WO2013067881A1 - 水溶性维生素e衍生物修饰的双亲性抗癌药物化合物和制剂、该化合物的制备方法及应用 - Google Patents
水溶性维生素e衍生物修饰的双亲性抗癌药物化合物和制剂、该化合物的制备方法及应用 Download PDFInfo
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- WO2013067881A1 WO2013067881A1 PCT/CN2012/083159 CN2012083159W WO2013067881A1 WO 2013067881 A1 WO2013067881 A1 WO 2013067881A1 CN 2012083159 W CN2012083159 W CN 2012083159W WO 2013067881 A1 WO2013067881 A1 WO 2013067881A1
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- Prior art keywords
- water
- soluble vitamin
- derivative
- ester
- anticancer drug
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—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
- C07F9/6552—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 six-membered ring
- C07F9/65522—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 six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/50—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
- 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
- A61K47/55—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 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
- A61K47/551—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 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
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- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2203/00—Applications
- C08L2203/02—Applications for biomedical use
Definitions
- Amphiphilic anticancer drug compound and preparation modified by water-soluble vitamin E derivative, preparation method and application of the same are Amphiphilic anticancer drug compound and preparation modified by water-soluble vitamin E derivative, preparation method and application of the same
- the invention relates to a novel anticancer drug compound, a preparation method and application thereof, in particular to a water-soluble vitamin E derivative modified amphiphilic anticancer drug compound, a preparation comprising the same, a preparation method thereof and an anticancer The application of drugs.
- Camptothecin (20(s)-camptothecin, formula 1, 1) and its derivatives have excellent antitumor activity and are an important class of DNA topoisomerase I (Top I) inhibitors.
- the I-DNA cleavable complex binds to form a CPT-Top I-DNA ternary complex, thereby stabilizing the cleavable complex, resulting in cell death.
- it due to its poor solubility and toxicity in water and other biocompatible solvents, it eventually failed to enter the clinic.
- many camptothecin derivatives have been synthesized.
- topotecan Form 1, 2
- irinotecan Irinotrcan, Formula 1, 3
- topotecan and irinotecan have significant disadvantages, including short half-lives and large side effects in the body.
- camptothecin derivatives are in clinical research.
- the E lactone ring in the camptothecin molecule is a functional group necessary for the anticancer activity of camptothecin and its derivatives, and rapidly opens under alkaline or physiological conditions to cause the disappearance of activity (Formula 2).
- Form 2 the E lactone ring in the camptothecin molecule is a functional group necessary for the anticancer activity of camptothecin and its derivatives, and rapidly opens under alkaline or physiological conditions to cause the disappearance of activity.
- the present invention provides a series of novel amphiphilic camptothecin derivatives which have good solubility in water and biocompatible organic solvents, can be directly dissolved in water or physiological saline, or can be prepared by using a formulation technique. Forming a drug dosage form such as micelles.
- the novel pharmaceutical compounds of the present invention are expected to increase the duration (half-life) and efficacy of the drug in vivo, as well as to reduce its side effects.
- the object of the present invention is to provide a novel amphiphilic anticancer drug compound, such a compound having anticancer activity can be dissolved in water or in a biocompatible esterophilic solvent, and such a compound is a parent.
- a novel amphiphilic anticancer drug compound such a compound having anticancer activity can be dissolved in water or in a biocompatible esterophilic solvent, and such a compound is a parent.
- Another object of the present invention is to provide a method for synthesizing the amphiphilic anticancer drug compound.
- Another object of the present invention is to provide a composition comprising the amphiphilic anticancer drug, wherein the amphiphilic anticancer drug compound is used as an active ingredient, directly dissolved in water or physiological saline to prepare an injection, or The drug compound, cosolvent, surfactant and aqueous phase are made into micelles.
- Another object of the present invention is to provide an application of the compound in the preparation of an anticancer drug.
- the amphiphilic anticancer drug compound of the present invention is a water-soluble vitamin E derivative modified camptothecin or camptothecin derivative, and the compound can be dissolved in water or in a biocompatible lipophilic ester.
- Polyethylene glycol ester or amide, amphiphilic water-soluble vitamin E alkoxy polyethylene glycol ester or amide molecule through a linking group such as succinyl: succinyl; glutaryl: glutaryl, diglycoside: oxydiacetyl , diglycoloyl, diglycolyl; methylene carbonyl: methylene carbonyl, methylphosphonoyl, methylphosphono, etc.
- a linking group such as succinyl: succinyl; glutaryl: glutaryl, diglycoside: oxydiacetyl , diglycoloyl, diglycolyl; methylene carbonyl: methylene carbonyl, methylphosphonoyl, methylphosphono, etc.
- a water-soluble vitamin E derivative-modified amphiphilic anticancer drug compound the molecular formula of which can be expressed by the following formula I or II:
- R is a polyethylene glycol monoalkyl ether group (or alkoxy polyethylene glycol group);
- R' is a C1-C6 alkyl group, a C1-C6 alkoxy group or an aryl group
- X is -0-, -NH- or -NR' -, wherein R' is a C1-C6 alkyl group;
- R 2 is H, C1-C6 alkyl or -Si(CH 3 ) 2 tB -CH 2 N(CH 3 ) 2 , H 2
- amphiphilic anticancer drug compound of the present invention is a water-soluble vitamin E derivative having an amphiphilic polyethylene glycol monoalkyl ether group selected from the group consisting of water-soluble vitamin E alkoxy polyethylene glycol ester or Amide.
- the polyethylene glycol monoalkyl ether group R is common and preferably has the following groups:
- polyethylene glycol monobutyl ether group (-(CH 2 CH 2 0) n -CH 2 CH 2 CH 2 CH 3 ).
- Water-soluble vitamin E is a water-soluble derivative of vitamin E.
- the chemical name is: 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (6-hydroxy) -2,5,7,8-tetramethylchroman-2-carboxylic acid), like vitamin E, is an antioxidant whose structure is shown in Formula 3.
- Trolox has two optical isomers, R-(+)-trol OX (; chemical name R-C+)-6-hydroxy-2,5,7,8-tetramethylchromanol- 2-carboxylic acid, R-C+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) and S-(-)-trolox (chemical name S-(-)-6-hydroxyl -2,5,7,8-tetramethylchroman-2-carboxylic acid, S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid); Its racemate is ( ⁇ )-trol OX (chemical name ( ⁇ )-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, ( ⁇ ) -6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid).
- the water-soluble vitamin E in the amphiphilic anticancer drug compound of the present invention includes an optical isomer or a racemate thereof.
- the water-soluble vitamin E ester (trolox ester) is an ester compound formed by reacting water-soluble vitamin E (trolox) with alkoxy polyethylene glycol, and their chemical structures are shown in Formula 4.
- Water-soluble vitamin E ester also has two optical isomers, namely R-C+)-trolox ester (; chemical name R-C+)-6-hydroxy-2,5,7,8-tetra Alkoxydiethylenepyran-2-carboxylic acid alkoxypolyethylene glycol ester, R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid alkoxypolyethylene glycol ester) S- (-) -trolox ester (chemical name S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid alkoxy poly(ethylene) Alcohol ester, S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2- carboxylic acid alkoxypolyethylene glycol ester); its Xibuxiaofang is ( ⁇ )-trolox ester (chemical name ( ⁇ )-6-hydroxy-2,5,7,8-tetra Alkoxydiethylene
- Water-soluble vitamin amide (trolox amide) is an amide formed by the reaction of water-soluble vitamin E (trolox) with an alkoxy group (such as methoxy, ethoxy, propoxy, butoxy; polyethylene glycol amine) Compounds, their chemical structures are shown in Formula 5.
- Water-soluble vitamin amide also has two optical isomers, namely R-(+)-trolox amide (chemical name R-(+)-N-alkoxy polyethylene glycol-6-hydroxyl -2,5,7,8-tetramethylbenzodihydropyran-2-carboxamide, R-(+)-N-(alkoxypolyethylene glycol)-6-hydroxy-2,5,7,8-tetramethylchroman -2-carboxamide) and S- (-) -trolox ester (chemical name is S-(-)-N-alkoxy polyethylene glycol-6-hydroxy-2,5,7,8-tetramethyl Racemic acid, S-(-)-N-(alkoxypolyethylene glycol)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide, racemic
- the body is ( ⁇ )-trolox ester (chemical name is ( ⁇ )-N-alkoxy polyethylene glycol-6-hydroxy-2,5,7
- the anticancer drug active part of the amphiphilic anticancer drug compound molecule of the present invention is a known camptothecin or camptothecin derivative having anticancer activity, and its structural formula is as shown in Formula 6, wherein is 11, C1- C6 alkyl or -Si(CH 3 ) 2 tBu;
- R 3 is H, N0 2 , -CH 2 N(CH 3 ) 2 , H 2 or ⁇ / ; is H, OH, C1-C6 alkyl or
- the anticancer active moiety is preferably camptothecin, d ⁇ ,
- amphiphilic anticancer drug compound molecule of the present invention comprises an anticancer drug active moiety and a parental moiety which are covalently bonded to a amphiphilic anticancer drug compound via a linking group.
- the active part of the anticancer drug is a camptothecin or a camptothecin derivative
- the amphiphilic part is a water-soluble vitamin E alkoxy polyethylene glycol ester (or amide), a hydroxyl group of a camptothecin or a camptothecin derivative (phenolic hydroxyl group)
- the hydroxy group on the lactone ring and the phenolic hydroxyl group of the amphiphilic water-soluble vitamin E alkoxy polyethylene glycol ester (or amide) are respectively covalently bonded to the reactive functional group of the linking molecule to form the amphiphilic anticancer drug compound of the present invention.
- succinyl succinyl
- glutaryl glutaryl
- diglycidyl oxydiacetyl, Diglycoloyl, diglycolyl
- the novel anticancer of the present invention is compared with a parent compound having anticancer activity (a derivative of camptothecin or camptothecin such as 10-hydroxycamptothecin and 7-ethyl-10-hydroxycamptothecin) Pharmaceutical compounds have better hydrophilicity and lipophilicity (lipophilicity).
- the novel compound of the present invention comprises an anticancer drug parent compound moiety and an amphiphilic group moiety, and the anticancer drug parent molecule and the amphiphilic molecule are covalently bonded via an ester bond to form the amphiphilic anticancer drug compound of the present invention.
- the present invention also relates to a method for preparing a water-soluble vitamin E derivative-modified amphiphilic anticancer drug compound, comprising the steps of:
- the water-soluble vitamin E is esterified or amidated with an alkoxy polyethylene glycol or an alkoxy polyethylene glycol amine to form a water-soluble vitamin E ester or a water-soluble vitamin E amide;
- Water-soluble vitamin E ester or water-soluble vitamin E amide phenolic hydroxyl group is esterified or etherified with a linking molecule to form a derivative of a water-soluble vitamin E ester or a derivative of a water-soluble vitamin E amide;
- Step 2) The obtained derivative of the water-soluble vitamin E ester or the derivative of the water-soluble vitamin E amide, or the acid chloride product thereof, is esterified with camptothecin or a derivative thereof to form a water-soluble vitamin An E-derivative modified amphiphilic anticancer drug compound;
- the linking molecule is one of the following molecules containing two or more reactive groups:
- Phosphoryl dichloroalkyl, alkoxy or aryl ester 0 P0R 'C1 2 , wherein R' is C1-C6 alkyl, C1-C6 alkoxy or aryl;
- a halogenated carboxylic acid or a halogenated carboxylic acid ester Z-(CH 2 ;> n C00R', wherein n 1-10, Z is Cl, Br or I, and R' is a hospital base.
- the method comprises the steps of:
- DMAP 4-dimethylaminopyridine
- CMPI 2-chloro-1-methylpyridine gun iodide
- DCC ⁇ '-dicyclohexylcarbodiimide
- DMAP 4 -Dimethylaminopyridine
- Water-soluble vitamin oxime ester (3) or water-soluble vitamin amide amide (9) are connected to each other according to one of the following methods.
- the molecule undergoes esterification or etherification to form a derivative of a water-soluble vitamin E ester or a derivative of a water-soluble vitamin E amide:
- water-soluble vitamin E ester (3) or water-soluble vitamin E amide (9) with a base such as triethylamine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate
- a base such as triethylamine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate
- Step 2) The derivative of the water-soluble vitamin E ester obtained in a) or b) (4, 15a) or the derivative of the water-soluble vitamin E amide (10, 15a) is 4-dimethylaminopyridine (DMAP) And 2-chloro-1-methylpyridine gun iodide (CMPI) or hydrazine, ⁇ '-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) as catalysts, directly with Camptotheca
- DMAP 2-chloro-1-methylpyridine gun iodide
- DCC ⁇ '-dicyclohexylcarbodiimide
- DMAP 4-dimethylaminopyridine
- Step 3) Derivation of the obtained acid chloride product (5, 11 or 16), or the derivative of the water-soluble vitamin E ester obtained in the step c) or d) (19) or the water-soluble vitamin E amide (19), using a base (such as triethylamine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate) as a catalyst, directly reacting with camptothecin or a derivative thereof; producing a water-soluble vitamin E derivative modified amphiphilic resistance Cancer drug compound (6, 12, 13, 14, 17, 18, 20 or 21).
- a base such as triethylamine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate
- Formula 8 exemplifies a synthetic route in which water-soluble vitamin E (trolox) (1) is reacted with alkoxy polyethylene glycol (2) (exemplified by methoxypolyethylene glycol) to 4-dimethyl Aminopyridine (DMAP) and 2-chloro-1-methylpyridine gun iodide (CMPI) Catalyst, or ruthenium, ⁇ '-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) as catalysts to form water-soluble vitamin E ester (3), water-soluble vitamin E ester (3) reacting with a cyclic acid anhydride (such as succinic anhydride, glutaric anhydride, diglycolic anhydride, etc.) to form a water-soluble vitamin E ester using tin (II) 2-ethylhexanoate (or cesium carbonate) as a catalyst Derivative (4).
- DMAP 2-chloro-1-methylpyridine
- the water-soluble vitamin E ester (3) can also be reacted with an excess of a difunctional compound such as a dibasic acid such as succinic acid, glutaric acid or diglycolic acid, with 4-dimethylaminopyridine (DMAP) and 2 -Chloro-1-methylpyridine gun iodide (CMPI) or hydrazine, ⁇ '-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) as catalysts to form water-soluble vitamin oxime esters
- DMAP 4-dimethylaminopyridine
- CMPI 2 -Chloro-1-methylpyridine gun iodide
- DCC ⁇ '-dicyclohexylcarbodiimide
- DMAP 4-dimethylaminopyridine
- the derivative (4), the compound (4) is then reacted with a thionyl (di)chloro compound to form an acid chloride derivative of the water-soluble vitamin
- the derivative of the water-soluble vitamin oxime ester (4) can also be directly reacted with a 10-hydroxy-substituted camptothecin such as 10-hydroxycamptothecin or 7-ethyl-10-hydroxycamptothecin to 4-dimethyl Aminopyridine (DMAP) and 2-chloro-1-methylpyridine gun iodide (CMPI) or hydrazine, ⁇ '-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) as catalysts,
- DMAP 2-chloro-1-methylpyridine gun iodide
- DCC ⁇ '-dicyclohexylcarbodiimide
- DMAP 4-dimethylaminopyridine
- Synthetic route 1 for new anticancer drug compounds As shown in Formula 9, another synthetic method of the amphiphilic anticancer drug compound of the present invention, the acid chloride functional group of the compound (5) is reacted with camptothecin (or a derivative thereof by a base such as triethylamine) The hydroxyl group on the lactone ring reacts to form the novel anticancer drug compound (7) of the present invention.
- the derivative of the water-soluble vitamin E ester (4) can also be directly reacted with camptothecin (or a derivative thereof) with 4-dimethylaminopyridine (DMAP) and 2-chloro-1-methylpyridine gun iodide (CMPI) or hydrazine, ⁇ '-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) are used as catalysts to form the anticancer drug compound (7) of the present invention.
- DMAP 4-dimethylaminopyridine
- CMPI 2-chloro-1-methylpyridine gun iodide
- DCC ⁇ '-dicyclohexylcarbodiimide
- DMAP 4-dimethylaminopyridine
- a further synthesis method of the amphiphilic anticancer drug compound of the present invention is as shown in Formula 10, and the water-soluble vitamin E (trolox) (1) is reacted with the alkoxy polyethylene glycol amine (8) to ⁇ , ⁇ ' - Dicyclohexylcarbodiimide (DCC) is a coupling agent to form a water-soluble vitamin amide (9), a water-soluble vitamin amide (9) and a cyclic anhydride (such as succinic anhydride, glutaric anhydride, digan Alkyd anhydride, etc.) reaction, using tin (II) 2-ethylhexanoate as a catalyst to form a derivative of water-soluble vitamin amide (10), and then compound (10) with camptothecin, 10-hydroxycamptothecin or Reaction of 7-ethy
- Compound (10) can also react with thionyl (di) chloride to form a water-soluble vitamin E ester.
- the acid chloride derivative (11), and then the acid chloride functional group of the compound (11) is selectively substituted with a 10-hydroxycamptothecin such as 10-hydroxycamptothecin or 7-ethyl-10-hydroxycamptothecin Reaction, or reacting with a hydroxyl group on a lactone ring of camptothecin (or a derivative thereof), using a base as a catalyst (such as triethylamine) to form an amphiphilic anticancer drug compound of the present invention (12), (13) And (14).
- a 10-hydroxycamptothecin such as 10-hydroxycamptothecin or 7-ethyl-10-hydroxycamptothecin Reaction
- a base such as a catalyst
- the water-soluble vitamin E ester or amide derivative (15a) can also be directly mixed with a 10-hydroxy-substituted camptothecin (such as 10-hydroxycamptothecin or 7-ethyl-10-hydroxycamptothecin) or camptothecin Reaction with 4-dimethylaminopyridine (DMAP) and 2-chloro-1-methylpyridine gun iodide (CMPI) or hydrazine, ⁇ '-two
- DMAP 4-dimethylaminopyridine
- CMPI 2-chloro-1-methylpyridine gun iodide
- CMPI 2-chloro-1-methylpyridine gun iodide
- HC cyclohexylcarbodiimide
- DMAP 4-dimethylaminopyridine
- Formula 13 describes a further synthesis method of the amphiphilic anticancer drug compound of the present invention, using a base (such as triethylamine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate) as a catalyst, water-soluble vitamin E ester 3 or water-soluble
- a base such as triethylamine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate
- water-soluble vitamin E ester 3 water-soluble
- the reaction of a vitamin E amide (9) with an alkylphosphonic dichloride (such as methylphosphonoyl dichloride) or an arylphosphonochloride (such as phenylphosphonic dichloride) to form a water-soluble vitamin E ester or amide (19).
- the compound (19) is directly reacted with camptothecin or a derivative thereof; and the amphiphilic anticancer drug compounds (20) and (21) modified by the water-soluble vitamin E derivative are produced.
- R i -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH ;
- R 2 H, -CH 2 CH 3
- the present invention also relates to a formulation formulation of the novel amphiphilic anticancer drug, which is directly soluble in water or physiological saline.
- the injection can also be made into a micelle preparation.
- the components of the micelle preparation include a novel anticancer drug compound, a solvent, and one or more surfactants and an aqueous phase.
- the pharmaceutical compound may be present in the formulation in an amount of from about 0.005% to about 5.0% by weight; preferably from about 0.01% to about 3.5% by weight; more preferably, the weight percent of the pharmaceutical compound in the formulation is about 0.1% to 2.0%.
- amphiphilic anticancer drug compound micelle preparation comprising:
- the micelle formulation includes the amphiphilic anticancer drug compound of the present invention, one or more surfactants, one or more solvents, and an aqueous phase.
- representative surfactants include:
- Polyethylene glycol surfactants such as polyoxyethylene castor oil EL (Cremophor EL;), Tween series of surfactants.
- Phospholipids such as lecithin and pegylated phospholipids.
- TPGS Polyethylene glycol vitamin E derivatives, such as d-a-tocopherol polyethylene glycol 1000 succinate (TPGS).
- Polyoxyethylene polyoxypropylene block copolymer Block copolymer of P0L0XAMERS or PLURONICS (H(OCH 2 CH 2 ) a (OC 3 H 6 ) b (OCH 2 CH 2 ) a OH).
- Representative solvents include:
- Ethanol polyethylene glycol, propylene glycol, glycerin, N-methylpyrrolidone, and the like.
- Polyethylene glycol (PEG) is hydrophilic, and the chemical structure of the repeating unit is -CH 2 CH 2 0-, and the formula is H-(CH 2 CH 2 ) n -OH.
- the molecular weight range is generally from 200 to 10,000. .
- the pharmaceutical compound is present in the formulation in an amount of from about 0.005% to about 5.0% by weight; preferably from about 0.01% to about 3.5% by weight; more preferably, the weight percent of the pharmaceutical compound in the formulation is about It is 0.1% to 2.0%.
- Suitable surfactants are present in the micelle formulation in an amount of from about 1% to about 10%, preferably from 2% to 6%; more preferably from 4% to 5%.
- the micelle formulation also includes other ingredients such as the solvents mentioned above.
- the micelle formulation comprises polyethylene glycol and a lower alkyl alcohol (e.g., ethanol).
- the solvent is about 2% to 20% by weight of the formulation.
- the aqueous phase is included in the micelle formulation.
- the aqueous phase comprises deionized water.
- the aqueous phase comprises physiological saline.
- the invention also provides the use of the newly invented pharmaceutical compound, that is, the use of the water-soluble vitamin E derivative-modified amphiphilic anticancer drug compound for preparing an anticancer drug.
- the pharmaceutical compounds of the invention are useful in the preparation of a medicament for the treatment of cancer.
- the pharmaceutical compound of the present invention can be used for the treatment of cancer including the blood system such as leukemia, lymphoma, myeloma; and non-blood cancer, such as solid tumor cancer (such as breast cancer, ovarian cancer, pancreatic cancer, colon cancer, rectal cancer, non- Small cell lung cancer, bladder cancer), sarcoma and glioma.
- the efficacy and toxicity of the pharmaceutical compounds of the present invention are determined by in vitro cell or in vivo animal experiments, such as ED50 (50% effective dose, half effective dose: 50% of the dose in the subject), LD50 (50% lethal dose) , a median lethal dose: kills half of the test subject's sputum.) GI GI50 (concentration of the anti-cancer drug that inhibits the growth of cancer cells by 50%, inhibits 50% of the concentration of the drug in the subject).
- the ratio of the median lethal dose (LD50) / half effective dose (ED50) is usually referred to as the treatment index to indicate the safety of the drug. Drugs with a large therapeutic index are safer than drugs with a small therapeutic index.
- the newly invented anticancer drug compound aims to improve the therapeutic index and the safety of the drug while also improving the therapeutic effect.
- the dose of the drug obtained from in vitro cell experiments and in vivo animal experiments can be used to formulate a dose range for the human body.
- the dose of such a compound is preferably in the range of ED50 with little or no toxicity.
- the dosage change will generally depend on the dosage form employed, the sensitivity of the patient, and the route of administration.
- a conventional dose of topotecan is 0.2-1.5 mg/m 2
- a conventional dose of irinotecan is 100 mg-350 mg/m.
- the pharmaceutical compounds of the invention may be used alone or in combination with one or more other therapeutic agents.
- the pharmaceutical compounds of the invention may be used with the following therapeutic agents, including but not limited to: androgen inhibitors, such as flutamide and luprolide; antiestrogens Tamoxifen
- tamoxifen antimetabolites and cytotoxic drugs, such as daunorubicin, pentafluorouracil
- adriamycin carmustine, lomustine, cytarabine, cyclophosphamide, doxorubicin, estramustine Alkretamine, hydroxyurea, ifosfamide, procarbazine, mutamycin, busulfan, mitoxantrone Mitoxantrone), carboplatin), cisplatin, streptozocin, bleomycin, dactinomycin, and idamycin; hormones, Such as medroxyprogesterone, ethinyl estradiol estradiol, leuprolide, megestrol, octreotide, diethylstilbestrol, Chlorotrianisene, etoposide, podophyllotoxin
- campophyllotoxin and goserelin
- nitrogen mustard derivatives such as melphalan, melidine Chlorambucil and thiotepa
- steroids such as betamethasone
- antitumor drugs such as live Mycobacterium bovis; dicarbazine , asparaginase, leucovorin, mitotane, vincristine, vinblastine, and taxotere.
- the invention covalently combines a drug compound molecule camptothecin or camptothecin derivative having anticancer activity with a water-soluble vitamin E alkoxy polyethylene glycol ester or amide through a linking group to obtain a water-soluble vitamin E derivative.
- a modified amphiphilic anticancer drug compound comprising an anticancer drug active moiety and a parental moiety, both soluble in water and in a biocompatible lipophilic solvent.
- the novel anticancer drug compound of the invention has high anticancer activity, has good solubility and stability, and can improve the sustained action time (half-life) of camptothecin or its derivative under physiological conditions in vivo and Efficacy, reduce its toxic side effects.
- the pharmaceutical compound can be formulated into an injection or a micelle preparation, and is widely used in the treatment of cancers of the blood system and non-hematological systems.
- the invention can modify various camptothecin and its derivatives, broaden the application fields of camptothecin and its derivatives, and provide a new method and approach for the clinical application of camptothecin and its derivatives.
- Figure 1 Mass spectrum of R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid methoxyheptadecyl glycol ester.
- Figure 2 Nuclear magnetic resonance spectrum of R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid methoxyheptaethylene glycol ester.
- Figure 6 7-Ethyl-10-hydroxycamptothecin R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid heptaethylene glycol Nuclear magnetic resonance spectrum of monomethyl ether ester-6-succinate.
- the synthesis of the amphiphilic anticancer drug compound comprises the following steps:
- reaction solution was added to 100 mL of ethyl acetate, stirred, and the mixture was washed three times with 50 mL of 0.1 N HCl solution, and then washed three times with 50 mL of water, and the organic phase was dried over anhydrous magnesium sulfate to remove sulfuric acid.
- Magnesium concentrate the solution to 10 mL, separate the column (230-400 mesh silica gel as stationary phase, hexane and acetone mixture as eluent) to obtain 962 mg R-C+)-6-hydroxy-2. 5,7,8-tetramethylchroman-2-carboxylic acid heptaethylene glycol monomethyl ether-6-succinic acid monoester, yield 71.5%.
- reaction solution was added to 100 mL of ethyl acetate, and the mixture was washed three times with 50 mL of water, and the organic phase was dried over anhydrous magnesium sulfate, then magnesium sulfate was removed, and then concentrated to 10 mL, column separation (230-400 mesh silica gel is the stationary phase, the mixture of hexane and acetone is the eluent) 277 mg 7-ethyl-10-hydroxycamptothecin R-(+)-6-hydroxy-2,5, 7,8-Tetramethylchroman-2-carboxylic acid heptaethylene glycol monomethyl ether-6-succinate, yield 53%.
- the synthesis of the amphiphilic anticancer drug compound comprises the following steps:
- reaction solution was added to 100 mL of ethyl acetate, the solid matter was removed, and the solution was concentrated to 10 mL, and the column was separated (230-400 mesh silica gel as a stationary phase, and a mixture of hexane and acetone was rinsed).
- Liquid) 661 mg 7-ethyl-10-hydroxycamptothecin N-methoxy heptaethylene glycol amine R- (+) _6-hydroxy-2, 5, 7, 8-tetramethyl benzo Dihydropyran-2-carboxamide-6-succinate, yield 63.2%.
- camptothecin R-( ⁇ )-6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid heptaethylene glycol monomethyl ether ester-6-oxyacetate yield 87. 0%.
- Camptothecin ( ⁇ )-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid heptaethylene glycol monomethyl ether-6-A Synthesis of phosphinyl esters
- an injection solution made of water or physiological saline, and a micelle liquid prepared by using a surfactant are included.
- the preparation formulation contains various amphiphilic anticancer drug compounds of the invention, and the content of each component in the formulation is in weight percent Ratio calculation.
- amphiphilic anticancer drug compound of the present invention can be prepared as follows according to the need of 7-ethyl-10-hydroxycamptothecin R_(+)-6-hydroxy-2, 5, 7, 8-tetra
- benzyl hexahydropyran-2-carboxylic acid methoxyheptadecyl-6-succinate includes:
- the resulting injection was filtered through a 0.2 micron filter and placed in a sterile glass vial.
- the resulting injection was filtered through a 0.2 micron filter and placed in a sterile glass vial.
- the prepared micelles were filtered through a 0.2 micron filter and placed in a sterile glass vial.
- Example 9 In vitro cytotoxicity assay of amphiphilic anticancer drug compounds
- the XTT method was used to detect the GI50 value of the amphipathic anticancer drug compound of the present invention inhibiting human ovarian cancer (A2780s), colon cancer cells (HT-29), liver cancer HePG 2 and lung cancer cells (A549) cells.
- A2780s human ovarian cancer
- HT-29 colon cancer cells
- A549 liver cancer HePG 2 and lung cancer cells
- concentration of the drug that inhibits 50% growth of cancer cells and compared with the anticancer drug irinotecan (irinotican), the in vitro cytotoxicity of the drug compound was evaluated.
- the experimental results show that the anticancer drug compound of the invention has obvious proliferation inhibition effect on human ovarian cancer (A2780S) cells, colon cancer cells (HT-29), liver cancer (HePG 2 ) cells and lung cancer cells (A549), and With the increase of drug concentration, its inhibition on cell proliferation is enhanced, showing a dose-dependent effect.
- the anticancer drug compound of the present invention has more obvious inhibitory effects on human ovarian cancer, colon cancer, liver cancer and lung cancer cells.
- the anticancer drug compound of the present invention inhibits the proliferation of human ovarian cancer cells (A2780S) colon cancer cells (HT-29), liver cancer (HePG 2 ) cells and lung cancer cells (A549), and is a class of potentially anti-human ovarian cancer.
- Drug compounds for colon cancer, liver cancer and lung cancer Taking MXL-004 as an example, the GI50 value thereof is shown in Table 1, and the anticancer drug compound of the present invention has a significantly reduced GI50 value as compared with irinotecan.
- MTT assay Take cells in logarithmic growth phase, adjust the cell density to 10 5 /mL, inoculate in 96-well culture plate, 100 ⁇ 7 well, change the culture medium after 18h of cell culture, and add different concentrations of drug samples. 150 ⁇ ! 7 holes.
- Three sets of holes are provided in each of the above groups.
- the cells were further cultured for 72 h, and 15 ⁇ 7 wells of MTT (5 mg/mL) solution were added, and the culture was continued for 4 h. The supernatant was aspirated, PBS 150 ⁇ 7 wells were added, and the mixture was shaken and mixed for 10 min. After the crystals were completely dissolved, the absorbance (D) of each well at a wavelength of 490 nm was detected on a microplate reader.
- Anticancer drug MXL-004 Irinotecan Ovarian cancer cells (A2780s) 0.009 ⁇ 19.30 ⁇ Colon cancer fines ( HT-29 ) 0.171 ⁇ 15.19 ⁇ Liver cancer cells ( HePG 2 ) 2.552 ⁇ 9.442 ⁇ Lung cancer fines ( A549 ) 1.378 ⁇ 58.07 ⁇
- MXL-004 7-ethyl-10-hydroxycamptothecin R-(+)-6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-carboxylic acid methoxy Heptaethylene glycol ester-6-succinate.
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Abstract
本发明公开了一种水溶性维生素E衍生物修饰的双亲性抗癌药物化合物,具有下式I或II的结构。抗癌药物活性部分喜树碱或喜树碱衍生物,和双亲部分水溶性维生素E烷氧基聚乙二醇酯或酰胺,通过连接基团共价结合形成所述的双亲性抗癌药物化合物。本发明还涉及所述药物化合物的制剂、制备方法及应用。
Description
水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物 和制剂、 该化合物的制备方法及应用
技术领域
本发明涉及一种新的抗癌药物化合物及其制备方法和应用, 特别是涉及一种水溶性维 生素 E衍生物修饰的双亲性抗癌药物化合物, 包含该化合物的制剂、 制备方法以及作为抗 癌药物的应用。
背景技术
许多具有抗癌活性的化合物由于不溶于水和 (或)其它生物相容性溶剂,或在水和生物相 容性溶剂中稳定性差已成为药物开发的一个障碍, 往往导致药物开发时间延迟。 据估计, 多达百分之四十经筛选出的具有潜在价值的候选药物化合物由于其水溶性差而被拒绝进入 制剂研究与开发阶段, 并且百分之三十的现有药物是难溶性的。 当前有数种技术正在研究 和开发之中,以解决药物化合物溶解度差的问题, 这些技术包括增加溶解度的配位剂技术, 纳米颗粒技术, 微乳液技术, 增强溶解度的制剂技术, 脂溶性和水溶性前药技术, 和新型 的聚合物载药技术等。
喜树碱 (20(s)-camptothecin, 式 1, 1 ) 及其衍生物具有很好的抗肿瘤活性, 是一类重 要的 DNA拓扑异构酶 I (Top I) 抑制剂, 它们能够与 Top I-DNA可裂解复合物结合, 形成 CPT-Top I-DNA三元络合物, 从而稳定可裂解复合物, 导致细胞死亡。 但因其在水和其他 生物相容性溶剂中溶解性差和毒性大的问题, 最终未能进入临床。 为了提高药物的水溶性 并保留母体化合物的抗肿瘤特性, 已合成了许多喜树碱衍生物。 然而, 只有衍生物拓扑替 康 (Topotecan, 式 1, 2) 和伊立替康 (Irinotrcan, 式 1, 3 ) 被美国食品与药物管理局批准 进入临床并已经上市, 分别用于治疗卵巢癌、 肺癌和直肠癌。 但是, 拓扑替康和伊立替康 具有明显的缺点, 包括在体内半衰期短和毒副作用大等。 目前, 有多个喜树碱衍生物处于 临床研究阶段。
此外, 喜树碱分子中的 E内酯环是喜树碱及其衍生物抗癌活性所必需的功能基, 在碱 性或生理条件下会迅速开环而导致活性的消失 (式 2)。 实验证明, 在血浆中内酯环结构和开 环结构存在平衡, 且人类血浆蛋白优先与开环结构分子结合, 促使平衡向开环形式转移, 导致药物在血浆中有效浓度降低, 进而降低了该类化合物的抗肿瘤活性。 进一步的研究证 实, 开环结构式是导致不良反应的根源, 如引起骨髓抑制、 呕吐和腹泻等。
1 , 20(S)-camptothecin: R=R =R2=H
2, topotecan: R=〇H, R1=(CH3)2NCH2-, R2=H
3, irinotecan: R-|=H, R2=Et,
R= N- N-C-O-
. II
〇
喜树碱、 拓扑替康 (topotecan)和伊立替康 (irinotecan)的化学结构 <
式 2 喜树碱在碱性或生理条件下的内酯环结构和开环结构间的平衡。 为了提高药物的溶解度, 乳液(Emulsion)和胶束(micelle)等技术被广泛用于水溶性 差或不溶于水的药物的制剂, 但是到目前为止还没有一种制剂技术可以适用于喜树碱, 因 为它在水和有机溶剂中溶解性极差。 因此, 仍然需要研发新的喜树碱衍生物, 既有较高的 抗癌活性又有较好的溶解性和稳定性。
本发明提供了一系列新的双亲性喜树碱衍生物, 它们在水和生物相容性的有机溶剂中 都有较好的溶解性, 可以直接溶于水或生理盐水, 或采用制剂技术制成胶束等药物剂型。 本发明的新的药物化合物可望提高药物在体内的持续时间 (半衰期) 和疗效, 以及降低其 副作用。
发明内容
本发明的目的在于提供一种新的双亲性抗癌药物化合物, 这类具有抗癌活性的化合物 既可以溶于水, 也可以溶于生物相容性的亲酯性溶剂, 这类化合物是双亲性的水溶性维生 素 E烷氧基聚乙二醇酯或酰胺修饰的喜树碱或喜树碱衍生物。
本发明的另一目的在于提供所述的双亲性抗癌药物化合物的合成方法。
本发明的另一目的还在于提供包含所述的双亲性抗癌药物的组合物, 以所述的双亲性 抗癌药物化合物为活性成分, 直接溶于水或生理盐水制成注射液, 或者将药物化合物、 共 溶剂、 表面活性剂和水相制成胶束液。
同时, 本发明的另一目的还在于提供所述化合物在制备抗癌药物中的应用。
本发明的双亲性抗癌药物化合物, 是一种水溶性维生素 E衍生物修饰的喜树碱或喜树 碱衍生物, 这类化合物既可以溶于水也可以溶于生物相容性的亲酯性溶剂, 所述的化合物 含有抗癌药物活性部分和双亲部分, 抗癌药物活性部分是具有抗癌活性的药物化合物分子 喜树碱或喜树碱衍生物, 双亲部分是水溶性维生素 E烷氧基聚乙二醇酯或酰胺, 双亲性水 溶性维生素 E烷氧基聚乙二醇酯或酰胺分子通过连接基团(如琥珀基: succinyl; 戊二酰基: glutaryl,二甘酉享酉先基: oxydiacetyl, diglycoloyl, diglycolyl;亚甲基羰基: methylene carbonyl, 甲基膦酰基, methylphosphono等)与抗癌药物化合物喜树碱(camptothecin)或其衍生物分 子共价结合形成本发明的双亲性抗癌药物化合物。
实现本发明目的采用以下技术方案: 一种水溶性维生素 E衍生物修饰的双亲性抗癌药 物化合物, 其分子式可以用以下通式 I或 II表示:
II
其中, R是聚乙二醇单烷基醚基 (或烷氧基聚乙二醇基);
是链接基团, 为下述基团之一:
a) -(C=0)-;
b) -P(=0)(R )-, 其中 R'是 C1-C6烷基、 C1-C6烷氧基或芳基;
c) -(C=0)(CH2)n(C=0)-, 其中 n = 1 - 10;
d) -(C=0)CH2-0-CH2(C=0)- ;
e) -(CH2)n(C=0)-, 其中 n = 1 - 10;
X是 -0-、 -NH-或 -NR' -, 其中 R'是 C1-C6烷基;
a)聚乙二醇单甲醚基 (-(CH2CH20)n-CH3);
b)聚乙二醇单乙醚基 (-(CH2CH20)n-CH2CH3);
c)聚乙二醇单丙醚基 (-(CH2CH20)n-CH2CH2CH3);
d)聚乙二醇单丁醚基 (-(CH2CH20)n-CH2CH2CH2CH3)。
其中 n = 1-200。
水溶性维生素 E (trolox) 是维生素 E 的水溶性衍生物, 化学名称为: 6-羟基 -2,5,7,8- 四甲基苯并二氢吡喃 -2-羧酸(6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), 像维 生素 E—样是一种抗氧化剂,其结构如式 3所示。 Trolox有两种旋光异构体,即 R-(+)-trolOX (;化学名为 R-C+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸, R-C+)-6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxylic acid)和 S- (-) -trolox (化学名为 S-(-)-6-羟基 -2,5,7,8-四甲基苯 并二氢吡喃 -2-羧酸, S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid);其外消旋 体为(±)-trolOX (化学名为(±)-6-羟基 -2,5,7,8-四 甲基苯并二氢吡喃 -2-羧酸, (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid)。
A B C 式 3 水溶性维生素 E (trolox)的化学结构, 其中 A: R-(+)-Trolox; B: S- (-) -Trolox; C: (士) -Trolox。
本发明的双亲性抗癌药物化合物中的水溶性维生素 E包括其光学异构体或外消旋体。 水溶性维生素 E 酯 (trolox ester) 是水溶性维生素 E (trolox) 与烷氧基聚乙二醇反应 生成的酯类化合物, 它们的化学结构如式 4所示。 水溶性维生素 E 酯 (trolox ester) 同样 有两种旋光异构体, 即 R-C+)-trolox ester (;化学名为 R-C+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡 喃 -2-羧酸烷氧基聚乙二醇酯, R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid alkoxypolyethylene glycol ester) 和 S- (-) -trolox ester (化学名为 S-(-)-6-羟基 -2,5,7,8-四甲基苯 并二氢吡喃 -2-羧酸烷氧基聚乙二醇酯, S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2- carboxylic acid alkoxypolyethylene glycol ester);其夕卜消方 体为 (±)-trolox ester (化学名为 (±)-6- 羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸烷氧基聚乙二醇酯, (±)-6-hydrOXy-2,5,7,8- tetramethylchroman-2-carboxylic acid alkoxypolyethylene glycol ester)。分子结构中的取代基 R 优选聚乙二醇单甲醚基 [-(CH2CH20)n-CH3]、 聚乙二醇单乙醚基 [-(CH2CH20)n-CH2CH3]、 聚 乙 二 醇 单 丙 醚 基 [-(CH2CH20)n-CH2CH2CH3] 或 聚 乙 二 醇 单 丁 醚 基 [-(CH2CH20)n-CH2CH2CH2CH3], 其中 n = 1-200。
A B C 式 4. 水溶性维生素 E (trolox) 烷氧基聚乙二醇酯的化学结构, 其中 A: R-(+)-trolox ester; B: S- (-) -trolox ester; C: (±)-trolox ester。
水溶性维生素 E酰胺 (trolox amide) 是水溶性维生素 E (trolox) 与烷氧基(如甲氧基、 乙氧基、 丙氧基、 丁氧基;)聚乙二醇胺反应生成的酰胺类化合物, 它们的化学结构如式 5所 示。水溶性维生素 E酰胺(trolox amide) 同样有两种旋光异构体, 即 R-(+)-trolox amide (化 学名为 R-(+)-N-烷氧基聚乙二醇 -6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-甲酰胺, R- (+) -N-(alkoxypolyethylene glycol)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide)禾口 S- (-) -trolox ester (化学名为 S-(-)-N-烷氧基聚乙二醇 -6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2- 甲酉先胺, S- (-) -N-(alkoxypolyethylene glycol)-6-hydroxy-2,5,7,8-tetramethylchroman-2- carboxamide), 其外消旋体为 (±)-trolox ester (化学名为 (±)-N-烷氧基聚乙二醇 -6-羟基 -2,5,7,8- 四甲基苯并二氢吡喃 -2-甲酰胺, (士) -N-(alkoxypolyethylene glycol)-6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxamide)。 分子结构中的官能团 R 优选聚乙二醇单甲醚基 [-(CH2CH20)„-CH3]、 聚乙二醇单乙醚基 [-(CH2CH20)n-CH2CH3]、 聚乙二醇单丙醚基 [-(CH2CH20)n-CH2CH2CH3] 或聚乙二醇单丁醚基 [-(CH2CH20)n-CH2CH2CH2CH3], 其中 n = 1-200; 1^为11或 C1-C6烷基。
A B C
式 5. 水溶性维生素 E (trolox) 烷氧基聚乙二醇酰胺的化学结构, 其中 A: R-(+)-trolox amide ; B: S- (-) -trolox amide; C: (±)-trolox amide。
本发明的双亲性抗癌药物化合物分子中的抗癌药物活性部分是已知的具有抗癌活性的 喜树碱或喜树碱衍生物, 其结构式如式 6所示, 其中 是11、 C1-C6烷基或 -Si(CH3)2tBu;
— H2CN NCH3
式 6 喜树碱和喜树碱衍生物分子的化学结构。
本发明的双亲性抗癌药物化合物分子中, 抗癌活性部分优选喜树碱(1, camptothecin), d丄、
10-羟基喜树碱 (2, 10-hydroxycamptothecin ) 禾 P 7-乙基 -10-羟基喜树碱 (3, 7-ethyl-10- hydroxycamptothecin ), 其分子结构如式 7所R丄 .示。
1 , 20(S)-camptothecin: R-, = R2 = H
2, 10-hydroxycamptothecin: R-ι = OH, R2 = H
3, 7-ethyl-10-hydroxycamptothecin: R-| = OH, R2 = Et
式 7. 喜树碱和喜树碱衍生物分子的优选的化学结构。 本发明的双亲性抗癌药物化合物分子包含抗癌药物活性部分与双亲部分, 这两个部分 通过连接基团共价结合成双亲性抗癌药物化合物。 抗癌药物活性部分是喜树碱或喜树碱衍 生物, 双亲部分是水溶性维生素 E烷氧基聚乙二醇酯(或酰胺), 喜树碱或喜树碱衍生物的 羟基 (酚羟基或内酯环上的羟基) 及双亲水溶性维生素 E烷氧基聚乙二醇酯 (或酰胺) 的 酚羟基分别与连接分子的活性官能团共价结合生成本发明的双亲性抗癌药物化合物。
所述的连接基团是由含两个或两个以上活性基团的连接分子所提供, 例如: 乙二酰氯 (0=CC12)提供羰基 -(C=0)-, 磷酰二氯酯(0=P0R'C12)提供 -P(=0)(OR')-基团, 卤代羧酸 酯提供亚烷基羰基 (_(CH2)nCO-), 不同的二元羧酸 (CH2)n(COOH)2或环状酸酐
与具有抗癌活性的母体化合物 (喜树碱或喜树碱的衍生物, 如 10-羟基喜树碱和 7-乙 基 -10-羟基喜树碱) 相比, 本发明的新的抗癌药物化合物具有更好的亲水和亲脂性 (亲油 性)。 本发明的新化合物包含一个抗癌药物母体化合物部分和双亲性基团部分, 抗癌药物母 体分子与双亲性分子通过一个酯键以共价键结合成为本发明的双亲性抗癌药物化合物。
本发明还涉及一种所述的水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物的制备 方法, 包括以下步骤:
1 )水溶性维生素 E与烷氧基聚乙二醇或烷氧基聚乙二醇胺发生酯化或酰胺化反应, 生 成水溶性维生素 E酯或水溶性维生素 E酰胺;
2)水溶性维生素 E酯或水溶性维生素 E酰胺的酚羟基与连接分子发生酯化或醚化反应, 生成水溶性维生素 E酯的衍生物或水溶性维生素 E酰胺的衍生物;
3 ) 步骤 2)所得到的水溶性维生素 E酯的衍生物或水溶性维生素 E酰胺的衍生物, 或 者它们的酰氯化产物, 与喜树碱或其衍生物发生酯化反应, 生成水溶性维生素 E衍生物修 饰的双亲性抗癌药物化合物;
所述的连接分子为含有两个以上活性基团的下列分子之一:
( 1 ) 乙二酰氯 0=CC12 ;
(2) 磷酰二氯烷基酯、烷氧基酯或芳基酯 0=P0R'C12, 其中 R'是 C1-C6烷基、 C1-C6 烷氧基或芳基;
(3 ) 二元羧酸 CCH2 ;C00H;h或环状酸酐 x。y, 其中 n = 1-10;
(4) 二甘醇酸或二甘醇酸酐;
( 5 ) 卤代羧酸或卤代羧酸酯 Z-(CH2;>nC00R', 其中 n = 1-10, Z为 Cl、 Br或 I, R'为 院基。
更具体和优化地, 所述的方法包括以下步骤:
1 ) 以 4-二甲氨基吡啶(DMAP)和 2-氯 -1-甲基吡啶鎗碘化物 (CMPI)为催化剂, 或以 Ν,Ν'-二环己基碳化二亚胺 (DCC) 和 4-二甲氨基吡啶 (DMAP)为催化剂, 水溶性维生素 Ε
( 1 ) 与烷氧基聚乙二醇 (2 ) 反应, 生成水溶性维生素 Ε酯 (3 ) ; 或以 Ν,Ν'-二环己基碳化 二亚胺 (DCC) 为催化剂, 水溶性维生素 Ε ( 1 ) 与烷氧基聚乙二醇胺 (8 ) 反应, 生成水 溶性维生素 Ε酰胺 (9)。
2) 水溶性维生素 Ε酯(3 )或水溶性维生素 Ε酰胺(9 )分别按以下方法之一, 与连接
分子发生酯化或醚化反应, 生成水溶性维生素 E酯的衍生物或水溶性维生素 E酰胺的衍生 物:
a) 水溶性维生素 E酯 (3) 或水溶性维生素 E酰胺 (9) 以 2-乙基己酸锡 (II) 或碳酸 化剂, 与环状酸酐 x。
铯为催 y或二甘醇酸酐反应; 或者以 4-二甲氨基吡啶 (DMAP) 和 2-氯 -1-甲基吡啶鎗碘化物 (CMPI) 或 Ν,Ν'-二环己基碳化二亚胺 (DCC) 和 4-二甲氨基 吡啶 (DMAP) 为催化剂, 与过量的二元羧酸 (CH2)n(COOH)2或二甘醇酸反应, 分别生成水 溶性维生素 E酯的衍生物 (4) 或水溶性维生素 E酰胺的衍生物 (10);
b) 水溶性维生素 E酯 (3) 或水溶性维生素 E酰胺 (9) 以碱 (如三乙胺, 吡啶, 碳酸 钠, 碳酸钾, 碳酸铯) 为催化剂, 与卤代羧酸反应生成水溶性维生素 E酯的衍生物 (15a, R' =H)或水溶性维生素 E酰胺的衍生物(15a),或与卤代羧酸酯反应,产物(15b, R'=alkyl) 脱烷基后生成水溶性维生素 E酯的衍生物 (15a) 或水溶性维生素 E酰胺的衍生物 (15a);
c) 水溶性维生素 E酯 (3) 或水溶性维生素 E酰胺 (9) 以碱 (如三乙胺, 吡啶, 碳酸 钠, 碳酸钾, 碳酸铯) 为催化剂, 与烷基膦酰二氯、 烷氧基膦酰二氯或芳基膦酰二氯反应, 生成水溶性维生素 E酯的衍生物 (19) 或水溶性维生素 E酰胺的衍生物 (19);
d) 水溶性维生素 E酯 (3) 或水溶性维生素 E酰胺 (9) 以碱 (如三乙胺或吡啶) 为催 化剂, 与乙二酰氯反应, 生成水溶性维生素 E酯的衍生物或水溶性维生素 E酰胺的衍生物。
3 ) 步骤 2) 中 a)或 b)所得到的水溶性维生素 E酯的衍生物 (4、 15a) 或水溶性维生素 E酰胺的衍生物(10、 15a)与亚硫酰 (二)氯化合物反应分别生成酰氯化产物(5、 11或 16)。
4) 步骤 2) 中 a)或 b)所得到的水溶性维生素 E酯的衍生物 (4、 15a) 或水溶性维生素 E酰胺的衍生物(10、 15a)以 4-二甲氨基吡啶(DMAP)和 2-氯 -1-甲基吡啶鎗碘化物(CMPI) 或 Ν,Ν'-二环己基碳化二亚胺 (DCC) 和 4-二甲氨基吡啶 (DMAP) 为催化剂, 直接与喜树 碱或其衍生物反应, 生成水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物(6、 12、 13、 14、 17或 18); 或
5 ) 步骤 3 )所得到酰氯化产物 (5、 11或 16), 或步骤 2) 中 c)或 d)所得到的水溶性维 生素 E酯的衍生物 (19) 或水溶性维生素 E酰胺的衍生物 (19), 以碱 (如三乙胺, 吡啶, 碳酸钠, 碳酸钾, 碳酸铯) 为催化剂, 直接与喜树碱或其衍生物反应; 生成水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物 (6、 12、 13、 14、 17、 18、 20或 21 )。
式 8例举了一种合成路线, 水溶性维生素 E (trolox) ( 1 ) 与烷氧基聚乙二醇 (2) (以 甲氧基聚乙二醇为例)反应,以 4-二甲氨基吡啶 (DMAP)和 2-氯 -1-甲基吡啶鎗碘化物 (CMPI)
为催化剂, 或以 Ν,Ν'-二环己基碳化二亚胺 (DCC) 和 4-二甲氨基吡啶 (DMAP)为催化齐 U, 生成水溶性维生素 E酯 (3), 水溶性维生素 E酯 (3) 再与环状酸酐 (如琥珀酸酐、 戊二酸 酐、 二甘醇酸酐等) 反应, 以 2-乙基己酸锡 (II) (或碳酸铯) 为催化剂, 生成水溶性维生 素 E酯的衍生物 (4)。 水溶性维生素 E酯 (3)也可与过量的具有双官能团的化合物 (如琥 珀酸、 戊二酸、 二甘醇酸等二元酸) 反应, 以 4-二甲氨基吡啶 (DMAP) 和 2-氯 -1-甲基吡 啶鎗碘化物 (CMPI) 或 Ν,Ν'-二环己基碳化二亚胺 (DCC) 禾 Ρ 4-二甲氨基吡啶 (DMAP) 为催化剂, 生成水溶性维生素 Ε酯的衍生物 (4), 化合物 (4) 接着与亚硫酰 (二)氯化合物 反应生成水溶性维生素 Ε酯的酰氯衍生物 (5), 然后化合物 (5) 的酰氯官能团选择性地与 10-羟基取代喜树碱, 如 10-羟基喜树碱或 7-乙基 -10-羟基喜树碱的酚羟基反应, 以碱为催 化剂 (如三乙胺), 生成本发明的双亲性抗癌药物化合物 (6)。 水溶性维生素 Ε酯的衍生物 (4)也可直接与 10-羟基取代的喜树碱, 如 10-羟基喜树碱或 7-乙基 -10-羟基喜树碱反应, 以 4-二甲氨基吡啶 (DMAP) 和 2-氯 -1-甲基吡啶鎗碘化物 (CMPI) 或 Ν,Ν'-二环己基碳化 二亚胺 (DCC) 和 4-二甲氨基吡啶 (DMAP) 为催化剂, 生成本发明的双亲性抗癌药物化 合物 (6)。
新的抗癌药物化合物的合成路线 1。
如式 9所示, 为本发明的双亲性抗癌药物化合物的另一种合成方法,化合物 (5) 的酰 氯官能团在碱 (如三乙胺) 的作用下与喜树碱 (或其衍生物) 的内酯环上的羟基反应, 生 成本发明的新抗癌药物化合物(7)。水溶性维生素 E酯的衍生物(4)也可直接与喜树碱(或 其衍生物) 反应, 以 4-二甲氨基吡啶(DMAP)和 2-氯 -1-甲基吡啶鎗碘化物 (CMPI)或 Ν,Ν'- 二环己基碳化二亚胺 (DCC) 和 4-二甲氨基吡啶 (DMAP)为催化剂, 生成本发明的抗癌药 物化合物 (7)。
R|; -CH2CH2-, -CH2CH2CH2-, -CH2OCH2- 式 9. 新的抗癌药物化合物的合成路线 2。 本发明的双亲性抗癌药物化合物的再一种合成方法如式 10 所示, 水溶性维生素 E (trolox) ( 1 ) 与烷氧基聚乙二醇胺 (8) 反应, 以 Ν,Ν'-二环己基碳化二亚胺 (DCC) 为偶 联剂, 生成水溶性维生素 Ε酰胺 (9), 水溶性维生素 Ε酰胺 (9) 再与环状酸酐 (如琥珀酸 酐、 戊二酸酐、 二甘醇酸酐等) 反应, 以 2-乙基己酸锡 (II) 为催化剂, 生成水溶性维生素 Ε酰胺的衍生物 (10),然后化合物 (10) 与喜树碱、 10-羟基喜树碱或 7-乙基 -10-羟基喜树碱等 反应, 以 4-二甲氨基吡啶 (DMAP) 和 2-氯 -1-甲基吡啶鎗碘化物 (CMPI) 或 Ν,Ν'-二环己 基碳化二亚胺 (DCC) 和 4-二甲氨基吡啶 (DMAP) 为催化剂, 分别生成本发明的新抗癌 药物化合物 (12), (13), (14)。 化合物 (10)也可与与亚硫酰 (二)氯反应生成水溶性维生素 E酯
的酰氯衍生物 (11), 然后化合物 (11)的酰氯官能团选择性地与 10-羟基取代喜树碱, 如 10- 羟基喜树碱或 7-乙基 -10-羟基喜树碱的酚羟基反应, 或与喜树碱 (或其衍生物) 的内酯环 上的羟基反应, 以碱为催化剂(如三乙胺), 生成本发明的双亲性抗癌药物化合物 (12)、 (13) 和 (14)。
,
式 10. 新抗癌药物化合物的合成路线 3。 本发明的双亲性抗癌药物化合物的再另一种合成方法如式 11和式 12所示, 以碱 (如 三乙胺, 吡啶, 碳酸钠, 碳酸钾, 碳酸铯) 为催化剂, 水溶性维生素 E酯 (3)或水溶性维生 素 E酰胺 (9)与卤 (碘、 溴、 氯) 代羧酸 (如溴代乙酸) 生成水溶性维生素 E酯或酰胺的衍 生物 (15a), 或与卤代羧酸酯 (如溴代乙酸乙酯) 反应生成 (15b), ( 15b) 与氢氧化锂反应 后再用酸处理生成 (15a)。 (15a)与亚硫酰 (二)氯反应生成酰氯衍生物 16, 然后化合物 16的 酰氯官能团选择性地与 10-羟基取代喜树碱, 如 10-羟基喜树碱或 7-乙基 -10-羟基喜树碱的 酚羟基反应, 或与喜树碱 (或其衍生物) 的内酯环上的羟基反应, 以碱为催化剂 (如三乙 胺), 生成本发明的双亲性抗癌药物化合物 (17)和 (18)。 水溶性维生素 E酯或酰胺的衍生物 (15a)也可直接与 10-羟基取代的喜树碱 (如 10-羟基喜树碱或 7-乙基 -10-羟基喜树碱) 或喜 树碱反应, 以 4-二甲氨基吡啶 (DMAP) 和 2-氯 -1-甲基吡啶鎗碘化物 (CMPI) 或 Ν,Ν'-二
环己基碳化二亚胺 (DCC) 和 4-二甲氨基吡啶 (DMAP) 为催化剂, 分别生成本发明的双 亲性抗癌药物化合物 (17)和 (18)。
式 13描述了本发明的双亲性抗癌药物化合物的又一种合成方法, 以碱(如三乙胺, 吡 啶, 碳酸钠, 碳酸钾, 碳酸铯) 为催化剂, 水溶性维生素 E酯 3或水溶性维生素 E酰胺 (9) 与烷基膦酰二氯 (如甲基膦酰二氯) 或芳基膦酰二氯 (如苯基膦酰二氯) 反应生成水溶性 维生素 E酯或酰胺的衍生物 (19)。 化合物 (19)直接与喜树碱或其衍生物反应; 生成水溶性维 生素 E衍生物修饰的双亲性抗癌药物化合物 (20)和 (21)。
Ri: -CH2CH2-, -CH2CH2CH2-, -CH2OCH;
R2: H, -CH2CH3
X: Ο, ΝΗ, NR", R": C1-C6 alkyl
I, CI
式 11. 新抗癌药物化合物的合成路线 4。
X: 0 NR", R": C1-C6 alkyl
m: 1-10
n: 1-200
式 12. 新抗癌药物化合物的合成路线
, 式 13. 新抗癌药物化合物的合成路线 6 本发明还涉及所述的新的双亲性抗癌药物的制剂配方, 这类新的双亲性抗癌药物化合 物可直接溶于水或生理盐水制成注射液, 也可以制成胶束制剂。 胶束制剂的成份包括新发 明的抗癌药物化合物、 溶剂和一种或多种表面活性剂和水相。
采用的技术方案为, 一种所述的双亲性抗癌药物化合物注射剂, 包含:
1 ) 具有式 I或 II结构的水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物;
2) 水或生理盐水。
所述的注射剂中, 药物化合物在配方中重量百分含量可以为约 0.005%至 5.0%; 优选重 量百分含量约为 0.01%至 3.5%;更优选药物化合物在配方中重量百分含量约为 0.1%至 2.0%。
或者, 一种所述的双亲性抗癌药物化合物胶束制剂, 包含:
1 ) 具有式 I或 II结构的水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物;
2) 表面活性剂;
3 ) 溶剂;
4) 水相。
所述的胶束制剂配方中, 包括本发明的双亲性抗癌药物化合物、 一种或多种表面活性 剂、 一种或多种溶剂和水相。 其中, 具有代表性的表面活性剂包括:
a)聚乙二醇表面活性剂, 如聚氧乙烯蓖麻油 EL(Cremophor EL;)、 吐温系列表面活性剂。 b)磷脂表面活性剂 (phospholipids ) , 如卵磷脂 (lecithin )、 聚乙二醇磷脂 (pegylated phospholipids )。
c)聚乙二醇维生素 E衍生物,如维生素 E琥珀酸酯聚乙二醇(d-a-tocopherol polyethylene glycol 1000 succinate, TPGS)。
d)聚氧乙烯聚氧丙烯嵌段共聚物: P0L0XAMERS 或 PLURONICS 的嵌段共聚物 (H(OCH2CH2)a(OC3H6)b (OCH2CH2)aOH)。 具有代表性的溶剂包括:
乙醇、 聚乙二醇、 丙二醇、 甘油、 N-甲基吡咯烷酮等。 聚乙二醇 (PEG) 是亲水性的, 重复单元的化学结构组成为 -CH2CH20-, 通式为 H-(CH2CH2)n-OH, 分子量范围一般从 200 至 10000。 例如, 聚乙二醇 200、 聚乙二醇 300、 聚乙二醇 400等。
所述的胶束制剂中, 药物化合物在配方中重量百分含量约为 0.005%至 5.0%; 优选重量 百分含量约为 0.01%至 3.5%; 更优选药物化合物在配方中重量百分含量约为 0.1%至 2.0%。 合适的表面活性剂在胶束制剂中的重量百分含量约为 1至 10%, 优选 2-6%; 更优选 4-5%。
胶束制剂配方还包括其它的成份, 如上面提到的溶剂。 在一个实施例中, 胶束配方中 包含聚乙二醇和较低的烷基醇 (如乙醇)。 溶剂约占配方重量的 2%至 20%。
胶束配方中包含水相。 在一个实施例中, 水相包括去离子水。 在另一个实施例中, 水 相包括生理盐水。
本发明还提供了新发明的药物化合物的应用, 即所述的水溶性维生素 E衍生物修饰的 双亲性抗癌药物化合物在制备抗癌药物中的应用。
例如, 本发明的药物化合物用于制备治疗癌症的药物。 本发明的药物化合物可用于治 疗包括血液系统的癌症, 如白血病, 淋巴瘤, 骨髓瘤; 和非血液癌症, 如实体瘤癌 (如乳 腺癌、 卵巢癌、 胰腺癌、 结肠癌、 直肠癌、 非小细胞肺癌、 膀胱癌), 肉瘤和胶质瘤等。
本发明的药物化合物的疗效和毒性用体外细胞或体内动物实验来确定,例如 ED50 (50% effective dose, 半数有效量: 50%实验对象出现阳性反应时的药量)、 LD50(50% lethal dose, 半数致死量: 杀死一半试验对象的齐 U量) 禾 B GI50 (concentration of the anti-cancer drug that inhibits the growth of cancer cells by 50%, 抑制 50%的实验对象生长的药物浓度)。通常将半 数致死量 (LD50) /半数有效量 (ED50) 的比值称为治疗指数, 用以表示药物的安全性。 治疗指数大的药物相对治疗指数小的药物更安全。
新发明的抗癌药物化合物旨在提高治疗指数和药物的安全性, 同时也提高治疗效果。 从体外细胞实验和体内动物实验获得的药物剂量可以用来制定用于人体的剂量范围。 这种 化合物的剂量最好在很少或根本没有毒性的 ED50 范围内。 剂量变化通常取决于采用的剂 型、 病人的敏感性和给药途径等。 通常可用相同或类似药物, 如拓扑替康和伊立替康的常 规剂量做参考。 例如拓扑替康的常规剂量为 0.2-1.5mg/m2、 伊立替康的常规剂量为 100mg-350mg/m
本发明的药物化合物可以单独使用, 也可与一个或多个其它的治疗药物一起使用。 例 如, 在癌症的治疗时, 本发明的药物化合物可与以下治疗药物一起使用, 包括但不限于: 雄激素抑制剂, 如氟他胺 (flutamide) 和鲁珀若利得 (luprolide); 抗雌激素, 如他莫昔芬
(tamoxifen) ; 抗代谢药物和细胞毒性药物, 如道诺红菌素 ( daunorubicin )、 五氟脲嘧啶
(fluorouracil)、氟尿苷 (floxuridine) α-干扰素 (interferon alpha ) 甲氨蝶呤( methotrexate )、 光神霉素 (plicamycin )、 硫基嘌吟 ( mecaptopurine ) 硫鸟嘌吟 ( thioguanine ) 阿霉素
( adriamycin)、 卡莫司汀 (carmustine)、 洛莫司汀 (lomustine)、 阿糖胞苷 ( cytarabine ) 环磷酉先胺 ( cyclophosphamide ) 阿霉素 ( doxorubicin )、 雌莫司汀 ( estramustine ) 六甲蜜 胺(altretamine)、 轻基脲 ( hydroxyurea ) 异环磷酉先胺 (ifosfamide)、 甲基节肼 (procarbazine)、 突变霉素 (mutamycin)、 白消安 (busulfan)、 米托蒽酉昆 (mitoxantrone)、 卡钼 carboplatin)、 顺钼( cisplatin)、链脲佐菌素 ( streptozocin)、博莱霉素 ( bleomycin )、放线菌素 ( dactinomycin )、 和依达比星 (idamycin);激素,如甲孕酮(medroxyprogesterone)、炔雌二醇(ethinyl estradiol ) 雌二醇 (estradiol, )、 亮丙瑞林(leuprolide)、 甲地孕酮 (megestrol)、 奥曲肽 (octreotide)、 己 烯雌酚 (diethylstilbestrol)、 氯烯雌醚 (chlorotrianisene)、 足叶乙甙 (etoposide)、 鬼臼毒素
(podophyllotoxin)和戈舍瑞林(goserelin); 氮芥衍生物, 如苯丙酸氮芥(melphalan)、 苯丁
酸氮芥(chlorambucil)和塞替派(thiotepa); 类固醇, 如倍他米松 (; betamethasone); 和其他 抗肿瘤药物, 如活牛分枝杆菌 (live Mycobacterium bovis;)、 达卡巴嗪 (dicarbazine)、 天冬酰 胺酶(asparaginase)、甲酰四氢叶酸(leucovorin)、米托坦(mitotane)、长春新碱( vincristine )、 长春碱 (vinblastine) 和多西紫杉醇 (taxotere) 等。
本发明将具有抗癌活性的药物化合物分子喜树碱或喜树碱衍生物与水溶性维生素 E烷 氧基聚乙二醇酯或酰胺通过连接基团共价结合, 得到水溶性维生素 E衍生物修饰的双亲性 抗癌药物化合物, 所述的化合物含有抗癌药物活性部分和双亲部分, 既可以溶于水也可以 溶于生物相容性的亲酯性溶剂。 本发明的新的抗癌药物化合物具有较高的抗癌活性, 同时 具有较好的溶解性和稳定性, 能够提高喜树碱或其衍生物在体内生理条件下的持续作用时 间 (半衰期) 和疗效, 降低其毒副作用。 所述的药物化合物可以制成注射剂或胶束制剂, 广泛应用于血液系统和非血液系统癌症的治疗。 本发明可对各种喜树碱及其衍生物进行修 饰, 拓宽喜树碱及其衍生物的应用领域, 为喜树碱及其衍生物的临床应用提供了一种新的 方法和途径。
下面结合具体实施例对本发明进行详细描述。 本发明的保护范围并不以具体实施方式 为限, 而是由权利要求加以限定。 附图说明
图 1 R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸甲氧基七聚乙二醇酯的质谱图。 图 2 R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸甲氧基七聚乙二醇酯的核磁共振 氢谱图。
图 3 R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯 -6-琥珀酸单 酯的质谱图。
图 4 R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯 -6-琥珀酸单 酯的核磁共振氢谱图。
图 5 7-乙基 -10-羟基喜树碱 R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二 醇单甲醚酯 -6-琥珀酸酯的质谱图。
图 6 7-乙基 -10-羟基喜树碱 R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二 醇单甲醚酯 -6-琥珀酸酯的核磁共振氢谱图。
图 7 (±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸聚乙二醇单甲醚酯 (聚乙二醇单甲 醚的平均分子量: Mn = 550 ) 的质谱图。
图 8 (±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸聚乙二醇单甲醚酯 (聚乙二醇单甲 醚的平均分子量: Mn = 550 ) 的核磁共振氢谱图。
图 9 (±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸聚乙二醇单甲醚酯 -6-琥珀酸单酯 (聚乙二醇单甲醚的平均分子量: Mn = 550 ) 的质谱图。
图 10(±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸聚乙二醇单甲醚酯 -6-琥珀酸单酯 (聚乙二醇单甲醚的平均分子量: Mn = 550 ) 的核磁共振氢谱图。
图 11 7-乙基 -10-羟基喜树碱 (±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸聚乙二醇 单甲醚酯 -6-琥珀酸酯 (聚乙二醇单甲醚的平均分子量: Mn = 550 ) 的质谱图。
图 12 7-乙基 -10-羟基喜树碱 (±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸聚乙二醇 单甲醚酯 -6-琥珀酸酯 (聚乙二醇单甲醚的平均分子量: Mn = 550 ) 的核磁共振氢谱图。 具体实施方式
下面的实施例用来说明本发明的新抗癌药物化合物的合成、 制剂和体外细胞实验等。 所述的实施例有助于对本发明的理解和实施, 并不构成对于本发明的限制。 实施例 1. 7-乙基 -10-羟基喜树碱 R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸甲氧基 聚乙二醇酯 -6-琥珀酸酯的合成
所述双亲性抗癌药物化合物的合成包括以下步骤:
1 ) R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸甲氧基七聚乙二醇酯的合成
在 50 mL的反应瓶中, 加入 978 mg ( 8 mmol) 4-二甲氨基吡啶、 1.022 mg (4 mmol) 2-氯 -1-甲基吡啶鎗碘化物和 1021mg (3 mmol) 七聚乙二醇单甲醚, 电磁搅拌, 慢慢向反应 液中滴加 751 mg ( 3 mmol) R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧盧和 10 mL N'N-
二甲基甲酰胺的溶液。 在室温和氮气的保护下反应 12 h, 过虑除去固体物质, 用旋转蒸发 仪将虑液浓缩至 10 mL, 柱层分离(230-400 mesh硅胶为固定相, 己烷和丙酮的混和液为淋 洗液), 得 821 mg R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯, 收率 47.8 %。
合成得到的化合物其质谱和核磁共振氢谱见图 1和图 2。
MS(Positive ESI): m/z = (M+Na)+: 595.4。
1H MR (400 MHz, CDC13): δ ppm: 4.639 (s, 1H), 4.243-4.125 (m, 2H), 3.626-3.329 (m, 29H), 2.605-2.420 (m, 3H), 2.148 (s, 3H), 2.130 (s, 3H), 2.050 (s, 3H), 1.869-1.793 (m, 1H), 1.589 (s, 3H)。
2) R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯 -6-琥珀酸单酯 的合成
在 50 mL的反应瓶中, 加入 1045 mg (2 mmol) R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡 喃 -2-羧酸七聚乙二醇单甲醚酯、 300 mg (3 mmol) 琥珀酸酐、 815 mg (2.5 mmol) 碳酸铯 和 20 mL N,N-二甲基甲酰胺, 电磁搅拌, 在室温和氮气的保护下反应 12 h。 将反应液加入 到 lOO mL 的乙酸乙酯中, 搅拌, 该混合液分别用 50 mL 的 0.1N HC1溶液洗三次, 再分别 用 50 mL水洗三次, 有机相用无水硫酸镁干燥, 过虑除去硫酸镁, 再将虑液浓缩至 10 mL, 柱层分离 (230-400 mesh硅胶为固定相, 己烷和丙酮的混和液为淋洗液)得 962 mg R-C+)-6- 羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯 -6-琥珀酸单酯, 收率 71.5 %。
谱见图 3和图 4。
MS(Positive ESI): m/z = (M+Na): 695.4。
1H NMR (400 MHz, CDC13): δ ppm: 4.245-4.125 (m, 2H), 3.630-3.301 (m, 29H):
2.901-2.871(t, J = 6 Hz, 2H), 2.735 (s, 2H), 2.607-2.429 (m, 3H), 2.133 (s, 3H), 1.997 (s, 3H), 1.909 (s, 3H), 1.861-1.774 (m, 1H), 1.603 (s, 3H)。
3 ) 7-乙基 -10-羟基喜树碱 R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇 单甲醚酯 -6-琥珀酸酯的合成
反应式如下:
实验步骤:
在 50 mL的反应瓶中, 加入 673 mg ( 1 mmol ) R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡 喃 -2-羧酸七聚乙二醇单甲醚酯 -6-琥珀酸单酯、 238 mg (2 mmol) 亚硫酰氯、 10 μ Ν,Ν-二 甲基甲酰胺和 20 mL无水甲苯, 电磁搅拌, 在室温和氮气的保护下反应 4 h。减压蒸熘除去 甲苯和过量的亚硫酰氯, 得到粘稠液体, 加入 10 mL无水氯仿得溶液 。
在 50 mL的反应瓶中,加入 196 mg (0.5 mmol) 7 -乙基 -10-羟基喜树碱、 61 mg (0.6 mmol) 无水三乙胺和 20 mL无水 N,N-二甲基乙酰胺, 搅拌, 慢慢加入 6 mL溶液 A, 在室温和氮 气的保护下反应 4 h, 薄层分析, 若仍有少量的 7-乙基 -10-羟基喜树碱未反应完, 再加入适 量的溶液 A和三乙胺至反应完毕。 将反应液加入到 100 mL 的乙酸乙酯中, 该混合液用分 别用 50 mL水洗三次, 有机相用无水硫酸镁干燥,过虑除去硫酸镁,再将虑液浓缩至 10 mL, 柱层分离 (230-400 mesh硅胶为固定相, 己烷和丙酮的混和液为淋洗液) 得 277 mg 7-乙基 -10-羟基喜树碱 R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯 -6- 琥珀酸酯, 收率 53 %。
MS(Positive ESI): m/z = (M+H)+: 1047.7, (M+Na) : 1069.6。
1H MR (400 MHz, CDC13): δ ppm: 8.224-8.201 (d, J = 9.2 Hz, 1H), 7.802-7.796 (d, J = 2.4 Hz, 1H), 7.623 (s, 1H), 7.556-7.527 (dd, Ji = 2.4 Hz, J2 = 9.2, 1H), 5.758-5.717 (d, J = 16.4 Hz, 1H), 5.313-5.272 (d, J = 16.4 Hz, 1H), 5.242 (s, 2H), 4.221-4.199 (t, J = 4.4 Hz, 2H), 3.724 (s, 1H), 3.627-3.508 (m, 26H), 3.352 (s, 3H), 3.144-3.028 (m, 6H), 2.589-2.402 (m, 3H), 2.143 (s, 3H), 2.017 (s, 3H), 1.927 (s, 3H), 1.901-1.820 (m, 1H), 1.601-1.590 (m, 5H), 1.373-1.335 (t, J = 7.6 Hz, 3H), 1.041-1.005 (t, J = 7.2 Hz, 3H)。 实施例 2. 7-乙基 -10-羟基喜树碱(±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸聚乙二醇 单甲醚酯 -6-琥珀酸酯的合成
1 ) (±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸聚乙二醇单甲醚酯的合成 (聚乙二醇 单甲醚的平均分子量: Mn = 550 )
反应式为
在 100 mL的反应瓶中,加入 2.20 g (4 mmol)聚乙二醇单甲醚(平均分子量为 Mn = 550)、 1.45 g ( 12 mmol) 4-二甲氨基吡啶、 1.53 g (6 mmol) 2-氯 -1-甲基吡啶鎗碘化物和 30 mL 二氧杂环已烷, 电磁搅拌, 慢慢向反应液中滴加 1.00 g (4 mmol) (±)-6-羟基 -2,5,7,8-四甲 基苯并二氢吡喃 -2-羧酸和 30 mL二氧杂环已烷的溶液。 在室温和氮气的保护下反应 12 h, 过虑除去固体物质, 用旋转蒸发仪将虑液浓缩至 10 mL, 柱层分离(230-400 mesh硅胶为固 定相, 己烷和丙酮的混和液为淋洗液) 得 1627 mg (±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃
-2-羧酸聚乙二醇单甲醚酯, 收率 52.
MS(Positive ESI): m/z = (M+Na): 595.3, 639.3, 683.3, 727.3, 771.3, 815.3, 859.4, 903.4, 947.4, 991.4, 1035.4, 1079.4 (聚合度: 7-15)。
1H MR (400 MHz, CDC13): δ ppm: 4.229-4.120 (m, 2H), 3.605-3.321 (m, 50H), 2.615-2.399 (m, 3H), 2.138 (s, 3H), 2.119 (s, 3H), 2.026 (s, 3H), 1.859-1.783 (m, 1H), 1.578 (s, 3H)
2) (±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸聚乙二醇单甲醚酯 -6-琥珀酸单酯的合 成 (聚乙二醇单甲醚平均分子量: Mn = 550 )
实验步骤:
在 100 mL的反应瓶中, 加入 1564 mg (2 mmol) (±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡 喃 -2-羧酸聚乙二醇单甲醚酯、 300 mg ( 3 mmol) 琥珀酸酐、 100 mg 2 - 乙基己酸锡 (II) 和 50 mL无水二甲苯, 在氮气的保护下加热回流 8 h, 过虑除去固体物质, 柱层分离 (230-400 mesh硅胶为固定相, 二氯甲烷和丙酮的混和液为淋洗液) 得 1423 mg (±)-6-羟基 -2,5,7,8-四 甲基苯并二氢吡喃 -2-羧酸聚乙二醇单甲醚酯 -6-琥珀酸单酯, 收率 80.7 %。
合成得到的化合物其质谱和核磁共振氢谱见图 9和图 10。
MS(Positive ESI): m/z = (M+Na)+: 695.4, 739.4, 783.4, 827.4, 871.5, 915.5, 959.5, 1003.6, 1047.6 (聚合度: 7-15)。
1H NMR (400 MHz, CDC13): δ ppm: 4.239-4.156 (m, 2H), 3.661-3.382 (m, 47H), 3.345 (s, 3H), 2.894-2.862 (t, J = 6.4 Hz, 2H), 2.751-2.721 (t, J = 6.0 Hz, 2H), 2.625-2.368 (m, 3H), 2.136 (s, 3H), 1.982 (s, 3H), 1.896 (s, 3H), 1.876-1.770 (m, 1H), 1.586 (s, 3H)。
3 ) 7-乙基 -10-羟基喜树碱 (±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸聚乙二醇单 甲醚酯 -6-琥珀酸酯的合成 (聚乙二醇单甲醚平均分子量: Mn = 550 )
反应式为
实验步骤如下:
在 50 mL的反应瓶中, 加入 1324 mg ( 1.5 mmol) (±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡 喃 -2-羧酸聚乙二醇单甲醚酯 -6-琥珀酸单酯、 357 mg (3 mmol) 亚硫酰氯、 10 LN,N-二甲 基甲酰胺和 30 mL无水甲苯, 电磁搅拌, 在室温和氮气的保护下反应 4 h。减压蒸熘除去甲 苯和过量的亚硫酰氯, 得到一粘稠液体, 加入 10 mL无水氯仿得溶液 。
在 50 mL的反应瓶中,加入 392 mg (1 mmol) 7 -乙基 -10-羟基喜树碱、 121 mg (1.2 mmol) 无水三乙胺和 20 mL无水 N,N-二甲基乙酰胺, 搅拌, 慢慢加入 6 mL溶液 A, 在室温和氮 气的保护下反应 4 h, 薄层分析, 若仍有少量的 7-乙基 -10-羟基喜树碱未反应完, 再加入适 量的溶液 A和三乙胺至反应完毕。 用旋转蒸发仪将虑液浓缩至 10 mL柱层分离 (230-400 mesh硅胶为固定相, 乙酸乙酯和丙酮的混和液为淋洗液)得 659 mg 7-乙基 -10-羟基喜树碱 (±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸聚乙二醇单甲醚酯 -6-琥珀酸酯,收率 52.4%。
合 的化合物其质谱和核磁共振氢谱见图 11和图 12。
MS(Positive ESI): m/z = (M+Na): 1069.5, 1113.5, 1157.6, 1201.6, 1245.6, 1289.6, 1334.7: 1377.7, 1422.7 (聚合度: 7-15)。
1H MR (400 MHz, CDC13): δ ppm: 8.224-8.201 (d, J = 9.2 Hz, 1H), 7.793 (s, 1H), 7.626 (s: 1H), 7.554-7.531 (d, J = 9.3Hz, 1H), 5.745-5.714 (d, J = 16 Hz, 1H), 5.310-5.270 (d, J = 16 Hz: 1H), 5.241 (s, 2H), 4.218-4.197 (t, J = 4.2 Hz, 2H), 3.740 (s, 1H), 3.630-3.511 (m, 47H), 3.353 (s: 3H), 3.141-3.080 (m, 6H), 2.641-2.394 (m, 3H), 2.140 (s, 3H), 2.014 (s, 3H), 1.911 (s, 3H): 1.899-1.771 (m, 3H), 1.601 (s, 3H), 1.371-1.332 (t, J = 7.8 Hz, 3H), 1.038-1.001 (t, J = 7.4 Hz: 3H
实施例 3. 7-乙基 -10-羟基喜树碱 N-甲氧基七聚乙二醇胺 R-(+)-6-羟基 -2,5,7,8-四甲基苯并 二氢吡喃 -2-甲酰胺 -6-琥珀酸酯的合成
所述双亲性抗癌药物化合物的合成包括以下步骤:
1 )N-甲氧基七聚乙二醇胺基 R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-甲酰胺的合成
在 50 mL的反应瓶中, 加入 825 mg (4 mmol) Ν,Ν'-二环己基碳化二亚胺 (DCC)、 1018 mg (3 mmol) 甲氧基七聚乙二醇胺、 751 mg (3 mmol) R-(+)-6-羟基 -2,5,7,8-四甲基 苯并二氢吡喃 -2-羧酸和 10 mLN,N-二甲基甲酰胺。 电磁搅拌, 在室温和氮气的保护下反应 12 h, 过虑除去固体物质, 用旋转蒸发仪将虑液浓缩至 10 mL, 柱层分离 (230-400 mesh 硅胶为固定相, 己烷和丙酮的混和液为淋洗液), 得 1303 mg N-甲氧基七聚乙二醇胺基 R-W-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-甲酰胺, 收率 52.4%。
2) N-甲氧基七聚乙二醇胺基 R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-甲酰胺 -6-琥 珀酸单酯的合成
在 50 mL的反应瓶中, 加入 1143 mg (2 mmol) N_甲氧基七聚乙二醇胺基 R-(+)_6_羟 基 -2, 5, 7, 8-四甲基苯并二氢吡喃 -2-甲酰胺、 300 mg (3 mmol) 琥珀酸酐、 100 mg 2-乙基 己酸锡 (Π) 和 50 mL无水二甲苯, 在氮气的保护下加热回流 8 h, 过虑除去固体物质, 柱 层分离 (230-400 mesh硅胶为固定相, 己烷和丙酮的混和液为淋洗液) 得 1110 mg N-甲氧 基七聚乙二醇胺基 R-(+)_6-羟基 -2, 5, 7, 8-四甲基苯并二氢吡喃 -2-甲酰 -6-琥珀酸单酯,收 率 82.6%。
3) 7-乙基 -10-羟基喜树碱 N-甲氧基七聚乙二醇胺基 1?-(+)-6-羟基-2,5,7,8-四甲基 苯并二氢吡喃 -2-甲酰胺 -6-琥珀酸酯的合成
反应式如下:
在 50 mL的反应瓶中, 加入 672 mg (1 mmol) N_甲氧基七聚乙二醇胺基 R-(+)_6_羟基
-2, 5, 7, 8_四甲基苯并二氢吡喃 -2-甲酰 -6-琥珀酸单酯、 238 mg ( 2 mmol) 亚硫酰氯、 10 μΐ 二甲基甲酰胺和 20 mL无水甲苯, 电磁搅拌, 在室温和氮气的保护下反应 4 h。 减压 蒸熘除去甲苯和过量的亚硫酰氯, 得到粘稠液体, 加入 10 mL无水氯仿得溶液 。
在 50 mL的反应瓶中,加入 196 mg (0. 5 mmol) 7-乙基 -10-羟基喜树碱、 61 mg (0. 6 mmol) 无水三乙胺和 20 mL无水 N, /^二甲基乙酰胺, 电磁搅拌, 慢慢加入 6 mL溶液 A, 在室温和 氮气的保护下反应 4 h, 薄层分析, 若仍有少量的 7-乙基 -10-羟基喜树碱未反应完, 再加 入适量的溶液 A和三乙胺至反应完毕。将反应液加入到 100 mL 的乙酸乙酯中, 过虑除去固 体物质, 再将虑液浓缩至 10 mL, 柱层分离(230-400 mesh硅胶为固定相, 己烷和丙酮的混 和液为淋洗液)得 661 mg 7-乙基 -10-羟基喜树碱 N-甲氧基七聚乙二醇胺基 R- (+) _6_羟基 -2, 5, 7, 8-四甲基苯并二氢吡喃 -2-甲酰胺 -6-琥珀酸酯, 收率 63.2 %。
实施例 4. 喜树碱 N-甲氧基七聚乙二醇胺 R-(+)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-甲 酰胺 -6-琥珀酸酯的合成
在 50 mL的反应瓶中, 加入 672 mg ( 1 mmol) N_甲氧基七聚乙二醇胺基 R- (+) _6_羟基 -2, 5, 7, 8-四甲基苯并二氢吡喃 -2-甲酰胺 -6-琥珀酸单酯、 348 mg (1. 0 mmol) 喜树碱、 289 mg (2.2 mmol) 4-二甲氨基吡啶、 281 mg ( l . l mmol) 2-氯 -1-甲基吡啶鎗碘化物和 20 mL无 水 W /^二甲基乙酰胺, 电磁搅拌,在室温和氮气的保护下反应 4 h。将反应液加入到 100 mL 的乙酸乙酯中, 过虑除去固体物质, 再将虑液浓缩至 10 mL, 柱层分离(230-400 mesh硅胶 为固定相, 己烷和丙酮的混和液为淋洗液) 得 716 mg 喜树碱 N-甲氧基七聚乙二醇胺基
R- (+) -6-羟基 -2, 5, 7, 8-四甲基苯并二氢吡喃 -2-甲酰胺 -6-琥珀酸酯, 收率 79.5 %。 实施例 5. 7-乙基 -10-羟基喜树碱(±) -6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二 醇单甲醚酯 -6-氧代乙酸酯的合成
1 )(±) -6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯 -6-氧乙酸乙酯的 合成
在 50 mL的反应瓶中, 加入 1144 mg (2 mmol) (±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯、 501 mg ( 3 mmol) 溴乙酸乙酯、 652 mg (2 mmol) 碳酸铯 和 25 mL无水 N,N-二甲基甲酰胺, 电磁搅拌, 在室温和氮气的保护下反应 12 h。 减压蒸熘 除去 N,N-二甲基甲酰胺, 再加入 100 mL 的乙酸乙酯, 搅拌, 过虑除去固体物质, 再将虑 液浓缩至 10 mL, 柱层分离 (230-400 mesh硅胶为固定相, 己烷和丙酮的混和液为淋洗液) 得 1187 mg (±) -6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯 -6-氧乙酸乙 酯, 收率 90. 1%。
2)(±) -6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯 -6-氧乙酸的合成 反应式如下:
在 50 mL的反应瓶中, 加入 1318 mg (2 mmol ) (±) -6-羟基 -2,5,7,8-四甲基苯并二氢吡 喃 -2-羧酸七聚乙二醇单甲醚酯 -6-氧乙酸乙酯和 20 mL 甲醇,电磁搅拌,然后加入 51 mg(2.1 mmol) 氢氧化锂和 5 mL水的溶液, 电磁搅拌, 在室温和氮气的保护下反应约 2 h至 (±) -6- 羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯 -6-氧乙酸乙酯完全反应。减压 蒸熘除去甲醇, 滴加 0.1NHC1至溶液的 pH值为 3-4, 冷冻干燥, 再加入 10 mL 的乙酸乙 酯, 搅拌, 过虑除去固体物质, 柱层分离 (230-400 mesh硅胶为固定相, 己烷和丙酮的混 和液为淋洗液) 得 1215 mg (±) -6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲 醚酯 -6-氧乙酸, 收率 96. 3%。
3 ) 7-乙基 -10-羟基喜树碱 (±) -6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇 单甲醚酯 -6-氧乙酸酯的合成
反应式如下:
实验步骤:
在 50 mL的反应瓶中,加入 392 mg (l mmol) 7 -乙基 -10-羟基喜树碱、 269 mg (2.2 mmol) 4-二甲氨基吡啶、 281 mg ( 1.1 mmol) 2-氯 -1-甲基吡啶鎗碘化物和 20 mL无水 二甲基 乙酰胺, 电磁搅拌, 慢慢加入 616 mg ( 1 mmol ) (±) -6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2- 羧酸七聚乙二醇单甲醚酯 -6-氧乙酸和 10 mL氯仿的溶液, 在室温和氮气的保护下反应 4 h。 过虑除去固体物质, 再将虑液减压浓缩至 10 mL, 柱层分离 (230-400 mesh硅胶为固定相, 己烷和丙酮的混和液为淋洗液) 得 574 mg 7-乙基 -10-羟基喜树碱 (±) -6-羟基 -2,5,7,8-四甲
基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯 -6-氧乙酸酯, 收率 58. 0%。 实施例 6. 喜树碱 (±) -6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯 -6- 氧乙酸酯的合成
反应式如下:
实验步骤:
在 50 mL的反应瓶中, 加入 348 mg (l mmol) 喜树碱、 269 mg ( 2.2 mmol) 4-二甲氨基 吡啶、 281 mg ( 1.1 mmol) 2-氯 -1-甲基吡啶鎗碘化物、 616 mg ( 1 mmol) (±) -6-羟基 -2,5,7,8- 四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯 -6-氧乙酸和 20 mL无水 Λ^ -二甲基乙酰 胺, 电磁搅拌, 在室温和氮气的保护下反应 4 h。 过虑除去固体物质, 再将虑液减压浓缩至 10 mL, 柱层分离 (230-400 mesh硅胶为固定相, 己烷和丙酮的混和液为淋洗液)得 824 mg 喜树碱 R-(±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯 -6-氧乙酸酯, 收率 87. 0%。 实施例 7. 喜树碱 (±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯 -6-甲 基膦酰酯的合成
实验步骤:
在 100 mL的反应瓶中, 加入 290 mg (2.2 mmol) 甲基膦酰二氯和 10 mL无水乙醚, 电磁搅拌, 再慢慢滴加 1117 mg (2 mmol) C±)-6-羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七 聚乙二醇单甲醚酯、 202 mg ( 2 mmol ) 无水三乙胺和 20 mL无水乙醚的溶液、 在室温和氮 气的保护下反应 8 h, 减压蒸熘除去乙醚, 真空干燥得 1287 mg (±)-6-羟基 -2,5,7,8-四甲基苯 并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯 -6-甲基膦酰氯酯, 收率 98. 4%。
在 50 mL的反应瓶中, 加入 348 mg (1 mmol) 喜树碱和 20 mL无水 N, 二甲基乙酰胺 电磁搅拌, 再加入 121 mg ( 1. 2 mmol ) 三乙胺、 721 mg ( 1.1 mmol) (±)-6-羟基 -2,5,7,8-四 甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯 -6-甲基膦酰氯酯和 20 mL无水 W /^二甲基乙 酰胺的溶液, 在室温和氮气的保护下反应 4 h。 过虑除去固体物质, 再将虑液减压浓缩至 10 mL, 柱层分离 (230-400 mesh硅胶为固定相, 己烷和丙酮的混和液为淋洗液)喜树碱 (±)-6- 羟基 -2,5,7,8-四甲基苯并二氢吡喃 -2-羧酸七聚乙二醇单甲醚酯 -6-甲基膦酰酯。 实施例 8. 双亲性抗癌药物化合物的制剂
本实施例中包括用水或生理盐水制成的注射液, 以及用表面活性剂制得的胶束液。 制 剂配方中含有本发明的各种双亲性抗癌药物化合物, 每一组分在配方中的含量按重量百分
比计算。
本发明的双亲性抗癌药物化合物可根据需要分别制得以下不同制剂, 以 7-乙基 -10-羟 基喜树碱 R_ (+) -6-羟基 -2, 5, 7, 8-四甲基苯并二氢吡喃 -2-羧酸甲氧基七聚乙二醇酯 -6-琥 珀酸酯为例, 包括:
A.7-乙基 -10-羟基喜树碱 R- (+) -6-羟基 -2, 5, 7, 8-四甲基苯并二氢吡喃 _2_羧酸甲氧基 七聚乙二醇酯 -6-琥珀酸酯的水溶液注射液
将 7-乙基 -10-羟基喜树碱 R- (+) -6-羟基 -2, 5, 7, 8-四甲基苯并二氢吡喃 _2_羧酸甲氧基 七聚乙二醇酯 -6-琥珀酸酯 (MXL-4)溶解于去离子水中, 搅拌后所生产的注射液的组成如 下:
MXL-004 0.1%
去离子水 99.9%。
制成的注射液通过一个 0.2微米的过滤器过滤, 再装入无菌的玻璃瓶中。
B. 7-乙基 -10-羟基喜树碱 R_ (+) -6-羟基 -2, 5, 7, 8-四甲基苯并二氢吡喃 -2-羧酸甲氧 基七聚乙二醇酯 -6-琥珀酸酯的生理盐水注射液
将 7-乙基 -10-羟基喜树碱 R- (+) -6-羟基 -2, 5, 7, 8-四甲基苯并二氢吡喃 _2_羧酸甲氧基七聚 乙二醇酯 -6-琥珀酸酯 (MXL-4)溶解于生理盐水中, 搅拌后所生产的注射液的组成如下:
MXL-004 1%
生理盐水 99%。
制成的注射液通过一个 0.2微米的过滤器过滤, 再装入无菌的玻璃瓶中。
C. 7-乙基 -10-羟基喜树碱 R- (+) -6-羟基 -2, 5, 7, 8-四甲基苯并二氢吡喃 _2_羧酸甲氧基 七聚乙二醇酯 -6-琥珀酸酯的胶束液
将 7-乙基 -10-羟基喜树碱 R- (+) -6-羟基 -2, 5, 7, 8-四甲基苯并二氢吡喃 _2_羧酸甲氧基 七聚乙二醇酯 -6-琥珀酸酯(MXL-4)溶解于吐温 80 (Tween 80)、乙醇和聚乙二醇 PEG(200) 的混合液中, 得到透明的液体, 再加入去离子水 (DI water), 然后搅拌, 所生产的胶束液 的组成如下:
MXL-004 0.1%
吐温 80 2%
乙醇 10%
PEG 200 5%
去离子水 至 100%。
制成的胶束液通过一个 0.2微米的过滤器过滤, 再装入无菌的玻璃瓶。
D. 7-乙基 -10-羟基喜树碱 R- (+) -6-羟基 -2, 5, 7, 8-四甲基苯并二氢吡喃 _2_羧酸甲氧基 七聚乙二醇酯 -6-琥珀酸酯的胶束液
将 7-乙基 -10-羟基喜树碱 R- (+) -6-羟基 -2, 5, 7, 8-四甲基苯并二氢吡喃 _2_羧酸甲氧基 七聚乙二醇酯 -6-琥珀酸酯 (MXL-4)溶解于 D- α -生育酚聚乙二醇 1000琥珀酸酯 (TPGS)、 乙醇和聚乙二醇 PEG (200) 的混合液中, 得到透明的液体, 再加入去离子水 (DI water), 然后搅拌, 所生产的胶束液的组成如下:
MXL-004 1%
TPGS 5%
乙醇 5%
PEG 200 5%
去离子水至 100%。
制成的胶束液通过一个 0.2微米的过滤器过滤, 再装入无菌的玻璃瓶。 实施例 9. 双亲性抗癌药物化合物的体外细胞毒性实验
本实施例中, 用 XTT 法来检测本发明的双亲性抗癌新药物化合物抑制人卵巢癌 (A2780s)、 结肠癌细胞(HT-29 )、 肝癌 HePG2和肺癌细胞 (A549 ) 细胞的 GI50值 (抑制 癌细胞 50%生长的药物浓度), 并与抗癌药伊立替康 (irinotican) 进行对比, 评价药物化合 物的体外细胞毒性。
实验结果表明, 本发明的抗癌药物化合物对人卵巢癌 (A2780S) 细胞、 结肠癌细胞 ( HT-29 )、 肝癌 (HePG2 ) 细胞和肺癌细胞 (A549) 具有明显的增殖抑制作用, 且随着药 物浓度的增加, 其对细胞的增殖抑制作用增强, 呈明显的剂量依赖效应。 与同浓度的阳性 药物伊立替康 (Irinotecan)相比, 本发明的抗癌药物化合物对人体卵巢癌、 结肠癌、肝癌和肺 癌细胞抑制效果更明显。 本发明的抗癌药物化合物具有抑制人卵巢癌细胞 (A2780S) 结肠 癌细胞(HT-29 )、 肝癌 (HePG2 ) 细胞和肺癌细胞 (A549) 的增殖作用, 是一类具有潜在 抗人卵巢癌、 结肠癌、 肝癌和肺癌作用的药物化合物。 以 MXL-004为例, 其 GI50值如表 1 所示, 本发明的抗癌药物化合物与伊立替康相比, 同样具有明显降低的 GI50值。
MTT法检测方法: 取对数生长期的细胞, 调整细胞密度为 105个 /mL, 接种于 96 孔培 养板中, 100μΙ7孔, 细胞培养 18h后更换培养液, 分别加入不同浓度的药物样品, 150 μ!7 孔。 以只加含 10%小牛血清的 RPMI 1640培养液而不加细胞的孔为空白组(用于调零), 阴
性对照组加入等体积 10%小牛血清的 RPMI 1640 培养液, 阳性对照组加入等体积 13ug/ml 阳性药物。 以上各组设 3个复孔。 细胞继续培养 72 h, 加入 MTT ( 5 mg/mL) 溶液 15μΙ7 孔, 继续培养 4 h。 吸弃上清液,加入 DMSO 150μΙ7孔, 振荡混匀 10 min, 待结晶完全溶解 后, 在酶标仪上检测波长为 490nm 处各孔的吸光度 (D) 值。 按以下公式计算细胞的生长 抑制率: 细胞生长抑制率 = ( 1一实验组平均 D值 1对照组平均 D值) x l00%。
表 1. 新抗癌药物 MXL-004与抗癌药伊立替康 GI50的对比
抗癌药物 MXL-004 Irinotecan 卵巢癌细胞 ( A2780s) 0.009 μΜ 19.30 μΜ 结肠癌细包 ( HT-29 ) 0.171 μΜ 15.19 μΜ 肝癌细胞 ( HePG2 ) 2.552 μΜ 9.442 μΜ 肺癌细包( A549 ) 1.378 μΜ 58.07 μΜ
MXL-004: 7-乙基 -10-羟基喜树碱 R- (+) -6-羟基 -2, 5, 7, 8-四甲基苯并二氢吡喃 _2_羧酸 甲氧基七聚乙二醇酯 -6-琥珀酸酯。
Claims
1. 一种水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物, 具有下式 I或 II的结构:
其中:
R是聚乙二醇单垸基醚基;
是链接基团, 为下述基团之一:
a) -(C=0)-;
b) -P(=0)(R , 其中 R'是 C1-C6垸基、 C1-C6垸氧基或芳基;
c) -(C=0)(CH2)n(C=0)-, 其中 n = 1 - 10 ;
d) -(C=0)CH2-0-CH2(C=0)- ;
e) -(CH2)„(C=0)-, 其中 n = 1 - 10;
X是 -0-、 -NH-或 -NR'-, 其中 R'是 C1-C6烷基;
2. 根据权利要求 1所述的水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物,其特征在 于, 所述的聚乙二醇单烷基醚基团 R为:
a)聚乙二醇单甲醚基 -(CH2CH20)n-CH3;
b)聚乙二醇单乙醚基 -(CH2CH20)n-CH2CH3 ;
c)聚乙二醇单丙醚基 -(CH2CH20)n-CH2CH2CH3 ;
d)聚乙二醇单丁醚基 -(CH2CH20)n-CH2CH2CH2CH3 ;
其中 n = 1-200。
3. 根据权利要求 1所述的水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物,其特征在 于, 具有下式 I或 II :
式 I中, R2是 H或 -CH2CH3。
4. 根据权利要求 1、 2或 3所述的水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物, 其特征在于, 所述的双亲性抗癌药物化合物中, 水溶性维生素 E包括其光学异构体或外消 旋体。
5. 一种权利要求 1所述的水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物的制备方 法, 包括以下步骤:
1 )水溶性维生素 E与烷氧基聚乙二醇或烷氧基聚乙二醇胺发生酯化或酰胺化反应, 生 成水溶性维生素 E酯或水溶性维生素 E酰胺;
2)水溶性维生素 E酯或水溶性维生素 E酰胺的酚羟基与连接分子发生酯化或醚化反应, 生成水溶性维生素 E酯的衍生物或水溶性维生素 E酰胺的衍生物;
3 ) 步骤 2)所得到的水溶性维生素 E酯的衍生物或水溶性维生素 E酰胺的衍生物, 或 者它们的酰氯化产物, 与喜树碱或其衍生物发生酯化反应, 生成水溶性维生素 E衍生物修 饰的双亲性抗癌药物化合物;
所述的连接分子为含有两个以上活性基团的下列分子之一:
( 1 ) 乙二酰氯 0=CC12 ;
(2) 磷酰二氯烷基酯、烷氧基酯或芳基酯 0=POR'Cl2, 其中 R'是 C1-C6烷基、 C1-C6
(4) 二甘醇酸或二甘醇酸酐;
( 5 ) 卤代羧酸或卤代羧酸酯 Z-(CH2;>nCOOR', 其中 n = 1-10, Z为 Cl、 Br或 I, R'为 院基。
6. 根据权利要求 5所述的水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物的制备方 法, 其特征在于, 所述的方法包括以下步骤:
1 ) 以 4-二甲氨基吡啶和 2-氯 -1-甲基吡啶鎗碘化物为催化剂, 或以 Ν,Ν'-二环己基碳化 二亚胺和 4—二甲氨基吡啶为催化剂, 水溶性维生素 Ε与烷氧基聚乙二醇反应, 生成水溶性 维生素 Ε酯; 或以 Ν,Ν'-二环己基碳化二亚胺为催化剂, 水溶性维生素 Ε与烷氧基聚乙二醇 胺反应, 生成水溶性维生素 Ε酰胺;
2)水溶性维生素 Ε酯或水溶性维生素 Ε酰胺按以下方法之一, 与连接分子发生酯化或 醚化反应, 生成水溶性维生素 Ε酯的衍生物或水溶性维生素 Ε酰胺的衍生物:
a) 水溶性维生素 E (3 ) 或水溶性维生素 E酰胺 (9 ) 以 2-乙基己酸锡 (II) 或碳酸 铯为催化剂, 与环状酸酐
或二甘醇酸酐反应; 或者以 4-二甲氨基吡啶和 2-氯 -1-甲 基吡啶鎗碘化物, 或 Ν,Ν'-二环己基碳化二亚胺和 4-二甲氨基吡啶为催化剂, 与过量的二元 羧酸 (CH2)n(COOH)2或二甘醇酸反应,分别生成水溶性维生素 E酯的衍生物或水溶性维生素 E酰胺的衍生物;
b) 水溶性维生素 E酯或水溶性维生素 E酰胺以碱为催化剂, 与卤代羧酸反应生成水溶 性维生素 E酯的衍生物或水溶性维生素 E酰胺的衍生物; 或与卤代羧酸酯反应, 产物脱烷
基后生成水溶性维生素 E酯的衍生物或水溶性维生素 E酰胺的衍生物;
c) 水溶性维生素 E酯或水溶性维生素 E酰胺以碱为催化剂, 与烷基膦酰二氯、 烷氧基 膦酰二氯或芳基膦酰二氯反应, 生成水溶性维生素 E酯的衍生物或水溶性维生素 E酰胺的 衍生物;
d) 水溶性维生素 E酯或水溶性维生素 E酰胺以碱为催化剂, 与乙二酰氯反应, 生成水 溶性维生素 E酯的衍生物或水溶性维生素 E酰胺的衍生物;
3 )步骤 2) 中 a)或 b)所得到的水溶性维生素 E酯的衍生物或水溶性维生素 E酰胺的衍 生物与亚硫酰 (二)氯化合物反应生成酰氯化产物;
4)步骤 2) 中 a)或 b)所得到的水溶性维生素 E酯的衍生物或水溶性维生素 E酰胺的衍 生物以 4-二甲氨基吡啶和 2-氯 -1-甲基吡啶鎗碘化物, 或 Ν,Ν'-二环己基碳化二亚胺和 4-二 甲氨基吡啶为催化剂, 与喜树碱或其衍生物反应, 生成水溶性维生素 Ε衍生物修饰的双亲 性抗癌药物化合物; 或
5 ) 步骤 3 ) 所得到酰氯化产物, 或步骤 2) 中 c)或 d)所得到的水溶性维生素 Ε酯的衍 生物或水溶性维生素 E酰胺的衍生物, 以碱为催化剂, 与喜树碱或其衍生物反应; 生成水 溶性维生素 E衍生物修饰的双亲性抗癌药物化合物。
7. 根据权利要求 6所述的水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物的制备方 法, 其特征在于, 所述的碱催化剂选自三乙胺、 吡啶、 碳酸钠、 碳酸钾或碳酸铯。
8. —种权利要求 1所述的水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物注射剂,包 含:
1 ) 具有式 I或 II结构的水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物;
2) 水或生理盐水。
9. 根据权利要求 8所述的水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物注射剂,其 特征在于, 所述的注射剂中, 药物化合物在配方中重量百分含量为 0.005%至 5.0%。
10. 一种权利要求 1所述的水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物胶束制剂, 包含:
1 ) 具有式 I或 II结构的水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物;
2) 表面活性剂;
3 ) 溶剂;
4) 水相。
11. 根据权利要求 10所述的水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物胶束制
剂,其特征在于,所述的胶束制剂中,药物化合物在配方中重量百分含量为 0.005%至 5.0%; 表面活性剂的重量百分含量约为 1%至 10%, 溶剂占配方重量的 2%至 20%。
12. 权利要求 1的水溶性维生素 E衍生物修饰的双亲性抗癌药物化合物在制备抗癌药物中 的应用。
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CN104817574B (zh) * | 2015-05-26 | 2016-12-14 | 遵义医学院 | 喜树碱衍生物及其抗肿瘤应用 |
CN105646546B (zh) * | 2015-12-29 | 2018-03-02 | 遵义医学院 | 酸敏感型的喜树碱‑20位酯衍生物及其抗肿瘤应用 |
CN105399757A (zh) * | 2015-12-29 | 2016-03-16 | 遵义医学院 | 酸敏感型喜树碱-20位去甲斑蝥酸酯衍生物及其抗肿瘤应用 |
CN105820188A (zh) * | 2016-02-22 | 2016-08-03 | 刘天军 | 一种含替诺福韦双(维生素e)酯的药物制剂和用途 |
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US20080045559A1 (en) * | 2003-10-29 | 2008-02-21 | Sonus Pharmaceuticals, Inc. | Tocopherol-modified therapeutic drug compounds |
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US20080045559A1 (en) * | 2003-10-29 | 2008-02-21 | Sonus Pharmaceuticals, Inc. | Tocopherol-modified therapeutic drug compounds |
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