CN102491981B - Amphiphilic anti-cancer drug compound modified by water-soluble vitamin E derivative, preparation, preparation method and application for compound - Google Patents
Amphiphilic anti-cancer drug compound modified by water-soluble vitamin E derivative, preparation, preparation method and application for compound Download PDFInfo
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- CN102491981B CN102491981B CN201110356393.6A CN201110356393A CN102491981B CN 102491981 B CN102491981 B CN 102491981B CN 201110356393 A CN201110356393 A CN 201110356393A CN 102491981 B CN102491981 B CN 102491981B
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- Prior art keywords
- watermiscible vitamin
- ester
- derivative
- cancer drug
- vitamin
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Classifications
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- 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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- 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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- 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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- 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
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Abstract
The invention discloses an amphiphilic anti-cancer drug compound modified by a water-soluble vitamin E derivative. The amphiphilic anti-cancer drug compound has the structure of the following formula I or II. The anti-cancer drug active part camptothecin or camptothecin derivative, and amphiphilic part water-soluble vitamin E alkoxy polyethylene glycol ester or amide are covalently bonded by linking groups to form the amphiphilic anti-cancer drug compound. The invention further relates to a preparation, a preparation method and application for the medicine compound.
Description
Technical field
The present invention relates to a kind of new anti-cancer drug compounds and its preparation method and application, the amphiphilic anti-cancer drug compounds that particularly relates to a kind of watermiscible vitamin E Derivatives Modified, the preparation that comprises this compound, preparation method and as the application of cancer therapy drug.
Background technology
Many compounds with antitumour activity are due to water insoluble and (or) other biocompatible solvent, or in water and biocompatible solvent, poor stability has become an obstacle of drug development, often causes drug development time lag.According to estimates, nearly 40 percent candidate drug compounds with potential value through filtering out is because its poorly water-soluble is denied access to preparation research and development phase, and 30 percent existing medicine is insoluble.Current have among few techniques researching and developing, to solve the problem of medical compounds poor solubility, these technology comprise increases the coordination agent of solubleness technology, nano particle technology, microemulsion technology, strengthen the preparation technique of solubleness, fat-soluble and water-soluble prodrug technology, and novel polymer drug-carried technology etc.
Camptothecine (20 (s)-camptothecin, formula 1,1) and derivative there is good anti-tumor activity, it is the important DNA topoisomerase I of a class (Top I) inhibitor, they can be combined with Top I-DNA cleavable mixture, form CPT-Top I-DNA ternary complex, thereby stablize cleavable mixture, cause necrocytosis.But because of its poorly soluble and large problem of toxicity in water and other biological compatible solvent, finally fail to enter clinical.In order to improve the water-soluble of medicine and to retain the antitumor properties of parent compound, many camptothecin derivatives have been synthesized.Yet, only have derivative topotecan (Topotecan, formula 1,2) and irinotecan (Irinotrcan, formula 1,3) are entered clinical and have gone on the market by FDA's approval, be respectively used to treat ovarian cancer, lung cancer and the rectum cancer.But topotecan and irinotecan have obvious shortcoming, be included in the short and toxic side effect of Half-life in vivo large etc.At present, there are a plurality of camptothecin derivatives in the clinical study stage.
In addition, the E lactonic ring in camptothecin molecule is the necessary function base of camptothecin analogues antitumour activity, can rapid open loop under alkalescence or physiological condition and cause active disappearance (formula 2).Experimental results show that, there is balance in lactonic ring structure and open loop structure in blood plasma, and human plasma albumen is preferentially combined with open loop structure molecule, impels balance to shift to open loop form, cause medicine effective concentration in blood plasma to reduce, and then reduced the anti-tumor activity of this compounds.Further studies confirm that, open loop structure formula is the root that causes untoward reaction, as causes bone marrow depression, vomiting and diarrhoea etc.
1,20(S)-camptothecin:R=R
1=R
2=H
2,topotecan:R=OH,R
1=(CH
3)
2NCH
2-,R
2=H
3.irinotecan:R
1=H,R
2=Et,
The chemical structure of formula 1 camptothecine, topotecan (topotecan) and irinotecan (irinotecan).
The lactonic ring structure of formula 2 camptothecine under alkalescence or physiological condition and the balance between open loop structure.
In order to improve the solubleness of medicine, the technology such as emulsion (Emulsion) and micella (micelle) are widely used in the preparation of poorly water-soluble or water-fast medicine, but up to the present also do not have a kind of preparation technique to go for camptothecine, because its solvability extreme difference in water and organic solvent.Therefore, still need to research and develop new camptothecin derivative, existing higher antitumour activity has again good solvability and stability.
The invention provides a series of new amphiphilic camptothecin derivatives, they have good solvability in the organic solvent of water and biocompatibility, and directly water-soluble or physiological saline, or employing preparation technique is made the pharmaceutical dosage forms such as micella.New medical compounds of the present invention is expected to improve medicine time length (transformation period) and curative effect in vivo, and reduces its side effect.
Summary of the invention
The object of the present invention is to provide a kind of new amphiphilic anti-cancer drug compounds, this class has the compound of antitumour activity both can be water-soluble, also can be dissolved in the close ester solvent of biocompatibility, this compounds is camptothecine or the camptothecin derivative that amphiphatic watermiscible vitamin E alkoxyl group macrogol ester or acid amides are modified.
Another object of the present invention is to provide the synthetic method of described amphiphilic anti-cancer drug compounds.
Another object of the present invention is also to provide the composition that comprises described amphiphilic cancer therapy drug, the described amphiphilic anti-cancer drug compounds of take is activeconstituents, directly water-soluble or physiological saline is made injection liquid, or medical compounds, cosolvent, tensio-active agent and water are made to Micellar Solution Which Is.
Meanwhile, another object of the present invention is also to provide the application of described compound in preparing cancer therapy drug.
Amphiphilic anti-cancer drug compounds of the present invention, a kind of camptothecine or camptothecin derivative of watermiscible vitamin E Derivatives Modified, this compounds both can water-solublely also can be dissolved in the close ester solvent of biocompatibility, described compound contains cancer therapy drug active part and parents' part, cancer therapy drug active part is medical compounds molecule camptothecine or the camptothecin derivative with antitumour activity, parents are partly watermiscible vitamin E alkoxyl group macrogol ester or acid amides, amphiphilic watermiscible vitamin E alkoxyl group macrogol ester or amide molecule pass through linking group (as amber base: succinyl, glutaryl-: glutaryl, glycol ether acyl group: oxydiacetyl, diglycoloyl, diglycolyl, methylene radical carbonyl: methylene carbonyl, methylphosphine acyl group, methylphosphono etc.) form amphiphilic anti-cancer drug compounds of the present invention with anti-cancer drug compounds camptothecine (camptothecin) or derivatives thereof molecule covalent attachment.
Realize the object of the invention by the following technical solutions: a kind of amphiphilic anti-cancer drug compounds of watermiscible vitamin E Derivatives Modified, its molecular formula can represent with following general formula I or II:
Wherein, R is polyalkylene glycol monoalkyl ether (or alkoxyl group polyethylene glycol groups);
R
1being link group, is one of following radicals:
a)-(C=O)-;
B)-P (=O) (R ')-, wherein R ' is C1-C6 alkyl, C1-C6 alkoxyl group or aryl;
C)-(C=O) (CH
2)
n(C=O)-, n=1-10 wherein;
d)-(C=O)CH
2-O-CH
2(C=O)-;
E)-(CH
2)
n(C=O)-, n=1-10 wherein;
X is-O-,-NH-or-NR '-, wherein R ' is C1-C6 alkyl;
R
2be H, C1-C6 alkyl or-Si (CH
3)
2tBu;
R
3h, NO
2,-CH
2n (CH
3)
2, NH
2or
R
4be H, C1-C6 alkyl or
Amphiphilic anti-cancer drug compounds of the present invention, parents are partly the watermiscible vitamin E derivatives with amphiphatic polyalkylene glycol monoalkyl ether group, are selected from watermiscible vitamin E alkoxyl group macrogol ester or acid amides.Common and the preferred following group of polyalkylene glycol monoalkyl ether group R:
A) poly glycol monomethyl ether base ((CH
2cH
2o)
n-CH
3);
B) polyethyleneglycol ether base ((CH
2cH
2o)
n-CH
2cH
3);
C) polyethyleneglycol propyl ether base ((CH
2cH
2o)
n-CH
2cH
2cH
3);
D) polyoxyethylene glycol monobutyl ether base ((CH
2cH
2o)
n-CH
2cH
2cH
2cH
3).
N=1-200 wherein.
Watermiscible vitamin E (trolox) is the soluble derivative of vitamin-E, chemical name is: 6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), as vitamin-E, be a kind of antioxidant, its structure is as shown in Equation 3.Trolox has two kinds of optically active isomers, be R-(+)-trolox (chemistry R-(+)-6-by name hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid, R-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) and S-(-)-trolox (chemistry S-(-)-6-by name hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid, S-(-)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid); Its racemic modification is (±)-trolox (chemistry (±)-6-by name hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid, (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid).
The chemical structure of formula 3 watermiscible vitamin Es (trolox), wherein A:R-(+)-Trolox; B:S-(-)-Trolox; C:(±)-Trolox.
Watermiscible vitamin E in amphiphilic anti-cancer drug compounds of the present invention comprises its optical isomer or racemic modification.
Watermiscible vitamin E ester (trolox ester) is that watermiscible vitamin E (trolox) reacts the ester compound generating with alkoxyl group polyoxyethylene glycol, and their chemical structure as shown in Equation 4.Watermiscible vitamin E ester (trolox ester) has two kinds of optically active isomers equally, be R-(+)-trolox ester (chemistry R-(+)-6-by name hydroxyl-2, 5, 7, 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid alkoxyl group macrogol ester, R-(+)-6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-carboxylic acid alkoxypolyethylene glycol ester) and S-(-)-trolox ester (chemistry S-(-)-6-by name hydroxyl-2, 5, 7, 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid alkoxyl group macrogol ester, S-(-)-6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-carboxylic acid alkoxypolyethylene glycol ester), its racemic modification is (±)-trolox ester (chemistry (±)-6-by name hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid alkoxyl group macrogol ester, (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid alkoxypolyethylene glycol ester).The preferred poly glycol monomethyl ether base of substituent R [(CH in molecular structure
2cH
2o)
n-CH
3], polyethyleneglycol ether base [(CH
2cH
2o)
n-CH
2cH
3], polyethyleneglycol propyl ether base [(CH
2cH
2o)
n-CH
2cH
2cH
3] or polyoxyethylene glycol monobutyl ether base [(CH
2cH
2o)
n-CH
2cH
2cH
2cH
3], n=1-200 wherein.
The chemical structure of formula 4. watermiscible vitamin Es (trolox) alkoxyl group macrogol ester, wherein A:R-(+)-trolox ester; B:S-(-)-trolox ester; C:(±)-trolox ester.
Watermiscible vitamin E acid amides (trolox amide) is that watermiscible vitamin E (trolox) reacts the amides generating with alkoxyl group (as methoxyl group, oxyethyl group, propoxy-, butoxy) polyoxamide, and their chemical structure as shown in Equation 5.Watermiscible vitamin E acid amides (trolox amide) has two kinds of optically active isomers equally, be R-(+)-trolox amide (chemistry R-(+)-N-alkoxyl group polyoxyethylene glycol-6-by name hydroxyl-2, 5, 7, 8-tetramethyl-benzo dihydropyrane-2-methane amide, R-(+)-N-(alkoxypolyethylene glycol)-6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-carboxamide) and S-(-)-trolox ester (chemistry S-(-)-N-alkoxyl group polyoxyethylene glycol-6-by name hydroxyl-2, 5, 7, 8-tetramethyl-benzo dihydropyrane-2-methane amide, S-(-)-N-(alkoxypolyethylene glycol)-6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-carboxamide), its racemic modification is (±)-trolox ester (chemistry (±)-N-alkoxyl group polyoxyethylene glycol-6-by name hydroxyl-2, 5, 7, 8-tetramethyl-benzo dihydropyrane-2-methane amide, (±)-N-(alkoxypolyethylene glycol)-6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-carboxamide).The preferred poly glycol monomethyl ether base of the R of functional group [(CH in molecular structure
2cH
2o)
n-CH
3], polyethyleneglycol ether base [(CH
2cH
2o)
n-CH
2cH
3], polyethyleneglycol propyl ether base [(CH
2cH
2o)
n-CH
2cH
2cH
3] or polyoxyethylene glycol monobutyl ether base [(CH
2cH
2o)
n-CH
2cH
2cH
2cH
3], n=1-200 wherein; R
1for H or C1-C6 alkyl.
The chemical structure of formula 5. watermiscible vitamin Es (trolox) alkoxyl group polyoxyethylene glycol acid amides, wherein A:R-(+)-trolox amide; B:S-(-)-trolox amide; C:(±)-trolox amide.
Cancer therapy drug active part in amphiphilic anti-cancer drug compounds molecule of the present invention is the known camptothecine with antitumour activity or camptothecin derivative, its structural formula as shown in Equation 6, R wherein
2be H, C1-C6 alkyl or-Si (CH
3)
2tBu;
R
3h, NO
2,-CH
2n (CH
3)
2, NH
2or
r
4be H, OH, C1-C6 alkyl or
The chemical structure of formula 6 camptothecine and camptothecin derivative molecule.
In amphiphilic anti-cancer drug compounds molecule of the present invention, antitumour activity part is camptothecine (1 preferably, camptothecin), 10-hydroxycamptothecine (2,10-hydroxycamptothecin) and SN38 (3,7-ethyl-10-hydroxycamptothecin), its molecular structure as shown in Equation 7.
1,20(S)-camptothecin:R
1=R
2=H
2,10-hydroxycamptothecin:R
1=OH,R
2=H
3.7-ethyl-10-hydroxycamptothecin:R
1=OH,R
2=Et
The preferred chemical structure of formula 7. camptothecine and camptothecin derivative molecule.
Amphiphilic anti-cancer drug compounds molecule of the present invention comprises cancer therapy drug active part and parents' part, and these two parts become amphiphilic anti-cancer drug compounds by linking group covalent attachment.Cancer therapy drug active part is camptothecine or camptothecin derivative, parents are partly watermiscible vitamin E alkoxyl group macrogol esters (or acid amides), and the phenolic hydroxyl group of the hydroxyl of camptothecine or camptothecin derivative (hydroxyl on phenolic hydroxyl group or lactonic ring) and parents' watermiscible vitamin E alkoxyl group macrogol ester (or acid amides) generates amphiphilic anti-cancer drug compounds of the present invention with the active function groups covalent attachment that is connected molecule respectively.
Described linking group is provided by the connection molecule containing two or more active groups, for example: oxalyl chloride (O=CCl
2) provide carbonyl-(C=O)-, phosphinylidyne dichloro ester (O=POR ' Cl
2) (=O) (OR ')-group is provided-P, halogenated carboxylic acid or halogenated carboxylic ester provide alkylidene group carbonyl ((CH
2)
ncO-), different di-carboxylic acid (CH
2)
n(COOH)
2or cyclic acid anhydride
amber base (succinyl), glutaryl-(glutaryl), glycol ether acyl group (oxydiacetyl, diglycoloyl, diglycolyl) etc. can be provided.
With the parent compound (derivative of camptothecine or camptothecine with antitumour activity, as 10-hydroxycamptothecine and SN38) to compare, new anti-cancer drug compounds of the present invention has better hydrophilic and lipotropy (lipophilicity).New compound of the present invention comprises a cancer therapy drug parent compound part and amphiphilic group part, and cancer therapy drug parent molecule and amphiphilic become amphiphilic anti-cancer drug compounds of the present invention by an ester bond with covalent bonds.
The preparation method who the invention still further relates to a kind of amphiphilic anti-cancer drug compounds of described watermiscible vitamin E Derivatives Modified, comprises the following steps:
1) watermiscible vitamin E and alkoxyl group polyoxyethylene glycol or the generation esterification of alkoxyl group polyoxamide or amidate action, generate watermiscible vitamin E ester or watermiscible vitamin E acid amides;
2) phenolic hydroxyl group of watermiscible vitamin E ester or watermiscible vitamin E acid amides be connected molecule generation esterification or etherification reaction, generate the derivative of watermiscible vitamin E ester or the derivative of watermiscible vitamin E acid amides;
3) the step 2) derivative of the derivative of resulting watermiscible vitamin E ester or watermiscible vitamin E acid amides, or their chloride product, with camptothecine or derivatives thereof generation esterification, generate the amphiphilic anti-cancer drug compounds of watermiscible vitamin E Derivatives Modified;
Described connection molecule is one of following molecule that contains two above active groups:
(1) oxalyl chloride O=CCl
2;
(2) phosphinylidyne dichloro alkyl ester, alkoxy ester or aryl ester O=POR ' Cl
2, wherein R ' is C1-C6 alkyl, C1-C6 alkoxyl group or aryl;
(3) di-carboxylic acid (CH
2)
n(COOH)
2or cyclic acid anhydride
n=1-10 wherein;
(4) diglycollic acid or anhydride diethylene glycol;
(5) halogenated carboxylic acid or halogenated carboxylic ester Z-(CH
2)
ncOOR ', n=1-10 wherein, Z is Cl, Br or I, R ' is alkyl.
More specifically and optimally, described method comprises the following steps:
1) take DMAP (DMAP) and the chloro-1-picoline of 2-iodide (CMPI) is catalyzer, or with N, N '-dicyclohexyl carbodiimide (DCC) and DMAP (DMAP) are catalyzer, watermiscible vitamin E (1) reacts with alkoxyl group polyoxyethylene glycol (2), generates watermiscible vitamin E ester (3); Or with N, N '-dicyclohexyl carbodiimide (DCC) is catalyzer, watermiscible vitamin E (1) reacts with alkoxyl group polyoxamide (8), generates watermiscible vitamin E acid amides (9).
2) watermiscible vitamin E ester (3) or watermiscible vitamin E acid amides (9) respectively one of by the following method, and are connected molecule generation esterification or etherification reaction, the derivative of generation watermiscible vitamin E ester or the derivative of watermiscible vitamin E acid amides:
A) to take 2 ethyl hexanoic acid tin (II) or cesium carbonate be catalyzer for watermiscible vitamin E ester (3) or watermiscible vitamin E acid amides (9), with cyclic acid anhydride
or diglycollic acid anhydride reactant; Or with DMAP (DMAP) and the chloro-1-picoline of 2-iodide (CMPI) or N, N '-dicyclohexyl carbodiimide (DCC) and DMAP (DMAP) are catalyzer, with excessive di-carboxylic acid (CH
2)
n(COOH)
2or diglycollic acid reaction, generate respectively the derivative (4) of watermiscible vitamin E ester or the derivative (10) of watermiscible vitamin E acid amides;
B) watermiscible vitamin E ester (3) or watermiscible vitamin E acid amides (9) with alkali (as triethylamine, pyridine, sodium carbonate, salt of wormwood, cesium carbonate) be catalyzer, derivative (15a with halogenated carboxylic acid water generation reaction soluble vitamin E ester, R '=H) or the derivative of watermiscible vitamin E acid amides (15a), or react with halogenated carboxylic ester, after the de-alkyl of product (15b, R '=alkyl), generate the derivative (15a) of watermiscible vitamin E ester or the derivative (15a) of watermiscible vitamin E acid amides;
C) watermiscible vitamin E ester (3) or watermiscible vitamin E acid amides (9) with alkali (as triethylamine, pyridine, sodium carbonate, salt of wormwood, cesium carbonate) be catalyzer, react with alkyl phosphonyl dichloride, alkoxyl group phosphonyl dichloride or aryl phosphonyl dichloride, generate the derivative (19) of watermiscible vitamin E ester or the derivative (19) of watermiscible vitamin E acid amides;
D) to take alkali (as triethylamine or pyridine) be catalyzer for watermiscible vitamin E ester (3) or watermiscible vitamin E acid amides (9), reacts with oxalyl chloride, generates the derivative of watermiscible vitamin E ester or the derivative of watermiscible vitamin E acid amides.
3) step 2) a) or b) derivative (4,15a) of resulting watermiscible vitamin E ester or the derivative of watermiscible vitamin E acid amides (10,15a) react and generate respectively chloride product (5,11 or 16) with thionyl (two) chlorine compound.
4) step 2) a) or b) derivative (4,15a) of resulting watermiscible vitamin E ester or the derivative of watermiscible vitamin E acid amides (10,15a) be with DMAP (DMAP) and the chloro-1-picoline of 2-iodide (CMPI) or N, N '-dicyclohexyl carbodiimide (DCC) and DMAP (DMAP) are catalyzer, directly react with camptothecine or derivatives thereof, generate the amphiphilic anti-cancer drug compounds (6,12,13,14,17 or 18) of watermiscible vitamin E Derivatives Modified; Or
5) step 3) resulting chloride product (5,11 or 16), or step 2) c in) or the d) derivative (19) of the derivative of resulting watermiscible vitamin E ester (19) or watermiscible vitamin E acid amides, with alkali (as triethylamine, pyridine, sodium carbonate, salt of wormwood, cesium carbonate) be catalyzer, directly react with camptothecine or derivatives thereof; Generate the amphiphilic anti-cancer drug compounds (6,12,13,14,17,18,20 or 21) of watermiscible vitamin E Derivatives Modified.
Formula 8 has exemplified a kind of synthetic route, watermiscible vitamin E (trolox) (1) reacts with alkoxyl group polyoxyethylene glycol (2) (take methoxy poly (ethylene glycol) as example), take DMAP (DMAP) and the chloro-1-picoline of 2-iodide (CMPI) is catalyzer, or with N, N '-dicyclohexyl carbodiimide (DCC) and DMAP (DMAP) are catalyzer, generate watermiscible vitamin E ester (3), watermiscible vitamin E ester (3) again with cyclic acid anhydride (as succinyl oxide, Pyroglutaric acid, anhydride diethylene glycol etc.) reaction, the 2 ethyl hexanoic acid tin (II) (or cesium carbonate) of take is catalyzer, generate the derivative (4) of watermiscible vitamin E ester.Watermiscible vitamin E ester (3) also can be with the excessive compound with bifunctional (as succsinic acid, pentanedioic acid, the diprotic acid such as diglycollic acid) reaction, with DMAP (DMAP) and the chloro-1-picoline of 2-iodide (CMPI) or N, N '-dicyclohexyl carbodiimide (DCC) and DMAP (DMAP) are catalyzer, generate the derivative (4) of watermiscible vitamin E ester, compound (4) is followed the chloride derivative (5) with thionyl (two) chlorine compound water generation reaction soluble vitamin E ester, then the acid chloride functional groups of compound (5) optionally with 10-hydroxyl substituted camptothecin, as the phenolic hydroxyl group reaction of 10-hydroxycamptothecine or SN38, take alkali as catalyzer (as triethylamine), generate amphiphilic anti-cancer drug compounds of the present invention (6).The derivative of watermiscible vitamin E ester (4) also can be directly and the camptothecine that replaces of 10-hydroxyl, as 10-hydroxycamptothecine or SN38 reaction, with DMAP (DMAP) and the chloro-1-picoline of 2-iodide (CMPI) or N, N '-dicyclohexyl carbodiimide (DCC) and DMAP (DMAP) are catalyzer, generate amphiphilic anti-cancer drug compounds of the present invention (6).
The synthetic route 1 of the anti-cancer drug compounds that formula 8. is new.
As shown in Equation 9, another kind of synthetic method for amphiphilic anti-cancer drug compounds of the present invention, the acid chloride functional groups of compound (5) under the effect of alkali (as triethylamine) with the lactonic ring of camptothecine (or derivatives thereof) on hydroxyl reaction, generate new anti-cancer drug compounds of the present invention (7).The derivative of watermiscible vitamin E ester (4) also can directly react with camptothecine (or derivatives thereof), with DMAP (DMAP) and the chloro-1-picoline of 2-iodide (CMPI) or N, N '-dicyclohexyl carbodiimide (DCC) and DMAP (DMAP) are catalyzer, generate anti-cancer drug compounds of the present invention (7).
The synthetic route 2 of the anti-cancer drug compounds that formula 9. is new.
Another synthetic method of amphiphilic anti-cancer drug compounds of the present invention as shown in Equation 10, watermiscible vitamin E (trolox) (1) reacts with alkoxyl group polyoxamide (8), with N, N '-dicyclohexyl carbodiimide (DCC) is coupling agent, generate watermiscible vitamin E acid amides (9), watermiscible vitamin E acid amides (9) again with cyclic acid anhydride (as succinyl oxide, Pyroglutaric acid, anhydride diethylene glycol etc.) reaction, the 2 ethyl hexanoic acid tin (II) of take is catalyzer, generate the derivative (10) of watermiscible vitamin E acid amides, then compound (10) and camptothecine, the reaction such as 10-hydroxycamptothecine or SN38, with DMAP (DMAP) and the chloro-1-picoline of 2-iodide (CMPI) or N, N '-dicyclohexyl carbodiimide (DCC) and DMAP (DMAP) are catalyzer, generate respectively new anti-cancer drug compounds of the present invention (12), (13), (14).Compound (10) also can with the chloride derivative (11) with thionyl (two) chlorine water generation reaction soluble vitamin E ester, then the acid chloride functional groups of compound (11) optionally with 10-hydroxyl substituted camptothecin, as the phenolic hydroxyl group reaction of 10-hydroxycamptothecine or SN38, or with the lactonic ring of camptothecine (or derivatives thereof) on hydroxyl reaction, take alkali as catalyzer (as triethylamine), generate amphiphilic anti-cancer drug compounds of the present invention (12), (13) and (14).
The synthetic route 3 of formula 10. new anti-cancer drug compounds.
The another kind of synthetic method again of amphiphilic anti-cancer drug compounds of the present invention suc as formula 11 and formula 12 shown in, with alkali (as triethylamine, pyridine, sodium carbonate, salt of wormwood, cesium carbonate) be catalyzer, watermiscible vitamin E ester (3) or watermiscible vitamin E acid amides (9) generate the derivative (15a) of watermiscible vitamin E ester or acid amides for carboxylic acid (as monobromo-acetic acid) with halogen (iodine, bromine, chlorine), or react generation (15b) with halogenated carboxylic ester (as bromoethyl acetate), after (15b) reacting with lithium hydroxide, with acid treatment, generate (15a) again.(15a) react with thionyl (two) chlorine and generate chloride derivative 16, then the acid chloride functional groups of compound 16 optionally with 10-hydroxyl substituted camptothecin, as the phenolic hydroxyl group reaction of 10-hydroxycamptothecine or SN38, or with the lactonic ring of camptothecine (or derivatives thereof) on hydroxyl reaction, take alkali as catalyzer (as triethylamine), generate amphiphilic anti-cancer drug compounds of the present invention (17) and (18).Camptothecine (as 10-hydroxycamptothecine or SN38) or camptothecine that the derivative of watermiscible vitamin E ester or acid amides (15a) also can directly replace with 10-hydroxyl are reacted, with DMAP (DMAP) and the chloro-1-picoline of 2-iodide (CMPI) or N, N '-dicyclohexyl carbodiimide (DCC) and DMAP (DMAP) are catalyzer, generate respectively amphiphilic anti-cancer drug compounds of the present invention (17) and (18).
Formula 13 has been described another synthetic method of amphiphilic anti-cancer drug compounds of the present invention, with alkali (as triethylamine, pyridine, sodium carbonate, salt of wormwood, cesium carbonate) be catalyzer, the derivative (19) of watermiscible vitamin E ester 3 or watermiscible vitamin E acid amides (9) and alkyl phosphonyl dichloride (as methyl phosphonyl dichloride) or aryl phosphonyl dichloride (as phenyl phosphonyl chloride) water generation reaction soluble vitamin E ester or acid amides.Compound (19) directly reacts with camptothecine or derivatives thereof; Generate amphiphilic anti-cancer drug compounds (20) and (21) of watermiscible vitamin E Derivatives Modified.
The synthetic route 4 of formula 11. new anti-cancer drug compounds.
The synthetic route 5 of formula 12. new anti-cancer drug compounds.
The synthetic route 6 of formula 13. new anti-cancer drug compounds.
The invention still further relates to the pharmaceutical formulation of described new amphiphilic cancer therapy drug, the new amphiphilic anti-cancer drug compounds of this class directly water-soluble or physiological saline is made injection liquid, also can make micell formulations.The composition of micell formulations comprises neoteric anti-cancer drug compounds, solvent and one or more tensio-active agents and water.
The technical scheme adopting is that a kind of described amphiphilic anti-cancer drug compounds injection, comprises:
1) there is the amphiphilic anti-cancer drug compounds of the watermiscible vitamin E Derivatives Modified of formula I or II structure;
2) water or physiological saline.
In described injection, medical compounds weight percentage in formula can be approximately 0.005% to 5.0%; Preferred weight percentage composition is about 0.01% to 3.5%; More preferably medical compounds weight percentage in formula is about 0.1% to 2.0%.
Or a kind of described amphiphilic anti-cancer drug compounds micell formulations, comprises:
1) there is the amphiphilic anti-cancer drug compounds of the watermiscible vitamin E Derivatives Modified of formula I or II structure;
2) tensio-active agent;
3) solvent;
4) water.
In described micell formulations formula, comprise amphiphilic anti-cancer drug compounds of the present invention, one or more tensio-active agents, one or more solvents and water.Wherein, representative tensio-active agent comprises:
A) polyglycol surfactants, as polyoxyethylenated castor oil EL (Cremophor EL), tween series of surfactants.
B) phosphatide tensio-active agent (phospholipids), as Yelkin TTS (lecithin), polyoxyethylene glycol phosphatide (pegylated phospholipids).
C) polyoxyethylene glycol vitamin e derivative, as VE-succinate polyoxyethylene glycol (d-α-tocopherol polyethylene glycol 1000 succinate, TPGS).
D) segmented copolymer of polyoxyethylene polyoxypropylene block copolymer: POLOXAMERS or PLURONICS (H (OCH
2cH
2)
a(OC
3h
6)
b(OCH
2cH
2)
aoH).
Representative solvent comprises:
Ethanol, polyoxyethylene glycol, propylene glycol, glycerine, N-Methyl pyrrolidone etc.Polyoxyethylene glycol (PEG) is hydrophilic, and the chemical structure of repeating unit is-CH
2cH
2o-, general formula is H-(CH
2cH
2)
n-OH, molecular weight ranges generally from 200 to 10000.For example, Macrogol 200, Liquid Macrogol, poly(oxyethylene glycol) 400 etc.
In described micell formulations, medical compounds weight percentage in formula is about 0.005% to 5.0%; Preferred weight percentage composition is about 0.01% to 3.5%; More preferably medical compounds weight percentage in formula is about 0.1% to 2.0%.The weight percentage of suitable tensio-active agent in micell formulations is about 1 to 10%, preferably 2-6%; More preferably 4-5%.
Micell formulations formula also comprises other composition, solvent as mentioned above.In one embodiment, in micella formula, comprise polyoxyethylene glycol and lower alkyl alcohol (as ethanol).Solvent accounts for 2% to 20% of formulation weight.
In micella formula, comprise water.In one embodiment, water comprises deionized water.In another embodiment, water comprises physiological saline.
The present invention also provides the application of neoteric medical compounds, i.e. the application of the amphiphilic anti-cancer drug compounds of described watermiscible vitamin E Derivatives Modified in preparing cancer therapy drug.
For example, medical compounds of the present invention is for the preparation of the medicine for the treatment of cancer.Medical compounds of the present invention can be used for the cancer that treatment comprises blood system, as leukemia, and lymphoma, myelomatosis; With non-hematologic cancers, as solid tumor cancer (as mammary cancer, ovarian cancer, carcinoma of the pancreas, colon and rectum carcinoma, nonsmall-cell lung cancer, bladder cancer), sarcoma and glioma etc.
The curative effect of medical compounds of the present invention and toxicity are determined with cell in vitro or interior animal experiment, ED50 (50%effective dose for example, dose when positive reaction appears in 50% experimental subjects), LD50 (50% lethal dose median effective dose:, the dosage that kills half subjects) and GI50 (concentration of the anti-cancer drug that inhibits the growth of cancer cells by 50% suppresses the drug level of 50% experimental subjects growth) medium lethal dose:.Conventionally the ratio of medium lethal dose (LD50)/median effective dose (ED50) is called to therapeutic index, in order to represent the security of medicine.The medicine that the relative therapeutic index of medicine that therapeutic index is large is little is safer.
Neoteric anti-cancer drug compounds is intended to improve the security of therapeutic index and medicine, also improves result for the treatment of simultaneously.From the drug dose of In vitro cell experiment and interior animal experiment acquisition, can be used for formulating the dosage range for human body.The dosage of this compound is preferably in seldom or does not have within the scope of virose ED50 at all.The formulation of employing, patient's susceptibility and route of administration etc. are depended in dosage variation conventionally.Common available identical or similar medicine, as the routine dose of topotecan and irinotecan makes reference.For example the routine dose of topotecan is 0.2-1.5mg/m
2, irinotecan routine dose be 100mg-350mg/m
2.
Medical compounds of the present invention can be used separately, also can use together with one or more other medicines.For example, when the treatment of cancer, medical compounds of the present invention can be used together with following medicine, includes but not limited to: inhibitor for androgen, as flutamide (flutamide) and Lu Poruoli get (luprolide), estrogen antagonist, as tamoxifen (tomoxifen), antimetabolite and cytotoxic drug, as daunorubicin (daunorubicin), 5-fluorouracil (fluorouracil), floxuridine (floxuridine), alpha-interferon (interferon alpha), methotrexate (methotrexate), mithramycin (plicamycin), sulfenyl purine (mecaptopurine), Tioguanine (thioguanine), Zorubicin (adriamycin), carmustine (carmustine), lomustine (lomustine), cytosine arabinoside (cytarabine), endoxan (cyclophosphamide), Zorubicin (doxorubicin), estramustine (estramustine), altretamine (altretamine), hydroxyurea (hydroxyurea), ifosfamide (ifosfamide), procarbazine (procarbazine), mutamycin (mutamycin), busulfan (busulfan), mitoxantrone (mitoxantrone), carboplatin carboplatin), cis-platinum (cisplatin), streptozotocin (streptozocin), bleomycin (bleomycin), actinomycin (dactinomycin), and darubicin (idamycin), hormone, as Zytron (medroxyprogesterone), alkynes estradiol (ethinyl estradiol), estradiol (estradiol), Leuprolide (leuprolide), megestrol (megestrol), Sostatin (octreotide), stilboestrol (diethylstilbestrol), Chlortrianisoestrol (chlorotrianisene), etoposide (etoposide), podophyllotoxin (podophyllotoxin) and goserelin (goserelin), nitrogen mustard derivatives, as phenyalamine mustard (melphalan), Chlorambucil (chlorambucil) and phosphinothioylidynetrisaziridine (thiotepa), steroid, as Betamethasone Valerate (betamethasone), with other antitumor drugs, as cattle on the hoof mycobacterium (live Mycobacterium bovis), Dacarbazine (dicarbazine), asparaginase (asparaginase), formyl tetrahydrofolic acid (leucovorin), mitotane (mitotane), vincristine(VCR) (vincristine), vinealeucoblastine(VLB) (vinblastine) and Docetaxel (taxotere) etc.
The present invention will have the medical compounds molecule camptothecine of antitumour activity or camptothecin derivative and watermiscible vitamin E alkoxyl group macrogol ester or acid amides by linking group covalent attachment, obtain the amphiphilic anti-cancer drug compounds of watermiscible vitamin E Derivatives Modified, described compound contains cancer therapy drug active part and parents' part, both can water-solublely also can be dissolved in the close ester solvent of biocompatibility.New anti-cancer drug compounds of the present invention has higher antitumour activity, there is good solvability and stability simultaneously, can improve camptothecine or derivatives thereof continuous action time (transformation period) and the curative effect under physiological condition in vivo, reduce its toxic side effect.Described medical compounds can be made injection or micell formulations, is widely used in the treatment of blood system and non-blood system cancer.The present invention can modify various camptothecin analogues, widens the Application Areas of camptothecin analogues, for the clinical application of camptothecin analogues provides a kind of new method and approach.
Below in conjunction with specific embodiment, describe the present invention.Protection scope of the present invention is not limited with embodiment, but is limited by claim.
Accompanying drawing explanation
The mass spectrum of Fig. 1 R-(+)-Trolox methoxyl group seven macrogol esters.
The hydrogen nuclear magnetic resonance spectrogram of Fig. 2 R-(+)-Trolox methoxyl group seven macrogol esters.
The mass spectrum of Fig. 3 R-(+)-Trolox seven poly glycol monomethyl ether ester-6-monomester succinates.
The hydrogen nuclear magnetic resonance spectrogram of Fig. 4 R-(+)-Trolox seven poly glycol monomethyl ether ester-6-monomester succinates.
The mass spectrum of Figure 57-ethyl-10-hydroxycamptothecin R-(+)-Trolox seven poly glycol monomethyl ether ester-6-succinates.
The hydrogen nuclear magnetic resonance spectrogram of Figure 67-ethyl-10-hydroxycamptothecin R-(+)-Trolox seven poly glycol monomethyl ether ester-6-succinates.
Fig. 7 (±)-Trolox poly glycol monomethyl ether ester (molecular-weight average of poly glycol monomethyl ether: mass spectrum Mn=550).
Fig. 8 (±)-Trolox poly glycol monomethyl ether ester (molecular-weight average of poly glycol monomethyl ether: hydrogen nuclear magnetic resonance spectrogram Mn=550).
Fig. 9 (±)-Trolox poly glycol monomethyl ether ester-6-monomester succinate (molecular-weight average of poly glycol monomethyl ether: mass spectrum Mn=550).
Figure 10 (±)-Trolox poly glycol monomethyl ether ester-6-monomester succinate (molecular-weight average of poly glycol monomethyl ether: hydrogen nuclear magnetic resonance spectrogram Mn=550).
Figure 117-ethyl-10-hydroxycamptothecin (±)-Trolox poly glycol monomethyl ether ester-6-succinate (molecular-weight average of poly glycol monomethyl ether: mass spectrum Mn=550).
Figure 127-ethyl-10-hydroxycamptothecin (±)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid poly glycol monomethyl ether ester-6-succinate (molecular-weight average of poly glycol monomethyl ether: hydrogen nuclear magnetic resonance spectrogram Mn=550).
Embodiment
The following examples are used for illustrating synthetic, the preparation of new anti-cancer drug compounds of the present invention and In vitro cell experiment etc.Described embodiment contributes to the understanding of the present invention and enforcement, does not form for restriction of the present invention.
Synthesizing of embodiment 1.7-ethyl-10-hydroxycamptothecin R-(+)-Trolox methoxy poly (ethylene glycol) ester-6-succinate
The synthetic of described amphiphilic anti-cancer drug compounds comprises the following steps:
1) R-(+)-Trolox methoxyl group seven macrogol esters is synthetic
Reaction formula is shown below:
Experimental procedure:
In the reaction flask of 50mL, add 978mg (8mmol) DMAP, 1.022mg (4mmol) 2-chloro-1-picoline iodide and 1021mg (3mmol) seven poly glycol monomethyl ethers, induction stirring, slowly in reaction solution, drip 751mg (3mmol) R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic
acidand 10mLN, the solution of N-dimethyl formamide.Under the protection of room temperature and nitrogen, react 12h; the overanxious solid matter of removing; with Rotary Evaporators, worry liquid is concentrated into 10mL; chromatography (230-400mesh silica gel is stationary phase, and the mixed liquid of hexane and acetone is leacheate), obtains 821mg R-(+)-6-hydroxyl-2; 5; 7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid, seven poly glycol monomethyl ether esters, yield 47.8%.
Synthetic its mass spectrum of compound and the proton nmr spectra obtaining is shown in Fig. 1 and Fig. 2.
MS(Positive ESI):m/z=(M+Na)
+:595.4。
1H NMR(400MHz,CDCl
3):δppm: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-(+)-Trolox seven poly glycol monomethyl ether ester-6-monomester succinates is synthetic
Reaction formula is as follows:
Experimental procedure:
In the reaction flask of 50mL; add 1045mg (2mmol) R-(+)-6-hydroxyl-2; 5; 7; 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ether esters, 300mg (3mmol) succinyl oxide, 815mg (2.5mmol) cesium carbonate and 20mL N; dinethylformamide, induction stirring is reacted 12h under the protection of room temperature and nitrogen.Reaction solution is joined in the ethyl acetate of 100mL, stir, this mixed solution is washed three times with the 0.1NHCl solution of 50mL respectively, again respectively with 50mL washing three times, organic phase anhydrous magnesium sulfate drying, the overanxious magnesium sulfate of removing, again worry liquid is concentrated into 10mL, (230-400mesh silica gel is stationary phase to chromatography, the mixed liquid of hexane and acetone is leacheate) 962mg R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ether ester-6-monomester succinates, yield 71.5%.
Synthetic its mass spectrum of compound and the proton nmr spectra obtaining is shown in Fig. 3 and Fig. 4.
MS(Positive ESI):m/z=(M+Na)
+:695.4。
1H NMR(400MHz,CDCl
3):δppm:4.245-4.125(m,2H),3.630-3.301(m,29H), 2.901-2.871(t,J=6Hz,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) SN38 R-(+)-Trolox seven poly glycol monomethyl ether ester-6-succinates is synthetic
Reaction formula is as follows:
Experimental procedure:
In the reaction flask of 50mL; add 673mg (1mmol) R-(+)-6-hydroxyl-2; 5; 7; 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ether ester-6-monomester succinates, 238mg (2mmol) thionyl chloride, 10 μ LN; dinethylformamide and 20mL dry toluene, induction stirring is reacted 4h under the protection of room temperature and nitrogen.Toluene and excessive thionyl chloride are removed in underpressure distillation, obtain thick liquid, add 10mL anhydrous chloroform to obtain solution A.
In the reaction flask of 50mL; add 196mg (0.5mmol) SN38,61mg (0.6mmol) anhydrous triethylamine and the anhydrous N of 20mL; N-N,N-DIMETHYLACETAMIDE; stir; slowly add 6mL solution A, under the protection of room temperature and nitrogen, react 4h, tlc analysis; if still have a small amount of SN38 unreacted complete, then add appropriate solution A and triethylamine to reacting complete.Reaction solution is joined in the ethyl acetate of 100mL, this mixed solution is with washing three times with 50mL respectively, organic phase anhydrous magnesium sulfate drying, the overanxious magnesium sulfate of removing, again worry liquid is concentrated into 10mL, (230-400mesh silica gel is stationary phase to chromatography, the mixed liquid of hexane and acetone is leacheate) 277mg SN38 R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ether ester-6-succinates, yield 53%.
Synthetic its mass spectrum of compound and the proton nmr spectra obtaining is shown in Fig. 5 and Fig. 6.
MS(Positive ESI):m/z=(M+H)
+:1047.7,(M+Na)
+:1069.6。
1H NMR(400MHz,CDCl
3):δppm:8.224-8.201(d,J=9.2Hz,1H),7.802-7.796(d,J=2.4Hz,1H),7.623(s,1H),7.556-7.527(dd,J1=2.4Hz,J2=9.2,1H),5.758-5.717(d,J=16.4Hz,1H),5.313-5.272(d,J=16.4Hz,1H),5.242(s,2H),4.221-4.199(t,J=4.4Hz,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=7.6Hz,3H),1.041-1.005(t,J=7.2Hz,3H)。
Synthesizing of embodiment 2.7-ethyl-10-hydroxycamptothecin (±)-Trolox poly glycol monomethyl ether ester-6-succinate
1) synthetic (molecular-weight average of poly glycol monomethyl ether: Mn=550) of (±)-Trolox poly glycol monomethyl ether ester
Reaction formula is
Experimental procedure:
In the reaction flask of 100mL, add 2.20g (4mmol) poly glycol monomethyl ether (molecular-weight average is Mn=550), 1.45g (12mmol) DMAP, 1.53g (6mmol) 2-chloro-1-picoline iodide and 30mL dioxane, induction stirring, slowly in reaction solution, drip 1.00g (4mmol) (±)-6-hydroxyl-2,5, the solution of 7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid and 30mL dioxane.Under the protection of room temperature and nitrogen, react 12h; the overanxious solid matter of removing; with Rotary Evaporators, worry liquid is concentrated into 10mL; (230-400mesh silica gel is stationary phase to chromatography; the mixed liquid of hexane and acetone is leacheate) 1627mg (±)-6-hydroxyl-2,5,7; 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid poly glycol monomethyl ether ester, yield 52.0%.
Synthetic its mass spectrum of compound and the proton nmr spectra obtaining is shown in Fig. 7 and Fig. 8.
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, the 1079.4 (polymerization degree: 7-15).
1H NMR(400MHz,CDCl
3):δppm: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) synthetic (the poly glycol monomethyl ether molecular-weight average: Mn=550) of (±)-Trolox poly glycol monomethyl ether ester-6-monomester succinate
Reaction formula is as follows:
Experimental procedure:
In the reaction flask of 100mL, add 1564mg (2mmol) (±)-6-hydroxyl-2, 5, 7, 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid poly glycol monomethyl ether ester, 300mg (3mmol) succinyl oxide, 100mg 2 ethyl hexanoic acid tin (II) and 50mL anhydrous dimethyl benzene, reflux 8h under the protection of nitrogen, the overanxious solid matter of removing, (230-400mesh silica gel is stationary phase to chromatography, the mixed liquid of methylene dichloride and acetone is leacheate) 1423mg (±)-6-hydroxyl-2, 5, 7, 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid poly glycol monomethyl ether ester-6-monomester succinate, yield 80.7%.
Synthetic its mass spectrum of compound and the proton nmr spectra obtaining is shown in Fig. 9 and Figure 10.
MS (Positive ESI): m/z=(M+Na)
+: 695.4,739.4,783.4,827.4,871.5,915.5,959.5,1003.6, the 1047.6 (polymerization degree: 7-15).
1H NMR(400MHz,CDCl
3):δppm:4.239-4.156(m,2H),3.661-3.382(m,47H),3.345(s,3H),2.894-2.862(t,J=6.4Hz,2H),2.751-2.721(t,J=6.0Hz,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) synthetic (the poly glycol monomethyl ether molecular-weight average: Mn=550) of SN38 (±)-Trolox poly glycol monomethyl ether ester-6-succinate
Reaction formula is
Experimental procedure is as follows:
In the reaction flask of 50mL; add 1324mg (1.5mmol) (±)-6-hydroxyl-2; 5; 7; 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid poly glycol monomethyl ether ester-6-monomester succinate, 357mg (3mmol) thionyl chloride, 10 μ LN; dinethylformamide and 30mL dry toluene, induction stirring is reacted 4h under the protection of room temperature and nitrogen.Toluene and excessive thionyl chloride are removed in underpressure distillation, obtain a thick liquid, add 10mL anhydrous chloroform to obtain solution A.
In the reaction flask of 50mL; add 392mg (1mmol) SN38,121mg (1.2mmol) anhydrous triethylamine and the anhydrous N of 20mL; N-N,N-DIMETHYLACETAMIDE; stir; slowly add 6mL solution A, under the protection of room temperature and nitrogen, react 4h, tlc analysis; if still have a small amount of SN38 unreacted complete, then add appropriate solution A and triethylamine to reacting complete.(230-400mesh silica gel is stationary phase with Rotary Evaporators, worry liquid to be concentrated into 10mL chromatography, the mixed liquid of ethyl acetate and acetone is leacheate) 659mg SN38 (±)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid poly glycol monomethyl ether ester-6-succinate, yield 52.4%.
Synthetic its mass spectrum of compound and the proton nmr spectra obtaining is shown in Figure 11 and Figure 12.
MS (Positive ESI): m/z=(M+Na)
+: 1069.5,1113.5,1157.6,1201.6,1245.6,1289.6,1334.7,1377.7, the 1422.7 (polymerization degree: 7-15).
1H NMR(400MHz,CDCl
3):δppm:8.224-8.201(d,J=9.2Hz,1H),7.793(s,1H),7.626(s,1H),7.554-7.531(d,J=9.3Hz,1H),5.745-5.714(d,J=16Hz,1H),5.310-5.270(d,J=16Hz,1H),5.241(s,2H),4.218-4.197(t,J=4.2Hz,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=7.8Hz,3H),1.038-1.001(t,J=7.4Hz,3H)。
Embodiment 3.7-ethyl-10-hydroxycamptothecin N-methoxyl group seven polyoxamide R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-methane amide-6-succinate synthetic
The synthetic of described amphiphilic anti-cancer drug compounds comprises the following steps:
1) N-methoxyl group seven polyoxyethylene glycol amido R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-methane amide synthetic
Reaction formula is shown below:
Experimental procedure:
In the reaction flask of 50mL, add 825mg (4mmol) N, N '-dicyclohexyl carbodiimide (DCC), 1018mg (3mmol) methoxyl group seven polyoxamides, 751mg (3mmol) R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid and 10mLN, dinethylformamide.Induction stirring; under the protection of room temperature and nitrogen, react 12h; the overanxious solid matter of removing, is concentrated into 10mL with Rotary Evaporators by worry liquid, and (230-400mesh silica gel is stationary phase to chromatography; the mixed liquid of hexane and acetone is leacheate); obtain 1303mg N-methoxyl group seven polyoxyethylene glycol amido R-(+)-6-hydroxyl-2,5,7; 8-tetramethyl-benzo dihydropyrane-2-methane amide, yield 52.4%.
2) N-methoxyl group seven polyoxyethylene glycol amido R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-methane amide-6-monomester succinate synthetic
Reaction formula is as follows:
Experimental procedure:
In the reaction flask of 50mL, add 1143mg (2mmol) N-methoxyl group seven polyoxyethylene glycol amido R-(+)-6-hydroxyl-2, 5, 7, 8-tetramethyl-benzo dihydropyrane-2-methane amide, 300mg (3mmol) succinyl oxide, 100mg 2 ethyl hexanoic acid tin (II) and 50mL anhydrous dimethyl benzene, reflux 8h under the protection of nitrogen, the overanxious solid matter of removing, (230-400mesh silica gel is stationary phase to chromatography, the mixed liquid of hexane and acetone is leacheate) 1110mg N-methoxyl group seven polyoxyethylene glycol amido R-(+)-6-hydroxyl-2, 5, 7, 8-tetramethyl-benzo dihydropyrane-2-formyl-6-monomester succinate, yield 82.6%.
3) SN38 N-methoxyl group seven polyoxyethylene glycol amido R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-methane amide-6-succinate synthetic
Reaction formula is as follows:
Experimental procedure:
In the reaction flask of 50mL; add 672mg (1mmol) N-methoxyl group seven polyoxyethylene glycol amido R-(+)-6-hydroxyl-2; 5; 7; 8-tetramethyl-benzo dihydropyrane-2-formyl-6-monomester succinate, 238mg (2mmol) thionyl chloride, 10 μ LN; dinethylformamide and 20mL dry toluene, induction stirring is reacted 4h under the protection of room temperature and nitrogen.Toluene and excessive thionyl chloride are removed in underpressure distillation, obtain thick liquid, add 10mL anhydrous chloroform to obtain solution A.
In the reaction flask of 50mL; add 196mg (0.5mmol) SN38,61mg (0.6mmol) anhydrous triethylamine and the anhydrous N of 20mL; N-N,N-DIMETHYLACETAMIDE; induction stirring; slowly add 6mL solution A, under the protection of room temperature and nitrogen, react 4h, tlc analysis; if still have a small amount of SN38 unreacted complete, then add appropriate solution A and triethylamine to reacting complete.Reaction solution is joined in the ethyl acetate of 100mL, the overanxious solid matter of removing, again worry liquid is concentrated into 10mL, (230-400mesh silica gel is stationary phase to chromatography, the mixed liquid of hexane and acetone is leacheate) 661mg SN38 N-methoxyl group seven polyoxyethylene glycol amido R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-methane amide-6-succinate, yield 63.2%.
Embodiment 4. camptothecine N-methoxyl group seven polyoxamide R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-methane amide-6-succinate synthetic
Reaction formula is as follows:
Experimental procedure:
In the reaction flask of 50mL; add 672mg (1mmol) N-methoxyl group seven polyoxyethylene glycol amido R-(+)-6-hydroxyl-2; 5; 7; 8-tetramethyl-benzo dihydropyrane-2-methane amide-6-monomester succinate, 348mg (1.0mmol) camptothecine, 289mg (2.2mmol) DMAP, 281mg (1.1mmol) 2-chloro-1-picoline iodide and the anhydrous N of 20mL; N-N,N-DIMETHYLACETAMIDE, induction stirring is reacted 4h under the protection of room temperature and nitrogen.Reaction solution is joined in the ethyl acetate of 100mL, the overanxious solid matter of removing, again worry liquid is concentrated into 10mL, (230-400mesh silica gel is stationary phase to chromatography, the mixed liquid of hexane and acetone is leacheate) 716mg camptothecine N-methoxyl group seven polyoxyethylene glycol amido R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-methane amide-6-succinate, yield 79.5%.
Synthesizing of embodiment 5.7-ethyl-10-hydroxycamptothecin (±)-Trolox seven poly glycol monomethyl ether ester-6-oxo acetic ester
1) synthesizing of (±)-Trolox seven poly glycol monomethyl ether ester-6-fluoroacetic acid ethyl esters
Reaction formula is as follows:
Experimental procedure:
In the reaction flask of 50mL; add 1144mg (2mmol) (±)-6-hydroxyl-2; 5; 7; 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ether esters, 501mg (3mmol) ethyl bromoacetate, 652mg (2mmol) cesium carbonate and the anhydrous N of 25mL; dinethylformamide, induction stirring is reacted 12h under the protection of room temperature and nitrogen.N is removed in underpressure distillation, dinethylformamide, then add the ethyl acetate of 100mL, stir, the overanxious solid matter of removing, again worry liquid is concentrated into 10mL, chromatography (230-400mesh silica gel is stationary phase, and the mixed liquid of hexane and acetone is leacheate) obtains 1187mg (±)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid, seven poly glycol monomethyl ether ester-6-fluoroacetic acid ethyl esters, yield 90.1%.
2) synthesizing of (±)-Trolox seven poly glycol monomethyl ether ester-6-fluoroacetic acid
Reaction formula is as follows:
Experimental procedure:
In the reaction flask of 50mL; add 1318mg (2mmol) (±)-6-hydroxyl-2; 5; 7; 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ether ester-6-fluoroacetic acid ethyl ester and 20mL methyl alcohol; induction stirring; then the solution that adds 51mg (2.1mmol) lithium hydroxide and 5mL water; induction stirring; under the protection of room temperature and nitrogen, react about 2h to (±)-6-hydroxyl-2; 5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid, seven poly glycol monomethyl ether ester-6-fluoroacetic acid ethyl ester complete reactions.Methyl alcohol is removed in underpressure distillation, dripping 0.1NHCl is 3-4 to the pH value of solution, lyophilize, then add the ethyl acetate of 10mL, stir, the overanxious solid matter of removing, chromatography (230-400mesh silica gel is stationary phase, and the mixed liquid of hexane and acetone is leacheate) obtains 1215mg (±)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid, seven poly glycol monomethyl ether ester-6-fluoroacetic acid, yield 96.3%.
3) SN38 (±)-Trolox seven poly glycol monomethyl ether ester-6-fluoroacetic acid esters is synthetic
Reaction formula is as follows:
Experimental procedure:
In the reaction flask of 50mL; add 392mg (1mmol) SN38,269mg (2.2mmol) DMAP, 281mg (1.1mmol) 2-chloro-1-picoline iodide and the anhydrous N of 20mL; N-N,N-DIMETHYLACETAMIDE; induction stirring; slowly add 616mg (1mmol) (±)-6-hydroxyl-2; 5; 7; the solution of 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ether ester-6-fluoroacetic acid and 10mL chloroform reacts 4h under the protection of room temperature and nitrogen.The overanxious solid matter of removing, again worry liquid is evaporated to 10mL, (230-400mesh silica gel is stationary phase to chromatography, the mixed liquid of hexane and acetone is leacheate) 574mg SN38 (±)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid, seven poly glycol monomethyl ether ester-6-fluoroacetic acid esters, yield 58.0%.
Synthesizing of embodiment 6. camptothecine (±)-Trolox seven poly glycol monomethyl ether ester-6-fluoroacetic acid esters
Reaction formula is as follows:
Experimental procedure:
In the reaction flask of 50mL; add 348mg (1mmol) camptothecine, 269mg (2.2mmol) DMAP, the chloro-1-picoline of 281mg (1.1mmol) 2-iodide, 616mg (1mmol) (±)-6-hydroxyl-2; 5; 7; 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ether ester-6-fluoroacetic acid and the anhydrous N of 20mL; N-N,N-DIMETHYLACETAMIDE, induction stirring is reacted 4h under the protection of room temperature and nitrogen.The overanxious solid matter of removing, again worry liquid is evaporated to 10mL, (230-400mesh silica gel is stationary phase to chromatography, the mixed liquid of hexane and acetone is leacheate) 824mg camptothecine R-(±)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid, seven poly glycol monomethyl ether ester-6-fluoroacetic acid esters, yield 87.0%.
Synthesizing of embodiment 7. camptothecine (±)-Trolox seven poly glycol monomethyl ether ester-6-methyl phosphonic esters
Reaction formula is as follows:
Experimental procedure:
In the reaction flask of 100mL, add 290mg (2.2mmol) methyl phosphonyl dichloride and 10mL anhydrous diethyl ether, induction stirring, slowly drip again 1117mg (2mmol) (±)-6-hydroxyl-2, 5, 7, 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ether esters, the solution of 202mg (2mmol) anhydrous triethylamine and 20mL anhydrous diethyl ether, under the protection of room temperature and nitrogen, react 8h, ether is removed in underpressure distillation, vacuum-drying obtains 1287mg (±)-6-hydroxyl-2, 5, 7, 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ether ester-6-methylphosphine acyl chlorides esters, yield 98.4%.
In the reaction flask of 50mL; add 348mg (1mmol) camptothecine and the anhydrous N of 20mL; N-N,N-DIMETHYLACETAMIDE induction stirring; add again 121mg (1.2mmol) triethylamine, 721mg (1.1mmol) (±)-6-hydroxyl-2; 5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid, seven poly glycol monomethyl ether ester-6-methylphosphine acyl chlorides ester and the anhydrous N of 20mL; the solution of N-N,N-DIMETHYLACETAMIDE reacts 4h under the protection of room temperature and nitrogen.The overanxious solid matter of removing, again worry liquid is evaporated to 10mL, (230-400mesh silica gel is stationary phase to chromatography, the mixed liquid of hexane and acetone is leacheate) camptothecine (±)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid, seven poly glycol monomethyl ether ester-6-methyl phosphonic esters.
The preparation of embodiment 8. amphiphilic anti-cancer drug compounds
The present embodiment comprises the injection liquid that water or physiological saline are made, and the Micellar Solution Which Is making with tensio-active agent.In pharmaceutical formulation, contain various amphiphilic anti-cancer drug compounds of the present invention, the content of each component in formula counts by weight percentage.
Amphiphilic anti-cancer drug compounds of the present invention can make respectively following different preparation as required, with SN38 R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid methoxyl group seven macrogol esters-6-succinate is example, comprising:
A.7-the aqueous solution injection liquid of ethyl-10-hydroxycamptothecin R-(+)-Trolox methoxyl group seven macrogol esters-6-succinate
By SN38 R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid methoxyl group seven macrogol esters-6-succinate (MXL-4) is dissolved in deionized water, stirs the composed as follows of the rear injection liquid of producing:
MXL-004 0.1%
Deionized water 99.9%.
The injection liquid of making filters by the strainer of 0.2 micron, reinstalls in aseptic vial.
B.7-the normal saline solution of ethyl-10-hydroxycamptothecin R-(+)-Trolox methoxyl group seven macrogol esters-6-succinate
By SN38 R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid methoxyl group seven macrogol esters-6-succinate (MXL-4) is dissolved in physiological saline, stirs the composed as follows of the rear injection liquid of producing:
MXL-004 1%
Physiological saline 99%.
The injection liquid of making filters by the strainer of 0.2 micron, reinstalls in aseptic vial.
C.7-the Micellar Solution Which Is of ethyl-10-hydroxycamptothecin R-(+)-Trolox methoxyl group seven macrogol esters-6-succinate
By SN38 R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid methoxyl group seven macrogol esters-6-succinate (MXL-4) is dissolved in the mixed solution of tween 80 (Tween 80), ethanol and polyoxyethylene glycol PEG (200), obtain transparent liquid, add again deionized water (DI water), then stir, the Micellar Solution Which Is of producing composed as follows:
MXL-004 0.1%
Tween 80 2%
Ethanol 10%
PEG200 5%
Deionized water to 100%.
The Micellar Solution Which Is of making filters by the strainer of 0.2 micron, reinstalls aseptic vial.
D.7-the Micellar Solution Which Is of ethyl-10-hydroxycamptothecin R-(+)-Trolox methoxyl group seven macrogol esters-6-succinate
By SN38 R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid methoxyl group seven macrogol esters-6-succinate (MXL-4) is dissolved in the mixed solution of D-alpha-tocopherol cetomacrogol 1000 succinate (TPGS), ethanol and polyoxyethylene glycol PEG (200), obtain transparent liquid, add again deionized water (DI water), then stir, the Micellar Solution Which Is of producing composed as follows:
MXL-004 1%
TPGS 5%
Ethanol 5%
PEG200 5%
Deionized water to 100%.
The Micellar Solution Which Is of making filters by the strainer of 0.2 micron, reinstalls aseptic vial.
The vitro cytotoxicity experiment of embodiment 9. amphiphilic anti-cancer drug compounds
In the present embodiment, by XTT method, detect amphiphilic PTS compounds of the present invention and suppress human ovarian cancer (A2780s), colon cancer cell (HT-29), liver cancer HePG
2and the GI50 value of lung carcinoma cell (A549) cell (drug level of anticancer 50% growth), and contrast with anticarcinogen irinotecan (irinotican), evaluate the vitro cytotoxicity of medical compounds.
Experimental result shows, anti-cancer drug compounds of the present invention is to human ovarian cancer (A2780s) cell, colon cancer cell (HT-29), liver cancer (HePG
2) cell and lung carcinoma cell (A549) have obvious inhibited proliferation, and along with the increase of drug level, its inhibited proliferation to cell strengthens, and is obvious dose-dependent effect.Compare with the positive drug irinotecan (Irinotecan) of same concentration, anti-cancer drug compounds of the present invention is more obvious to human body ovarian cancer, colorectal carcinoma, liver cancer and lung carcinoma cell inhibition.Anti-cancer drug compounds of the present invention has inhibition Proliferation of Human Ovarian Cell (A2780s) colon cancer cell (HT-29), liver cancer (HePG
2) proliferation function of cell and lung carcinoma cell (A549), be the medical compounds that a class has potential anti-human ovarian carcinoma, colorectal carcinoma, liver cancer and lung cancer effect.Take MXL-004 as example, and its GI50 value is as shown in table 1, and anti-cancer drug compounds of the present invention is compared with irinotecan, has equally the GI50 value of obvious reduction.
Mtt assay detection method: the cell in the vegetative period of taking the logarithm, adjusting cell density is 10
5individual/mL, is inoculated in 96 well culture plates, and 100 μ L/ holes, change nutrient solution after cell cultures 18h, add respectively the drug sample of different concns, 150 μ L/ holes.Take that only to add the hole that does not add cell containing the RPMI RPMI-1640 of 10% calf serum be blank group (for zeroing), negative control group adds the RPMI RPMI-1640 of equal-volume 10% calf serum, and positive controls adds equal-volume 13ug/ml positive drug.Each group is established 3 multiple holes above.Cell continues to cultivate 72h, adds MTT (5mg/mL) solution 15 μ L/ holes, continues to cultivate 4h.Supernatant liquor is abandoned in suction, adds DMSO 150 μ L/ holes, and vibration mixes 10min, after dissolving completely to be crystallized, detects the absorbancy that wavelength is each hole, 490nm place (D) value in microplate reader.Calculate as follows the growth inhibition ratio of cell: inhibitory rate of cell growth=(the average D value of the average D value/control group of 1-experimental group) * 100%.
The contrast of table 1. new anti-cancer drug thing MXL-004 and anticarcinogen irinotecan GI50
MXL-004:7-ethyl-10-hydroxycamptothecin R-(+)-Trolox methoxyl group seven macrogol esters-6-succinate.
Claims (10)
1. an amphiphilic anti-cancer drug compounds for watermiscible vitamin E Derivatives Modified, has the structure of following formula I or II:
Wherein:
R is polyalkylene glycol monoalkyl ether; Be selected from
A) poly glycol monomethyl ether base-(CH
2cH
2o)
n-CH
3;
B) polyethyleneglycol ether base-(CH
2cH
2o)
n-CH
2cH
3;
C) polyethyleneglycol propyl ether base-(CH
2cH
2o)
n-CH
2cH
2cH
3;
D) polyoxyethylene glycol monobutyl ether base-(CH
2cH
2o)
n-CH
2cH
2cH
2cH
3;
N=1-200 wherein;
R
1being link group, is one of following radicals:
A)-P (=O) (R ')-, wherein R ' is C1-C6 alkyl or C1-C6 alkoxyl group;
B)-(C=O) (CH
2)
n(C=O)-, n=1-10 wherein;
c)-(C=O)CH
2-O-CH
2(C=O)-;
D)-(CH
2)
n(C=O)-, n=1-10 wherein;
X is-O-or-NH-;
R
2h or C1-C6 alkyl;
R
3, R
4h.
2. the amphiphilic anti-cancer drug compounds of watermiscible vitamin E Derivatives Modified according to claim 1, is characterized in that, has the structure of following formula I or II:
In formula I, R
2be H or-CH
2cH
3.
3. the amphiphilic anti-cancer drug compounds of watermiscible vitamin E Derivatives Modified according to claim 1 and 2, is characterized in that, in described amphiphilic anti-cancer drug compounds, watermiscible vitamin E is selected from its optical isomer or racemic modification.
4. a preparation method for the amphiphilic anti-cancer drug compounds of watermiscible vitamin E Derivatives Modified claimed in claim 1, comprises the following steps:
1) watermiscible vitamin E and alkoxyl group polyoxyethylene glycol or the generation esterification of alkoxyl group polyoxamide or amidate action, generate watermiscible vitamin E ester or watermiscible vitamin E acid amides;
2) phenolic hydroxyl group of watermiscible vitamin E ester or watermiscible vitamin E acid amides be connected molecule generation esterification or etherification reaction, generate the derivative of watermiscible vitamin E ester or the derivative of watermiscible vitamin E acid amides;
3) the step 2) derivative of the derivative of resulting watermiscible vitamin E ester or watermiscible vitamin E acid amides, or their chloride product, with camptothecine or derivatives thereof generation esterification, generate the amphiphilic anti-cancer drug compounds of watermiscible vitamin E Derivatives Modified;
In described alkoxyl group polyoxyethylene glycol or alkoxyl group polyoxamide, the carbonatoms of alkoxyl group is C1-C4, and the polymerization degree of polyoxyethylene glycol is 1-200;
Described camptothecine or derivatives thereof has structure shown in following formula, wherein R
2h or C1-C6 alkyl, R
3h, R
4h or OH;
Described connection molecule is one of following molecule that contains two above active groups:
(1) phosphinylidyne dichloro alkyl ester or alkoxy ester O=POR ' Cl
2, wherein R ' is C1-C6 alkyl or C1-C6 alkoxyl group;
(2) di-carboxylic acid (CH
2)
n(COOH)
2or cyclic acid anhydride
n=1-10 wherein;
(3) diglycollic acid or anhydride diethylene glycol;
(4) halogenated carboxylic acid or halogenated carboxylic ester Z-(CH
2)
ncOOR ', n=1-10 wherein, Z is Cl, Br or I, R ' is methyl or ethyl.
5. the preparation method of the amphiphilic anti-cancer drug compounds of watermiscible vitamin E Derivatives Modified according to claim 4, is characterized in that, described method comprises the following steps:
1) take the chloro-1-picoline of DMAP and 2-iodide is catalyzer, or with N, N '-dicyclohexyl carbodiimide and DMAP are catalyzer, and watermiscible vitamin E reacts with alkoxyl group polyoxyethylene glycol, generate watermiscible vitamin E ester; Or with N, N '-dicyclohexyl carbodiimide is catalyzer, watermiscible vitamin E reacts with alkoxyl group polyoxamide, generates watermiscible vitamin E acid amides;
2) watermiscible vitamin E ester or watermiscible vitamin E acid amides one of by the following method, and are connected molecule generation esterification or etherification reaction, generate the derivative of watermiscible vitamin E ester or the derivative of watermiscible vitamin E acid amides:
A) to take 2 ethyl hexanoic acid tin (II) or cesium carbonate be catalyzer for watermiscible vitamin E ester or watermiscible vitamin E acid amides, with cyclic acid anhydride
or diglycollic acid anhydride reactant; Or with DMAP and the chloro-1-picoline of 2-iodide, or N, N '-dicyclohexyl carbodiimide and DMAP are catalyzer, with excessive di-carboxylic acid (CH
2)
n(COOH)
2or diglycollic acid reaction, generate respectively the derivative of watermiscible vitamin E ester or the derivative of watermiscible vitamin E acid amides;
B) watermiscible vitamin E ester or watermiscible vitamin E acid amides be take alkali as catalyzer, with the derivative of halogenated carboxylic acid water generation reaction soluble vitamin E ester or the derivative of watermiscible vitamin E acid amides; Or react with halogenated carboxylic ester, after the de-alkyl of product, generate the derivative of watermiscible vitamin E ester or the derivative of watermiscible vitamin E acid amides;
C) watermiscible vitamin E ester or watermiscible vitamin E acid amides be take alkali as catalyzer, react with alkyl phosphonyl dichloride, alkoxyl group phosphonyl dichloride or aryl phosphonyl dichloride, generate the derivative of watermiscible vitamin E ester or the derivative of watermiscible vitamin E acid amides;
3) step 2) a) or b) derivative of resulting watermiscible vitamin E ester or the derivative of watermiscible vitamin E acid amides react generation chloride product with thionyl chloride or thionyl chloride;
4) step 2) a) or b) derivative of resulting watermiscible vitamin E ester or the derivative of watermiscible vitamin E acid amides be with DMAP and the chloro-1-picoline of 2-iodide, or N, N '-dicyclohexyl carbodiimide and DMAP are catalyzer, react with camptothecine or derivatives thereof, generate the amphiphilic anti-cancer drug compounds of watermiscible vitamin E Derivatives Modified; Or
5) step 3) resulting chloride product, or step 2) in c) derivative of resulting watermiscible vitamin E ester or the derivative of watermiscible vitamin E acid amides, take alkali as catalyzer, react with camptothecine or derivatives thereof; Generate the amphiphilic anti-cancer drug compounds of watermiscible vitamin E Derivatives Modified;
Alkaline catalysts described in above step is selected from triethylamine, pyridine, sodium carbonate, salt of wormwood or cesium carbonate.
6. an amphiphilic anti-cancer drug compounds injection for watermiscible vitamin E Derivatives Modified claimed in claim 1, comprises:
1) there is the amphiphilic anti-cancer drug compounds of the watermiscible vitamin E Derivatives Modified of formula I or II structure;
2) water or physiological saline.
7. the amphiphilic anti-cancer drug compounds injection of watermiscible vitamin E Derivatives Modified according to claim 6, is characterized in that, in described injection, medical compounds weight percentage in formula is 0.005% to 5.0%.
8. an amphiphilic anti-cancer drug compounds micell formulations for watermiscible vitamin E Derivatives Modified claimed in claim 1, comprises:
1) there is the amphiphilic anti-cancer drug compounds of the watermiscible vitamin E Derivatives Modified of formula I or II structure;
2) tensio-active agent;
3) solvent;
4) water.
9. the amphiphilic anti-cancer drug compounds micell formulations of watermiscible vitamin E Derivatives Modified according to claim 8, is characterized in that, in described micell formulations, medical compounds weight percentage in formula is 0.005% to 5.0%; The weight percentage of tensio-active agent is 1% to 10%, and solvent accounts for 2% to 20% of formulation weight.
10. the application of the amphiphilic anti-cancer drug compounds of the watermiscible vitamin E Derivatives Modified of claim 1 in preparing cancer therapy drug.
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PCT/CN2012/083159 WO2013067881A1 (en) | 2011-11-11 | 2012-10-18 | Water-soluble vitamin e derivative-modified amphiphilic anticancer medicament compound and preparation, method for preparing the compound, and application thereof |
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CN105315294B (en) * | 2014-06-26 | 2018-05-01 | 王杭祥 | 7-Ethyl-10-hydroxycamptothecin prodrug and its preparation method and application |
CN104817574B (en) * | 2015-05-26 | 2016-12-14 | 遵义医学院 | Camptothecin derivative and antitumor application thereof |
CN105399757A (en) * | 2015-12-29 | 2016-03-16 | 遵义医学院 | Acid-sensitive camptothecin-site 20 norcantharidate derivative and antineoplastic application thereof |
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CN105820188A (en) * | 2016-02-22 | 2016-08-03 | 刘天军 | Medicinal preparation containing tenofovir disoproxil fumarate (vitamin E), and use thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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CN1875022A (en) * | 2003-10-29 | 2006-12-06 | 搜讷斯医药股份有限公司 | Tocopherol-modified therapeutic drug compounds |
CN102060991A (en) * | 2010-11-26 | 2011-05-18 | 浙江大学 | Amphiphilic prodrug of 7- ethyl-10-hydroxycamptothecin and preparation method thereof |
CN102070644A (en) * | 2009-11-24 | 2011-05-25 | 江苏正大天晴药业股份有限公司 | Method for preparing camptothecin derivatives and intermediates thereof |
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KR101493125B1 (en) * | 2008-11-24 | 2015-02-12 | 세다르스-신나이 메디칼 센터 | Antioxidant camptothecin derivatives and antioxidant antineoplastic nanospheres thereof |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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CN102070644A (en) * | 2009-11-24 | 2011-05-25 | 江苏正大天晴药业股份有限公司 | Method for preparing camptothecin derivatives and intermediates thereof |
CN102060991A (en) * | 2010-11-26 | 2011-05-18 | 浙江大学 | Amphiphilic prodrug of 7- ethyl-10-hydroxycamptothecin and preparation method thereof |
Non-Patent Citations (2)
Title |
---|
A Versatile Prodrug Approach for Liposomal Core-Loading of Water-Insoluble Camptothecin Anticancer Drugs;Xinli Liu,等;《J.AM.CHEM.SOC.》;20020607;第124卷(第26期);第7651页路线1 * |
Xinli Liu,等.A Versatile Prodrug Approach for Liposomal Core-Loading of Water-Insoluble Camptothecin Anticancer Drugs.《J.AM.CHEM.SOC.》.2002,第124卷(第26期),第7651页路线1. * |
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