ABIRATERONE DERIVATIVE, PREPARATION AND APPLICATION THEREOF

Abstract

Disclosed in the present invention are an abiraterone derivative and preparation method thereof. The abiraterone derivative provided by the present invention shows relatively few abdominal distension phenomena with respect to abiraterone and has better drug effect and tolerance, and pharmacokinetic experiments show that the plasma concentration of M1 after intragastric administration of equal molar dose is significantly higher than that of abiraterone acetate. The prostate cancer inhibiting effect is obviously better than that of abiraterone, and the side effects on the gastrointestinal tract is smaller than that of abiraterone. A compound provided by the present invention also has the effect of treating acne.

Claims

1. A compound of formula I: ##STR00041## formula I, In formula I, R is selected from: ##STR00042## Ar represents a substituted or unsubstituted aromatic ring, specifically a benzene ring or a pyridine ring; the substituent could be C1-C8 alkyl group, C1-C8 alkoxy group, or halogen; wherein, R1 or R2 is independently selected from any one of the following groups: H, (C3-C8) carbocycloalkyl, substituted or unsubstituted (C1-C18) alkane, (C2-C8) alkenes or (C2-C8) alkenyl containing substituents, (C2-C8) alkynyl or (C2-C8) alkynyl containing substituents, (C6-C20) aryl or (C6-C20) aryl containing substituents, (C2-C20) heterocyclic or (C2-C20) heterocyclic containing substituents; alternatively, R1 and R2 form a ring with each other as (C3-C8) heterocycloalkyl or substituted (C3-C8) heterocycloalkyl, (C6-C20) heteroaryl or substituted (C6-C20) heteroaryl; when R is: ##STR00043## R1 or R2 is not alkane with 1 or more unsubstituted carbon atoms.

2. Abiraterone derivative shown in formula I of claim 1, wherein the abiraterone derivative has any one of the following structure: ##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050##

3. Use of abiraterone derivative shown in formula I according to claim 1, 1) for the preparation of eukaryotic tumor cell proliferation inhibitors; or 2) for the preparation of a drug for the prevention and/or treatment of tumors.

4. The use of abiraterone derivative according to claim 3, wherein, the eukaryote is a mammal; the tumor cells are cancer cells; the cancer cells are prostate cancer cells; the tumor is carcinoma; the carcinoma is prostate cancer.

5. The use of abiraterone derivative according to claim 4, wherein, the disease is metastatic castration-resistant prostate cancer after prior docetaxel chemotherapy.

6. A eukaryotic tumor cell proliferation inhibitor comprises the abiraterone derivative shown in formula I according to claim 1.

7. The use of abiraterone derivative according to in claim 1 for the preparation of a drug for treating acne.

8. A drug for treating acne, which comprises the abiraterone derivative shown in formula I according to claim 1.

Description

DESCRIPTION OF SPECIFIC EMBODIMENTS

[0031] Although the present invention will be described below through specific examples, it is not intended to be limited thereto.

[0032] The methods given in examples below are all conventional methods, unless otherwise stated. The materials and reagents are all commercially available unless otherwise stated.

Example 1

[0033] Synthesis of (8S,9S,10R,13S,14S)-10, 13-Dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenteno[a]phenanthrene-3(2H)-one O-((2-(dimethylamino)ethyl)carbamoyl)oxime

##STR00016## [0034] 1) (8S,9S,10R,13S,14S)-10, 13-Dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenteno[a]phenanthrenyl-3(2H)-one

##STR00017##

Abiraterone (35.0 g, 100 mmol, 1.0 eq.), aluminum isopropoxide (20.5 g, 100 mmol, 1.0 eq.), cyclohexanone (29.5 g, 300 mmol, 3.0 eq.) were weighed into a round bottom reaction flask, and toluene (210 mL) was added. Under the protection of nitrogen, and be heated at 100? C. for 16 h. The reaction solution was cooled, and added with NaCl aqueous solution, then the insoluble materials were filtered with celite, separated the organic layer, and purified by column chromatography to obtain a white solid (8S, 9S, 10R, 13S,14S)-10,13-dimethyl-17-(pyridine-3-yl)-6,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenteno[a]phenanthrenyl -3(2H)-one (30.2 g, 87.0%). 1H NMR(DMSO-d6 400 MHZ): ? 8.47(s, 1H), 8.33(d, 1H), 7.77-7.29(m, 2H), 5.96(m, 1H), 5.85(s, 1H), 2.99(m, 2H), 2.37-1.27(m, 21H). ESI-MS m/z: 348.1[M+H]+. [0035] 2) (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenta [a]phenanthrenyl-3(2H)-ketoxime

##STR00018##

(8S, 9S, 10R, 13S, 14S)-10,13-dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one (30.0 g, 86.5 mmol, 1.0 eq.) was weighted and dissolved in absolute ethanol (250 mL), and then hydroxylamine hydrochloride (12.0 g, 173 mmol, 2.0 eq.), sodium acetate (21.3 g, 260 mmol, 3.0 eq.) were added, and react at room temperature for 3 h. Excess water was added to the reaction solution, and a white solid was precipitated. The crude product was filtered and recrystallized from ethanol to obtain (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-6,7,8,9, 10,11,12,13,14,15-Decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-ketoxime (25.0 g, 80.0%). 1H NMR (DMSO-d6 400 MHZ) ? 8.47(s, 1H), 8.33(d, 1H), 7.77-7.29(m, 2H), 5.96(m, 1H), 5.85(s, 1H), 4.62(s, 1H), 2.99(m, 2H), 2.37-1.27(m, 21H). ESI-MS m/z: 363.1[M+H]+. [0036] 3) (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenta[a]phenanthrene-3(2H)-one O-(1H-imidazole-1-carbonyl)oxime

##STR00019##

(8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-ketoxime (2.0 g, 5.52 mmol, 1.0 eq.) was dissolved in dichloromethane (20 mL), and triethylamine (1.11 g, 11.0 mmol. 2.0 eq.), carbonyldiimidazole (1.78 g, 11.0 mmol. 2.0 eq.) were added respectively, and the solution was stirred at room temperature for 8 h. The reaction solution was extracted with water, the organic phase was concentrated, and (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenteno[a]phenanthrene-3(2H)-one O-(1H-imidazole-1-carbonyl)oxime was obtained by column chromatography (2.0 g, 79.5%). 1H NMR (DMSO-d6 400 MHZ): ? 8.47(s, 1H), 8.33(d, 1H), 8.14(s, 1H), 7.77-7.14(m, 4H), 5.96(m, 1H), 5.85(s, 1 H), 2.99(m, 2H), 2.37-1.27(m, 21H). ESI-MS m/z: 457.1[M+H]+. [0037] 4) (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenta[a]phenanthrene-3(2H)-one O-((2-(dimethylamino)ethyl)carbamoyl)oxime

##STR00020##

(8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14, 15-Decahydro-1H-cyclopenta[a]phenanthrene-3(2H)-one O-(1H-imidazole-1-carbonyl)oxime (2.0 g, 4.39 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL), then N,N-dimethylethylenediamine (0.58 g, 6.58 mmol, 1.5 eq.) was added dropwise, and the solution was stirred at room temperature for 5 h. The reaction solution was concentrated and purified by column chromatography to obtain solid (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenteno[a]phenanthrene -3(2H)-one O-((2-(dimethylamino)ethyl)carbamoyl)oxime (1.5 g, 7.8%). 1H NMR(DMSO-d6 400 MHZ): ? 8.47(s, 1H), 8.33(d, 1H), 7.77-7.29(m, 2H), 5.96(m, 1H), 5.85(s, 1H), 3.28-3.26 (d, 4H), 2.36(s, 6H), 2.37-1.27(m, 23H). ESI-MS m/z: 477.1[M+H]+.

Example 2

[0038] Synthesis of (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) 6,7,8,9,10,11,12,13,14,15- decahydro-1H-cyclopenta[a]phenanthrene-3(2H)-one O-dimethylcarbamoyl oxime

##STR00021##

[0039] (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-ketoxime (2.0 g, 5.52 mmol, 1.0 eq.), triethylamine (1.11 g, 11.0 mmol. 2.0 eq.) respectively dissolve in dichloromethane (20 mL), and dimethylcarbamoyl chloride (1.19 g, 11.0 mmol, 2.0 eq.) was added dropwise, and react at room temperature for 5 h. The reaction solution was concentrated, and white solid (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenta[a]phenanthrene-3(2H)-one O-dimethylcarbamoyl oxime (2.0 g, 83.7%) was obtained by column chromatography gave. 1H NMR (DMSO-d6 400 MHZ): ? 8.47(s, 1H), 8.33(d, 1H), 7.77-7.29(m, 2H), 5.96(m, 1H), 5.85(s, 1H), 3.47(s, 6H), 2.37-1.27(m, 23H). ESI-MS m/z: 434.1[M+H]+.

Example 3

[0040] Synthesis of (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-(bis(2-chloroethyl)carbamoyl)oxime

##STR00022##

[0041] The synthetic method of Examples 1-2 was merged. After the esterification of bis(2-chloroethyl) carbamoyl chloride and (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridine-3-yl)-6,7,8,9,10,11,12,13,14,15-decahydro-1H- cyclopenteno[a]phenanthrenyl-3(2H)-ketoxime intermediate, a white solid (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-(bis(2-chloroethyl)carbamoyl)oxime was obtained. 1H NMR (DMSO-d6 400 MHZ): ? 8.47(s, 1H), 8.33(d, 1H), 7.77-7.29(m, 2H), 5.96(m, 1H), 5.62(s, 1H), 3.64(m, 4H), 3.24(m, 4H), 2.37-1.27(m, 23H). ESI-MS m/z: 532.1[M+H]+.

Example 4

[0042] Synthesis of (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15- decahydro-1H-cyclopentene[a]phenanthrenyl-3(2H)-one O-([1,4-bipiperidine]-1-carbonyl)oxime

##STR00023##

[0043] The synthetic method of Examples 1-2 was merged. After the esterification of [1,4-bipiperidine]-1-carbonyl chloride and (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenteno[a]phenanthrenyl-3(2H) -ketoxime intermediate, a white solid (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopentene[a]phenanthrenyl-3(2H)-one O-([1,4-bipiperidine]-1-carbonyl)oxime was obtained. 1H NMR (DMSO-d6 400 MHZ): ? 8.47(s, 1H), 8.33(d, 1H), 7.77-7.29(m, 2H), 5.96(m, 1H), 5.62(s, 1H), 3.39(m, 4H), 2.62-2.42(m, 5H), 2.37-1.27(m, 33H). ESI-MS m/z: 557.1[M+H]+.

Example 5

[0044] Synthesis of (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-(2-methylbenzoyl)oxime

##STR00024##

[0045] The synthetic method of Examples 1-2 was merged. After the esterification of o-toluyl chloride and (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenteno[a]phenanthrenyl-3(2H)-ketoxime intermediate, a white solid (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-decahydro-1H-Cyclopenteno[a]phenanthrenyl-3(2H)-one O-(2-methylbenzoyl)oxime was obtained. 1H NMR(DMSO-d6 400MHz): ? 8.47(s, 1H), 8.33(d, 1H), 7.88-7.29(m, 6H), 5.96(m, 1H), 5.62(s, 1H), 2.37-1.27 (m, 26H). ESI-MS m/z: 481.1[M+H]+.

Example 6

[0046] Synthesis of (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-(3-(methylamino)propionyl)oxime

##STR00025##

[0047] The synthetic method of Examples 1-2 was merged. After the esterification of 3-methylaminopropionic acid and (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenteno[a]phenanthrenyl-3(2H)-ketoxime intermediate, a white solid (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl)-6,7,8,9, 10,11,12,13,14,15-decahydro-1H -cyclopenta[a]phenanthrenyl-3(2H)-one O-(3-(methylamino)propionyl)oxime was obtained by deprotection. 1H NMR (DMSO-d6 400 MHz) : ? 8.47(s, 1H), 8.33(d, 1H), 7.77-7.29(m, 2H), 5.96(m, 1H), 5.62(s, 1H), 3.62(s, 3H), 2.83-2.63(m, 4H), 2.37-1.27(m, 23H). ESI-MS m/z: 448.1[M+H]+.

Example 7

[0048] Synthesis of (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15- decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-acetyloxime

##STR00026##

[0049] The synthetic method of Examples 1-2 was merged. After the esterification of acetic anhydride and (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenteno[a]phenanthrenyl-3(2H)-ketoxime intermediate, a white solid (8S,9S,10R,13S,14S)-10,13-Dimethyl-17 -(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-decahydro-1H-Cyclopenteno[a]phenanthrenyl-3(2H)-one O-acetyl oxime was obtained by deprotection. 1H NMR(DMSO-d6 400 MHZ): ? 8.47(s, 1H), 8.33(d, 1H), 7.77-7.29(m, 2H), 5.96(m, 1H), 5.62(s, 1H), 2.37-1.27 (m, 26H). ESI-MS m/z: 405.1[M+H]+.

Example 8

[0050] Synthesis of ((((((8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl) -7,8,9,11,12,13,14,15-octahydro-1H-cyclopenta[a]phenanthrenyl-3(2H,6H,10H) -ylidene)amino)oxy)carbonyl)oxy)methyl isobutyrate

##STR00027##

[0051] The synthetic method of Examples 1-2 was merged. After the esterification of chloromethyl chloroformate and (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-ketoxime intermediate, a white solid (((((8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl) -7,8,9,11,12,13,14,15-Octahydro-1H-cyclopenta[a]phenanthrenyl-3(2H,6H,10H) -ylidene)amino)oxy)carbonyl)oxy)methyl isobutyrate was obtained by esterification with isobutyric acid. 1H NMR (DMSO-d6 400 MHz): ? 8.47(s, 1H), 8.33(d, 1H), 7.70-7.29(m, 2H), 6.95(s, 1H), 5.96(m, 1H), 5.62(s, 1H), 2.67-1.14(m, 30H). ESI-MS m/z: 507.1[M+H]+.

Example 9

[0052] Synthesis of (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-((2-morpholineethoxycarbonyl)oxime

##STR00028##

[0053] The synthetic method of Examples 1-2 was merged. 2-morpholine ethanol and (8S,9S, 10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-Decahydro-1H -cyclopenta[a]phenanthrenyl-3(2H)-ketoxime intermediate were reacted in a triphosgene environment to form a carbonate and (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-decahydro-1H-Cyclopenteno[a]phenanthrenyl-3(2H)-one O-((2-morpholineethoxycarbonyl)oxime was obtained. 1H NMR(DMSO-d6 400 MHZ): ? 8.47(s, 1H), 8.33(d, 1H), 7.70-7.29(m, 2H), 5.96(m, 1H), 5.62(s, 1H), 4.43(m, 2H), 3.65(m, 4H), 2.97(m, 2H), 2.36(m, 4H), 2.12-1.12(m, 23H). ESI-MS m/z: 520.1[M+H]+.

Example 10

[0054] Synthesis of (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-piperidine-4-carbonyl oxime

##STR00029##

[0055] The synthetic method of Examples 1-2 was merged. After the esterification of 4-piperidinecarboxylic acid and (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-6, 7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H )-ketoxime intermediate, a white solid (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-decahydro-1H -Cyclopenteno[a]phenanthrenyl-3(2H)-one O-piperidine-4-carbonyl oxime was obtained. 1H NMR(DMSO-d6 400 MHZ): ? 8.47(s, 1H), 8.33(d, 1H), 7.70-7.29(m, 2H), 5.96(m, 1H), 5.62(s, 1H), 2.79(m, 4H), 2.33-1.27(m, 28H). ESI-MS m/z: 474.1[M+H]+.

Example 11

[0056] Synthesis of (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-(1-methylpiperidine-4-carbonyl)oxime

##STR00030##

[0057] The synthetic method of Examples 1-2 was merged. After the esterification of 1-methylpiperidine-4-carboxylic acid and (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin -3-yl)-6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-ketoxime intermediate, a white solid (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-(1-methylpiperidine-4-carbonyl)oxime. 1H NMR(DMSO-d6 400 MHZ): ? 8.47(s, 1H), 8.33(d, 1H), 7.70-7.29(m, 2H), 5.96(m, 1H), 5.62(s, 1H), 2.79(m, 4H), 2.33-1.27(m, 31H). ESI-MS m/z: 488.1[M+H]+.

Example 12

[0058] Synthesis of 1-(4-(((((8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl) -7,8,9,11,12,13,14,15-octahydro-1H-cyclopenteno[a]phenanthrenyl-3(2H,6H, 10H) -ylidene)amino)oxy)carbonyl)piperidin-1-yl)ethanone

##STR00031##

[0059] The synthetic method of Examples 1-2 was merged. After the esterification of 1-acetylpiperidine-4-carboxylic acid and (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridine-3-base)-6,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenteno[a]phenanthrenyl-3(2H)-ketoxime intermediate, a white Solid 1-(4-(((((8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl)-7,8,9,11,12,13,14,15-Octahydro-1H-cyclopenta[a]phenanthrenyl -3(2H,6H,10H)-ylidene)amino)oxy)carbonyl)piperidin-1-yl)ethanone was obtained. 1H NMR (DMSO-d6 400 MHZ): ? 8.47(s, 1H), 8.33(d, 1H), 7.70-7.29(m, 2H), 5.96(m, 1H), 5.62(s, 1H), 3.39(m, 4H), 2.33-1.27(m, 31H). ESI-MS m/z: 516.1[M+H]+.

Example 13

[0060] Synthesis of (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-(1-(2-(dimethylamino)ethyl)piperidine-4-carbonyl)oxime

##STR00032##

[0061] The synthetic method of Examples 1-2 was merged. After the esterification of 1-(2-(dimethylamino)ethyl)piperidine-4-carboxylic acid and (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridine-3-base)-6,7,8,9,10,11,12,13,14,15-decahydro-1H -cyclopenteno[a]phenanthrenyl-3(2H)-ketoxime intermediate, a white solid (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15Decahydro-1H-cyclopenteno[a]phenanthrenyl-3(2H)-one O-(1-(2-(dimethylamino)ethyl)piperidine-4-carbonyl)oxime was obtained. 1H NMR(DMSO-d6 400 MHz): ? 8.47(s, 1H), 8.33(d, 1H), 7.70-7.29(m, 2H), 5.96(m, 1H), 5.62(s, 1H), 2.66(m, 6H), 2.41-2.37(m, 8H), 2.36-1.27(m, 28H). ESI-MS m/z: 545.1[M+H]+.

Example 14

[0062] Synthesis of (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) 6,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-(1-(cyclopropanesulfonyl)piperidine-4-carbonyl)oxime

##STR00033##

[0063] The synthetic method of Examples 1-2 was merged. After the esterification of 1-(cyclopropanesulfonyl) piperidine-4-carboxylic acid and (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(Pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-decahydro-1H -cyclopenta[a]phenanthrenyl-3(2H)-ketoxime intermediate, a white solid (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-(1-(cyclopropanesulfonyl)piperidine-4-carbonyl)oxime was obtained. 1H NMR (DMSO-d6 400 MHZ): ? 8.47(s, 1H), 8.33(d, 1H), 7.70-7.29(m, 2H), 5.96(m, 1H), 5.62(s, 1H), 2.91(m, 4H), 2.36-1.27(m, 33H). ESI-MS m/z: 578.1[M+H]+.

Example 15

[0064] Synthesis of (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-(1-(cyclopropanemethyl)piperidine-4-carbonyl)oxime

##STR00034##

[0065] The synthetic method of Examples 1-2 was merged. After the esterification of 1-(cyclopropanemethyl) piperidine-4-carboxylic acid and (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(Pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-decahydro-1H -cyclopenta[a]phenanthrenyl-3(2H)-ketoxime intermediate, a white solid (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-(1-(cyclopropanemethyl)piperidine-4-carbonyl)oxime was obtained. 1H NMR(DMSO-d6 400 MHZ): ? 8.47(s, 1H), 8.33(d, 1H), 7.70-7.29(m, 2H), 5.96(m, 1H), 5.62(s, 1H), 2.41(m, 4H), 2.36-1.27(m, 35H). ESI-MS m/z: 528.1[M+H]+.

Example 16

[0066] Synthesis of (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-((S)-1-methylpyrrolidine-2-carbonyl)oxime

##STR00035##

[0067] The synthetic method of Examples 1-2 was merged. After the esterification of (S)-1-methylpyrrolidine-2-carboxylic acid and (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(Pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-ketoxime intermediate, a white solid (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-((S)-1-methylpyrrolidine-2-carbonyl)oxime was obtained. 1H NMR(DMSO-d6 400 MHZ): ? 8.47(s, 1H), 8.33(d, 1H), 7.70-7.29(m, 2H), 5.96(m, 1H), 5.62(s, 1H), 3.08(m, 1H), 2.36-1.27(m, 32H). ESI-MS m/z: 474.1[M+H]+.

Example 17

[0068] Synthesis of (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15- decahydro-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-tetrahydro-2H-pyran-4-carbonyl oxime

##STR00036##

[0069] The synthetic method of Examples 1-2 was merged. After the esterification of tetrahydropyran-4-carboxylic acid and (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin -3-yl)-6,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenta[a]phenanthreny1-3(2H)-ketoxime intermediate, a white solid (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl)-6,7,8,9,10,11,12,13,14,15-10 Hydrogen-1H-cyclopenta[a]phenanthrenyl-3(2H)-one O-tetrahydro-2H-pyran-4-carbonyl oxime. 1H NMR(DMSO-d6 400 MHZ): ? 8.47(s, 1H), 8.33(d, 1H), 7.70-7.29(m, 2H), 5.96(m, 1H), 5.62(s, 1H), 3.55(m, 4H), 2.36-1.27(m, 28H). ESI-MS m/z: 475.1[M+H]+.

Example 18

[0070] Synthesis of (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-Decahydro-1H-Cyclopenteno[a]phenanthrenyl-3(2H)-one O-Nicotinoxime

##STR00037##

[0071] The synthetic method of Examples 1-2 was merged. After the esterification of nicotinic acid and (8S,9S,10R,13S,14S)-10,13-dimethyl-17-(pyridin-3-yl) -6,7,8,9,10,11,12,13,14,15-Decahydro-1H-cyclopenteno[a]phenanthrenyl-3(2H)-ketoxime intermediate, a white solid (8S,9S,10R,13S,14S)-10,13-Dimethyl-17-(pyridin-3-yl) 6,7,8,9,10,11,12,13,14,15-decahydro-1H-cyclopenta Ekeno[a]phenanthrenyl-3(2H)-one O-nicotinoyl oxime. 1H NMR (DMSO-d6 400 MHZ): ? 8 8.88(s, 1H), 8.65(d, 1H), 8.47(s, 1H), 8.33(d, 1H), 7.70-7.29(m, 4H), 5.96(m, 1H), 5.62(s, 1H), 2.36-1.27(m, 23H). ESI-MS m/z: 468.1[M+H]+.

Example 19: Prostate Tumor Pharmacodynamics Experiment

[0072] Test the inhibitory effects of the compounds of ZONK1901 series (compounds of the present invention) and ZONK1901-10 (abiraterone acetate) on the growth of human prostate cancer cell VCaP nude mouse transplanted tumor model in vivo.

[0073] Test sample: compound (B) of Example 1, compound (C) of Example 2, compound (D) of Example 3, Example 4 (E), Example 5 (F), Example 6 (G), Example 7 (H) and ZONK 1901-19, ZONK1901-10 (I) (abiraterone acetate)

##STR00038##

[0074] ZONK1901-19 (Group J).

Reagent

[0075] DMEM culture solution; fetal bovine serum; trypsin; penicillin-streptomycin double antibody; dimethyl sulfoxide (DMSO); TPGS; Matrigel; PBS (pH7.4, 0.01M).

[0076] Male BALB/c nude mice (number: 90; age: 6-7 weeks) purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., were raised in the SPF animal room of Suzhou Shengsu New Drug Development Co., Ltd. at a temperature of 20?25? C. and a relative humidity 40%?70%, and bright and dark illumination for 12 hours respectively; these mice were allowed to drink and eat freely. After normal feeding for about 6 days, mice with good physical signs can be selected for this experiment after veterinary inspection. Before grouping, animals were identified at their base of tail using marking pens. After grouping, each animal was identified by ear clipping.

[0077] Human prostate cancer cells VCaP were obtained from the Shanghai Cell Bank of the Chinese Academy of Sciences (CAS, cryopreserved in liquid nitrogen in our laboratory).

[0078] Under a culture condition of 5% CO2 and 37? C., VCaP cells were routinely cultured in DMEM medium containing 10% fetal bovine serum. Digested with 0.25% trypsin and passaged, VCaP cells were passaged 2-3 times per week based on cell growth, with a passage ratio of 1:3 to 1:5.

[0079] The VCaP cells in logarithmic growth phase were collected, counted, and resuspended in 50% DMEM basal medium and 50% Matrigel Matrix, and the cell concentration was adjust to 5?107 cells/mL; the cells was placed in an ice box; Cell suspension was aspirated with a 1 ml syringe, and injected subcutaneously to the anterior right armpit of nude mice. Each animal was inoculated with 200 ?L (1?107 cells/mouse), and a VCaP transplant tumor model in nude mice was established. Regularly observe the status of mice, measure the diameter of the tumor with an electronic vernier caliper, input the data into Excel spreadsheets, calculate the tumor volume, and monitor its growth. When the tumor volume reached 100-300 mm3, 60 mice with good health and similar tumor volume were selected, and divided into 10 groups (n=6) based on the tumor volume using random block method, while ensuring that the average body weight of each group remained consistent as much as possible. The day of grouping was taken as the first day of the experiment (D1). The tumor diameters were measured twice a week after the initiation of the experiment, the tumor volumes were calculated, and the body weights of the animals were weighed and recorded at the same time.

[0080] The calculation formula of the tumor volume (TV) was as follows:

TV (mm3)=1?w2/2

[0081] wherein, 1 represents the long diameter of the tumor (mm); w represents the short diameter of the tumor (mm).

[0082] Preparation of DMSO&PEG400&PG (v:v:v, 10:60:30): appropriate volumes of DMSO, PEG400 and PG were drawed respectively, and mixed well. The ratio of DMSO, PEG400 and PG in the mixture is 10:60:30 (v:v:v), and this mixture is used as a blank solvent and stored at room temperature.

Preparation of the Dosing Formulations

[0083] Appropriate amount of the test compound was weighed and added into a glass bottle, appropriate volume of solvent DMSO was added, be treated with vortex ultrasonication, then appropriate volumes of PEG400 and PG were added in turn, be vortex mixed to obtain a dosing formulation with a final concentration of 0.05M. The dosing formulation was stored in refrigerator at 2-8? C. after subpackaging, and was stirred evenly with vortex before each administration. The dosing formulation was prepared every 7 days, and was subpackaged and stored in refrigerator at 4? C.

Preparation of the ZONK1901-10 Dosing Formulations

[0084] Appropriate amount of ZONK1901-10 was weighed and added into a glass bottle, appropriate volume of corn oil, was added, be treated with vortex ultrasonication evenly, a dosing formulation with a final concentration of 19.58 mg.Math.mL-1 (0.05 M) was obtained. The dosing formulation was stored in refrigerator at 2-8? C. after subpackaging, and was stirred evenly with vortex before each administration. The dosing formulation was prepared every 7 days, and was subpackaged and stored in refrigerator at 4? C.

[0085] The grouping of animals and the dosing regimens were shown in Table 1. The test samples were administered on the day of grouping, and the experiment was ended 28 days later or when the tumor volume of solvent control group reached 2000 mm3 (whichever was reached earlier), and all the administration volume was 10 mL.Math.kg-1. Group A was the blank solvent group, and the blank solvent (DMSO&PEG400&PG(v:v:v, 10:60:30)) was administered intragastrically, once a day (QD). Other groups were intragastrically administered the test compounds, once a day (QD). Group I was intragastrically administered ZONK1901-10 at a dose of 195.8 mg.Math.kg-1 (0.5 mmol.Math.kg-1), once a day (QD).

TABLE-US-00001 TABLE 1 Dosing regimen for drug efficacy experiment of nude mouse transplanted tumor model Dosage Administration Number of (mmol .Math. volume Administration Administration Group Sample animals kg.sup.?1) (mL .Math. kg.sup.?1) route frequency ***A DMSO&PEG400&PG 6 10 i.g. QD 10:60:30) B Example 1 6 0.5 10 i.g. QD C Example 2 6 0.5 10 i.g. QD D Example 3 6 0.5 10 i.g. QD E Example 4 6 0.5 10 i.g. QD F Example 5 6 0.5 10 i.g. QD G Example 6 6 0.5 10 i.g. QD H Example 7 6 0.5 10 i.g. QD I ZONK1901-10 6 0.5 10 i.g. QD J ZONK1901-19 6 0.5 10 i.g. QD

[0086] On the last day of the experiment, the animals were euthanized (CO2) after weighing the body weight and measuring the tumor diameter. The tumor tissue was stripped, weighed and photographed, and the tumor weight inhibition rate was calculated. The animals were dissected grossly, and the internal organs were visually observed for abnormalities. Animal carcasses and tumor tissues were stored in refrigerator for unified treatment.

Data Record, Calculation Formula

[0087] The calculation formula of relative tumor volume (RTV) is:

RTV=TVt/TVinitial

[0088] wherein, TVinitial is the tumor volume measured during group administration; TVt is the tumor volume at each measurement during administration.

[0089] The calculation formula of relative tumor proliferation rate (% T/C) is:

% T/C=100%?(RTVT/RTVC)

[0090] wherein, RTVT represents the RTV of the treatment group; RTVC represents the RTV of the solvent control group.

[0091] The calculation formula of tumor growth inhibition rate TGI (%) is:

TGI=100%?[1?(TVt(T)?TVinitial(T)/(TVt(C)?TVinitial(C))]

[0092] wherein, TVt(T) represents the tumor volume measured each time in the treatment group; TVinitial(T) represents the tumor volume of the treatment group measured during group administration; TVt(C) represents the tumor volume measured each time in the solvent control group; TVinitial(C) represents the tumor volume of the solvent control group during group administration.

[0093] The calculation formula of animal weight loss rate is:

Animal weight loss rate=100%?(BWinitial-BWt)/BWinitial

[0094] Wherein, BWt represents the animal body weight measured each time during the administration period; BWinitial represents the animal body weight at the time of group administration.

[0095] The calculation formula of tumor weight inhibition rate IR (%) is:

IR=100%?(WC?WT)/WC

[0096] Wherein, WC represents the tumor weight in the solvent control group; WT represents the tumor weight in the treatment group.

[0097] Tumor volume and tumor growth inhibition rate of animals in each group during the administration period

TABLE-US-00002 A (sol- Group vent) B C D E F G H I J Day 1 226 ? 12 228 ? 14 230 ? 12 225 ? 7 238 ? 16 280 ? 15 227 ? 21.sup. 228 ? 14 274 ? 18.sup. 252 ? 21.sup. day 25 1103 ? 66 384 ? 32 ** 393 ? 25 ** 478 ? 64 ** 377 ? 37 ** 410 ? 44 ** 405 ? 15 * 492 ? 30 ** 765 ? 46 * 790 ? 49 * Growth 82.2% ** 81.4% ** 71.2% ** 84.2% ** 85.2% ** 80.7% ** 69.3% ** 44.1% * 38.7% * Inhibi- tion rate (GI) Note: * indicates that there is a significant difference between the tumor volume and the solvent control group (P < 0.05); ** indicates that there is a very significant difference between the tumor volume and the solvent control group (P < 0.01)

[0098] Note: * indicates that there is a significant difference between the tumor volume and the solvent control group (P<0.05); ** indicates that there is a very significant difference between the tumor volume and the solvent control group (P<0.01)

Example 20: Pharmacokinetic Experiment

[0099] ##STR00039##

ZONK1901-19(Group H)

[0100] To study the pharmacokinetic properties after intragastric administration in mice.

[0101] 45 male mice are randomly divided into 9 groups (each group contains 5), embodiment 1 compound (B), embodiment 2 compound (C), embodiment 3 compound (D), embodiment 4 (E), embodiment 5(F), embodiment 6(G), and ZONK1901-19(H), ZONK1901-10(I) (abiraterone acetate).

[0102] Each mouse was collected at 2-3 discrete points in time.

[0103] An LC-MS/MS analysis method for determining the concentrations of ZONK 1901-1 and ZONK1901-2 in mouse whole blood was established. At the same time, the obtained plasma concentration data was calculated by using the pharmacokinetic processing software Pharsight Phoenix WinNonlin8.0 non-compartmental model to calculate relevant pharmacokinetic parameters.

##STR00040##

[0104] The main pharmacokinetic parameters of the metabolites ZONK1901-1 and ZONK1901-2 after intragastric administration in each group are as follows:

TABLE-US-00003 t.sub.1/2 T.sub.max C.sub.max AUC.sub.0-t AUC.sub.0-inf Group Compoud (h) (h) (nM) (nM .Math. h) (nM .Math. h) B ZONK1901-1 4.58 2.00 654 2156 2236 ZONK1901-2 2.92 2.00 1039 3425 3702 C ZONK1901-1 2.30 2.00 1094 3916 4021 ZONK1901-2 2.75 2.00 532 3125 3150 D ZONK1901-1 2.30 2.00 1258 4916 4021 ZONK1901-2 2.75 2.00 568 2879 3021 E ZONK1901-1 1.35 4.00 1219 6527 6554 ZONK1901-2 1.95 4.00 644 4558 4669 F ZONK1901-1 2.73 2.00 661 2227 2308 ZONK1901-2 3.17 2.00 398 2127 2276 G ZONK1901-1 2.73 2.00 679 2103 2396 ZONK1901-2 3.17 2.00 421 2237 2287 H ZONK1901-1 4.58 0.500 112 554 563 ZONK1901-2 2.92 0.500 103 342 370 I ZONK1901-1 4.58 0.500 101 454 360 ZONK1901-2 NR NR NR NR

Example 21: Pharmacodynamics Evaluation of Acne

[0105] There are 140 male healthy Japanese big-ear white rabbits, weighing 2.0-2.5 kg. After one week of adaptive rearing, 10 rabbits were randomly selected according to their body weights as the normal control group, and the remaining 130 rabbits were coated with coal tar once a day in the area of 2?2 cm2 at 2 cm outside the opening of ear canal, with a thickness of about 0.5 mm (Before coating, the coal tar was heated to melt in a water bath, and the last coal tar shell was removed before each application; the rabbits in normal control group were coated with olive oil by the same method as before). After 3 weeks for modeling, according to the degree of skin lesion, 130 rabbits were randomly divided into 13 groups which is model control group, Example 1 compound (1 group), Example 2 compound (2 groups), Example 3 compound (3 groups), Example 4 (4 groups), Example 5 (5 groups), Example 6 (6 groups), Example 7 (7 groups), Example 8 (8 groups), Example 9 (9 groups), Example 10 (10 groups), Example 11 (11 groups), Example 12 (12 groups), Example 13 (13 groups), and each group had 10 rabbits. After grouping, each dose group were continued to be coated coal tar in the morning, and after the coal tar was removed in the afternoon, apply the test drug or control drug (both 0.01%/10 g ointment, apply 1 g ointment per animal) on the lesion, once a day, for two consecutive weeks (the model control group and the normal control group were coated with the same amount of matrix). 24 hours after the last administration, the animals were sacrificed by air embolism, and the skin (full thickness) of the ear where the administration was administered was taken, fixed with 4% paraformaldehyde solution, stained with HE, and routinely observed for pathology.1.

1. Experimental Results

[0106] Effects on keratinization of hair follicles in experimental rabbit ear acne

TABLE-US-00004 Degree of keratinization Group ? + ++ +++ normal control group 10 0 0 0 ** model control group 0 0 5 5 1 0 6 4 0 * 2 0 5 5 0 * 3 0 6 4 0 * 4 1 7 3 0 * 5 0 6 4 0 * 6 0 5 5 0 * 7 0 6 4 0 * 8 0 5 5 0 * 9 0 6 4 0 * 10 1 6 3 0 * 11 0 7 3 0 * 12 0 5 5 0 * 13 0 4 6 0 * * means P < 0.05, compared with the model control group; ** means P < 0.01, compared with the model control group;

[0107] It can be seen from the above table that compared with the model control group, the keratinization in the hair follicles of the rabbit ears in each group was improved. 3.2 Effects on the degree of inflammatory cell infiltration in the experimental rabbit ear acne model

TABLE-US-00005 degree of inflammatory cell infiltration Group ? + ++ +++ normal control group 10 0 0 0 ** model control group 0 0 5 5 1 0 5 3 2 * 2 0 4 4 2 * 3 0 5 4 1 * 4 0 5 3 2 * 5 0 6 3 1 * 6 0 6 3 1 * 7 0 5 3 2 * 8 0 4 4 2 * 9 0 5 4 1 * 10 0 5 3 2 * 11 0 6 3 1 * 12 0 5 4 1 * 13 0 6 3 1 * ** indicates that compared with the model control group, P < 0.01; * indicates that compared with the model control group, P < 0.05

[0108] It can be seen from the above table that compared with the model control group, the infiltration of otitis cells in rabbits in each group has improved.