Paclitaxel derivatives, process for their preparation and their use in medicine

Abstract

The present application relates to a paclitaxel derivative, its preparation method and its application. Specifically, the present application relates to a paclitaxel derivative represented by general formula (I), its stereoisomer or pharmaceutically acceptable salt, its preparation method, and a pharmaceutical composition containing the same and its use in the preparation of a medicament. The structure of the compound of general formula (I) is shown below, and the definitions of the groups are consistent with the definitions in the specification.

Description

Technical Field

[0001] This invention relates to methods for preparing paclitaxel derivatives, pharmaceutical compositions containing this series of compounds, and their use as therapeutic agents, particularly for the treatment of tumors. Background Technology

[0002] Paclitaxel (PTX), also known as yew oil, was originally isolated from the bark of the yew tree (Taxus brevifolia). It is a novel antimicrotubule drug approved for market by the U.S. Food and Drug Administration (FDA) in 1992. Paclitaxel is a broad-spectrum anticancer drug widely used clinically to treat ovarian cancer, breast cancer, head and neck cancer, and lung cancer. Its main mechanism of action is to promote microtubule polymerization and inhibit microtubule depolymerization, leading to the loss of normal spindle function, cell cycle arrest at the G2 / M phase, and mitosis cessation.

[0003] Paclitaxel, a standard chemotherapy drug for cancer patients, has significant side effects and is suitable for use during chemotherapy. However, its water solubility is less than 4 μg / mL, greatly limiting its application. Common side effects of paclitaxel injection include hair loss in 80% of patients, pain in 18.2% of patients, and hypersensitivity reactions in individuals with certain conditions (hypertension, diabetes, ulcers), which may prevent continued use.

[0004] Since there are still issues with paclitaxel in terms of efficacy, safety and bioavailability, it is still necessary to research and develop new paclitaxel derivatives. Summary of the Invention

[0005] To address the shortcomings and deficiencies of existing technologies, this invention provides a novel paclitaxel derivative that improves its stability and water solubility, thereby enhancing the characteristics of drug absorption, metabolism, and distribution in vivo, increasing oral bioavailability, reducing dosage and frequency of administration, improving patient compliance, enhancing safety, and prolonging duration of action.

[0006] This invention provides a compound of general formula (I) or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0007]

[0008] R 1 Selected from hydrogen atoms, R 2 Selected from

[0009] Or, R 1 Selected from R 2 Selected from hydrogen atoms;

[0010] R 3 Selected from -C(=O)OC 1-6 alkyl or

[0011]

[0012] R 4 Selected from

[0013] R a Selected from hydrogen atoms or C 1-6 alkyl;

[0014] R b and R b’ Each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl or natural or pharmaceutically acceptable amino acid side chains;

[0015] R c Selected from C 1-6 Alkyl or benzyl;

[0016] L is selected from

[0017] X1 is selected from key or C 1-4 Alkylene, wherein the alkyl group is optionally further divided by 0 to 4 elements selected from halogens or C 1-4 The substituents of the alkoxy group; X1 is connected to the P atom;

[0018] X2 is selected from bond, -C(=O)O- or -OC(=O)-;

[0019] X3 is selected from key or C 1-4 Alkylene, wherein the alkyl group is optionally further divided by 0 to 4 elements selected from halogens or C 1-4 The substituents of the alkoxy group;

[0020] X4 is selected from the key, -OC (=O)- or -C (=O)-.

[0021] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of general formula (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0022]

[0023] Where R 1 and R 2 The definition is as stated in general formula (I).

[0024] A preferred embodiment of the present invention is a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

[0025] R a Selected from hydrogen atoms;

[0026] R b and R b’ Each is independently selected from either a hydrogen atom or a methyl group;

[0027] R c Selected from methyl, ethyl, propyl, isopropyl, or benzyl;

[0028] L is selected from the bond, -CH2-OC(=O)- or -CH2-OC(=O)-C2H4-C(=O)-.

[0029] Typical compounds of the present invention include, but are not limited to:

[0030]

[0031]

[0032] Or its stereoisomers, tautomers, or medicinal salts.

[0033] The present invention also provides a pharmaceutical composition comprising a therapeutically effective dose of the compound of the present invention and its stereoisomers or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier or excipient.

[0034] The present invention also provides the use of compounds of general formula (I), their stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of antitumor drugs.

[0035] Figure 1 shows the growth curve of compound A549 xenograft tumors in nude mice as measured in Test 2 of this invention.

[0036] Figure 2 shows the tumor weight of each group in Test 2 of this invention, measured 35 days after administration of compound A549 to nude mice xenografts.

[0037] Detailed description of the invention

[0038] Unless otherwise stated, some terms used in this specification and claims are defined as follows:

[0039] The elements carbon, hydrogen, oxygen, nitrogen, or halogen involved in the groups and compounds described in this invention include their isotopes. The elements carbon, hydrogen, oxygen, or nitrogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include... 12 C 13 C and 14C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18 O, isotopes of nitrogen include 14 N and 15 N, an isotope of fluorine 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0040] "Natural or medicinally acceptable amino acids": The basic backbone of a protein molecule is the amino acid sequence. There are 20 basic amino acids that make up proteins. These 20 basic amino acids are the basis for later protein modifications in organisms. In addition, based on these basic amino acids, derived amino acids such as hydroxyproline and hydroxylysine are biosynthesized. These biosynthesized amino acids are collectively called "natural amino acids." Amino acids synthesized artificially are called "non-natural amino acids." "Medicinally acceptable amino acids" refer to pharmaceutically acceptable natural or non-natural amino acids.

[0041] "Side chain of an amino acid" refers to the part covalently attached to the structure of a D or L-amino acid and can be represented as -CH(COOH)(NH2)-R. For example, in the case of alanine -CH(COOH)(NH2)(CH3), the side chain of amino acid (R) is -CH3.

[0042] In this invention, “=O” is a common usage in the art, referring to an oxygen atom connected by a double bond, such as the double oxygen atom connected to a carbon atom in a carbonyl group.

[0043] The carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds described in this invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), and tritium (T, also known as superheavy hydrogen), and the isotopes of oxygen include... 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, an isotope of fluorine19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0044] When "alkyl" is used as a group or part of a group, it refers to a straight-chain or branched aliphatic hydrocarbon group comprising 1 to 20 carbon atoms. Preferably, there are 1 to 10 alkyl groups, more preferably 1 to 6 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups: alkyl, alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, cycloalkyloxy, or amino.

[0045] "alkylene" is a divalent alkyl group. Preferably, it is a C1-C10 alkylene group, more preferably a C1-C6 alkylene group, and particularly preferably a C1-C4 alkylene group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, and n-propylene. Alkylene groups can be substituted or unsubstituted.

[0046] "Cycloalkyl" refers to an aromatic ring system consisting of a saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring, but in which none of the rings has fully conjugated π electrons. Preferably, it is a 3- to 12-membered cycloalkyl group, more preferably a 3- to 8-membered cycloalkyl group, and most preferably a 3- to 6-membered cycloalkyl group. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc., with cyclopropyl and cyclohexenyl being preferred.

[0047] "Fused ring group" refers to a 5- to 18-membered aromatic ring system containing two or more ring structures sharing a pair of carbon atoms. One or more rings may contain one or more double bonds, but none of the rings has fully conjugated π electrons. Preferably, it is a 6- to 12-membered aromatic ring system, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, pyridone, or polycyclic fused ring alkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused ring alkyl" include, but are not limited to:

[0048]

[0049] "Bridged cycloalkyl" refers to a 5- to 18-membered aromatic ring system containing two or more cyclic structures sharing two non-directly connected carbon atoms. One or more rings may contain one or more double bonds, but none of the rings possess fully conjugated π electrons. Preferably, it is a 6- to 12-membered aromatic ring system, more preferably 7- to 10-membered. More preferably, it is a 6- to 14-membered system, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, pyridone, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or pyridone, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to:

[0050]

[0051] "Spirocycloalkyl" refers to a polycyclic group consisting of 5 to 18-membered monocyclic rings sharing a single carbon atom (called a spiro atom). It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Based on the number of shared spiro atoms between the rings, spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl. Monospirocycloalkyl is preferred. Non-limiting examples of spirocycloalkyl groups include, but are not limited to:

[0052]

[0053] The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups: alkyl, alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, cycloalkyloxy, or amino.

[0054] "Alkoxy" refers to an (alkyl-O-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0055] "Cycloalkyloxy" refers to a (cycloalkyl-O-) group. Cycloalkyl groups are defined in the relevant section of this document. C3-C8 cycloalkoxy groups are preferred. Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy groups.

[0056] "Hydroxy" refers to -OH.

[0057] "Amino" refers to -NH2.

[0058] "Halogens" refer to fluorine, chlorine, bromine, and iodine.

[0059] "Benzyl" refers to -CH2-phenyl.

[0060] “vehicle” refers to blank solvent.

[0061] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or possibility that the event or environment may or may not occur. For example, "optionally substituted F alkyl" means that the alkyl group may but does not have to be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

[0062] "Pharmaceutical composition" means a mixture of one or more compounds described in this text or their physiologically / pharmaceutically acceptable salts with other components, wherein the other components include physiologically / pharmaceutically acceptable carriers and excipients.

[0063] "Carrier" refers to a carrier or diluent that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the given compound.

[0064] "Excipients" refer to inert substances added to a pharmaceutical composition to further deliver the drug in a compound-dependent manner. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrants, etc.

[0065] "Prodrug" refers to a drug that can be converted into a drug under physiological conditions or through solvation. Biological activity The drug of the present invention is prepared by modifying the functional group in estradiol, which can be done by conventional operation or removed in vivo to obtain estradiol.

[0066] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0067] "Effective dose" refers to the amount of a compound that elicits a physiological or medical response in an tissue, system, or subject. This amount is sought, including the amount of a compound, when administered to a subject, sufficient to prevent the occurrence of one or more symptoms of the treated disease or condition or condition, or to alleviate them to some extent.

[0068] "Pharmaceutical acceptable salts" refer to pharmaceutically acceptable non-toxic salts of acids or bases, including salts of inorganic acids and bases, and salts of organic acids and bases. Detailed Implementation

[0069] The following embodiments are used to further describe the present invention, but these embodiments are not intended to limit the scope of the present invention.

[0070] Example

[0071] The examples provide preparation and structural identification data for representative compounds represented by formula (I). It must be noted that the following examples are illustrative of the invention and not intended to limit it. 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplyt, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0072] Mass spectrometry is performed using an LC / MS instrument, and the ionization method can be ESI or APCI.

[0073] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0074] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0075] In the following examples, unless otherwise specified, all temperatures are in Celsius; unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods; commercially available materials and reagents are used directly without further purification; unless otherwise specified, commercial manufacturers include, but are not limited to, Aldrich Chemical Company, Acros Organics, Bidex Pharmaceuticals Technology Co., Ltd., and Aladdin Biochemical Technology Co., Ltd.

[0076] CD3OD: Deuterated methanol

[0077] CDCl3: Deuterated chloroform

[0078] DMSO-d6: Deuterated dimethyl sulfoxide

[0079] Argon atmosphere refers to a reaction flask connected to an argon gas balloon with a volume of approximately 1L.

[0080] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0081] The compound was purified by silica gel column chromatography and thin-layer chromatography. The eluent or developing solvent system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane and ethyl acetate system. The volume ratio of the solvent varied depending on the polarity of the compound. Small amounts of acidic or basic reagents, such as acetic acid or triethylamine, could also be added for adjustment.

[0082] Example 1

[0083] Paclitaxel-(2S)-2-(((isopropoxycarbonyl)phosphoryl)amino)propionate ethyl ester

[0084]

[0085] Isopropyl dichlorophosphorylcarbamate (0.6 g, 2.93 mmol) was dissolved in 10 mL of dichloromethane and cooled to -60 °C under argon protection. A mixed dichloromethane solution (20 mL) of paclitaxel (2 g, 2.34 mmol) and triethylamine (0.6 g, 5.82 mmol) was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 30 minutes. Then, a dichloromethane solution (5 mL) of L-alanine ethyl ester hydrochloride (0.59 g, 3.8 mmol) was added dropwise, followed by the addition of triethylamine (0.6 g, 5.82 mmol). The reaction mixture was allowed to warm naturally to room temperature for 3 hours. The reaction solution was washed successively with 1 M hydrochloric acid and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 1:50–1:30) to give product 1 (0.5 g white solid), yield: 19.4%.

[0086] MS m / z(ESI): 1126.3 [M+23]

[0087] 1 H NMR (400MHz, CDCl3) δ8.22–8.04(m,2H),7.92–7.86(m,2H),7.83–7.69(m,2H),7.58–7.35(m,6H), 7.25–7.19(m,1H),6.29(s,1H),6.09–5.93(m,1H),5.68(d,J=7.1Hz,1H),5.54(d,1H),5.06–4.92 (m,1H),4.54–4.37(m,1H),4.30(m,1H),4.21–3.88(m,4H),3.87–3.74(m,2H),2.89–2.50(m,1H), 2.44(s,3H),2.22(s,3H),2.05–2.11(m,1H),1.75-1.69(m,1H),1.68(s,3H),1.35–1.07(m,12H).

[0088] Example 2

[0089] Paclitaxel-(bis((((S)-1-isopropoxy-1-oxopropane-2-yl)amino)phosphoryl)methyl-succinate

[0090] first step

[0091]

[0092] Succinic anhydride (0.5 g, 5 mmol) and triethylamine (0.21 g, 2.1 mmol) were dissolved in 50 mL of ethyl acetate. Paclitaxel (4.3 g, 5 mmol) was added in portions. After the addition was complete, the mixture was allowed to react overnight at room temperature. 100 mL of EA was added. The mixture was washed successively with 1 N hydrochloric acid and saturated brine, dried over sodium sulfate, filtered, and evaporated to dryness. Methyl tert-butyl ether / petroleum ether (V / V) = 1:1 was slurried, filtered, and dried to give title product 2a (4.3 g white solid), yield: 89.6%.

[0093] MS m / z (ESI): 952.5 [M⁻¹]

[0094] 1 H NMR (400MHz, CDCl3) δ8.22–8.04(m,2H),7.83–7.69(m,2H),7.61(s,1H),7.51(dd,J=9.4,5.7Hz,2H),7.40 (dt,J=11.7,4.9Hz,6H),7.00(s,1H),6.29(s,1H),6.09–5.93(m,1H),5.68(d,J=7.1Hz,1H),5.54(d,J=3.3 Hz,1H),5.06–4.92(m,1H),4.54–4.37(m,1H),4.30(s,1H),4.21(s,1H),3.87–3.74(m,1H),3.22(s,2H),2. 89–2.50(m,6H),2.44(s,3H),2.40–2.28(m,1H),2.22(s,3H),1.91(s,3H),1.68(s,3H),1.27–1.07(m,5H).

[0095] Step 2

[0096]

[0097] (2S,2'S)-2,2'-(((hydroxymethyl)phosphoryl)bis(azadiacyl)diisopropyl ester 2b (0.32 g, 0.95 mmol), paclitaxel-butyric acid 2a (0.9 g, 0.95 mmol), N,N-diisopropylethylamine (0.18 g, 1.42 mmol), and Carter's condensing agent (0.5 g, 1.14 mmol) were added sequentially to 20 mL of tetrahydrofuran and stirred overnight. 50 mL of ethyl acetate was added, and the reaction mixture was washed sequentially with 1 M hydrochloric acid, sodium carbonate solution, and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (V / V) = 1:50–1:20) to give title product 2 (0.6 g white solid), yield: 50.2%.

[0098] MS m / z(ESI): 1274.7 [M+1]

[0099] 1H NMR(400MHz, CDCl3)δ1.08-1.16(m,3H)1.19-1.27(m,16H)1.39(d,3H)1.37(d,3H)1.68(s,3H)1.83-1.98(m,5H)2.05(s,2H)2.14 -2.20(m,1H)2.20-2.28(m,3H)2.45(s,3H)2.54(m,2H)2.66-2.78(m,3H)2.78-2.91(m,1H)3.77(d,1H)3.88-4.00(m,2H)4.04(dd ,1H)4.13(q,1H)4.19(d,1H)4.27-4.35(m,2H)4.42(dd,1H)4.93-5.06(m,3H)5.53(d,1H)5.66(d,1H)5.93(dd,1H)6.16(t,1H)6. 28(s,1H)7.27-7.31(m,1H)7.38-7.47(m,6H)7.48-7.58(m,3H)7.61-7.67(m,1H)7.70(d,1H)7.82-7.88(m,2H)8.11-8.17(m,2H)

[0100] Examples 3 and 4

[0101]

[0102] Paclitaxel (0.75 g, 0.88 mmol) and 4-dimethylaminopyridine (0.12 g, 0.95 mmol) were dissolved in 8 mL of tetrahydrofuran. The solution was cooled to 0 °C under argon protection. 1 mL of triphosgene (86 mg, 0.29 mmol) in dichloromethane was added dropwise. The mixture was then allowed to react at room temperature for 30 minutes. 8 mL of a dichloromethane solution containing 4-dimethylaminopyridine (0.12 g, 0.95 mmol) and (2S,2'S)-2,2'-(((hydroxymethyl)phosphonyl)bis(azadiacyl)dipropionate diisopropyl ester 2b (0.36 g, 1.05 mmol) was added under ice bath conditions. The reaction mixture was reacted overnight at room temperature. 50 mL of dichloromethane was added, and the reaction solution was washed successively with 1 M hydrochloric acid and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Title product 3 (0.13 g white solid) was prepared, yield: 13%. MS m / z (ESI): 1219 [M+1]

[0103] 1H NMR(400MHz, CDCl3)δ1.14(s,3H)1.19-1.29(m,14H)1.36(dd,2.81Hz,6H)1.69(s,3H)1.75(br.s.,3H)1.85- 1.92(m,1H)1.92-1.98(m,3H)2.16(dd,1H)2.24(s,3H)2.37(dd,1H)2.48(s,3H)2.52-2.62(m,1H)3.30(br.s .,2H)3.82(d,1H)4.01(dd,2H)4.21(d,1H)4.28-4.42(m,2H)4.42-4.56(m,2H)4.90-5.07(m,3H)5.41(d,1H) 5.69(d,1H)6.03(dd,1H)6.22-6.34(m,2H)7.30-7.50(m,9H)7.53(t,2H)7.59-7.65(m,1H)8.11-8.22(m,2H). PNMR(400MHz,CDCl3)δ17.72

[0104] And 4 (40 mg white solid), yield: 4%.

[0105] MS m / z(ESI): 1219 [M+1]

[0106] 1H NMR (400MHz, CDCl3) δ1.17 (s, 3H) 1.19-1.31 (m, 14H) 1.40 (d, J = 4.65Hz, 3H) 1.39 ( d,J=4.40Hz,3H)1.64(br.s.,4H)1.69(br.s.,1H)1.75(br.s.,1H)1.81(s,3H)1. 88(s,3H)1.92-2.01(m,1H)2.18(s,3H)2.29-2.38(m,2H)2.41(s,3H)2.55-2.68( m,1H)3.68(br.s.,1H)3.91(d,J=7.09Hz,1H)3.98-4.13(m,3H)4.18(d,J=8.56Hz, 1H)4.26-4.36(m,2H)4.53(dd,J=14.18,7.58Hz,1H)4.80(d,J=2.45Hz,1H)4.93- 5.08(m,3H)5.49(dd,J=10.64,7.21Hz,1H)5.66(d,J=6.85Hz,1H)5.84(dd,J=8.6 8,2.32Hz,1H)6.17-6.26(m,2H)7.24(d,J=8.80Hz,1H)7.33-7.39(m,1H)7.39-7. 46(m,4H)7.46-7.56(m,5H)7.58-7.68(m,1H)7.77-7.86(m,2H)8.08-8.17(m,2H).

[0107] PNMR (400MHz, CDCl3) δ 18.45

[0108] Biological evaluation

[0109] Test Example 1: Rat Pharmacokinetic Test

[0110] Male SD rats, 180–220g, 6–8 weeks old, were purchased from Chengdu Dashuo Experimental Animal Co., Ltd. The animals were housed in an SPF environment at a temperature of 20–22℃ and a relative humidity of 40–70%, with 12-hour / 12-hour light / dark illumination, and free access to food and water. The experiment began after 5 days of acclimatization observation.

[0111] Accurately weigh a certain amount of paclitaxel or the compound of Example 1, dissolve it in DMSO, add Solutol HS-15 to solubilize it, and then add physiological saline. The final solvent ratio is DMSO:Solutol HS-15:physiological saline = 5:5:90. Vortex mix to obtain a clear and transparent solution. All test compounds were freshly prepared immediately before use.

[0112] On the day of the experiment, nine SD rats were randomly divided into three groups of three each, based on their body weight. The rats were fasted for 12–14 hours prior to administration but allowed free access to water. Food was administered four hours after administration. Group 1 received paclitaxel 5.0 mg / kg via tail vein injection (IV); Group 2 received paclitaxel 20.0 mg / kg via oral gavage (PO); and Group 3 received the compound from Example 1 at 20.0 mg / kg (calculated based on the original drug). The total administration volume was 10.0 mL / kg. Approximately 0.10 ml of venous blood was collected from each group of rats before and after administration at the following time points. The blood samples were anticoagulated with EDTA-K2, centrifuged at 6000 rpm (3500 g) for 10 min at 4°C, and plasma was collected. All plasma samples were stored at -80°C before analysis. Blood samples were collected at the following time points: before administration and 5 minutes, 15 minutes, 0.5, 1, 2, 4, 8, and 24 hours after administration; blood samples were collected at the following time points: before administration and 15 minutes, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration.

[0113] The concentration of the parent drug paclitaxel in all plasma samples was analyzed by LC-MS / MS, and the main pharmacokinetic parameters were analyzed using the Winnolin 8.2 non-compartmental model. The results are shown in Table 1 below.

[0114] Table 1. Results of pharmacokinetic studies of paclitaxel and the compounds in the examples in rats.

[0115]

[0116] Conclusion: The pharmacokinetic results in rats show that the bioavailability of the compound in Example 1, as a prodrug of paclitaxel, is 33% when administered orally by gavage, which is significantly improved compared to the oral bioavailability of paclitaxel technical drug (6.12%).

[0117] Test Example 2: Drug Efficacy Test in a Nude Mouse Xenograft Tumor Model

[0118] Human lung cancer cells A549 were cultured in DMEM medium supplemented with 10% fetal bovine serum (FBS) at 37°C in a 5% CO2 incubator. When the cells reached the exponential growth phase, they were trypsinized, collected, counted, and resuspended in PBS buffer for inoculation. BALB / c nude mice were acclimatized to the laboratory environment for 5 days, and A549 cells were subcutaneously inoculated into the right rib area at a dose of 1×102. 6 Cells / animal, inoculation volume 0.1 ml. Incubate until tumors grow to approximately 200 mm. 3Around 30 animals were selected for the study and divided into three groups of 10 animals each, based on tumor size using an S-shaped grouping method. Group 1 received a blank solvent (DMSO: Solutol H15: physiological saline = 5:5:90, volume ratio) via gavage every 4 days. Group 2 received paclitaxel at 15 mg / kg via tail vein injection every 4 days. Group 3 received the compound from the example at 58 mg / kg via oral gavage every 4 days. Each group was observed for 35 days, with tumor volume measured twice weekly to calculate the tumor growth inhibition rate. Venous blood was collected 1 and 6 hours after the last administration, and plasma was separated for drug concentration determination. Simultaneously, mice were sacrificed 1 and 6 hours after administration, and tumor tissue was collected for tumor weight measurement and sampling for drug concentration determination within the tumor tissue.

[0119] The tumor growth curves are shown in Figure 1, and the tumor weight at the experimental endpoint for each group is shown in Figure 2. Paclitaxel 15 mg / kg administered intravenously every 4 days showed a tumor growth inhibition rate (TGI) of 88.53%; compound 1 (test compound) 58 mg / kg administered orally every 4 days showed a TGI of 82.91%. There was no statistically significant difference in tumor growth inhibition rates between the two groups. The tumor inhibition rates calculated based on tumor weight were 76.07% and 70.7%, respectively. The drug concentrations in mouse plasma and tumor tissue at 1 and 6 hours after the last administration are shown in Table 2, and Figures 1 and 2.

[0120] Table 2. Paclitaxel concentrations in plasma and tumor tissue after the last dose.

[0121]

[0122] The results show that oral administration of the compound of Example 1 achieved a tumor-suppressive effect comparable to intravenous administration of paclitaxel; the drug concentration in tumor tissue was well correlated with the efficacy; and the plasma drug concentration showed that the plasma paclitaxel exposure after oral administration of the compound of Example 1 was lower than that after intravenous administration of paclitaxel, resulting in a lower systemic safety risk.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: in: R 1 Selected from R 2 Selected from hydrogen atoms; R 3 Selected from -C(=O)OC 1-6 alkyl; R 4 Selected from ; R a Selected from hydrogen atoms; R b and R b’ Each is independently selected from either a hydrogen atom or a methyl group; R c Selected from methyl, ethyl, propyl, or benzyl; L is selected from the key.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R c It is isopropyl.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein it is a compound of general formula (II) or a pharmaceutically acceptable salt thereof. Where R 1 and R 2 The definition is as described in claim 1.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 。 5. A pharmaceutical composition comprising a therapeutically effective dose of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

6. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 5, in the preparation of a medicament for treating lung cancer.

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