CN116217619A - Paclitaxel derivatives, preparation method and medical application thereof - Google Patents

Paclitaxel derivatives, preparation method and medical application thereof Download PDF

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CN116217619A
CN116217619A CN202111482498.6A CN202111482498A CN116217619A CN 116217619 A CN116217619 A CN 116217619A CN 202111482498 A CN202111482498 A CN 202111482498A CN 116217619 A CN116217619 A CN 116217619A
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pharmaceutically acceptable
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stereoisomer
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林其先
方建
李昀
刘建余
王玮
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Aochuang Pharmaceutical Co ltd
Sichuan Xiapaisen Pharmaceutical Technology Co ltd
Ti Yashi
Shanghai Blue Technology Co ltd
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Sichuan Xiapaisen Pharmaceutical Technology Co ltd
Ti Yashi
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    • C07F9/65512—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a four-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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Abstract

The invention relates to a taxol derivative, a preparation method and application thereof. In particular, the invention relates to a taxol derivative shown in a general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the taxol derivative and the stereoisomer or the pharmaceutically acceptable salt, and application of the taxol derivative and the stereoisomer or the pharmaceutically acceptable salt in preparation of medicines. The structure of the compound of the general formula (I) is shown as follows, and the definition of the group is consistent with the definition of the instruction book.

Description

Paclitaxel derivatives, preparation method and medical application thereof
Technical Field
The present invention relates to a process for the preparation of derivatives of taxol, pharmaceutical compositions containing the series of compounds and their use as therapeutic agents, in particular for the treatment of tumors.
Background
Paclitaxel (Paclitaxel PTX), an alias taxol, was originally isolated from the bark of Taxus brevifolia (Taxusbrev), a new class of anti-microtubule agents approved by the U.S. Food and Drug Administration (FDA) into the market in 1992. Paclitaxel is a broad-spectrum anticancer drug which has been widely used for treating ovarian cancer, breast cancer, head and neck cancer and lung cancer in clinic, and has the main action mechanism of promoting cell microtubule polymerization, inhibiting microtubule depolymerization, causing the cell spindle to lose normal function, and stopping cell cycle in G2/M phase and mitosis.
Paclitaxel, which is used as a standard chemotherapeutic drug for cancer patients, has great side effects and is suitable for use during chemotherapy; meanwhile, the solubility of the taxol in water is less than 4 mug/mL, so that the application of the taxol is greatly limited. The common side effects of the paclitaxel injection at present: 80% of patients have lost their hair and 18.2% of patients have pain and in addition, the use of paclitaxel injection in special constitutions (hypertension, diabetes, ulcer) can produce hypersensitive reaction, which results in no continued use.
Since paclitaxel still has problems in terms of effectiveness, safety, bioavailability and the like at present, there is still a need to research and develop new paclitaxel derivatives.
Disclosure of Invention
In order to solve the defects and shortcomings in the prior art, the invention provides a novel taxol derivative, which can improve the stability and water solubility of the taxol derivative, further improve the characteristics of the medicine in vivo absorption and metabolism distribution, improve the oral bioavailability of the medicine, reduce the dosage and frequency of administration, improve the use compliance of patients, improve the safety and prolong the action time.
The invention provides a compound shown in a general formula (I) or stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
Figure BDA0003395391390000011
R 1 selected from hydrogen atoms, R 2 Selected from the group consisting of
Figure BDA0003395391390000012
/>
Alternatively, R 1 Selected from the group consisting of
Figure BDA0003395391390000021
R 2 Selected from hydrogen atoms;
R 3 selected from-C (=o) O-C 1-6 Alkyl or
Figure BDA0003395391390000022
R 4 Selected from the group consisting of
Figure BDA0003395391390000023
R a Selected from hydrogen atoms or C 1-6 An alkyl group;
R b and R is b’ Each independently selected from hydrogen atoms, C 1-6 Alkyl or a natural or pharmaceutically acceptable amino acid side chain;
R c selected from C 1-6 Alkyl or benzyl;
l is selected from
Figure BDA0003395391390000024
X 1 Selected from bonds or C 1-4 Alkylene, said alkyl optionally being further substituted with 0 to 4 groups selected from halogen or C 1-4 Substituted by alkoxy; x is X 1 Is connected with the P atom;
X 2 selected from the group consisting of bond, -C (=o) O-, or-OC (=o) -;
X 3 selected from bonds or C 1-4 Alkylene groups, said alkyl groups optionally being further substituted with 0 to 4 groups selected from halogen orC 1-4 Substituted by alkoxy;
X 4 selected from the group consisting of bond, -OC (=o) -or-C (=o) -.
In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II):
Figure BDA0003395391390000025
wherein R is 1 And R is 2 The definition of (C) is as described in the general formula (I).
In a preferred embodiment of the present invention, a compound represented by the general formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
R a selected from hydrogen atoms;
R b and R is b’ Each independently selected from a hydrogen atom or a methyl group;
R c selected from methyl, ethyl, propyl, isopropyl or benzyl;
l is selected from bond, -CH 2 -OC (=o) -or-CH 2 -OC(＝O)-C 2 H 4 -C(＝O)-。
Typical compounds of the present invention include, but are not limited to:
Figure BDA0003395391390000031
/>
Figure BDA0003395391390000041
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
The invention also provides a pharmaceutical composition comprising a therapeutically effective dose of a compound of the invention, its stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or excipient.
The invention also provides application of the compound shown in the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing antitumor drugs.
FIG. 1 in test 2 of the present invention, a graph of the growth of compound A549 nude mice engrafted tumor was determined.
Figure 2 in test 2 of the present invention, a graph of tumor weights of each group 35 days after compound a549 nude mice engrafted tumor administration was determined.
Detailed description of the invention
Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:
the elemental carbon, hydrogen, oxygen, nitrogen or halogen referred to in the groups and compounds of the invention include isotopic instances thereof, which are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C、 13 C and C 14 Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include 16 O、 17 O and 18 isotopes of O, nitrogen include 14 N and 15 isotopes of N, fluorine 19 Isotopes of F, chlorine include 35 Cl and Cl 37 Isotopes of Cl, bromine include 79 Br and 81 Br。
"Natural or pharmaceutically acceptable amino acids": the basic skeleton of protein molecule is amino acid sequence, and the basic amino acids constituting protein are 20 kinds, and these 20 kinds of basic amino acids are the basis for post-modification of protein, and based on these basic amino acids, amino acid types derived from hydroxyproline, hydroxylysine, etc. are also biosynthesized, and these biosynthesized amino acids are collectively called "natural amino acids"; the amino acid synthesized by the artificial method is an unnatural amino acid. "pharmaceutically acceptable amino acid" refers to a natural or unnatural amino acid that is pharmaceutically acceptable.
"side chain of an amino acid" means a side chain that is covalently attached to a D or L-amino acid structure and can be represented as-CH (COOH) (NH 2 ) -a moiety of R. For example, in alanine-CH (COOH) (NH 2 )(CH 3 ) In the case of (C), the side chain of the amino acid (R) is-CH 3 。
The term "=o" as used in the art refers to an oxygen atom attached by a double bond, such as a double bond oxygen atom attached to a carbon atom in a carbonyl group.
The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention include isotopes thereof, and the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C、 13 C and C 14 Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include 16 O、 17 O and 18 isotopes of O, sulfur include 32 S、 33 S、 34 S and 36 isotopes of S, nitrogen include 14 N and 15 isotopes of N, fluorine 19 Isotopes of F, chlorine include 35 Cl and Cl 37 Isotopes of Cl, bromine include 79 Br and 81 Br。
"alkyl" when used as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group comprising 1 to 20 carbon atoms. Preferably 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-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups: alkyl, alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, cycloalkyloxy or amino.
"alkylene" is a divalent alkyl group. Preferably C1-C10 alkylene, more preferably C 1 -C 6 Alkylene, particularly preferably C 1 -C 4 An alkylene group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, n-propylene, and the like. The alkylene group may be substituted or unsubstituted.
"cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocycles, but none of the rings have an aromatic ring system with fully conjugated pi electrons. Preferably 3 to 12 membered cycloalkyl, more preferably 3 to 8 membered cycloalkyl, most preferably 3 to 6 membered cycloalkyl. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred.
"fused ring group" means an aromatic ring system having 5 to 18 members, preferably 6 to 12 members, more preferably 7 to 10 members, in which the system contains two or more all-carbon polycyclic groups having cyclic structures sharing a pair of carbon atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has fully conjugated pi electrons. Depending on the number of constituent rings, it is possible to divide the bicyclic, tricyclic, pyridone or polycyclic fused ring alkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups. Non-limiting examples of "fused ring alkyl" include, but are not limited to:
Figure BDA0003395391390000061
"bridged ring radical" means an aromatic ring system having 5 to 18 members, the system comprising two or more ring structures sharing two all-carbon polycyclic groups not directly attached to a carbon atom, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron, preferably 6 to 12 members, more preferably 7 to 10 members. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, pyridone or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or pyridone, more preferably a bicyclic or tricyclic ring. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to:
Figure BDA0003395391390000062
"spirocycloalkyl" refers to a polycyclic group having one carbon atom (referred to as a spiro atom) common between 5-to 18-membered monocyclic rings, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl groups are classified as single spirocycloalkyl, double spirocycloalkyl or multiple spirocycloalkyl groups according to the number of common spiro atoms between rings. Preferably a mono-spirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include, but are not limited to:
Figure BDA0003395391390000063
cycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups: alkyl, alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, cycloalkyloxy or amino.
"alkoxy" refers to a group of (alkyl-O-). Wherein alkyl is as defined herein. C (C) 1 -C 6 Is preferably selected. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
"Cycloalkyloxy" refers to a group of (cycloalkyl-O-). Wherein cycloalkyl is as defined herein. C (C) 3 -C 8 Is a preferred choice. Examples include, but are not limited to: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
"hydroxy" refers to-OH.
"amino" means-NH 2 。
"halogen" refers to fluorine, chlorine, bromine and iodine.
"benzyl" means-CH 2 -phenyl.
"vehicle" refers to a blank vehicle.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl may be, but is not necessarily, substituted with F, and is intended to include both cases where the alkyl is substituted with F and cases where the alkyl is not substituted with F.
"pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt thereof with other ingredients, wherein the other ingredients comprise a physiologically/pharmaceutically acceptable carrier and excipient.
"Carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not negate the biological activity and properties of the compound being administered.
"excipient" refers to an inert substance added to a pharmaceutical composition to further depend on the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like.
"prodrug" means a prodrug that can be converted to the form of a complex under physiological conditions or by solvolysisBiological activityIs a medicine of (a). Prodrugs of the invention are prepared by modifying functional groups in estradiol, which modification may be removed by conventional procedures or in vivo to provide estradiol.
"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
An "effective dose" refers to an amount of a compound that elicits a physiological or medical response in a tissue, system, or subject, that is being sought, including an amount of the compound that is sufficient to prevent or reduce to some degree one or more symptoms of the disorder or condition being treated when administered to a subject.
"pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
Detailed Description
The invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention.
Examples
The preparation of representative compounds represented by formula (I) and related structural identification data are presented in the examples. It must be noted that the following examples are given by way of illustration and not by way of limitation. 1 The H NMR spectrum was determined with a Bruker instrument (400 MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation method: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
In the examples below, all temperatures are in degrees celsius unless otherwise indicated, and unless otherwise indicated, the various starting materials and reagents are either commercially available or synthesized according to known methods, and are used without further purification, and unless otherwise indicated, commercially available manufacturers include, but are not limited to Aldrich Chemical Company, acros Organics, pichia pharmaceutical technologies, inc.
CD 3 OD: deuterated methanol
CDCl 3 : deuterated chloroform
DMSO-d 6 : deuterated dimethyl sulfoxide
The argon atmosphere means that the reaction flask is connected to an argon balloon of about 1L volume.
The examples are not particularly described, and the solution in the reaction is an aqueous solution.
Purifying the compound by silica gel column chromatography and thin layer chromatography, wherein the eluent or developing agent system is selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: methylene chloride and methanol systems; c: dichloromethane and ethyl acetate; the volume ratio of the solvent is different according to the polarity of the compound, and can be adjusted by adding a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine.
Example 1
Paclitaxel- (2S) -2- (((isopropoxycarbonyl) phosphoryl) amino) propanoic acid ethyl ester
Figure BDA0003395391390000081
Isopropyl dichlorophosphoryl formate (0.6 g,2.93 mmol) was dissolved in 10mL dichloromethane and cooled to-60℃under argon. 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 dripping, the reaction is carried out for 30 minutes under the heat preservation. A solution (5 ml) of L-alanine ethyl ester hydrochloride (0.59 g,3.8 mmol) in methylene chloride was further added dropwise, followed by triethylamine (0.6 g,5.82 mmol) dropwise. Naturally heating to room temperature for reaction for 3 hours. The reaction solution was washed with 1M hydrochloric acid and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin. The crude product was purified by silica gel column chromatography (dichloromethane/methanol (V/V) =1:50-1:30) to give the title product 1 (0.5 g white solid), yield: 19.4%.
MS m/z(ESI):1126.3[M+23]
1 H NMR(400MHz,CDCl 3 )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).
Example 2
Paclitaxel- (bis (((S) -1-isopropoxy-1-oxopropan-2-yl) amino) phosphoryl) methyl-succinate
Figure BDA0003395391390000091
First step
Figure BDA0003395391390000101
Succinic anhydride (0.5 g,5 mmol) and triethylamine (0.21 g,2.1 mmol) were dissolved in 50ml ethyl acetate. Paclitaxel (4.3 g,5 mmol) was added in portions. After the addition, the reaction was carried out at room temperature overnight. 100ml of EA was added. Sequentially washing with 1N hydrochloric acid and saturated saline, drying with sodium sulfate, filtering, and spin-drying. Methyl tert-butyl ether/petroleum ether (V/V) =1:1 beaten filtration, oven drying gave the title product 2a (4.3 g white solid), yield: 89.6%.
MS m/z(ESI):952.5[M-1]
1 H NMR(400MHz,CDCl 3 )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＝3.3Hz,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).
Second step
Figure BDA0003395391390000102
Diisopropyl (2 s, 2's) -2,2' - (((hydroxymethyl) phosphoryl) bis (azadiacyl) dipropionate 2b (0.32 g,0.95 mmol), paclitaxel-butyric acid 2a (0.9 g,0.95 mmol), N-diisopropylethylamine (0.18 g,1.42 mmol) and carte condensing agent (0.5 g,1.14 mmol) were added sequentially to 20ml tetrahydrofuran and stirred overnight, 50ml ethyl acetate was added, the reaction solution was sequentially dried with 1M hydrochloric acid, sodium carbonate solution and saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the dried-over-the-air crude product was purified by silica gel column chromatography (methanol/dichloromethane (V/V) =1:50-1:20) to give the title product 2 (0.6 g white solid) in 50.2% yield.
MS m/z(ESI):1274.7[M+1]
1H NMR(400MHz,CDCl 3 )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)
Examples 3 and 4
Figure BDA0003395391390000111
Paclitaxel (0.75 g,0.88 mmol) and 4-dimethylaminopyridine (0.12 g,0.95 mmol) were dissolved in 8mL tetrahydrofuran. And cooling to 0 ℃ under the protection of argon. 1mL of triphosgene (86 mg,0.29 mmol) in dichloromethane was added dropwise. Then the reaction mixture was warmed to room temperature and reacted for 30 minutes. To a solution of 8mL of 4-dimethylaminopyridine (0.12 g,0.95 mmol) and (2S, 2 'S) -2,2' - (((hydroxymethyl) phosphoryl) diisopropyl bis (azadiacyl) dipropionate 2b (0.36 g,1.05 mmol) in methylene chloride was added under ice bath and reacted overnight at room temperature, 50mL of methylene chloride was added, the reaction mixture was washed successively with 1M hydrochloric acid and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and dried by spin-on-dry to give the title product 3 (0.13 g of white solid) in 13%. MS M/z (ESI): 1219[ M+1]
1H NMR(400MHz,CDCl 3 )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,CDCl 3 )δ17.72
And 4 (40 mg white solid), yield: 4%.
MS m/z(ESI):1219[M+1]
1H NMR(400MHz,CDCl 3 )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＝8.68,2.32Hz,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)。
PNMR(400MHz,CDCl 3 )δ18.45
Biological evaluation
Test example 1 rat pharmacokinetic test
Male SD rats, 180-220 g, 6-8 weeks old, were purchased from Chengdu laboratory animal Co. The animals are raised in SPF environment, the temperature is 20-22 ℃, the relative humidity is 40-70%, the light and dark illumination is 12 hours/12 hours, the free diet drinking water is carried out, and the test is started after the adaptability is observed for 5 days.
Accurately weighing a certain amount of taxol or the compound of the embodiment 1, dissolving in DMSO, adding Solutol HS-15 for solubilization, then adding normal saline, and finally mixing the solvent with the final proportion of DMSO: solutol HS-15: normal saline=5:5:90, and a clear solution was obtained by vortexing. All compounds tested were freshly prepared immediately prior to use.
On the day of the test, 9 SD rats were randomly divided into 3 groups of 3 by body weight. The food is fasted for 1 day before administration, and is not forbidden for 12-14 hours, and the food is fed for 4 hours after administration. The first group was given 5.0mg/kg paclitaxel via tail vein Injection (IV); a second group of oral gavages (PO) administered paclitaxel 20.0mg/kg; the third group was given 20.0mg/kg (calculated as crude drug) of the compound of example 1; the administration volume was 10.0mL/kg. Each group of rats was collected with venous blood of about 0.10ml, EDTA-K2 anticoagulated, and centrifuged at 6000rpm (3500 g) at 4℃for 10min at the following time points before and after administration, and plasma was collected. All plasma samples were pre-analyzed at-80 ℃. The blood sampling time points of the tail vein administration group are 5 minutes, 15 minutes, 0.5, 1,2, 4, 8 and 24 hours before administration; the blood sampling time points of the stomach-filling administration group are 15 minutes before administration and after administration, and 0.5, 1,2, 4, 6, 8 and 24 hours.
All plasma samples were analyzed by LC-MS/MS to detect the concentration of the proto-drug paclitaxel and by Winnolin 8.2 non-compartmental model to analyze the main pharmacokinetic parameters, the results of which are shown in table 1 below.
TABLE 1 results of rat pharmacokinetic testing of paclitaxel and example compounds
Figure BDA0003395391390000131
Conclusion: as can be seen from the pharmacokinetic results of rats, the bioavailability of the compound of example 1 as a paclitaxel prodrug administered by oral gavage was 33%, which is significantly improved compared with the oral bioavailability of the paclitaxel prodrug of 6.12%.
Test example 2 efficacy test of nude mouse allograft tumor model
Human lung cancer cell A549 was cultured in DMEM+10% Fetal Bovine Serum (FBS) medium at 37deg.C, 5% CO 2 Culturing in incubator, digesting and collecting cells with pancreatin when the cells are in exponential growth phase, counting, and re-suspending in PBS buffer for inoculation. BALB/c nude mice laboratory environment was adapted for 5 days, mice were inoculated subcutaneously with A549 cells, 1X 10, on the right rib 6 The cell/cell inoculum size was 0.1ml. To the extent that the tumor grows to about200mm 3 When the method is used for left and right, 30 animals are screened into groups, and the animals are divided into 3 groups according to the tumor volume size by an S-shaped grouping method, and 10 animals are in each group. The first group was given blank vehicle (DMSO: solutol H15: saline = 5:5:90, volume ratio) by gavage once every 4 days; the second group was given 15mg/kg paclitaxel by tail vein injection, once every 4 days; the third group was given 58mg/kg of the example compound orally by gastric lavage, once every 4 days. Tumor growth inhibition was calculated by measuring tumor volume 2 times per week for 35 days of each group administration observation; venous blood is collected 1 hour and 6 hours after the last administration, and plasma is separated and used for measuring the concentration of the medicine; at the same time, mice were sacrificed 1 and 6 hours after administration, and tumor tissues were collected for tumor weight measurement and sampling for drug concentration determination in tumor tissues.
The growth curve of the transplanted tumor is shown in figure 1, and the endpoint tumor weight of each group of experiments is shown in figure 2. Paclitaxel 15mg/kg was administered intravenously, once every 4 days, with Tumor Growth Inhibition (TGI) of 88.53%; the compound of example 1 (test compound) was administered 58mg/kg by gavage once every 4 days with a Tumor Growth Inhibition (TGI) of 82.91%; there was no statistical difference in tumor growth inhibition rates between the two dosing groups. The tumor inhibition rates calculated according to the weight of the tumor are 76.07 percent and 70.7 percent respectively. The drug concentrations in the plasma and tumor tissues of the mice 1 and 6 hours after the last administration are shown in Table 2, FIG. 1 and FIG. 2.
TABLE 2 concentration of paclitaxel in plasma and tumor tissues after last administration
Figure BDA0003395391390000141
From the results, it can be seen that the compound of example 1 administered orally by gavage can achieve a tumor-suppressing effect equivalent to that of paclitaxel administered by intravenous injection; the concentration of the drug in tumor tissues has good correlation with the drug effect; plasma drug concentrations showed lower exposure of paclitaxel in plasma following oral administration of the example compounds than paclitaxel administered by intravenous injection, with lower systemic safety risks.

Claims (6)

1. A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:
Figure FDA0003395391380000011
wherein:
R 1 selected from hydrogen atoms, R 2 Selected from the group consisting of
Figure FDA0003395391380000012
Alternatively, R 1 Selected from the group consisting of
Figure FDA0003395391380000013
R 2 Selected from hydrogen atoms;
R 3 selected from-C (=o) O-C 1-6 Alkyl or
Figure FDA0003395391380000014
R 4 Selected from the group consisting of
Figure FDA0003395391380000015
R a Selected from hydrogen atoms or C 1-6 An alkyl group;
R b and R is b’ Each independently selected from hydrogen atoms, C 1-6 Alkyl or a natural or pharmaceutically acceptable amino acid side chain;
R c selected from C 1-6 Alkyl or benzyl;
l is selected from
Figure FDA0003395391380000016
X 1 Selected from bonds or C 1-4 Alkylene, said alkyl optionally being further substituted with 0 to 4 groups selected from halogen or C 1-4 Substituted by alkoxy; x is X 1 Is connected with the P atom;
X 2 selected from the group consisting of bond, -C (=o) O-, or-OC (=o) -;
X 3 selected from bonds or C 1-4 Alkylene, said alkyl optionally being further substituted with 0 to 4 groups selected from halogen or C 1-4 Substituted by alkoxy;
X 4 selected from the group consisting of bond, -OC (=o) -or-C (=o) -.
2. The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
Figure FDA0003395391380000021
wherein R is 1 And R is 2 Is defined as in claim 1.
3. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
R a selected from hydrogen atoms;
R b and R is b’ Each independently selected from a hydrogen atom or a methyl group;
R c selected from methyl, ethyl, propyl, isopropyl or benzyl;
l is selected from bond, -CH 2 -OC (=o) -or-CH 2 -OC(＝O)-C 2 H 4 -C(＝O)-。
4. A compound according to claim 1 or 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure FDA0003395391380000022
/>
Figure FDA0003395391380000031
5. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-4, and stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or excipient.
6. Use of a compound according to any one of claims 1-4, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5 for the preparation of an anti-tumour medicament.
CN202111482498.6A 2021-12-06 2021-12-06 Paclitaxel derivatives, preparation method and medical application thereof Pending CN116217619A (en)

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