Steroidal derivatives, pharmaceutical compositions thereof and uses thereof

Abstract

This invention discloses a steroid derivative, a pharmaceutical composition thereof, and its uses. The steroid derivative is shown in formula (I0). The compound has antiviral, antitumor, and anti-inflammatory effects.

Description

Technical Field

[0001] This invention relates to, but is not limited to, the field of pharmaceutical chemistry, and particularly to a steroid derivative, its pharmaceutical composition, and its uses. Background Technology

[0002] Chinese patent CN102076344B discloses a steroid compound with the following chemical structure:

[0003]

[0004] These compounds are a class of non-hormonal steroidal modulators of NF-κB, which can be used to treat and prevent muscular atrophy diseases, including traumatic brain injury, spinal cord injury, and other diseases.

[0005] NF-κB is associated with a variety of diseases in the human body. Modifying steroidal compounds can regulate or even alter their effects to some extent. Therefore, it is still necessary to develop steroidal drugs with novel structures to discover more drug uses. Summary of the Invention

[0006] The inventors have developed a novel steroid derivative with antiviral, antitumor, and anti-inflammatory effects, which can be used for the treatment or adjuvant treatment of certain viral infections, solid tumors, etc.

[0007] In one aspect, this invention provides a steroidal compound, tautomer, stereoisomer, and pharmaceutically acceptable salt thereof, as shown in formula (I0):

[0008]

[0009] In formula (I0), there is a double bond between carbon atom 4 and carbon atom 5, and a single bond between carbon atom 5 and carbon atom 6; or there is a double bond between carbon atom 5 and carbon atom 6, and a single bond between carbon atom 4 and carbon atom 5.

[0010] Q1 and Q2 are independent of each other. However, Q1 and Q2 are not simultaneously...

[0011] Y1 is NH, O, or S;

[0012] Y2 is N, O, or S, where R3 does not exist when Y2 is O or S;

[0013] Y3 is N;

[0014] R1 and R2 are each independently selected from hydrogen or from the following groups substituted or unsubstituted with group A: C1-C12 alkyl groups, -C(O)-O-R7, -C(O)-R7, -(CH2). m -OC(O)-R7、-(CH2)m -OC(O)-O-R7; where m is 1, 2, 3, 4, or 5; R7 is selected from the following groups: C1-C18 alkyl groups and C1-C18 olefin groups;

[0015] R3 is selected from the following groups: absent, hydrogen, C1-C8 alkyl, -C(O)-R8, -C(O)-(CH2). n -NH-C(O)-O-R8; where n is 1, 2 or 3, and R8 is selected from: hydrogen, C1-C8 alkyl, C6-C14 aryl-substituted C1-C8 alkyl;

[0016] R4 is selected from the following groups: hydrogen, C1-C18 alkyl, -C(O)-O-R9, -C(O)-N(R9)2, -C(O)-NH-R9; wherein R9 is selected from the following groups: C1-C18 alkyl, hydroxyl or mercapto-substituted C1-C18 alkyl;

[0017] R5 and R6 are each independently selected from hydrogen or the following groups: C1-C18 alkyl, hydroxyl or mercapto-substituted C1-C18 alkyl;

[0018] The group A is selected from the following groups: halogen, OH, -N(R) 10 )2、-NHR 10 -C(O)N(R) 10 )2,-C(O)OR 10 ;where R 10 It is hydrogen or a C1-C8 alkyl group.

[0019] In some embodiments, the present invention provides a steroidal derivative, tautomer, stereoisomer, or pharmaceutically acceptable salt thereof as shown in formula (I) or formula (II):

[0020]

[0021] In formula (I) or formula (II), there is a double bond between carbon atom 4 and carbon atom 5, and a single bond between carbon atom 5 and carbon atom 6; or there is a double bond between carbon atom 5 and carbon atom 6, and a single bond between carbon atom 4 and carbon atom 5.

[0022] Y1 is NH, O, or S, and Y2 is N, O, or S. When Y2 is O or S, R3 does not exist.

[0023] R1 and R2 are each independently selected from hydrogen or from the following groups substituted or unsubstituted with group A: C1-C12 alkyl groups, -C(O)-O-R7, -C(O)-R7, -(CH2). m -OC(O)-R7、-(CH2) m-OC(O)-O-R7; where m is 1, 2, 3, 4, or 5; R7 is selected from the following groups: C1-C18 alkyl groups and C1-C18 olefin groups;

[0024] R3 is selected from the following groups: absent, hydrogen, C1-C8 alkyl, -C(O)-R8, -C(O)-(CH2). n -NH-C(O)-O-R8; where n is 1, 2 or 3; R8 is selected from: hydrogen, C1-C8 alkyl, C6-C14 aryl-substituted C1-C8 alkyl;

[0025] R4 is selected from the following groups: hydrogen, C1-C18 alkyl, -C(O)-O-R9, -C(O)-N(R9)2, -C(O)-NH-R9; wherein R9 is selected from the following groups: C1-C18 alkyl, hydroxyl or mercapto-substituted C1-C18 alkyl;

[0026] R5 and R6 are each independently selected from hydrogen or the following groups: C1-C18 alkyl, hydroxyl or mercapto-substituted C1-C18 alkyl;

[0027] The group A is selected from the following groups: halogen, OH, -N(R) 10 )2、-NHR 10 -C(O)N(R) 10 )2,-C(O)OR 10 R10 is hydrogen or a C1-C8 alkyl group.

[0028] In some embodiments, the present invention provides a steroidal derivative, tautomer, stereoisomer, or pharmaceutically acceptable salt thereof as shown in formula (III) or (IV):

[0029]

[0030] The substituents in formula (III) or formula (IV) are defined as described above.

[0031] In some embodiments, the present invention provides a steroidal derivative, tautomer, stereoisomer, or pharmaceutically acceptable salt thereof as shown in formula (V) or formula (VI):

[0032]

[0033] The substituents in formula (V) or formula (VI) are defined as described above.

[0034] In some embodiments, the present invention provides a steroidal derivative, tautomer, stereoisomer, or pharmaceutically acceptable salt thereof as shown in formula (VII) or (VIII):

[0035]

[0036] The substituents in formula (VII) or formula (VIII) are defined as described above.

[0037] In some embodiments, the present invention provides a steroidal compound, tautomer, stereoisomer, and pharmaceutically acceptable salt thereof as shown in formula (IX):

[0038]

[0039] The substituents in formula (IX) are defined as described above.

[0040] In some embodiments, in formula (I0), formula (I), formula (II) or formula (IX), there is a double bond between carbon atom 4 and carbon atom 5, and a single bond between carbon atom 5 and carbon atom 6; in other embodiments, there is a double bond between carbon atom 5 and carbon atom 6, and a single bond between carbon atom 4 and carbon atom 5.

[0041] In some implementations, in equation (I0), Q1 and Q2 are both In some implementations, in equation (I0), Q1 and Q2 are both In some implementations, Q1 in equation (I0) is Q2 is In some implementations, Q1 in equation (I0) is But Q2 is

[0042] In some implementations, in formula (I0), formula (I), or formula (II), Y1 and Y2 are simultaneously N (or NH), O, or S; in some implementations, in formula (I0), formula (I), or formula (II), Y1 is NH, O, or S, and Y2 is N; in some implementations, in formula (I0), formula (I), or formula (II), Y1 is NH, and Y2 is O or S, in which case R3 does not exist; in some implementations, in formula (I0), formula (I), or formula (II), Y1 is O, and Y2 is S, in which case R3 does not exist; in some implementations, in formula (I0), formula (I), or formula (II), Y1 is S, and Y2 is O, in which case R3 does not exist.

[0043] In some implementations, Y3 is N and Y1 is S in equation (I0) or equation (IX); in some implementations, Y3 is N and Y1 is O in equations (I0) and (IX).

[0044] In some implementations, R1 and R2 are both hydrogen in formula (I0), formula (I), or formula (II);

[0045] In some embodiments, R1 is hydrogen and R2 is not hydrogen in formula (I0), formula (I) or formula (II); in some embodiments, R1 is not hydrogen and R2 is hydrogen in formula (I0), formula (I) or formula (II); in some embodiments, neither R1 nor R2 is hydrogen in formula (I0), formula (I) or formula (II).

[0046] In some embodiments, when R1 and / or R2 are not hydrogen, they may be selected from C1-C12 alkyl groups substituted or unsubstituted by group A; in some embodiments, when R1 and / or R2 are not hydrogen, they may be selected from the following groups substituted or unsubstituted by group A: -C(O)-O-R7, -C(O)-R7, wherein R7 is selected from the following groups: C1-C18 alkyl groups, C1-C18 olefin groups;

[0047] In some embodiments, when R1 and / or R2 are not hydrogen, they may be selected from the following groups, substituted or unsubstituted with group A: -(CH2). m -OC(O)-R7、-(CH2) m -OC(O)-O-R7, wherein m is 1, 2, 3, 4, or 5; R7 is selected from the following groups: C1-C18 alkyl groups, C1-C18 olefin groups; preferably, m is 1, 2, or 3.

[0048] In some embodiments, R3 is hydrogen in formula (I0), formula (I) or formula (II) above; in some embodiments, R3 is a C1-C8 alkyl group in formula (I0), formula (I) or formula (II) above.

[0049] In some embodiments, in the above formula (I0), formula (I) or formula (II), R3 is -C(O)-R8, wherein R8 is selected from: hydrogen, C1-C8 alkyl, C6-C14 aryl-substituted C1-C8 alkyl; preferably, R8 is C1-C8 alkyl;

[0050] In some implementations, R3 is -C(O)-(CH2) in formula (I0), formula (I), or formula (II) above. n -NH-C(O)-O-R8, wherein n is 1, 2 or 3, and R8 is selected from: hydrogen, C1-C8 alkyl, C6-C14 aryl-substituted C1-C8 alkyl; preferably, n is 1, and R8 is a C1-C8 alkyl or a phenyl-substituted C1-C8 alkyl.

[0051] In some embodiments, R4 is hydrogen in formula (I0), formula (I) or formula (II) above; in some embodiments, R4 is a C1-C18 alkyl group in formula (I0), formula (I) or formula (II) above.

[0052] In some embodiments, in formula (I0), formula (I) or formula (II) above, R4 is selected from the following groups: -C(O)-O-R9, -C(O)-N(R9)2, -C(O)-NH-R9, wherein R9 is selected from C1-C18 alkyl groups; in some embodiments, in formula (I0), formula (I) or formula (II) above, R4 is selected from the following groups: -C(O)-O-R9, -C(O)-N(R9)2, -C(O)-NH-R9, wherein R9 is selected from C1-C18 alkyl groups substituted with hydroxyl or mercapto, preferably, R9 is selected from C2-C8 alkyl groups substituted with hydroxyl or mercapto.

[0053] In some embodiments, R5 and R6 are both hydrogen in formula (I0), formula (I), or formula (II) above; in some embodiments, R5 is hydrogen and R6 is not hydrogen in formula (I0), formula (I), or formula (II); in some embodiments, R1 and R2 are not hydrogen in formula (I0), formula (I), or formula (II); in some embodiments, when R5 and / or R5 is not hydrogen, it may be selected from C1-C18 alkyl groups; in some embodiments, when R5 and / or R5 is not hydrogen, it may be selected from hydroxyl-substituted C1-C18 alkyl groups; in some embodiments, when R5 and / or R5 is not hydrogen, it may be selected from mercapto-substituted C1-C18 alkyl groups.

[0054] In some implementations, R4, R5 and R6 are all hydrogen in the above formula (I0), formula (I) or formula (II), and in this case, Y1 and Y2 are not both O;

[0055] In some embodiments, in formula (I0), formula (I), or formula (II) above, the group A is selected from the following groups: halogen, -OH, -NH2, -COOH; -C(O)NH2; in some embodiments, in formula (I0), formula (I), or formula (II) above, the group A is selected from the following groups: -N(R 10 )2、-NHR 10 -C(O)N(R) 10 )2,-C(O)OR 10 , where R10 is a C1-C8 alkyl group.

[0056] In some embodiments, the steroidal compounds provided by the present invention are selected from the following compounds:

[0057]

[0058]

[0059]

[0060] On the other hand, the present invention provides a pharmaceutical composition comprising the above-mentioned steroid derivatives, tautomers, stereoisomers, and pharmaceutically acceptable salts thereof.

[0061] This invention discloses a pharmaceutical composition comprising, as an active ingredient or one of the main active ingredients, the steroid derivatives, tautomers, stereoisomers, and pharmaceutically acceptable salts thereof described in this invention, supplemented by a pharmaceutically acceptable carrier.

[0062] Thirdly, the present invention provides that the above-mentioned steroid derivatives, tautomers, stereoisomers, and pharmaceutically acceptable salts have antiviral, antitumor, and anti-inflammatory effects.

[0063] The steroid derivatives described in this invention can be formulated into pharmaceutical compositions and administered to patients via a variety of suitable routes of administration, including systemic (e.g., oral or parenteral), intravenous, intramuscular, transdermal, or subcutaneous routes.

[0064] definition:

[0065] A pharmaceutically acceptable solvate, which forms part of this invention, can be a crystalline hydrate or a crystallizer with other solvents, such as ethanol.

[0066] A pharmaceutically acceptable salt forms part of this invention:

[0067] If the compound of the present invention is basic, then a suitable "pharmaceutically acceptable salt" includes conventional non-toxic salts of the compound of the present invention formed by the reaction of the compound of the present invention with an inorganic or organic acid. For example, this includes salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc., as well as salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethylsulfonic acid, trifluoroacetic acid, etc.

[0068] If the compounds of this invention are acidic, then a suitable "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic alkali, including inorganic and organic alkalis. Salts derived from inorganic alkalis include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts, etc.

[0069] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain, branched-chain alkyl or cycloalkyl groups, which may be substituted or unsubstituted. When it is a substituted alkyl group, the substituent is preferably one or more, more preferably one to three, and most preferably one or two substituents.

[0070] The term "alkenyl" refers to an aliphatic hydrocarbon group containing an unsaturated carbon-carbon double bond, including straight-chain, branched, or cyclic hydrocarbon groups; it can be substituted or unsubstituted. There can be one or more carbon-carbon double bonds.

[0071] The term "cycloalkyl" refers to a monocyclic or fused-ring group consisting entirely of carbon atoms (a "fused" ring means that each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system), wherein one or more rings do not have a fully connected π-electron system. Examples of cycloalkyl groups (but not limited to) include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane, and cyclohepttriene. Cycloalkyl groups can be substituted or unsubstituted.

[0072] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic group with 6 to 14 carbon atoms and a fully conjugated π-electron system. Non-limiting examples of aryl groups include phenyl, naphthyl, and anthracene. Aryl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two, or three, and even more preferably one or two.

[0073] The term "hydroxyl group" refers to the -OH group.

[0074] The term "amino" refers to the -NH2 group.

[0075] The term "carboxyl group" refers to the -COOH group.

[0076] The term "thiol" refers to the -SH group.

[0077] The term "halogen" refers to fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine.

[0078] The numerical range mentioned in this application, such as "C1-C18", means that the group can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 18 carbon atoms.

[0079] The steroidal derivatives described in this invention possess antiviral, antitumor, and anti-inflammatory effects, and can be used for the treatment or adjuvant therapy of certain viral infections and solid tumors. The viral infections include, but are not limited to, infections caused by papillomavirus, herpesvirus, poxvirus, measles virus, etc.; the solid tumors include, but are not limited to, skin cancer, gastrointestinal cancer, kidney cancer, prostate cancer, breast cancer, etc.; these compounds are effective against some types of inflammation, including exudative or specific inflammation. Attached Figure Description

[0080] Figure 1 This describes the therapeutic effect of the compound of the present invention on skin lesions caused by HSV-1 virus infection in guinea pigs. Detailed Implementation

[0081] The following examples will enable those skilled in the art to more fully understand the present invention, but do not limit the invention in any way. The structures of all compounds have been analyzed by MS or... 1 H-NMR confirmed.

[0082] Example 1:

[0083]

[0084] Synthesis of compound DSC2901:

[0085] 1 g of compound 1, 0.46 g of cysteine ​​ethyl ester hydrochloride, and 10 ml of pyridine were added to a reaction flask. The system was reacted at room temperature for 8 hours under nitrogen protection. The system was concentrated to dryness under reduced pressure, and about 50 ml of dichloromethane and 10 ml of water were added. The organic phase was dried over anhydrous sodium sulfate and then concentrated to dryness. 25 ml of anhydrous ethanol was added to the system, and the mixture was heated to boiling. After hot filtration, the system was cooled and crystallized to give 0.41 g of compound DSC2901, yield 31%, ESI-MS (+): m / z 534.19 [M+H].

[0086] Example 2:

[0087]

[0088] Synthesis of compound DSC2902:

[0089] 1 g of compound 1, 2.77 g of cysteine ​​ethyl ester hydrochloride, and 20 mL of pyridine were added to a reaction flask. The system was reacted at room temperature for 10 hours under nitrogen protection. The system was concentrated to dryness under reduced pressure, and about 50 mL of dichloromethane and 10 mL of water were added. The organic phase was dried over anhydrous sodium sulfate and then concentrated to dryness. 25 mL of anhydrous ethanol was added to the system, and after heating, the system was cooled and crystallized to give 1.06 g of compound DSC2902, yield 64%, ESI-MS (+): m / z 665.37 [M+H].

[0090] Example 3:

[0091]

[0092] Synthesis of compound DSC2903:

[0093] 8.86 g of cysteine ​​ethyl ester hydrochloride and 40 ml of dichloromethane were added to a reaction flask, followed by the slow addition of 10 ml of triethylamine. The system was stirred vigorously at room temperature for 1 hour. The system was then filtered and concentrated to dryness to obtain an oily substance.

[0094] 3.20 g of compound 1 and 30 mL of pyridine were added to the above reaction solution, and the system was reacted at room temperature for 4 days under nitrogen protection. The system was filtered and crystallized with ethyl acetate to give 2.33 g of compound DSC2903, yield 44%, ESI-MS(+): m / z 665.36 [M+H].

[0095] Example 4:

[0096]

[0097] Synthesis of compound DSC2904:

[0098] 25 ml of approximately 80% acetic acid was added to the reaction flask and heated to 65 °C. 1.0 g of compound DSC2902 was added, and the mixture was stirred for 5 minutes while maintaining this temperature. The system was rapidly neutralized with 400 ml of ice water containing 25 g of sodium carbonate. The resulting suspension was filtered to obtain a solid, which was dried and crystallized with 8 ml of ethanol to give 0.24 g of compound DSC2904, yield 30%. ESI-MS (+): m / z 534.21 [M+H].

[0099] Example 5:

[0100]

[0101] Synthesis of compound DSC2905:

[0102] 3 g of compound 1, 3.45 g of aminoethanethiol, and 20 mL of pyridine were added to a reaction flask. The system was reacted at room temperature for 8 hours under nitrogen protection. The system was concentrated to dryness under reduced pressure, and approximately 100 mL of dichloromethane and 150 mL of water were added. The organic phase was dried over anhydrous sodium sulfate and then concentrated to dryness. 10 mL of hot anhydrous ethanol was added to the system for crystallization. After cooling and filtration, 1.34 g of compound DSC2905 was obtained, with a yield of 39%. ESI-MS (+): m / z 462.29 [M+H];

[0103] Synthesis of compound DSC2906:

[0104] 0.8 g of compound DSC2905 and 10 mL of dichloromethane were added to a reaction flask. 0.55 g of acetic anhydride was then added to the system, and the reaction was carried out at room temperature for 24 hours under nitrogen protection. 50 mL of dichloromethane and 40 mL of water were added to the system, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness. The system was crystallized from 3 mL of hot anhydrous methanol, cooled, and filtered to obtain 0.25 g of compound DSC2906, yield 27%, ESI-MS (+): m / z 546.22 [M+H].

[0105] Example 6:

[0106]

[0107] Synthesis of compound 4:

[0108] Under argon protection at -78°C, LDA (lithium diisopropylamino, 25 mL, 49.9 mmol) was slowly added to a tetrahydrofuran (200 mL) solution of compound 2 (11.78 g, 41.6 mmol). After reacting for 1 hour, n-pentanal (compound 3, 5.31 mL, 49.9 mmol) was slowly added, and the temperature was slowly raised to 0°C. The reaction of the starting materials was confirmed by TLC to be complete. The reaction was quenched with saturated sodium bicarbonate solution, tetrahydrofuran was removed under reduced pressure, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain compound 4 (6.1 g, 40%).

[0109] Synthesis of compound 5:

[0110] Palladium hydroxide (610 mg) was added to an ethanol (40 mL) solution of compound 4 (6.1 g, 16.6 mmol), the mixture was purged with hydrogen three times, heated for 8 hours, and the reaction was confirmed to be complete by TLC. The mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure, and column chromatography was used to obtain compound 5 (1.8 g, 60%).

[0111] Synthesis of compound 6:

[0112] At 0 °C, triethylamine (3.8 mL) was slowly added dropwise to a DCM (30 mL) solution of compound 5 (1.64 g, 8.66 mmol), and the mixture was stirred for 10 minutes. Then, BOC anhydride (3.98 mL, 17.32 mmol) was added, and the mixture was reacted at room temperature for 5 hours. The reaction was confirmed to be complete by TLC. The reaction was quenched with water, extracted with DCM, washed with 1 M hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain compound 6 (2.0 g, 80%).

[0113] Synthesis of compound 7:

[0114] At 0 °C, triethylamine (3.1 mL, 22.36 mmol) was added to a DCM (40 mL) solution of compound 6 (5.0 g, 17.2 mmol) and stirred for 10 minutes. MsCl (methanesulfonyl chloride, 1.4 mL, 18.06 mmol) was added and the reaction was allowed to proceed for 40 minutes. The reaction was confirmed by TLC to be complete. The reaction was quenched with water, extracted with DCM, washed with 1 M hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 7 (6.3 g, 99%).

[0115] Synthesis of compound 8:

[0116] Potassium thioacetate (2.92 g, 25.6 mmol) was added to a DMF (150 mL) solution of compound 7 (6.3 g, 17.1 mmol) at room temperature, stirred for 3 hours, and then moved to 60 °C for 5 hours. The reaction was confirmed to be complete by TLC. The reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to obtain compound 8 (4.0 g, 67%).

[0117] Synthesis of compound 9:

[0118] Sodium ethoxide (970.4 mg, 14.26 mmol) was added to an ethanol (30 mL) solution of compound 8 (4.5 g, 12.96 mmol) at 0 °C. The reaction was carried out at 20 °C for 8 hours. The reaction was confirmed to be complete by TLC. The ethanol was removed under reduced pressure, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography to obtain compound 9 (1.8 g, 45%).

[0119] Synthesis of compound 10:

[0120] At 0°C, 1.3 mL of hydrochloric acid-ethanol (6N) solution was added to an ethanol (10 mL) solution of compound 9 (600 mg, 1.97 mmol / L). The reaction was allowed to proceed for 5 hours. The reaction was confirmed to be complete by TLC. The ethanol was removed by concentration under reduced pressure. Diethyl ether (20 mL) was added and the mixture was cooled to 0°C. A white solid precipitated out. The solid was filtered and dried to obtain compound 10 (270 mg, 57%).

[0121] Synthesis of compound DSC2922:

[0122] At 20°C, compound 1 (50 mg, 0.124 mmol), compound 10 (239.2 mg, 0.992 mmol), methanol (3 mL), and formic acid (10 μL) were added sequentially to a 25 mL single-necked flask. The reaction was allowed to proceed for 48 hours. The reaction was confirmed to be complete by TLC. The mixture was concentrated under reduced pressure and column chromatography was used to obtain compound DSC2922 (23 mg, 35%). ESI-MS (+): m / z 590.35 [M+H]; 1 H NMR(CDCl3,300MHz): δ5.25-5.49(m,1H),5.21-5.43(m,4H),3.33-3.75(m,2H),2.92-3.17(m,1H),2.49-2.81(m,1H),2.37-2.51(m, 2H),2.18-2.34(m,1H),1.5-2.04(m,16H),1.29-1.38(m,9H),1.13-1.19(m,3H),1.01-1.03(m,3H),0.87-0.92(m,4H),0.66(s,3H).

[0123] Example 7:

[0124]

[0125] 1 g of compound 1 and 1 g of 2-aminoethanethiol were added to a reaction flask, followed by 30 mL of ethyl acetate and 0.1 mL of glacial acetic acid. The system was heated under reflux for 3 hours. The system was concentrated to dryness under reduced pressure, and dichloromethane and water were added to the solution. The organic phase was dried over anhydrous sodium sulfate and then concentrated to dryness. Purification by silica gel column chromatography yielded 0.48 g of compound DSC2924, 42% yield, ESI-MS (+): m / z 462.36 [M+H].

[0126] The compounds of the following examples were synthesized using the same method as in the above embodiments, either commercially available compounds or intermediate compounds appropriately synthesized from commercially available compounds.

[0127]

[0128]

[0129]

[0130] Example 8: In vitro anti-VZV and HSV-1 virus activity experiments

[0131] MRC-5 cells were loaded at 2×10 5 Cells were seeded at a density of 200 μL / ml in 96-well plates and cultured. Experiments began when cells reached 80% confluence. The cell culture supernatant was removed, and 50 μL of the test drug solution (diluted 3-fold with culture medium) was added to each well. A blank control group (cells only) and a positive control group (Chloroquine group) were set up, with three replicates for each concentration. The 96-well plates were incubated at 37°C and 5% CO2 for 5 hours. Then, 50 μL of VZV or HSV-1 virus solution was added to each well, and cells were cultured in maintenance medium (MEM containing 2% FBS). One hour after infection, the virus was washed off, and 100 μL of the corresponding drug concentration was added again. The plates were incubated at 37°C and 5% CO2 for 72 hours. 100 μL of CellTiter-Glo cell viability assay reagent was added to each well, and after sufficient contact with the cells, the supernatant was transferred to microplates and analyzed using PerkinElmer VICTOR. TM X2 was used to detect cell fluorescence signals at a wavelength of 560 nm, and the cytopathic effect inhibition rate and half-maximal effective concentration (EC50) were calculated based on the cell fluorescence signals. 50 The results are shown in Table 1:

[0132] Table 1: In vitro activity assays of pitted VZV and HSV-1 viruses

[0133]

[0134] The results showed that the compound of the present invention has a strong inhibitory effect on VZV virus and HSV-1 virus, which is significantly better than Chloroquine.

[0135] Example 9: Sample solution preparation and stability test

[0136] Accurately weigh 60.47 mg of compound DSC2922 and 5.986 g of dipropylene glycol into a clean dispensing container. After complete dispersion, dissolve by sonication to obtain a 1% yellow solution of DSC2922 (g / g).

[0137] A 1% solution of compound 1 and a 1% solution of DSC2901 were prepared using a similar method.

[0138] The stability of 1% solution of compound 1, 1% solution of DSC2901 and 1% solution of DSC2922 was investigated by placing them at 25℃±2℃ for 0d, 1d, 3d and 7d. The results showed that each sample was stable under the experimental conditions for 7d.

[0139] Example 10: Therapeutic effect on guinea pig skin herpes

[0140] Twenty healthy male guinea pigs, weighing 280±20g, were randomly divided into four groups: A, B, C, and D, with five animals in each group. Each guinea pig underwent hair removal on its back using 8% Na2S depilatory agent. After washing, four deep punctures were made on the skin of each guinea pig's back using a plum blossom needle, followed by the application of 30μL of undiluted HSV-1 solution. Two hours after infection, a blank solution or the corresponding drug solution was applied to the infected skin. The total volume of drug solution applied to the four infected skin sites was 0.5ml per animal in each group. In groups A through D, group A received a blank solution, group B received compound 1 solution, group C received DSC2901 solution, and group D received DSC2922 solution. The treatment was administered three times daily for 7 days. The lesions were observed daily for 10 days. The severity of skin lesions was observed and recorded according to the evaluation criteria in Table 2. The t-test was used to determine the significance of differences between groups; p<0.05 was considered statistically significant. Results are shown below. Figure 1 .

[0141] Table 2: Evaluation Criteria for the Severity of Skin Lesions

[0142]

[0143] The results showed that the compounds of this invention had therapeutic effects on skin lesions caused by HSV-1 virus infection in guinea pigs, while the control group (group B, compound 1) did not show significant therapeutic effects. The compounds of this invention (group C DSC2901 and group DSC2922) showed significant differences at each observation time point compared with the model group (group A) and the control group (group B) (P < 0.05–0.01). Furthermore, from Figure 1 It is evident that after the 6th day of the experiment, the skin lesions caused by the compound of this invention showed a significant reduction trend.

[0144] Example 11: Inhibitory effect on the proliferation of B16-F10 skin cancer cells

[0145] Cells in the logarithmic growth phase were harvested and treated with 7.5 × 10⁻⁶ cells. 3 Cells / well were seeded at a density of 100 μL / well in 96-well plates and incubated at 37°C and 5% CO2 for 24 hours, after which the culture medium was discarded. Then, 100 μL of serially diluted (3-fold) concentrations of the test drug were added to each well. Separate wells were provided for a blank control, a drug-treated control, and a positive control, with three replicates for each concentration. The 96-well plates were incubated at 37°C and 5% CO2 for 48 hours. Based on the principle of live cell metabolism reducing tetramethylazoazole salt, the OD value at 492 nm was measured using a microplate reader, and the cell inhibition rate was calculated (cell inhibition rate % = (1 - OD value of drug-treated group / OD value of blank control group) × 100%). The IC50 was calculated using nonlinear regression fitting. 50 As shown in Table 3.

[0146] Table 3: Inhibitory effect on the proliferation of B16-F10 skin cancer cells

[0147] compound <![CDATA[IC 50 (μM)]]> compound <![CDATA[IC 50 (μM)]]> DSC2901 24.07 DSC2908 >50 DSC2913 20.16 DSC2914 28.12 DSC2915 25.42 DSC2916 >50 DSC2920 >50 DSC2922 19.33

[0148] The results showed that the compound of the present invention has a certain inhibitory effect on the proliferation of skin cancer cells.

[0149] Example 12: Pharmacodynamic test in a mouse skin cancer model

[0150] Mineral oil containing 60% DMBA (dimethylbenzyl anthracene) was applied to the back skin of mice after hair removal for 10 consecutive days. Forty-eight mice that successfully developed the model were randomly divided into four groups of 12 mice each. Mice were administered the drug orally once daily for four weeks. Group 1 received 2 mg / kg of compound DSC2908; Group 2 received 2 mg / kg of compound DSC2922; Group 3 received 2 mg / kg of triptolide; and Group 4 received a combination of 2 mg / kg triptolide and 2 mg / kg of compound DSC2922. Mice were euthanized by cervical dislocation the day after the last administration. The skin at the treatment site was disinfected with iodine tincture and alcohol. The tumor skin was aseptically removed and completely removed on a clean bench. The tumor mass was weighed using an electronic balance. The tumor inhibition rate was calculated using the formula (tumor inhibition rate % = 1 - average tumor mass of the treated group / average tumor mass of the model control group). The results are shown in Table 4 below.

[0151] Table 4: Inhibition rate against mouse skin cancer

[0152]

[0153]

[0154] The results showed that the compound of the present invention had a weak inhibitory effect on mouse skin cancer. When triptolide was used alone, the inhibition rate was approximately 45.8%, but when used in combination with the compound DSC2922 of the present invention, the tumor inhibition rate was significantly improved.

Claims

1. A steroidal derivative as shown in (I0) and a pharmaceutically acceptable salt thereof: In formula (I0), there is a double bond between carbon atom 4 and carbon atom 5, and a single bond between carbon atom 5 and carbon atom 6; or there is a double bond between carbon atom 5 and carbon atom 6, and a single bond between carbon atom 4 and carbon atom 5. Q1 is Q2 is Y1 is S; Y2 is N; Y3 is N; R1 and R2 are each independently selected from hydrogen or the following groups: -C(O)-O-R7, -C(O)-R7; R7 is selected from the following groups: methyl, ethyl; R3 is selected from the following groups: absent, hydrogen, C1-C8 alkyl, -C(O)-R8, -C(O)-(CH2). n -NH-C(O)-O-R8; where n is 1, 2 or 3, and R8 is selected from: hydrogen, C1-C8 alkyl, phenyl-substituted C1-C8 alkyl; R4 is selected from the following groups: hydrogen, C1-C8 alkyl, -C(O)-O-R9; wherein R9 is selected from the following groups: C1-C18 alkyl, hydroxyl or mercapto-substituted C2-C8 alkyl; R5 and R6 are each independently selected from hydrogen or the following groups: C1-C18 alkyl, hydroxyl or mercapto-substituted C1-C18 alkyl.

2. A steroidal derivative as shown in (III) and its pharmaceutically acceptable salt: The substituents in formula (III) are defined as defined in formula (I0) of claim 1.

3. A steroidal derivative as shown in (V) and its pharmaceutically acceptable salt: The substituents in formula (V) are defined as in formula (I0) of claim 1.

4. A steroidal derivative as shown in formula (VII) and a pharmaceutically acceptable salt thereof: The substituents in formula (VII) are defined as defined in formula (I0) of claim 1.

5. A steroidal derivative as shown in formula (IX) and a pharmaceutically acceptable salt thereof: The substituents in formula (IX) are defined as defined in formula (I0) of claim 1.

6. The steroid derivative and its pharmaceutically acceptable salt as described in any one of claims 1 to 5, selected from the following compounds:

7. A pharmaceutical composition comprising a steroid derivative as described in any one of claims 1 to 6 and a pharmaceutically acceptable salt thereof.

8. Use of the steroid derivative and its pharmaceutically acceptable salt as described in any one of claims 1 to 6, or the pharmaceutical composition as described in claim 7, in the preparation of antiviral and anti-skin cancer drugs.

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