIX (X-Y) and auxiliary materials are sieved by a 100-mesh sieve. Mixing MIX (X-Y), lactose, microcrystalline cellulose, polyvinylpolypyrrolidone and starch; taking the hydroxypropyl methylcellulose with the prescription amount, preparing a solution with the concentration of 10% based on the hydroxypropyl methylcellulose, adjusting the pH to 3.0-4.0 by using lactic acid, adding the solution into the mixed material to prepare a soft material, granulating by using a 16-mesh sieve, and drying for 3-4 h at 80 ℃. Sieving with 16 mesh sieve, adding prescription amount of silica gel micropowder and magnesium stearate, mixing, and tabletting to obtain tablet with weight of about 500 mg.

Claims (9)

1. Use of a composition comprising a first cyclopenta-hydrophenanthrene derivative and a second cyclopenta-hydrophenanthrene derivative, which are different from each other and are selected from the group consisting of compounds 1 to 39 shown below, for the preparation of a medicament for the treatment of tumors:
compound 1: (3S,8R,9S,10R,13S,14S) -17-acetyl-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 2: (3S,8R,9S,10R,13S,14S) -3-hydroxy-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-17-yl trifluoromethanesulfonate,
compound 3: (3S,8R,9S,10R,13S,14S) -17- (1- (hydroxyimino) ethyl) -10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 4: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (((trifluoromethyl) sulfonyl) oxy) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 5: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (2- (((trifluoromethyl) sulfonyl) oxy) acetyl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 6: (3S,8R,9S,10R,13S,14S) -3- (((3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-3-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl) oxy) -10, 13-dimethyl-1, 2,3,4,7,8,9,10,11,12,13,14,15, 16-decatetrahydro-17H-cyclopenta [ a ] phenanthren-17-one,
compound 7: 3- ((3S,8R,9S,10R,13S,14S) -3-hydroxy-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-17-yl) pyridine 1-oxide,
compound 8: (3S,6aS,6bS,9aS,11aS,11bR) -9a,11 b-dimethyl-9- (pyridin-3-yl) -1,2,3,4,5a,6,6a,6b,7,9a,10,11,11a,11 b-decahydrocyclopentano [1,2] phenanthro [8a,9-b ] oxiran-3-ol,
compound 9: (3S,6aS,6bS,9aS,11aS,11bR) -9a,11 b-dimethyl-9- (pyridin-3-yl) -1,2,3,4,5a,6,6a,6b,7,9a,10,11,11a,11 b-decatetrahydrocyclopenta [1,2] phenanthro [8a,9-b ] oxiran-3-yl acetate,
compound 10: (3R,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-3-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 11: 3- ((8R,9S,10R,13S,14S) -10, 13-dimethyl-2, 7,8,9,10,11,12,13,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-17-yl) pyridine,
compound 12: (4S,6aR,6bS,8aS,8bR,9aR,10aS,10bR) -6a,8 a-dimethyl-8 b- (pyridin-3-yl) -3,4,5,6,6a,6b,7,8,8a,8b,9a,10,10a,10 b-tetradecahydro-1H-naphtho [2',1':4,5] indeno [1,2-b ] oxiran-4-yl acetate,
compound 13: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-7-oxo-17- (pyridin-3-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 14: 1- ((8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-3-yl) -2,7,8,9,10,11,12,13,14, 15-decahydro-1H-cyclopenta [ a ] phenanthren-3-yl) ethan-1-one,
compound 15: 3- ((3S,8R,9S,10R,13S,14S) -3- ((1-chloro-2-methylpropan-2-yl) oxy) -10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-17-yl) pyridine,
compound 16: 3- ((3S,8R,9S,10R,13S,14S) -3-ethoxy-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-17-yl) pyridine,
compound 17: 3- ((3S,8R,9S,10R,13S,14S) -3-isopropoxy-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-17-yl) pyridine,
compound 18: 3- ((8R,9S,10R,13S,14S) -3-chloro-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-17-yl) pyridine,
compound 19: (5S,8R,9S,10S,13S,14S) -10, 13-dimethyl-17- (pyridin-3-yl) -1,2,4,5,6,7,8,9,10,11,12,13,14, 15-tetradecahydro-3H-cyclopenta [ a ] phenanthren-3-one,
compound 20: 3- ((3S,8R,9S,10R,13S,14S) -3- (4-chlorobutoxy) -10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-17-yl) pyridine,
compound 21: 4- (((3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-3-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl) oxy) -4-oxobutanoic acid,
compound 22: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17-oxo-2, 3,4,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 23: (3S,3' S,8R,8' R,9S,9' S,10R,10' R,13S,13' S,14S,14' S) -3,3' -oxybis (10, 13-dimethyl-1, 2,3,4,7,8,9,10,11,12,13,14,15, 16-decatetrahydro-17H-cyclopenta [ a ] phenanthren-17-one),
compound 24: (3S,8R,9S,10R,13S,14S) -17-ethyl-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 25: (3S,8R,9S,10R,13S,14S) -17-iodo-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-ol,
compound 26: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-3-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-ylsulfonic acid sodium salt,
compound 27: (3S,8R,9S,10R,13S,14S) -3-hydroxy-10, 13-dimethyl-1, 2,3,4,7,8,9,10,11,12,13,14,15, 16-decatetrahydro-17H-cyclopenta [ a ] phenanthren-17-one,
compound 28: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-3-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-ylmethylsulfonate,
compound 29: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-2-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 30: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-2-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-ol,
compound 31: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-4-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-ol,
compound 32: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (pyridin-4-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 33: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17- (1-oxopyridin-3-yl) -2,3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-3-ylsulfonic acid sodium salt,
compound 34: (3S,8R,9S,10R,13S,14S) -10, 13-dimethyl-17-oxo-2, 3,4,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-1H-cyclopenta [ a ] phenanthren-3-ylsulfonate,
compound 35: (3S,8R,9S,10S,13S,14S) -10, 13-dimethyl-17- (pyridin-3-yl) -2,3,4,5,6,7,8,9,10,11,12,13,14, 15-tetradecahydro-1H-cyclopenta [ a ] phenanthren-3-yl acetate,
compound 36: 3- ((3S,8R,9S,10R,13S,14S) -3-acetoxy-10, 13-dimethyl-2, 3,4,7,8,9,10,11,12,13,14, 15-dodecahydro-1H-cyclopenta [ a ] phenanthren-17-yl) pyridine 1-oxide,
compound 37: (4S,6aR,6bS,8aS,8bS,9aS,10aS,10bR) -6a,8 a-dimethyl-8 b- (pyridin-3-yl) -3,4,5,6,6a,6b,7,8,8a,8b,9a,10,10a,10 b-tetradecahydro-1H-naphtho [2',1':4,5] indeno [1,2-b ] oxiran-4-yl acetate,
compound 38:
Figure FDA0002479120000000031
compound 39:
Figure FDA0002479120000000032
2. use according to claim 1, characterized in that the mass ratio of the first cyclopenta-polyhydrophenanthrene derivative to the second cyclopenta-polyhydrophenanthrene derivative is between 0.01: 1-100: 1.
3. The use according to claim 1 or 2, wherein the tumor is one selected from the group consisting of prostate cancer, stomach cancer and esophageal cancer.
4. Use according to claim 3, characterized in that the tumour is prostate cancer.
5. The use of claim 4, wherein the prostate cancer is selected from the group consisting of castration resistant prostate cancer and castration sensitive prostate cancer.
6. Use according to claim 1 or 2, characterized in that said composition further comprises pharmaceutically acceptable adjuvants.
7. The use according to claim 6, characterized in that the pharmaceutically acceptable excipients are one or more selected from lactose, microcrystalline cellulose, crospovidone, starch, hypromellose, aerosil and magnesium stearate.
8. Use according to claim 1 or 2, characterized in that the medicament is formulated as an oral solid preparation.
9. The use according to claim 8, wherein the oral solid preparation is one selected from the group consisting of capsules, tablets and granules.
CN202010373777.8A 2020-05-06 2020-05-06 Application of composition containing cyclopentanoperhydrophenanthrene derivative in preparation of anti-tumor medicine Withdrawn CN111450103A (en)

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Publication number Priority date Publication date Assignee Title
WO2023155846A1 (en) * 2022-02-18 2023-08-24 上海醇健医药技术有限公司 17-PYRIDYL-10α-METHYL-STEROID DERIVATIVE AND INTERMEDIATE COMPOUND, PREPARATION METHOD THEREFOR, USE THEREOF, AND PHARMACEUTICAL COMPOSITION THEREOF

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023155846A1 (en) * 2022-02-18 2023-08-24 上海醇健医药技术有限公司 17-PYRIDYL-10α-METHYL-STEROID DERIVATIVE AND INTERMEDIATE COMPOUND, PREPARATION METHOD THEREFOR, USE THEREOF, AND PHARMACEUTICAL COMPOSITION THEREOF

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