CN109574960B - Docetaxel derivative and preparation method and application thereof - Google Patents
Docetaxel derivative and preparation method and application thereof Download PDFInfo
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- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
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Abstract
The invention discloses a docetaxel derivative which has a structural general formula shown in a formula I. Docetaxel and p- [ bis (2-chloroethyl) amino group]Phenylalkyl alcohol (amine) or p- [ bis (2-chloroethyl) amino group]Phenol (amine) covalently bound through a linking group to form the drug compound. The invention also relates to a preparation, a preparation method and application of the pharmaceutical compound.
Description
Technical Field
The invention relates to a novel anticancer drug compound, a preparation method and application thereof, in particular to a docetaxel derivative, a preparation method of the compound and application of the compound as an anticancer drug.
Background
Docetaxel (docetaxel, formula 1) also known as docetaxel, is a lipophilic taxane antitumor drug, belongs to a cell inhibitor drug, and forms a stable non-functional microtubule bundle by enhancing tubulin polymerization and inhibiting microtubule depolymerization, thereby destroying mitosis of tumor cells to achieve antitumor effect. Docetaxel has intracellular concentration 3 times higher than that of taxol and long intracellular retention time, so that docetaxel has stronger antitumor activity than taxol. The traditional Chinese medicine composition is mainly used for treating advanced breast cancer, ovarian cancer, non-small cell lung cancer, head and neck cancer and small cell lung cancer clinically; it also has therapeutic effect on gastric cancer, pancreatic cancer, and melanoma.
Docetaxel has high anti-tumor activity and better safety and tolerance, has wide clinical application since the market, but has no selective recognition effect on tumor cells and normal cells like other anti-tumor medicaments, so that the side effect is particularly remarkable, the reports about the side effect are gradually increased, the main side effects discovered at present are retention of body fluid, and the skin toxicity is such as erythema, pruritus and rash of the whole body, severe weakness and paralysis; hematologic toxicities include leukopenia, neutropenia, and febrile neutropenia; non-hematologic toxicities include alopecia, sensory and motor neurotoxicity, stomatitis, weakness, and digestive system reactions such as nausea, vomiting, diarrhea, etc.
In order to reduce the toxic and side effects of docetaxel and expand the clinical application range thereof, a plurality of pharmaceutical researchers at home and abroad are dedicated to the research and development of a novel docetaxel formulation. Docetaxel is insoluble in water, so that the drug loading of a clinical dosage form is small, the administration dosage of the docetaxel is limited, and the clinical curative effect is influenced; it has poor oral bioavailability of less than 8%. At present, the formulation of docetaxel on the market is docetaxel injection, tween 80 is used as a solvent in the preparation, and the docetaxel has certain toxic and side effects, is easy to degrade in aqueous solution and is difficult to store.
To overcome the above drawbacks, many researchers have been devoted to research and development of novel drug delivery systems. Like (1) the liposome preparation, the docetaxel nanometer lipid carrier is prepared by adopting a film ultrasonic method, and the purposes of small particle size, high drug encapsulation efficiency and controlled release can be achieved; (2) the growth and circulation preparation prepared by carrying docetaxel by a carrier material modified by hydrophilic substance polyethylene glycol can escape from phagocytosis of a liver-spleen reticuloendothelial system in vivo and prolong the circulation time of the liver-spleen reticuloendothelial system in blood; (3) the injectable docetaxel microemulsion is prepared by taking soybean oil and triacylglycerol as oil phases and poloxamer 188 and soybean phospholipid as emulsifiers, the microemulsion is good in stability, and the particle size and the drug encapsulation efficiency are not influenced by the increase of drug loading; (4) the micelle preparation, the commonly used micelle carrier for loading docetaxel, comprises polyethylene glycol-polylactic acid block copolymer, polyvinylpyrrolidone-racemic polylactic acid block copolymer and the like, as well as pH sensitive block copolymer micelle and heat sensitive polymer micelle; (5) research on active target nano drug delivery system of docetaxel. The novel dosage forms surround the water solubility of docetaxel, reduce toxic and side effects and improve the bioavailability of the medicament, and make great progress, thereby not only providing possibility for improving the water solubility of docetaxel, reducing toxic and side effects and improving the bioavailability of the medicament, but also providing hope of safer administration for cancer patients. However, various drug delivery systems have more or less defects, such as low encapsulation efficiency, drug leakage and stability, and the like, and further problems need to be solved.
Disclosure of Invention
The invention aims to provide a novel docetaxel derivative, which is a novel anticancer compound, has high antitumor activity and low toxic and side effects, and is easy to prepare emulsion, liposome agent, micelle agent and the like.
The invention also aims to provide a synthesis method of the docetaxel derivative.
The invention also aims to provide the preparation of the docetaxel derivative, which comprises liposome, emulsion, micelle and the like.
Meanwhile, the invention also aims to provide the application of the docetaxel derivative in preparing anti-cancer drugs.
The docetaxel derivative is formed by covalently combining p- [ bis (2-chloroethyl) amino ] benzyl alcohol or p- [ bis (2-chloroethyl) amino ] phenol or p- [ bis (2-chloroethyl) amino ] phenylamine or p- [ bis (2-chloroethyl) amino ] aniline with an anticancer drug compound docetaxel (docetaxel) through ester bonds through a connecting molecule.
The purpose of the invention is realized by adopting the following technical scheme: a docetaxel derivative having a formula represented by the following general formula I:
wherein n = an integer from 0 to 10, X is O or NH;
r is a linking group, and is one of the following groups:
a)-(C＝O)-；
b) -P (= O) (R ') -, wherein R' is C1-C6 alkyl, C1-C6 alkoxy or aryl;
c)-(C＝O)(CH 2 ) m( c = O) -, wherein m = an integer from 1 to 10;
d)-(C＝O)CH 2 -O-CH 2 (C＝O)-；
e)-(CH 2 ) m (C = O) -, wherein m = an integer from 1 to 10.
The invention relates to a drug compound molecule docetaxel and p- [ bis (2-chloroethyl) amino with anticancer activity]Phenylalkyl alcohol or p- [ bis (2-chloroethyl) amino group]Phenol or p- [ bis (2-chloroethyl) amino]Phenylalkylamines or p- [ bis (2-chloroethyl) amino]Aniline is covalently combined through a connecting group, and the obtained docetaxel derivative has high anticancer activity and low toxic and side effects. The linking group is provided by a linking molecule comprising two or more reactive groups, for example: oxalyl chloride (O = CCl) 2 ) Providing carbonyl- (C = O) -, phosphorus oxychloride (O = POR' Cl) 2 ) Providing a group of-P (= O) (OR') -, halocarboxylic acid OR halocarboxylic acid ester providing an alkylene carbonyl (- (CH) 2 ) n CO-), different dicarboxylic acids (CH) 2 ) n (COOH) 2 Or cyclic acid anhydrides
Examples of the group include succinyl, glutaryl, diglycoyl and the like.
The invention also relates to a preparation method of the docetaxel derivative, which comprises the following steps:
1) Carrying out esterification or etherification reaction on the p- [ bis (2-chloroethyl) amino ] benzyl alcohol or the p- [ bis (2-chloroethyl) amino ] phenol and a connecting molecule to generate a derivative of the p- [ bis (2-chloroethyl) amino ] benzyl alcohol or the p- [ bis (2-chloroethyl) amino ] phenol; or p- [ bis (2-chloroethyl) amino ] phenylamine or p- [ bis (2-chloroethyl) amino ] aniline and a connecting molecule are subjected to amidation reaction to generate derivatives of p- [ bis (2-chloroethyl) amino ] phenylamine or p- [ bis (2-chloroethyl) amino ] aniline;
2) Carrying out esterification reaction on the p- [ bis (2-chloroethyl) amino ] phenylalkyl alcohol or the derivative of p- [ bis (2-chloroethyl) amino ] phenol, or the derivative of p- [ bis (2-chloroethyl) amino ] phenylamine or p- [ bis (2-chloroethyl) amino ] aniline, or the acyl chlorination products of the p- [ bis (2-chloroethyl) amino ] phenylamine and the derivative of p- [ bis (2-chloroethyl) amino ] aniline, which are obtained in the step 1) and docetaxel under the action of a catalyst to generate the docetaxel derivative I.
More specifically and optimally, the method comprises the following steps:
1) Carrying out esterification or etherification reaction on hydroxyl of p- [ bis (2-chloroethyl) amino ] phenylalkyl alcohol or p- [ bis (2-chloroethyl) amino ] phenol and a connecting molecule to generate p- [ bis (2-chloroethyl) amino ] phenylalkyl ester or ether or p- [ bis (2-chloroethyl) amino ] phenyl ester or ether derivative; or the amidation reaction of the amino group of p- [ bis (2-chloroethyl) amino ] phenylamine or p- [ bis (2-chloroethyl) amino ] aniline with a linker molecule to produce p- [ bis (2-chloroethyl) amino ] phenylalkylamide or p- [ bis (2-chloroethyl) amino ] phenylamide derivatives; the resulting derivatives contain carboxyl, acyl chloride or phosphoryl chloride groups;
2) Reacting the p- [ bis (2-chloroethyl) amino ] phenylalkyl ester, ether or amide derivative containing a carboxyl group obtained in the step 1) with an acyl chlorination reagent (preferably thionyl chloride) to generate an acyl chlorination product;
3) Performing esterification reaction on the acyl chlorination product obtained in the step 2) or the phosphoryl chloride compound obtained in the step 1) and docetaxel by using alkali as a catalyst to generate the docetaxel derivative I; or
The p- [ bis (2-chloroethyl) amino ] phenylalkyl ester, ether or amide derivative containing carboxyl obtained in the step 1) or the p- [ bis (2-chloroethyl) amino ] phenyl ester, ether or amide derivative directly undergoes an esterification reaction with docetaxel by taking 4-dimethylaminopyridine and 2-chloro-1-methylpyridinium iodide or N, N' -dicyclohexylcarbodiimide and 4-dimethylaminopyridine as catalysts to generate the docetaxel derivative I.
In the above method, the linker molecule is one of the following molecules containing two or more reactive groups:
(1) Oxalyl chloride O = CCl 2 ；
(2) Phosphoryl dichloro alkyl, alkoxy or aryl ester O = POR' Cl 2 Wherein R' is C1-C6 alkyl, C1-C6 alkoxy or aryl;
(3) Dicarboxylic acid (CH) 2 ) n (COOH) 2 Or cyclic acid anhydrides
Wherein n = an integer from 1-10;
(4) Diglycolic acid or diglycolic anhydride;
(5) Halogenated carboxylic acids or esters Z- (CH) 2 ) n COOR ', wherein n = an integer from 1 to 10, Z is Cl, br or I, R' is an alkyl group.
In the preparation method of the docetaxel derivative I, the base catalyst in the step 3) is selected from triethylamine, pyridine, 4-dimethylamino pyridine, sodium carbonate, potassium carbonate or cesium carbonate and the like.
For example: the docetaxel derivative I is synthesized by taking 4- { p- [ bis (2-chloroethyl) amino ] benzene } butanol (1) as a raw material, and the synthesis method comprises the following steps (shown in a formula 2):
1) 4- { p- [ bis (2-chloroethyl) amino ] benzene } butanol (1) is reacted with diglycolic anhydride or cyclic anhydride (such as: succinic anhydride, glutaric anhydride, adipic anhydride, etc.), or with an excess of diglycolic acid or dicarboxylic acid (such as: succinic acid, glutaric acid, adipic acid and the like) to generate dicarboxylic acid 4- { p- [ bis (2-chloroethyl) amino ] benzene } butanol monoester (2);
2) 4- { p- [ bis (2-chloroethyl) amino ] benzene } butanol monoester of dicarboxylic acid (2) reacts with thionyl chloride to generate an acyl chloride product (3);
3) Reacting the acylchlorination product (3) with docetaxel by using alkali as a catalyst to generate a docetaxel derivative I; or 4-dimethylamino pyridine (DMAP) and 2-chloro-1-methylpyridinium iodide (CMPI) are used as catalysts, or N, N' -Dicyclohexylcarbodiimide (DCC) and 4-dimethylamino pyridine (DMAP) are used as catalysts, and dicarboxylic acid 4- { p- [ bis (2-chloroethyl) amino ] benzene } butanol monoester (2) is reacted with docetaxel to generate docetaxel derivative I.
It will be understood by those skilled in the art that the reaction of p- [ bis (2-chloroethyl) amino ] benzenealkyl alcohol or p- [ bis (2-chloroethyl) amino ] phenol with other linker molecules can be carried out under the conditions of the prior art, for example, by reacting with a halogenated carboxylic acid in the presence of a base (e.g., triethylamine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate) as a catalyst, or by dealkylating the product after reaction with a halogenated carboxylic acid ester to produce a carboxylic acid; or reacting with alkyl phosphonic dichloride, alkoxy phosphonic dichloride or aryl phosphonic dichloride by using alkali (such as triethylamine, pyridine, sodium carbonate, potassium carbonate and cesium carbonate) as a catalyst to generate a derivative containing a phosphoryl chloride group; alkali (such as triethylamine or pyridine) is used as a catalyst to react with oxalyl chloride to generate the derivative containing acyl chloride groups.
The amidation reaction or the reaction of the p- [ bis (2-chloroethyl) amino ] phenylamine or p- [ bis (2-chloroethyl) amino ] aniline with the linker molecule with the substituted amine group is carried out under substantially the same conditions as the above-mentioned esterification or etherification reaction.
The invention also relates to a preparation of the docetaxel derivative as an anticancer drug compound, which comprises a liposome agent, an emulsion, a micelle agent and the like, wherein the docetaxel derivative I is contained. The liposome agent comprises the newly invented anticancer drug compound, phospholipid (most typically lecithin, phosphatidylcholine), cholesterol or vitamin E acetate, and water phase. The emulsion comprises the newly invented anticancer drug compound, one or more surfactants, an oil phase (lipophilic medium) and an aqueous phase. Emulsions may be of the oil-in-water or water-in-oil type. The micelle agent comprises the novel anticancer drug compound, a cosolvent, one or more surfactants and an aqueous phase.
The liposome preparation of the docetaxel derivative anticancer drug compound comprises the following components:
1) Docetaxel derivatives having the structure of formula i;
2) Phospholipids (lecithin, phosphatidylcholine or soya lecithin);
3) Cholesterol, vitamin E or vitamin E acetate;
4) An aqueous phase.
The emulsion of the docetaxel derivative anticancer drug compound comprises the following components:
1) An oil phase comprising:
a) Docetaxel derivatives having the structure of formula i;
b) A biocompatible lipophilic medium;
2) Surfactants and cosolvents;
3) An aqueous phase.
The micelle agent of the docetaxel derivative anticancer drug compound comprises the following components:
1) A docetaxel derivative having the structure of formula i;
2) A surfactant;
3) A cosolvent;
4) An aqueous phase.
In the above formulations, the aqueous phase includes, but is not limited to, deionized water, physiological saline (0.9% sodium chloride), dextrose (5%) solution, sucrose solution, and the like.
Representative biocompatible lipophilic media for the above formulations include:
a) Fat-soluble vitamin E and derivatives. Vitamin E refers to the natural or synthetic series of vitamin E commonly referred to as tocopherols and tocotrienols (tocophenols and tocotrienols), and tocopherols include alpha-tocopherol (D, DL, L), beta-tocopherol (D, DL, L), gamma-tocopherol (D, DL, L) and delta-tocopherol (D, DL, L). Tocotrienols are similar in structure to tocopherols, but tocotrienols have three double bonds in the carbon-2 side chain phytyl (phytyl). Tocotrienols include alpha-tocotrienol (D, DL, L), beta-tocotrienol (D, DL, L), gamma-tocotrienol (D, DL, L) and delta-tocotrienol (D, DL, L). The vitamin E derivatives include all derivatives of tocopherol and tocotrienol, such as vitamin E succinate, vitamin E acetate, etc.
b) Oils and fats that can be used as lipophilic medium include fatty acids and esters of varying chain length, which are mostly linear but may also be branched, such as capric acid, caprylic acid, caproic acid, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid, and other saturated or unsaturated fatty acids and esters.
c) The mono-, di-or triglycerides formed by the esterification of fatty acids with glycerol, whether synthetic or natural, can be used as lipophilic media, for example, glycerides such as soybean oil, cottonseed oil, rapeseed oil, fish oil, acetylated monoglycerides, glycerol monooleate, glycerol triacetate, and diacetyl tartrate, monoglycerides, castor oil, etc.
d) Fatty alcohols such as benzyl alcohol, stearyl alcohol, lauryl alcohol, etc., or their esters or ethers, such as benzyl benzoate.
Representative surfactants in the above formulations include:
a) Polyethylene glycol surfactants, such as polyoxyethylene castor oil EL (Cremophor EL) and Tween series surfactants.
b) Phospholipid surfactants (phospholipids), such as lecithin (lecithin), polyethylene glycol phospholipids (pegylated phospholipids).
c) Polyethylene glycol vitamin E derivatives, such as vitamin E succinate polyethylene glycol (d-alpha-tocopherol 1000succinate, TPGS).
d) Polyoxyethylene polyoxypropylene block copolymer: block copolymers of POLOXAMERS or PLURONICS (H (OCH 2CH 2) a (OC 3H 6) b (OCH 2CH 2) aOH).
Representative solvents in the above formulations include:
ethanol, polyethylene glycol and propylene glycolAlcohols, glycerol, N-methylpyrrolidone, and the like. Polyethylene glycol (PEG) is hydrophilic and the chemical structure of the repeat unit is-CH 2 CH 2 O-is represented by the formula H- (CH) 2 CH 2 ) n -OH, molecular weight generally ranging from 200 to 10000. For example, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, and the like.
The formulations of the various preparations comprise an effective treatment amount of the docetaxel derivative antitumor drug compound and optional auxiliary materials.
The invention also provides application of the novel docetaxel derivative anticancer drug compound in preparation of anticancer drugs. The docetaxel derivatives of the present invention are useful as anticancer drug compounds for treating cancers, including but not limited to (1) cancers of the blood system, such as leukemia, lymphoma, myeloma; (2) non-hematologic cancers, such as solid tumor cancers (e.g., breast, ovarian, pancreatic, colon, rectal, non-small cell lung, bladder, gastric, liver, etc.), sarcomas, skin cancers, and gliomas.
The therapeutic efficacy and toxicity of the docetaxel derivative anticancer drug compounds of the present invention are determined using in vitro cell or in vivo animal experiments, such as ED50 (50% effective dose: the amount of drug at which 50% of the subjects showed a positive reaction), LD50 (50% lethal dose: the amount of drug at which half of the subjects were killed) and GI50 (the concentration of drug at which the anti-cancer drug is present in the growth of the cells of 50% of the subjects). The ratio of half lethal dose (LD 50)/half effective dose (ED 50) is generally referred to as therapeutic index to indicate the safety of the drug. Drugs with a large therapeutic index are safer than drugs with a small therapeutic index.
The novel docetaxel derivative anticancer drug compound aims at improving the therapeutic index and the safety of the drug and simultaneously improving the therapeutic effect. The drug dose obtained from in vitro cell experiments and in vivo animal experiments can be used to formulate a range of doses for use in humans. The dosage of such compounds is preferably within the ED50 range where there is little or no toxicity. The dosage will generally vary depending on the agent employedType, sensitivity of the patient, and route of administration, among others. The same or similar drugs can generally be used, e.g.
Ailanthus, etc.
The docetaxel derivative anticancer drug compound of the present invention can be used alone or together with one or more other therapeutic drugs. For example, in the treatment of cancer, the pharmaceutical compounds of the present invention may be used with the following therapeutic agents, including but not limited to: androgen inhibitors such as flutamide (flutamide) and lupperoid (luprolide); antiestrogens, such as tamoxifen (tomoxifen); antimetabolites and cytotoxic drugs such as daunorubicin (daunorubicin), pentafluorouracil (fluoroouracil), floxuridine (floxuridine), interferon-alpha (interferon alpha), methotrexate (methotrexate), mithramycin (plicamycin), thiopurine (mecaptopurine), thioguanine (thioguanine), adriamycin (adriamycin), carmustine (carmustine), lomustine (lomustine), cytarabine (cytarabine), cyclophosphamide (cyclophoramide), doxorubicin (doxorubicin), estramustine (estramustine), altretamine (altretamine), hydroxyurea (hyxyurea), ifosfamide (ifosfamide), procarbazine (procarbazine), promycin (mutrytin), leucomycin (butoxyanthraquinone), butoxyurea (bleomycin), carboplatin (carboplatin), cisplatin (carboplatin), and cisplatin); hormones, such as megestrol (medroxyprogesterone), ethinyl estradiol (ethinyl estradiol), estradiol (estradiol),. Leuprolide (leuprolide), megestrol (medestrenol), octreotide (octreotide), diethylstilbestrol (diethylstilbestrol), chlorostilbene (chlorotrianisene), etoposide (etoposide), podophyllotoxin (podophyllotoxin) and goserelin (goserelin); nitrogen mustard derivatives, such as mechlorethamine phenylpropionate (melphalan), chlorambucil (chlorambucil), and thiotepa (thiotepa); steroids, such as betamethasone (betamethasone); and other antitumor agents such as live Mycobacterium bovis (live Mycobacterium bovis), dacarbazine (dicarbazine), asparaginase (aspargine), leucovorin (leucovorin), mitotane (mitotane), vincristine (vincristine), and vinblastine (vinblastine), and the like.
Has the advantages that: the invention covalently combines the drug compound molecule docetaxel with anticancer activity and 4- [ bis (2-chloroethyl) amino ] phenylbutanol through a connecting group to obtain the docetaxel derivative anticancer drug compound. The novel anticancer drug compound has higher anticancer activity and lower toxic and side effects. The medicine compound can be prepared into injections, is widely applied to treatment of cancers in blood systems and non-blood systems, and provides a new method and approach for clinical application of docetaxel.
The present invention will be described in detail with reference to specific examples. It is intended that the scope of the invention be limited not by this detailed description, but rather by the claims appended hereto.
Drawings
Figure 1 docetaxel derivative anticancer drug compounds: nuclear magnetic resonance hydrogen spectrum of (4- { p- [ bis (2-chloroethyl) amino ] benzene } butanol docetaxel-2' -diglycolate).
Figure 2 docetaxel derivative anticancer drug compounds: (4- { p- [ bis (2-chloroethyl) amino ] benzene } butanol docetaxel-2' -diglycolate) mass spectrum.
Detailed Description
The following examples are intended to illustrate the synthesis, formulation, in vivo pharmacodynamics, etc., of the docetaxel derivatives of the present invention. In the examples, applicants describe in detail (4- [ bis (2-chloroethyl) amino ] phenylbutanol docetaxel-2' -diglycolate as an example, and other docetaxel derivatives within the scope of the present invention may be synthesized using the same or similar methods and have been shown to have the same or similar results.
EXAMPLE 1.4 Synthesis of { p- [ bis (2-chloroethyl) amino ] benzene } butanol docetaxel-2' -diglycolate (YY-015)
The synthesis of the docetaxel derivative comprises the following steps:
1) Synthesis of 4- { p- [ bis (2-chloroethyl) amino ] benzene } butanol
The reaction formula is shown as the following formula:
the experimental steps are as follows:
chlorambucil (608.4mg, 2.0mmol) was dissolved in 20ml of tetrahydrofuran, and stirred at 0 ℃, borane methyl sulfide (1.2ml, 2.4mmol,2.0M tetrahydrofuran solution) was slowly added dropwise to the above solution, stirring was continued at 0 ℃ for 4 hours, 1ml of methanol was added to the reaction solution, and 20ml of ethyl acetate was further added thereto, and stirring was carried out, and the reaction solution was washed three times (20 ml. Times.3) with 1N sodium bicarbonate solution. The combined organic phases were dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel to give 0.501g of product in 86% yield.
2) Synthesis of 4- { p- [ bis (2-chloroethyl) amino ] benzene } butanol diglycolic acid monoester
The reaction formula is shown as the following formula:
the experimental steps are as follows:
the method comprises the following steps: in a 100mL round bottom flask, 0.697g (2.4 mmol) of dried 4- [ bis (2-chloroethyl) amino ] phenylbutanol, 0.557g (4 mmol) of diglycolic anhydride and 200mg of tin 2-ethylhexanoate were added, 30mL of xylene was added, stirred, and heated under nitrogen reflux until the reaction was complete. After removing xylene from the reaction solution by a rotary evaporator, 20mL of ethyl acetate was added, the mixture was stirred, 10mL of diethyl ether was added to precipitate a white solid, the solid was removed by filtration, the filtrate was concentrated to 10mL by a rotary evaporator, and the column layer was separated to obtain 0.802g of 4- { p- [ bis (2-chloroethyl) amino ] benzene } butanol monoester diglycolic acid with a yield of 82.3%.
The second method comprises the following steps: a100 mL round-bottomed flask was charged with 0.644g (4.8 mmol) of diglycolic acid, 1.450g (12 mmol) of 4-dimethylaminopyridine, 1.530g (6 mmol) of 2-chloro-1-methylpyridinium iodide and 30mL of N, N-dimethylacetamide, and stirred magnetically, and a solution of 0.697g (2.4 mmol) of 4- { p- [ bis (2-chloroethyl) amino ] benzene } butanol and 30mLN, N-dimethylacetamide was slowly added dropwise to the reaction mixture. Reacting for 12h at room temperature under the protection of nitrogen, concentrating filtrate to 10mL by using a rotary evaporator, and separating a column layer to obtain 0.619g of 4- { p- [ bis (2-chloroethyl) amino ] benzene } butanol monoester diglycolic acid with the yield of 65.1%.
3) Synthesis of 4- { p- [ bis (2-chloroethyl) amino ] benzene } butanol docetaxel-2' -diglycolate
The reaction formula is shown as the following formula:
the experimental steps are as follows:
in a 100mL round bottom flask, 0.609g (1.50 mmol) of 4- { p- [ bis (2-chloroethyl) amino ] benzene } butanoic acid monoester diglycolic acid was dissolved in 30mL of anhydrous toluene, and 550. Mu.L (7.45 mmol) of thionyl chloride, 2 drops of DMF was added. And (4) magnetically stirring, and reacting for 4 hours at room temperature under the protection of nitrogen. The toluene and excess thionyl chloride were distilled off under reduced pressure to give a viscous liquid, and 10mL of anhydrous chloroform was added to give solution A.
In a 50mL reaction flask, 0.958g (1.18 mmol) of docetaxel was dissolved in 20mL of chloroform, 495.9. Mu.L (3.558 mmol) of dried triethylamine was added, the mixture was cooled in an ice salt bath, stirred, and 10mL of solution A was slowly added, and the mixture was reacted for 4 hours at room temperature under nitrogen. After completion of the reaction, chloroform in the reaction solution was removed by distillation under reduced pressure, and then 20mL of ethyl acetate was added to the reaction flask, followed by stirring, filtration to remove a white solid, and concentration of the filtrate to 10mL. Separating the column layer to obtain 0.932g of 4- { p- [ bis (2-chloroethyl) amino ] benzene } butanol docetaxel-2' -diglycolic acid ester I with the yield of 63.6 percent.
The hydrogen nuclear magnetic resonance spectrum and the mass spectrum of the synthesized compound are shown in figures 1 and 2.
MS(Positive ESI):m/z＝1217.47，1195.49.
1 H NMR(300MHz,CDCl 3 ):δppm:8.1304～8.1058(d,2H,J＝7.38Hz),7.6311～7.5819(t,1H,J＝7.38Hz),7.5252～7.4755(t,2H,J＝7.45Hz)，7.4099～7.3626(t,2H,J＝7.10Hz),7.3267～7.2581(m,3H),7.1019-7.0741(d，2H，J＝8.34Hz)，6.7508～6.7235(d，2H，J＝6.69Hz)，6.2842～6.2275(t,1H，J＝8.50Hz),5.7065～5.6832(d,1H,J＝6.99Hz),5.4864～5.3789(m,3H),5.2156(s,1H),4.9793～4.9513(d,1H,J＝8.40Hz),4.3515～4.0696(m,9H),3.9524～3.9289(d,1H，J＝7.05Hz),3.7005～3.6294(m,8H),2.6500～2.5427(m,3H),2.4403(s,3H),2.3800～2.2000(m,2H),1.9550(s,3H),1.9000～1.8100(m,1H),1.7574(s,3H),1.6598～1.5353(m,7H),1.3272(s,9H),1.2571(s,3H),1.1288(s,3H)。
EXAMPLE 2.4 Synthesis of docetaxel-2' -succinate- { p- [ bis (2-chloroethyl) amino ] benzene } butanoi-ne (YY-019)
The synthesis of the docetaxel derivative comprises the following steps:
1) Synthesis of succinic acid 4- { p- [ bis (2-chloroethyl) amino ] benzene } butanol monoester
The reaction formula is shown as the following formula:
the experimental steps are as follows:
in a 100ml round bottom flask, 1g (6.45 mmol) of 4- [ bis (2-chloroethyl) amino ] phenylbutanol, 0.587g (5.87 mmol) of succinic anhydride, 1.4g (3.45 mmol) of stannous octoate and 20ml of toluene were added, stirred and heated under nitrogen at reflux until the reaction was complete. After toluene was removed from the reaction mixture by a rotary evaporator, column layer separation was carried out to obtain 1.10g of 4- { p- [ bis (2-chloroethyl) amino ] benzene } butanoic acid monoester succinate in a yield of 81.5%.
2) Synthesis of 4- { p- [ bis (2-chloroethyl) amino ] benzene } butanol docetaxel-2' -succinate
The reaction formula is shown as the following formula:
the experimental steps are as follows:
in a 100mL round bottom flask, 1.1g (2.81 mmol) of 4- { p- [ bis (2-chloroethyl) amino ] benzene } butanoic acid monoester succinate was dissolved in 15mL of chloroform, and 1mL (14 mmol) of thionyl chloride, 2 drops of DMF were added. And (4) magnetically stirring, and reacting for 4 hours at room temperature under the protection of nitrogen. Chloroform and excess thionyl chloride were distilled off under reduced pressure to give a viscous liquid, and 10mL of anhydrous chloroform was added to give solution A.
In a 50mL reaction flask, 0.950g (1.17 mmol) of docetaxel was dissolved in 30mL of chloroform, 410. Mu.L (3.558 mmol) of dried triethylamine was added, the mixture was cooled in an ice-salt bath, stirred, 10mL of solution A was slowly added, and the mixture was reacted for 4 hours at room temperature under nitrogen. After completion of the reaction, chloroform in the reaction solution was removed by distillation under reduced pressure, and then 20mL of ethyl acetate was added to the reaction flask, followed by stirring, filtration to remove a white solid, and concentration of the filtrate to 10mL. Separating the column layer to obtain 1.0g4- { p- [ bi (2-chloroethyl) amino ] benzene } butanol docetaxel-2' -succinate I with the yield of 47.6%.
EXAMPLE 3 Liposomal lyophilized powder formulation of docetaxel derivative (YY-015) anticancer drug Compound
Weighing 5g of docetaxel derivative, 70g of phospholipid and 5.5g of cholesterol, adding the mixture into a round-bottom flask, adding an appropriate amount of chloroform to dissolve the mixture into transparent liquid, placing the transparent liquid in a 50 ℃ water bath for decompression and drying to form a film, preserving the heat for 1.5h, adding an appropriate amount of 5% sucrose solution to dissolve the film, ultrasonically crushing the film by an ultrasonic instrument, homogenizing the film by a high-pressure homogenizer, filtering the film by a 0.22 mu m filter membrane, and subpackaging the film in ampoule bottles so that each bottle contains 10mg of docetaxel derivative. Freeze drying, introducing inert gas, and sealing to obtain white solid docetaxel derivative liposome preparation.
Example 4 emulsion of docetaxel derivative (YY-015) anticancer drug Compound
In this example, the content of each component in the formulation is calculated by weight percentage. The drug compounds in the formulation may be replaced with other anti-cancer drug compounds of the present invention (e.g., YY-019).
Emulsion one: dissolving docetaxel derivative in a mixture of soybean oil, D-alpha-tocopheryl polyethylene glycol 1000succinate (TPGS) and polyethylene glycol PEG (200), adding deionized water (DI water), stirring, ultrasonic treating, homogenizing and emulsifying to obtain emulsion with the following composition:
the resulting emulsion drug was filtered through a filter with a pore size of 0.22 microns and then packaged in sterile glass vials.
Emulsion II: docetaxel derivatives were dissolved in a mixture of D- α -tocopheryl acetate, D- α -tocopheryl polyethylene glycol 1000succinate (TPGS) and polyethylene glycol PEG (200), and deionized water (DI water) was added, followed by stirring, sonication, and homogeneous emulsification, producing an emulsion having the following composition:
the resulting emulsion drug was filtered through a filter with a pore size of 0.22 microns and then packaged in sterile glass vials.
Example 5 micelle agent of docetaxel derivative (YY-015) anticancer drug Compound
Dissolving appropriate amount of docetaxel derivative in Tween 80 (Tween 80) to obtain transparent liquid, and packaging in sterile glass bottle.
Before use, adding appropriate amount of normal saline or 5% glucose injection, and shaking to form transparent liquid for use. The composition of the produced micellar solution was as follows:
docetaxel derivative 2.5%
Tween 80% to
Deionized water to 100%
Example 6 determination of particle size of docetaxel derivative (YY-015) anticancer drug Compound liposomes
The particle size of nanoparticles formed after the docetaxel derivative anticancer drug compound liposome is dissolved in water is measured by a Zetaplus type laser scattering particle size analyzer of BROOKHAVEN company in America, and the measuring method comprises the following steps: weighing 5mg and 10mg of liposome freeze-dried powder medicine, respectively adding the liposome freeze-dried powder medicine into 2mL of distilled water, carrying out ultrasonic stirring to fully dissolve the liposome freeze-dried powder medicine, standing for 10min, adding the liquid into a sample cell (cuvette) after bubbles disappear, paying attention to the fact that the bubbles cannot be generated in the process of adding the sample, then putting the cuvette into a corresponding groove of a base of the sample cell, starting to measure, and respectively carrying out parallel measurement on each sample for three times to obtain the average value.
The results show that: when the concentration of the aqueous solution of the docetaxel derivative anticancer drug compound liposome is 2.5mg/mL and 5mg/mL, the average particle size is between 100 and 200 nanometers respectively.
Example 7 inhibition of docetaxel derivative anticancer drug Compound (Compound YY-015 of example 1) micelles and lyophilized powder to animal transplanted tumor H22
1) The preparation method of the medicine comprises the following steps:
the preparation method of the YY-015 micelle preparation comprises the following steps: 0.146g of YY-015 powder was accurately weighed out, 1.168g of pharmaceutical grade Tween 80 was added, and stirred until dissolved. During each dosage, 43.22mg of the above solution was weighed and dissolved in 3ml of 0.9% sodium chloride injection (0.9% sodium chloride injection manufacturer: anhui Shuanghe pharmaceutical industry, ltd.; lot: 170120G; specification: 100ml. 0.9%) by shaking, to prepare a 1.48mg/ml solution, the administration volume was 0.2ml/20g, that is, 14.8mg/kg. It is prepared as before use.
YY-015 liposome lyophilized powder: 0.4585g of YY-015 freeze-dried powder (preparation code: 30) was accurately weighed, and dissolved in 3ml of 0.9% sodium chloride injection (0.9% sodium chloride injection manufacturer: anhui Shuangyao drug industry, LLC; lot number: 170120G; specification: 100ml 0.9%) by shaking, to prepare a 1.48mg/ml solution, the administration volume was 0.2ml/20g, i.e., the dose was 14.8mg/kg. It is prepared fresh before each application.
The preparation method of the docetaxel injection comprises the following steps: the specification of each bottle of the original docetaxel injection is 20mg/0.5ml (Jiangsu Henrei medicine GmbH, batch No. 15011215), 0.5ml of docetaxel for injection with the specification is taken and added into 1.5ml of docetaxel injection solvent, the concentration is 10mg/ml, the docetaxel is fully diluted to 1mg/ml by physiological saline, the administration volume is 0.2ml/20g, and the dosage is 10mg/kg.
2) Laboratory animal
ICR mouse, clean grade, provided by Qinglong mountain animal breeding farm in Jiangning district of Nanjing city, license number: SCXK (threo) 2017-0001; weight: 18-22g; sex: and (4) a female.
3) Grouping of laboratory animals
4) Tumor strain
H22 was originally provided by Kayji Biotechnology Co., ltd, nanjing, inoculated with ascites after the culture, the cell fluid was collected after the ascites became mature and frozen, and inoculated directly with ascites from mice, and after 4 passages on the mice, the mice were replanted and administered (ZMY 005/P58, cell code: H22-X-17-12-27-F4).
5) Experimental methods
ICR mice were taken and inoculated with ascites tumor according to the transplantation tumor study method (ascites was taken under aseptic conditions, PBS solution was diluted according to 1 1 ) The first administration. The tail vein injection scheme is applied for 1 time/2 days, and the application is performed for 4 times. The administration volumes were all 0.2ml/20g. On day 8 after inoculation (d) 8 ) Tumor-bearing mice were sacrificed and the tumor masses were separated and weighed and the data obtained were statistically processed (t-test).
6) Conclusion of the experiment
Results show that compared with a model control group, the YY-015 micelle (14.8 mg/kg) has a relatively obvious inhibition effect on the growth of the H22 tumor, and the YY-015 freeze-dried powder (14.8 mg/kg) and the docetaxel (10 mg/kg) group have a very obvious inhibition effect on the growth of the H22 tumor; after administration, YY-015 freeze-dried powder (14.8 mg/kg) and docetaxel (10 mg/kg) groups have significant influence on the body weight of the experimental mice, and meanwhile, YY-015 micelle (14.8 mg/kg) groups have more significant influence on the body weight of the experimental mice.
TABLE 1YInhibition effect of Y-015 micelle and freeze-dried powder on mouse transplantation tumor H22
Example 8 inhibition of YY-015 micelles and lyophilized powder of drug on animal transplantable tumors S180
1) The preparation method of the medicine comprises the following steps:
14.8mg/kgYY-015 micelle preparation method: accurately weigh 16.19mg of YY-015 powder and add 399.87mg of pharmaceutical grade Tween (m) yy-015 :m Tween80 =1:27 Stirring until dissolved. In each dosage, 166.31mg of micelles were weighed and dissolved in 4ml of 0.9% sodium chloride injection (0.9% sodium chloride injection manufacturer: anhui, shuanghe pharmaceutical industry, ltd.; lot: 170120C grid: 100ml x 0.9%) to prepare a 1.48mg/ml solution with an administration volume of 0.2ml/20g, i.e., a dosage of 14.8mg/kg. It is prepared fresh before each application.
The preparation method of the YY-015 liposome freeze-dried powder of 14.8mg/kg comprises the following steps: 0.4585g of YY-015 freeze-dried powder (preparation code: 30) was accurately weighed, and dissolved in 3ml of 0.9% sodium chloride injection (0.9% sodium chloride injection manufacturer: anhui Shuanghe pharmaceutical industry, ltd.; lot: 170120C grid: 100ml. 0.9%) by shaking to prepare a 1.48mg/ml solution, the administration volume was 0.2ml/20g, that is, 14.8mg/kg. It is prepared fresh before each application.
The preparation method of the docetaxel injection with the concentration of 10mg/kg comprises the following steps: accurately weighing 10mg of docetaxel bulk drug, adding 270mg of dried medicinal Tween, stirring until the docetaxel bulk drug is dissolved, firstly using 1ml of 13% ethanol solution to vibrate and dissolve during administration, and then adding 400 mul of the solution into 3600 mul of physiological saline to dilute the solution to prepare liquid with the concentration of 1.0mg/ml, wherein the administration volume is 0.2ml/20g, namely the administration dose is 10mg/kg. ( 0.9% sodium chloride injection manufacturer: anhui double crane pharmaceutical industry, inc.; batch number: 170120 9C, lattice: 100ml 0.9% )
2) Laboratory animal
ICR mouse, cleaning grade (provided by the animal reproduction farm in the green dragon mountain of Jiangning district, nanjing city, license number: SCXK (Su) 2017-0001), weight: 18-22g, sex: and (4) a female.
3) Origin of tumor
S180 is initially provided by Kayji biotechnology limited company of Nanjing, inoculated with ascites after culture, extracted and cryopreserved cell sap after the ascites is mature, recovered for 1 count in No. 2018-8-20, inoculated with 54 mice in No. 2018-9-16 after three cell cultures, and administered for the first time after 24 hours (ZMY 005/P91-P96), cell code: S180-X-18-9-16-F4).
4) Grouping of laboratory animals
Totally 5 groups
5) Experimental methods
ICR mice were taken and inoculated with ascites tumor according to the transplantation tumor study method (ascites was taken under aseptic conditions, PBS solution was diluted according to 1 1 ) The first administration. The tail vein injection is given 1 time/2 days for 4 times. The administration volumes were all 0.2ml/20g. On day 9 post inoculation (d) 9 ) Tumor-bearing mice were sacrificed and the tumor masses were weighed, and the data were statistically processed (t-test).
6) The experimental results are as follows:
results show that compared with a model control group, YY-015 micelle (14.8 mg/kg), YY-015 freeze-dried powder (14.8 mg/kg) and docetaxel (10 mg/kg) have very obvious inhibition effect on S180 tumor growth; docetaxel (10 mg/kg) group had a very significant effect on body weight in the experimental mice after administration.
TABLE 2 YY-015 micelle and lyophilized powder for inhibiting mouse transplanted tumor S180
Claims (9)
1. A docetaxel derivative having the structure of formula I:
wherein n = an integer from 0 to 10, X is O or NH;
r is a linking group, and is one of the following groups:
a)-(C＝O)-；
b) -P (= O) (R ') -, wherein R' is C1-C6 alkyl or C1-C6 alkoxy;
c)-(C＝O)(CH 2 ) m( c = O) -, wherein m = an integer from 1 to 10;
d)-(C＝O)CH 2 -O-CH 2 (C＝O)-；
e)-(CH 2 ) m (C = O) -, wherein m = an integer from 1 to 10.
2. A process for the preparation of docetaxel derivative as claimed in claim 1, comprising the steps of:
1) Carrying out esterification or etherification reaction on the p- [ bis (2-chloroethyl) amino ] benzyl alcohol or the p- [ bis (2-chloroethyl) amino ] phenol and a connecting molecule to generate a derivative of the p- [ bis (2-chloroethyl) amino ] benzyl alcohol or the p- [ bis (2-chloroethyl) amino ] phenol; or para- [ bis (2-chloroethyl) amino ] phenylalkylamine or para- [ bis (2-chloroethyl) amino ] aniline and a linker molecule are subjected to amidation reaction to generate para- [ bis (2-chloroethyl) amino ] phenylalkylamine or para- [ bis (2-chloroethyl) amino ] aniline derivatives;
2) Carrying out esterification reaction on the p- [ bis (2-chloroethyl) amino ] phenylalkyl alcohol or the derivative of p- [ bis (2-chloroethyl) amino ] phenol, or the derivative of p- [ bis (2-chloroethyl) amino ] phenylamine or p- [ bis (2-chloroethyl) amino ] aniline, or the acyl chlorination products of the p- [ bis (2-chloroethyl) amino ] phenylamine and the derivative of p- [ bis (2-chloroethyl) amino ] aniline, which are obtained in the step 1) and docetaxel under the action of a catalyst to generate the docetaxel derivative I;
the connecting molecule is one of the following molecules:
(1) Oxalyl chloride O = CCl 2 ；
(2) Phosphoryl dichloro alkyl ester, alkoxy ester O = POR' Cl 2 Wherein R' is C1-C6 alkyl, C1-C6 alkoxy;
(3) Dicarboxylic acid (CH) 2 ) n (COOH) 2 Or cyclic acid anhydrides
Wherein n = an integer from 1-10;
(4) Diglycolic acid or diglycolic anhydride;
(5) Halogenated carboxylic acids or esters Z- (CH) 2 ) n COOR ', wherein n = an integer from 1 to 10, Z is Cl, br or I, R' is an alkyl group.
3. The process for the preparation of docetaxel derivatives according to claim 2, wherein the process comprises the steps of:
1) Carrying out esterification or etherification reaction on hydroxyl of p- [ bis (2-chloroethyl) amino ] phenylalkyl alcohol or p- [ bis (2-chloroethyl) amino ] phenol and a connecting molecule to generate p- [ bis (2-chloroethyl) amino ] phenylalkyl ester or ether or p- [ bis (2-chloroethyl) amino ] phenyl ester or ether derivative; or the amidation reaction of the amino group of p- [ bis (2-chloroethyl) amino ] phenylamine or p- [ bis (2-chloroethyl) amino ] aniline with a linking molecule to produce p- [ bis (2-chloroethyl) amino ] phenylalkylamide or p- [ bis (2-chloroethyl) amino ] phenylamide derivative; the resulting derivatives contain carboxyl, acyl chloride or phosphoryl chloride groups;
2) Reacting the p- [ bis (2-chloroethyl) amino ] phenylalkyl ester, ether or amide derivative containing carboxyl obtained in the step 1) with an acyl chlorination reagent to generate an acyl chlorination product;
3) Performing esterification reaction on the acyl chlorination product obtained in the step 2) or the phosphoryl chloride compound obtained in the step 1) and docetaxel by taking alkali as a catalyst to generate the docetaxel derivative I;
or, the p- [ bis (2-chloroethyl) amino ] phenylalkyl ester, ether or amide derivative containing carboxyl obtained in the step 1) or the p- [ bis (2-chloroethyl) amino ] phenyl ester, ether or amide derivative directly undergoes an esterification reaction with docetaxel in the presence of 4-dimethylaminopyridine and 2-chloro-1-methylpyridinium iodide or N, N' -dicyclohexylcarbodiimide and 4-dimethylaminopyridine as catalysts to generate the docetaxel derivative I.
4. The method for preparing docetaxel derivative according to claim 3, wherein the base catalyst is triethylamine, pyridine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate or cesium carbonate.
5. A formulation of the docetaxel derivative of claim 1, comprising a liposome, an emulsion or a micelle comprising the docetaxel derivative of claim 1.
6. The docetaxel derivative formulation as set forth in claim 5, wherein the liposome formulation comprises:
1) Docetaxel derivatives having the structure of formula i;
2) A phospholipid;
3) Cholesterol, vitamin E or vitamin E acetate;
4) An aqueous phase.
7. The docetaxel derivative formulation as set forth in claim 5, wherein the emulsion comprises:
1) An oil phase comprising:
a) Docetaxel derivatives having the structure of formula i;
b) A biocompatible lipophilic medium;
2) Surfactants and cosolvents;
3) An aqueous phase.
8. The docetaxel derivative formulation as set forth in claim 5, wherein the micelle agent comprises:
1) Docetaxel derivatives having the structure of formula i;
2) A surfactant;
3) A cosolvent;
4) An aqueous phase.
9. Use of the docetaxel derivative of claim 1 for the preparation of an anticancer drug.
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