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CN102491981A - 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 PDF

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CN102491981A
CN102491981A CN2011103563936A CN201110356393A CN102491981A CN 102491981 A CN102491981 A CN 102491981A CN 2011103563936 A CN2011103563936 A CN 2011103563936A CN 201110356393 A CN201110356393 A CN 201110356393A CN 102491981 A CN102491981 A CN 102491981A
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watermiscible vitamin
ester
verivate
cancer drug
vitamin
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张跃华
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NANJING MEIXINING MEDICAL TECHNOLOGY Co Ltd
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NANJING MEIXINING MEDICAL TECHNOLOGY Co Ltd
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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 an application for the medicine compound.

Description

The preparation method and the application of the amphiphilic anti-cancer drug compounds of watermiscible vitamin E derivative modified and preparation, this compound
Technical field
The present invention relates to a kind of new anti-cancer drug compounds; The amphiphilic anti-cancer drug compounds that particularly relates to a kind of watermiscible vitamin E derivative modified comprises the preparation, preparation method of this compound and as the application of cancer therapy drug.
Background technology
Many compounds with antitumour activity since water insoluble with (or) other biocompatible solvent, or poor stability has become an obstacle of drug development in water and biocompatible solvent, often causes the drug development time lag.According to estimates, nearly 40 percent through the candidate drug compounds that filters out with potential value because its poorly water-soluble is rejected entering preparation research and development phase, and 30 percent existing medicine is an insoluble.Current have among few techniques researching and developing; To solve the problem of medical compounds poor solubility, these technology comprise the coordination agent technology that increases solubleness, nano particle technology; Microemulsion technology; Strengthen the preparation technique of solubleness, fat-soluble and water-soluble prodrug technology and new type of polymer drug delivery technologies etc.
NSC 94600 (20 (s)-camptothecin; Formula 1,1) and verivate have good antitumor activity, be one type of important DNA topoisomerase I (Top I) suppressor factor; They can combine with Top I-DNA cleavable mixture; Form CPT-Top I-DNA ternary complex, thereby stablize the cleavable mixture, cause necrocytosis.But, finally fail to get into clinical because of its poorly soluble and big problem of toxicity in water and other biological compatible solvent.In order to improve the antitumor characteristic of the water-soluble of medicine and reservation parent compound, many camptothecin derivatives have been synthesized.Yet, have only verivate TPT (Topotecan, formula 1,2) and irinotecan (Irinotrcan, formula 1,3) to be got into clinical and gone on the market by FDA approval, be respectively applied for treatment ovarian cancer, lung cancer and the rectum cancer.But TPT and irinotecan have significant disadvantages, comprise that in vivo short and toxic side effect of transformation period is big etc.At present, there are a plurality of camptothecin derivatives to be in the clinical study stage.
In addition, the E lactonic ring in the camptothecin molecule is NSC 94600 and the necessary functional group of verivate antitumour activity thereof, can rapid open loop under alkalescence or physiological condition and cause active disappearance (formula 2).The experiment proof; There are balance in lactonic ring structure and open loop structure in blood plasma, and human plasma albumen preferentially combines with the open loop structure molecule, impel balance to shift to the open loop form; Cause medicine effective concentration in blood plasma to reduce, and then reduced the anti-tumor activity of this compounds.Further research confirms that the open loop structure formula is the root that causes untoward reaction, as causes bone marrow depression, vomiting and diarrhoea etc.
Figure BDA0000107473090000021
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，
Figure BDA0000107473090000022
The chemical structure of formula 1 NSC 94600, TPT (topotecan) and irinotecan (irinotecan).
Figure BDA0000107473090000023
Formula 2 NSC 94600s are in lactonic ring structure under alkalescence or the physiological condition and the balance between open loop structure.
In order to improve the solubleness of medicine; Emulsion (Emulsion) and micella technology such as (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 NSC 94600, because its solvability extreme difference in water and organic solvent.Therefore, still need research and develop new camptothecin derivative, existing higher anti-cancer activity has solvability and stability preferably again.
The invention provides a series of new amphiphilic camptothecin derivatives, they all have solvability preferably in the organic solvent of water and biocompatibility, and directly water-soluble or saline water, or employing preparation technique is processed 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 spinoff.
Summary of the invention
The object of the present invention is to provide a kind of new amphiphilic anti-cancer drug compounds; This type has the compound of antitumour activity both can be water-soluble; Also can be dissolved in the close ester property solvent of biocompatibility, this compounds is NSC 94600 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 compound method of described amphiphilic anti-cancer drug compounds.
Another object of the present invention also is to provide the compsn that comprises described amphiphilic cancer therapy drug; With described amphiphilic anti-cancer drug compounds is activeconstituents; Directly water-soluble or saline water is processed injection liquid, perhaps medical compounds, cosolvent, tensio-active agent and water is processed micella liquid.
Simultaneously, another object of the present invention also is to provide the application of said compound in the preparation cancer therapy drug.
Amphiphilic anti-cancer drug compounds of the present invention; Be a kind of NSC 94600 or camptothecin derivative of watermiscible vitamin E derivative modified; This compounds both can water-solublely also can be dissolved in the close ester property solvent of biocompatibility; Described compound contains cancer therapy drug active part and parents' part; The cancer therapy drug active part is medical compounds molecule NSC 94600 or the camptothecin derivative with antitumour activity, and parents partly are watermiscible vitamin E alkoxyl group macrogol ester or acid amides, and amphiphilic watermiscible vitamin E alkoxyl group macrogol ester or amide molecule pass through linking group (like amber base: succinyl; Glutaryl-: glutaryl, glycol ether acyl group: oxydiacetyl, diglycoloyl, diglycolyl; Methylene radical carbonyl: methylene carbonyl, methylphosphine acyl group, methylphosphono etc.) forms amphiphilic anti-cancer drug compounds of the present invention with anti-cancer drug compounds NSC 94600 (camptothecin) or derivatives thereof molecule covalent attachment.
Realize that the object of the invention adopts following technical scheme: a kind of amphiphilic anti-cancer drug compounds of watermiscible vitamin E derivative modified, its molecular formula can be represented with following general formula I or II:
Figure BDA0000107473090000031
Wherein, R is polyalkylene glycol monoalkyl ether (or alkoxyl group polyethylene glycol groups);
R 1Be the link group, be 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 the C1-C6 alkyl;
R 2Be H, C1-C6 alkyl or-Si (CH 3) 2TBu;
R 3Be H, NO 2,-CH 2N (CH 3) 2, NH 2Or
Figure BDA0000107473090000041
R 4Be H, C1-C6 alkyl or
Figure BDA0000107473090000042
Amphiphilic anti-cancer drug compounds of the present invention, parents partly are the watermiscible vitamin E verivates 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, and 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), be a kind of inhibitor as vitamin E, its structure is suc as formula shown in 3.Trolox has two kinds of optically active isomers, i.e. R-(+)-trolox (chemistry R-(+) by name-6-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-(-) by name-6-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-hydroxyl-2,5,7 by name, 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid, (±)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid).
Figure BDA0000107473090000051
The chemical structure of formula 3 watermiscible vitamin Es (trolox), wherein A:R-(+)-Trolox; B:S-(-)-Trolox; C: (±)-Trolox.
Watermiscible vitamin E in the 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 that generates with the alkoxyl group polyoxyethylene glycol, and their chemical structure is suc as formula shown in 4.Watermiscible vitamin E ester (trolox ester) has two kinds of optically active isomers equally, i.e. R-(+)-trolox ester (chemistry R-(+) by name-6-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-(-) by name-6-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-hydroxyl-2 by name; 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 in the molecular structure [(CH 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.
Figure BDA0000107473090000052
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 that generates with alkoxyl group (like methoxyl group, oxyethyl group, propoxy-, butoxy) polyoxamide, and their chemical structure is suc as formula shown in 5.Watermiscible vitamin E acid amides (trolox amide) has two kinds of optically active isomers equally, i.e. R-(+)-trolox amide (chemistry R-(+) by name-N-alkoxyl group polyoxyethylene glycol-6-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-(-) by name-N-alkoxyl group polyoxyethylene glycol-6-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 by name-6-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 the 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 1Be H or C1-C6 alkyl.
Figure BDA0000107473090000061
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 the amphiphilic anti-cancer drug compounds molecule of the present invention is known NSC 94600 or camptothecin derivative with antitumour activity, and its structural formula is suc as formula shown in 6, wherein R 2Be H, C1-C6 alkyl or-Si (CH 3) 2TBu;
R 3Be H, NO 2,-CH 2N (CH 3) 2, NH 2Or
Figure BDA0000107473090000062
R 4Be H, OH, C1-C6 alkyl or
Figure BDA0000107473090000063
Figure BDA0000107473090000071
The chemical structure of formula 6 NSC 94600s and camptothecin derivative molecule.
In the amphiphilic anti-cancer drug compounds molecule of the present invention; The preferred NSC 94600 (1 of antitumour activity part; Camptothecin), 10-hydroxycamptothecine (2; 10-hydroxycamptothecin) (3,7-ethyl-10-hydroxycamptothecin), its molecular structure is suc as formula shown in 7 with 7-ethyl-10-hydroxycamptothecine.
Figure BDA0000107473090000072
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. NSC 94600s 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 through the linking group covalent attachment.The cancer therapy drug active part is NSC 94600 or camptothecin derivative; Parents partly are watermiscible vitamin E alkoxyl group macrogol esters (or acid amides), and the phenolic hydroxyl group of the hydroxyl of NSC 94600 or camptothecin derivative (hydroxyl on phenolic hydroxyl group or the 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 of link molecule respectively.
Described linking group is to be provided by the link molecule that contains two or more reactive groups, for example: oxalyl chloride (O=CCl 2) provide carbonyl-(C=O)-, the phosphinylidyne dichloro ester (O=POR ' Cl 2) provide-P (=O) (OR ')-group, 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
Figure BDA0000107473090000073
Can provide amber base (succinyl), glutaryl-(glutaryl), glycol ether acyl group (oxydiacetyl, diglycoloyl, diglycolyl) etc.
Compare with the parent compound with antitumour activity (verivate of NSC 94600 or NSC 94600 is like 10-hydroxycamptothecine and 7-ethyl-10-hydroxycamptothecine), new anti-cancer drug compounds of the present invention has better hydrophilic and lipotropy (oleophilicity).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 through an ester bond with covalent bonds.
The invention still further relates to a kind of preparation method of amphiphilic anti-cancer drug compounds of described watermiscible vitamin E derivative modified, may further comprise the steps:
1) watermiscible vitamin E and alkoxyl group polyoxyethylene glycol or 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 and link molecule generation esterification or etherification reaction generate the verivate of watermiscible vitamin E ester or the verivate of watermiscible vitamin E acid amides;
3) the step 2) verivate of the verivate of resulting watermiscible vitamin E ester or watermiscible vitamin E acid amides; Perhaps their chloride product; With NSC 94600 or derivatives thereof generation esterification, generate the amphiphilic anti-cancer drug compounds of watermiscible vitamin E derivative modified;
Described link molecule is one of following molecule that contains two above reactive 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
Figure BDA0000107473090000081
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 an alkyl.
More specifically and optimally, described method may further comprise the steps:
1) be catalyzer with 4-Dimethylamino pyridine (DMAP) and 2-chloro-1-picoline iodide (CMPI); Or with N; N '-dicyclohexyl carbodiimide (DCC) and 4-Dimethylamino pyridine (DMAP) are catalyzer; Watermiscible vitamin E (1) and alkoxyl group polyoxyethylene glycol (2) reaction generate watermiscible vitamin E ester (3); Or with N, N '-dicyclohexyl carbodiimide (DCC) is a catalyzer, and watermiscible vitamin E (1) and alkoxyl group polyoxamide (8) reaction generate watermiscible vitamin E acid amides (9).
2) watermiscible vitamin E ester (3) or watermiscible vitamin E acid amides (9) with link molecule generation esterification or etherification reaction, generate the verivate of watermiscible vitamin E ester or the verivate of watermiscible vitamin E acid amides respectively by one of following method:
A) watermiscible vitamin E ester (3) or watermiscible vitamin E acid amides (9) are catalyzer with 2 ethyl hexanoic acid tin (II) or cesium carbonate, with cyclic acid anhydride
Figure BDA0000107473090000091
Or diglycollic acid anhydride reactant; Perhaps with 4-Dimethylamino pyridine (DMAP) and 2-chloro-1-picoline iodide (CMPI) or N, N '-dicyclohexyl carbodiimide (DCC) and 4-Dimethylamino pyridine (DMAP) are catalyzer, with excessive di-carboxylic acid (CH 2) n(COOH) 2Or the diglycollic acid reaction, generate the verivate (4) of watermiscible vitamin E ester or the verivate (10) of watermiscible vitamin E acid amides respectively;
B) watermiscible vitamin E ester (3) or watermiscible vitamin E acid amides (9) with alkali (like triethylamine, pyridine, yellow soda ash; Salt of wormwood, cesium carbonate) be catalyzer, with the verivate (15a of halogenated carboxylic acid water generation reaction soluble vitamin E ester; R '=H) or the verivate of watermiscible vitamin E acid amides (15a); Or with halogenated carboxylic ester reaction, (15b, R '=alkyl) generate the verivate (15a) of watermiscible vitamin E ester or the verivate (15a) of watermiscible vitamin E acid amides after taking off alkyl to product;
C) watermiscible vitamin E ester (3) or watermiscible vitamin E acid amides (9) with alkali (like triethylamine; Pyridine; Yellow soda ash, salt of wormwood, cesium carbonate) be catalyzer; With alkyl phosphonyl dichloride, alkoxyl group phosphonyl dichloride or the reaction of aryl phosphonyl dichloride, generate the verivate (19) of watermiscible vitamin E ester or the verivate (19) of watermiscible vitamin E acid amides;
D) watermiscible vitamin E ester (3) or watermiscible vitamin E acid amides (9) are catalyzer with alkali (like triethylamine or pyridine), with the oxalyl chloride reaction, generate the verivate of watermiscible vitamin E ester or the verivate of watermiscible vitamin E acid amides.
3) step 2) a) or b) verivate (4,15a) of resulting watermiscible vitamin E ester or the verivate of watermiscible vitamin E acid amides (10,15a) generate chloride product (5,11 or 16) respectively with the reaction of thionyl (two) cl cpd.
4) step 2) a) or b) verivate (4,15a) of resulting watermiscible vitamin E ester or the verivate of watermiscible vitamin E acid amides (10,15a) be with 4-Dimethylamino pyridine (DMAP) and 2-chloro-1-picoline iodide (CMPI) or N; N '-dicyclohexyl carbodiimide (DCC) and 4-Dimethylamino pyridine (DMAP) are catalyzer; Direct and NSC 94600 or derivatives thereof reacts, and generates the amphiphilic anti-cancer drug compounds (6,12,13,14,17 or 18) of watermiscible vitamin E derivative modified; Or
5) the resultant chloride product of step 3) (5,11 or 16); Or step 2) c in) or the d) verivate (19) of the verivate of resulting watermiscible vitamin E ester (19) or watermiscible vitamin E acid amides, with alkali (like triethylamine, pyridine; Yellow soda ash; Salt of wormwood, cesium carbonate) be catalyzer, direct and NSC 94600 or derivatives thereof reaction; Generate the amphiphilic anti-cancer drug compounds (6,12,13,14,17,18,20 or 21) of watermiscible vitamin E derivative modified.
Formula 8 a kind of synthetic route of having given an example; Watermiscible vitamin E (trolox) (1) and alkoxyl group polyoxyethylene glycol (2) (is example with the methoxy poly (ethylene glycol)) reaction; With 4-Dimethylamino pyridine (DMAP) and 2-chloro-1-picoline iodide (CMPI) is catalyzer, or with N, N '-dicyclohexyl carbodiimide (DCC) and 4-Dimethylamino pyridine (DMAP) are catalyzer; Generate watermiscible vitamin E ester (3); Watermiscible vitamin E ester (3) reacts with cyclic acid anhydride (like succinyl oxide, Pyroglutaric acid, anhydride diethylene glycol etc.) again, is catalyzer with 2 ethyl hexanoic acid tin (II) (or cesium carbonate), generates the verivate (4) of watermiscible vitamin E ester.Watermiscible vitamin E ester (3) also can react with the excessive compound with bifunctional (like diprotic acid such as succsinic acid, pentanedioic acid, diglycollic acid); With 4-Dimethylamino pyridine (DMAP) and 2-chloro-1-picoline iodide (CMPI) or N; N '-dicyclohexyl carbodiimide (DCC) and 4-Dimethylamino pyridine (DMAP) are catalyzer; Generate the verivate (4) of watermiscible vitamin E ester; Compound (4) then with the chloride derivative (5) of thionyl (two) cl cpd water generation reaction soluble vitamin E ester, then the acid chloride functional groups of compound (5) optionally with 10-hydroxyl substituted camptothecin, like the phenolic hydroxyl group reaction of 10-hydroxycamptothecine or 7-ethyl-10-hydroxycamptothecine; With alkali is catalyzer (like triethylamine), generates amphiphilic anti-cancer drug compounds of the present invention (6).The verivate of watermiscible vitamin E ester (4) also can be directly and the substituted NSC 94600 of 10-hydroxyl; Like 10-hydroxycamptothecine or 7-ethyl-10-hydroxycamptothecine reaction; With 4-Dimethylamino pyridine (DMAP) and 2-chloro-1-picoline iodide (CMPI) or N; N '-dicyclohexyl carbodiimide (DCC) and 4-Dimethylamino pyridine (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.
Shown in 9; Another kind of compound method for amphiphilic anti-cancer drug compounds of the present invention; The acid chloride functional groups of compound (5) under the effect of alkali (like triethylamine) with the lactonic ring of NSC 94600 (or derivatives thereof) on hydroxyl reaction, generate new anti-cancer drug compounds of the present invention (7).The verivate of watermiscible vitamin E ester (4) also can be directly and NSC 94600 (or derivatives thereof) reaction; With 4-Dimethylamino pyridine (DMAP) and 2-chloro-1-picoline iodide (CMPI) or N; N '-dicyclohexyl carbodiimide (DCC) and 4-Dimethylamino pyridine (DMAP) are catalyzer, generate anti-cancer drug compounds of the present invention (7).
Figure BDA0000107473090000111
The synthetic route 2 of the anti-cancer drug compounds that formula 9. is new.
Another compound method of amphiphilic anti-cancer drug compounds of the present invention is suc as formula shown in 10; Watermiscible vitamin E (trolox) (1) and alkoxyl group polyoxamide (8) reaction, with N, N '-dicyclohexyl carbodiimide (DCC) is a coupling agent; Generate watermiscible vitamin E acid amides (9); Watermiscible vitamin E acid amides (9) reacts with cyclic acid anhydride (like succinyl oxide, Pyroglutaric acid, anhydride diethylene glycol etc.) again, is catalyzer with 2 ethyl hexanoic acid tin (II), generates the verivate (10) of watermiscible vitamin E acid amides; Reactions such as compound (10) and NSC 94600,10-hydroxycamptothecine or 7-ethyl-10-hydroxycamptothecine then; With 4-Dimethylamino pyridine (DMAP) and 2-chloro-1-picoline iodide (CMPI) or N, N '-dicyclohexyl carbodiimide (DCC) and 4-Dimethylamino pyridine (DMAP) are catalyzer, generate new anti-cancer drug compounds of the present invention (12) respectively; (13), (14).Compound (10) also can with the chloride derivative (11) of 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; Phenolic hydroxyl group reaction like 10-hydroxycamptothecine or 7-ethyl-10-hydroxycamptothecine; Or with the lactonic ring of NSC 94600 (or derivatives thereof) on hydroxyl reaction, be catalyzer (like triethylamine) with alkali, generate amphiphilic anti-cancer drug compounds of the present invention (12), (13) and (14).
Figure BDA0000107473090000121
The synthetic route 3 of formula 10. new anti-cancer drug compounds.
The another kind of again compound method of amphiphilic anti-cancer drug compounds of the present invention suc as formula 11 with formula 12 shown in; With alkali (like triethylamine; Pyridine, yellow soda ash, salt of wormwood; Cesium carbonate) is catalyzer; Watermiscible vitamin E ester (3) or watermiscible vitamin E acid amides (9) and halogen (iodine, bromine, chlorine) generate the verivate (15a) of watermiscible vitamin E ester or acid amides for carboxylic acid (like monobromo-acetic acid), or generate (15b) with halogenated carboxylic ester (like bromoethyl acetate) reaction, (15b) with after the Lithium Hydroxide MonoHydrate reaction generate (15a) with s.t. again.(15a) generate chloride derivative 16 with the reaction of thionyl (two) chlorine; Then the acid chloride functional groups of compound 16 optionally with 10-hydroxyl substituted camptothecin; Phenolic hydroxyl group reaction like 10-hydroxycamptothecine or 7-ethyl-10-hydroxycamptothecine; Or with the lactonic ring of NSC 94600 (or derivatives thereof) on hydroxyl reaction, be catalyzer (like triethylamine) with alkali, generate amphiphilic anti-cancer drug compounds of the present invention (17) and (18).The verivate of watermiscible vitamin E ester or acid amides (15a) also can be directly and substituted NSC 94600 of 10-hydroxyl (like 10-hydroxycamptothecine or 7-ethyl-10-hydroxycamptothecine) or NSC 94600 reaction; With 4-Dimethylamino pyridine (DMAP) and 2-chloro-1-picoline iodide (CMPI) or N; N '-dicyclohexyl carbodiimide (DCC) and 4-Dimethylamino pyridine (DMAP) are catalyzer, generate amphiphilic anti-cancer drug compounds of the present invention (17) and (18) respectively.
Formula 13 has been described another compound method of amphiphilic anti-cancer drug compounds of the present invention; With alkali (like triethylamine; Pyridine, yellow soda ash, salt of wormwood; Cesium carbonate) is catalyzer, the verivate (19) of watermiscible vitamin E ester 3 or watermiscible vitamin E acid amides (9) and alkyl phosphonyl dichloride (like the methyl phosphonyl dichloride) or aryl phosphonyl dichloride (like phenyl phosphonyl chloride) water generation reaction soluble vitamin E ester or acid amides.Direct and the NSC 94600 or derivatives thereof reaction of compound (19); Generate amphiphilic anti-cancer drug compounds (20) and (21) of watermiscible vitamin E derivative modified.
The synthetic route 4 of formula 11. new anti-cancer drug compounds.
Figure BDA0000107473090000141
The synthetic route 5 of formula 12. new anti-cancer drug compounds.
Figure BDA0000107473090000142
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 type directly water-soluble or saline water is processed injection liquid, also can process 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 that adopts is that a kind of described amphiphilic anti-cancer drug compounds injection comprises:
1) has the amphiphilic anti-cancer drug compounds of the watermiscible vitamin E derivative modified of formula I or II structure;
2) water or saline water.
In the described injection, medical compounds weight percentage in prescription can be about 0.005% to 5.0%; The preferred weight percentage composition is about 0.01% to 3.5%; More preferably medical compounds weight percentage in prescription is about 0.1% to 2.0%.
Perhaps, a kind of described amphiphilic anti-cancer drug compounds micell formulations comprises:
1) has the amphiphilic anti-cancer drug compounds of the watermiscible vitamin E derivative modified of formula I or II structure;
2) tensio-active agent;
3) solvent;
4) water.
In the described micell formulations prescription, 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 is like Witconol 5909 EL (Cremophor EL), tween series of surfactants.
B) phosphatide tensio-active agent (phospholipids) is like Yelkin TTS (lecithin), polyoxyethylene glycol phosphatide (pegylated phospholipids).
C) polyoxyethylene glycol vitamin e derivative, as the 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, Ucar 35, glycerine, N-Methyl pyrrolidone etc.Polyoxyethylene glycol (PEG) is hydrophilic, and the chemical structure of repeating unit consists of-CH 2CH 2O-, general formula are H-(CH 2CH 2) n-OH, molecular weight ranges generally from 200 to 10000.For example, Macrogol 200, Liquid Macrogol, PEG 400 etc.
In the described micell formulations, medical compounds weight percentage in prescription is about 0.005% to 5.0%; The preferred weight percentage composition is about 0.01% to 3.5%; More preferably medical compounds weight percentage in prescription is about 0.1% to 2.0%.The weight percentage of suitable tensio-active agent in micell formulations is about 1 to 10%, preferred 2-6%; More preferably 4-5%.
The micell formulations prescription also comprises other composition, solvent as mentioned above.In one embodiment, comprise polyoxyethylene glycol and lower alkyl alcohol (like ethanol) in the micella prescription.Solvent accounts for 2% to 20% of formulation weight.
Comprise water in the micella prescription.In one embodiment, water comprises deionized water.In another embodiment, water comprises saline water.
The present invention also provides the application of neoteric medical compounds, the application of the amphiphilic anti-cancer drug compounds of promptly described watermiscible vitamin E derivative modified in the preparation cancer therapy drug.
For example, medical compounds of the present invention is used to prepare the medicine of treating cancer.Medical compounds of the present invention can be used for treating the cancer that comprises blood system, like white blood disease, and lymphoma, myelomatosis; With non-hematologic cancers, like solid tumor cancer (like mammary cancer, ovarian cancer, carcinoma of the pancreas, colorectal carcinoma, the rectum cancer, nonsmall-cell lung cancer, bladder cancer), sarcoma and glioma etc.
The curative effect of medical compounds of the present invention and toxicity are confirmed with cell in vitro or interior animal experiment; ED50 (50%effective dose for example; The 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(LD&-{50}):.Usually the ratio with medium lethal dose(LD&-{50}) (LD50)/median effective dose (ED50) is called therapeutic index, in order to the security of expression medicine.The medicine that the relative therapeutic index of the medicine that therapeutic index is big is little is safer.
Neoteric anti-cancer drug compounds is intended to improve the security of therapeutic index and medicine, also improves result of treatment simultaneously.Can be used for formulating the dosage range that is used for human body from the drug dose of cell in vitro experiment and interior animal experiment acquisition.The dosage of this compound is preferably in seldom or does not have in the toxic ED50 scope at all.Dosage changes the formulation depend on employing usually, patient's susceptibility and route of administration etc.Usually available identical or similar medicine is done reference like the routine dose of TPT and irinotecan.For example the routine dose of TPT is 0.2-1.5mg/m 2, irinotecan routine dose be 100mg-350mg/m 2
Medical compounds of the present invention can use separately, also can use with one or more other medicines.For example, when treatment for cancer, medical compounds of the present invention can use with following medicine, includes but not limited to: inhibitor for androgen, like flutamide (flutamide) and Lu Poruolide (luprolide); Estrogen antagonist is like tamoxifen (tomoxifen); Antimetabolite and cytotoxic drug are like 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), NSC-3053 (dactinomycin) and darubicin (idamycin); Hormone; Like Zytron (medroxyprogesterone), alkynes Theelin,dihydro-(ethinyl estradiol), Theelin,dihydro-(estradiol), leuprorelin (leuprolide), megestrol (megestrol), Sostatin (octreotide), stilboestrol (diethylstilbestrol), Chlortrianisoestrol (chlorotrianisene), etoposide (etoposide), podophyllotoxin (podophyllotoxin) and goserelin (goserelin); Nitrogen mustard derivatives, like phenyalamine mustard (melphalan), TV (chlorambucil) and plug for sending (thiotepa); Steroid is like Betamethasone Valerate (betamethasone); With other antitumor drugs, like cattle on the hoof mycobacterium (live Mycobacterium bovis), dicarbazine (dicarbazine), asparaginase (asparaginase), LEUCOVORIN ACETATE (leucovorin), mitotane (mitotane), vincristine(VCR) (vincristine), vinealeucoblastine(VLB) (vinblastine) and Docetaxel (taxotere) etc.
The present invention will have medical compounds molecule NSC 94600 or camptothecin derivative and watermiscible vitamin E alkoxyl group macrogol ester or the acid amides of antitumour activity through the linking group covalent attachment; Obtain the amphiphilic anti-cancer drug compounds of watermiscible vitamin E derivative modified; Described compound contains cancer therapy drug active part and parents' part, both can water-solublely also can be dissolved in the close ester property solvent of biocompatibility.New anti-cancer drug compounds of the present invention has higher anti-cancer activity, has solvability and stability preferably simultaneously, can improve NSC 94600 or derivatives thereof continuous action time (transformation period) and the curative effect under the physiological condition in vivo, reduces its toxic side effect.Described medical compounds can be processed injection or micell formulations, is widely used in the treatment of blood system and non-blood system cancer.The present invention can modify various NSC 94600s and verivate thereof, widens the Application Areas of NSC 94600 and verivate thereof, for the clinical application of NSC 94600 and verivate thereof provides a kind of new method and approach.
Describe the present invention below in conjunction with specific embodiment.Protection scope of the present invention is not exceeded with embodiment, but is limited claim.
Description of drawings
Fig. 1 R-(+)-6-hydroxyl-2,5,7, the mass spectrum of 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid methoxyl group seven macrogol esters.
Fig. 2 R-(+)-6-hydroxyl-2,5,7, the hydrogen nuclear magnetic resonance spectrogram of 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid methoxyl group seven macrogol esters.
Fig. 3 R-(+)-6-hydroxyl-2,5,7, the mass spectrum of 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-monomester succinate.
Fig. 4 R-(+)-6-hydroxyl-2,5,7, the hydrogen nuclear magnetic resonance spectrogram of 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-monomester succinate.
Figure 57-ethyl-10-hydroxycamptothecine R-(+)-6-hydroxyl-2,5,7, the mass spectrum of 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-succinate.
Figure 67-ethyl-10-hydroxycamptothecine R-(+)-6-hydroxyl-2,5,7, the hydrogen nuclear magnetic resonance spectrogram of 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-succinate.
Fig. 7 (±)-6-hydroxyl-2,5,7, the 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid poly glycol monomethyl ether ester (molecular-weight average of poly glycol monomethyl ether: mass spectrum Mn=550).
Fig. 8 (±)-6-hydroxyl-2,5,7, the 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid poly glycol monomethyl ether ester (molecular-weight average of poly glycol monomethyl ether: hydrogen nuclear magnetic resonance spectrogram Mn=550).
Fig. 9 (±)-6-hydroxyl-2,5,7, the 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid poly glycol monomethyl ether ester-6-monomester succinate (molecular-weight average of poly glycol monomethyl ether: mass spectrum Mn=550).
Figure 10 (±)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid 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-hydroxycamptothecine (±)-6-hydroxyl-2,5,7, the 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid poly glycol monomethyl ether ester-6-succinate (molecular-weight average of poly glycol monomethyl ether: mass spectrum Mn=550).
Figure 127-ethyl-10-hydroxycamptothecine (±)-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
Below embodiment be used for explaining synthetic, preparation and the cell in vitro experiment etc. of new anti-cancer drug compounds of the present invention.Described embodiment helps understanding of the present invention and enforcement are not constituted for restriction of the present invention.
Embodiment 1.7-ethyl-10-hydroxycamptothecine R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid methoxy poly (ethylene glycol) ester-6-succinate synthetic
The synthetic of said amphiphilic anti-cancer drug compounds may further comprise the steps:
1) R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid methoxyl group seven macrogol esters synthetic
Reaction formula is shown below:
Figure BDA0000107473090000181
Experimental procedure:
In the reaction flask of 50mL; Add 978mg (8mmol) 4-Dimethylamino pyridine, 1.022mg (4mmol) 2-chloro-1-picoline iodide and 1021mg (3mmol) seven poly glycol monomethyl ethers; Induction stirring slowly drips 751mg (3mmol) R-(+)-6-hydroxyl-2,5 in reaction solution; 7,8-tetramethyl-benzo dihydropyrane-2-carboxylic AcidAnd 10mLN, the solution of N-N.Under room temperature and protection of nitrogen gas, react 12h, the overanxious solid matter of removing will be considered liquid with Rotary Evaporators and will be concentrated into 10mL; The post layer separates (230-400mesh silica gel is stationary phase, and the mixed liquid of hexane and acetone is leacheate), gets 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 that obtains seen 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-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-monomester succinate synthetic
Reaction formula is following:
Figure BDA0000107473090000191
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 room temperature and protection of nitrogen gas.Reaction solution is joined in the ETHYLE ACETATE of 100mL, stir, this mixed solution is given a baby a bath on the third day after its birth inferior respectively with the 0.1NHCl solution of 50mL; Respectively with 50mL washing three times, organic phase is used anhydrous magnesium sulfate drying, the overanxious sal epsom of removing again; To consider liquid again and be concentrated into 10mL, the post layer separates (230-400mesh silica gel is stationary phase, and the mixed liquid of hexane and acetone is leacheate) and gets 962mg R-(+)-6-hydroxyl-2; 5; 7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-monomester succinate, yield 71.5%.
Synthetic its mass spectrum of compound and the proton nmr spectra that obtains seen 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) 7-ethyl-10-hydroxycamptothecine R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-succinate synthetic
Reaction formula is following:
Figure BDA0000107473090000201
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 ethers ester-6-monomester succinate, 238mg (2mmol) THIONYL CHLORIDE 97,10 μ LN; Dinethylformamide and 20mL dry toluene, induction stirring is reacted 4h under room temperature and protection of nitrogen gas.Toluene and excessive THIONYL CHLORIDE 97 are removed in underpressure distillation, obtain thick liquid, add the 10mL anhydrous chloroform and get solution A.
In the reaction flask of 50mL, add 196mg (0.5mmol) 7-ethyl-10-hydroxycamptothecine, 61mg (0.6mmol) anhydrous triethylamine and the anhydrous DMAC N,N of 20mL; Stir; Slowly add the 6mL solution A, under room temperature and protection of nitrogen gas, react 4h, tlc analysis; If still have a spot of 7-ethyl-10-hydroxycamptothecine unreacted intact, add an amount of solution A and triethylamine to reaction again and finish.Reaction solution is joined in the ETHYLE ACETATE of 100mL, with 50mL washing three times, organic phase is used anhydrous magnesium sulfate drying to this mixed solution with respectively; The overanxious sal epsom of removing will be considered liquid again and will be concentrated into 10mL, and (230-400mesh silica gel is stationary phase to the separation of post layer; The mixed liquid of hexane and acetone is leacheate) 277mg 7-ethyl-10-hydroxycamptothecine R-(+)-6-hydroxyl-2,5,7; 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-succinate, yield 53%.
Synthetic its mass spectrum of compound and the proton nmr spectra that obtains seen Fig. 5 and Fig. 6.
Figure BDA0000107473090000211
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)。
Embodiment 2.7-ethyl-10-hydroxycamptothecine (±)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid poly glycol monomethyl ether ester-6-succinate synthetic
1) (±)-6-hydroxyl-2,5,7, the synthetic (molecular-weight average of poly glycol monomethyl ether: Mn=550) of 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid poly glycol monomethyl ether ester
Reaction formula does
Figure BDA0000107473090000212
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) 4-Dimethylamino pyridine, 1.53g (6mmol) 2-chloro-1-picoline iodide and 30mL dioxane; Induction stirring slowly drips 1.00g (4mmol) (±)-6-hydroxyl-2,5 in reaction solution; 7, the solution of 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid and 30mL dioxane.Under room temperature and protection of nitrogen gas, react 12h, the overanxious solid matter of removing will be considered liquid with Rotary Evaporators and will be concentrated into 10mL; (230-400mesh silica gel is stationary phase to the separation of post layer; 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 that obtains seen 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) (±)-6-hydroxyl-2,5,7, synthetic (the poly glycol monomethyl ether molecular-weight average: Mn=550) of 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid poly glycol monomethyl ether ester-6-monomester succinate
Reaction formula is following:
Figure BDA0000107473090000222
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 protection of nitrogen gas; The overanxious solid matter of removing, post layer separate (230-400mesh silica gel is stationary phase, and the mixed liquid of methylene dichloride and acetone is leacheate) and get 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 that obtains seen 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) 7-ethyl-10-hydroxycamptothecine (±)-6-hydroxyl-2,5,7, synthetic (the poly glycol monomethyl ether molecular-weight average: Mn=550) of 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid poly glycol monomethyl ether ester-6-succinate
Reaction formula does
Experimental procedure is following:
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 97,10 μ LN; Dinethylformamide and 30mL dry toluene, induction stirring is reacted 4h under room temperature and protection of nitrogen gas.Toluene and excessive THIONYL CHLORIDE 97 are removed in underpressure distillation, obtain a thick liquid, add the 10mL anhydrous chloroform and get solution A.
In the reaction flask of 50mL, add 392mg (1mmol) 7-ethyl-10-hydroxycamptothecine, 121mg (1.2mmol) anhydrous triethylamine and the anhydrous DMAC N,N of 20mL; Stir; Slowly add the 6mL solution A, under room temperature and protection of nitrogen gas, react 4h, tlc analysis; If still have a spot of 7-ethyl-10-hydroxycamptothecine unreacted intact, add an amount of solution A and triethylamine to reaction again and finish.To consider liquid with Rotary Evaporators is concentrated into 10mL post layer and separates that (230-400mesh silica gel is stationary phase; The mixed liquid of ETHYLE ACETATE and acetone is leacheate) 659mg 7-ethyl-10-hydroxycamptothecine (±)-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 that obtains seen Figure 11 and Figure 12.
Figure BDA0000107473090000232
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-hydroxycamptothecine N-methoxyl group seven polyoxamide R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-methane amide-6-succinate synthetic
The synthetic of said amphiphilic anti-cancer drug compounds may further comprise the 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:
Figure BDA0000107473090000241
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 is reacted 12h under room temperature and protection of nitrogen gas, the overanxious solid matter of removing; To consider liquid with Rotary Evaporators and be concentrated into 10mL, the post layer separates (230-400mesh silica gel is stationary phase, and the mixed liquid of hexane and acetone is leacheate); Get 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 following:
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 protection of nitrogen gas; The overanxious solid matter of removing, post layer separate (230-400mesh silica gel is stationary phase, and the mixed liquid of hexane and acetone is leacheate) and get 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) 7-ethyl-10-hydroxycamptothecine 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 following:
Figure BDA0000107473090000252
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 97,10 μ LN; Dinethylformamide and 20mL dry toluene, induction stirring is reacted 4h under room temperature and protection of nitrogen gas.Toluene and excessive THIONYL CHLORIDE 97 are removed in underpressure distillation, obtain thick liquid, add the 10mL anhydrous chloroform and get solution A.
In the reaction flask of 50mL, add 196mg (0.5mmol) 7-ethyl-10-hydroxycamptothecine, 61mg (0.6mmol) anhydrous triethylamine and the anhydrous DMAC N,N of 20mL; Induction stirring; Slowly add the 6mL solution A, under room temperature and protection of nitrogen gas, react 4h, tlc analysis; If still have a spot of 7-ethyl-10-hydroxycamptothecine unreacted intact, add an amount of solution A and triethylamine to reaction again and finish.Reaction solution is joined in the ETHYLE ACETATE of 100mL, the overanxious solid matter of removing will be considered liquid again and will be concentrated into 10mL; (230-400mesh silica gel is stationary phase to the separation of post layer; The mixed liquid of hexane and acetone is leacheate) 661mg 7-ethyl-10-hydroxycamptothecine 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. NSC 94600 N-methoxyl groups seven polyoxamide R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-methane amide-6-succinate synthetic
Reaction formula is following:
Figure BDA0000107473090000261
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) NSC 94600,289mg (2.2mmol) 4-Dimethylamino pyridine, 281mg (1.1mmol) 2-chloro-1-picoline iodide and the anhydrous N of 20mL; The N-N,N-DIMETHYLACETAMIDE, induction stirring is reacted 4h under room temperature and protection of nitrogen gas.Reaction solution is joined in the ETHYLE ACETATE of 100mL, the overanxious solid matter of removing will be considered liquid again and will be concentrated into 10mL; (230-400mesh silica gel is stationary phase to the separation of post layer; The mixed liquid of hexane and acetone is leacheate) 716mg NSC 94600 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%.
Embodiment 5.7-ethyl-10-hydroxycamptothecine (±)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-oxo acetic ester synthetic
1) (±)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-fluoroacetic acid ethyl ester synthetic
Reaction formula is following:
Figure BDA0000107473090000271
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) METHYL BROMOACETATE, 652mg (2mmol) cesium carbonate and the anhydrous N of 25mL; Dinethylformamide, induction stirring is reacted 12h under room temperature and protection of nitrogen gas.N is removed in underpressure distillation, and dinethylformamide adds the ETHYLE ACETATE of 100mL again; Stir, the overanxious solid matter of removing will be considered liquid again and will be concentrated into 10mL; The post layer separates (230-400mesh silica gel is stationary phase, and the mixed liquid of hexane and acetone is leacheate) and gets 1187mg (±)-6-hydroxyl-2,5; 7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-fluoroacetic acid ethyl ester, yield 90.1%.
2) (±)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-fluoroacetic acid synthetic
Reaction formula is following:
Figure BDA0000107473090000272
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 ethers ester-6-fluoroacetic acid ethyl ester and 20mL methyl alcohol, induction stirring; The solution that adds 51mg (2.1mmol) Lithium Hydroxide MonoHydrate and 5mL water then, induction stirring, the about 2h of reaction is to (±)-6-hydroxyl-2 under room temperature and protection of nitrogen gas; 5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-fluoroacetic acid ethyl ester complete reaction.Methyl alcohol is removed in underpressure distillation, and dropping 0.1NHCl is 3-4 to the pH value of solution, lyophilize; The ETHYLE ACETATE that adds 10mL again stirs the overanxious solid matter of removing; The post layer separates (230-400mesh silica gel is stationary phase, and the mixed liquid of hexane and acetone is leacheate) and gets 1215mg (±)-6-hydroxyl-2,5; 7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-fluoroacetic acid, yield 96.3%.
3) 7-ethyl-10-hydroxycamptothecine (±)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-fluoroacetic acid ester synthetic
Reaction formula is following:
Figure BDA0000107473090000281
Experimental procedure:
In the reaction flask of 50mL, add 392mg (1mmol) 7-ethyl-10-hydroxycamptothecine, 269mg (2.2mmol) 4-Dimethylamino pyridine, 281mg (1.1mmol) 2-chloro-1-picoline iodide and the anhydrous DMAC N,N of 20mL; 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 ethers ester-6-fluoroacetic acid and 10mL chloroform reacts 4h under room temperature and protection of nitrogen gas.The overanxious solid matter of removing; To consider liquid again and be evaporated to 10mL, the post layer separates (230-400mesh silica gel is stationary phase, and the mixed liquid of hexane and acetone is leacheate) and gets 574mg 7-ethyl-10-hydroxycamptothecine (±)-6-hydroxyl-2; 5; 7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-fluoroacetic acid ester, yield 58.0%.
Embodiment 6. NSC 94600s (±)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-fluoroacetic acid ester synthetic
Reaction formula is following:
Experimental procedure:
In the reaction flask of 50mL; Add 348mg (1mmol) NSC 94600,269mg (2.2mmol) 4-Dimethylamino pyridine, 281mg (1.1mmol) 2-chloro-1-picoline iodide, 616mg (1mmol) (±)-6-hydroxyl-2,5,7; 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-fluoroacetic acid and anhydrous N of 20mL; The N-N,N-DIMETHYLACETAMIDE, induction stirring is reacted 4h under room temperature and protection of nitrogen gas.The overanxious solid matter of removing; To consider liquid again and be evaporated to 10mL, the post layer separates (230-400mesh silica gel is stationary phase, and the mixed liquid of hexane and acetone is leacheate) and gets 824mg NSC 94600 R-(±)-6-hydroxyl-2; 5; 7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-fluoroacetic acid ester, yield 87.0%.
Embodiment 7. NSC 94600s (±)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-methyl phosphonic ester synthetic
Reaction formula is following:
Figure BDA0000107473090000301
Experimental procedure:
In the reaction flask of 100mL, add 290mg (2.2mmol) methyl phosphonyl dichloride and 10mL anhydrous diethyl ether, induction stirring; Slowly drip 1117mg (2mmol) (±)-6-hydroxyl-2,5 again, 7; The solution of 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ether esters, 202mg (2mmol) anhydrous triethylamine and 20mL anhydrous diethyl ether, under room temperature and protection of nitrogen gas, react 8h, ether is removed in underpressure distillation, and vacuum-drying gets 1287mg (±)-6-hydroxyl-2; 5; 7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-methylphosphine acyl chlorides ester, yield 98.4%.
In the reaction flask of 50mL, add 348mg (1mmol) NSC 94600 and the anhydrous DMAC N,N induction stirring of 20mL; Add 121mg (1.2mmol) triethylamine, 721mg (1.1mmol) (±)-6-hydroxyl-2 again; 5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-methylphosphine acyl chlorides ester and anhydrous N of 20mL; The solution of N-N,N-DIMETHYLACETAMIDE reacts 4h under room temperature and protection of nitrogen gas.The overanxious solid matter of removing; To consider liquid again and be evaporated to 10mL; The post layer separates (230-400mesh silica gel is stationary phase, and the mixed liquid of hexane and acetone is leacheate) NSC 94600 (±)-6-hydroxyl-2,5; 7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid seven poly glycol monomethyl ethers ester-6-methyl phosphonic ester.
The preparation of embodiment 8. amphiphilic anti-cancer drug compounds
Comprise the injection liquid that water or saline water are processed in the present embodiment, and the micella liquid that makes with tensio-active agent.Contain various amphiphilic anti-cancer drug compounds of the present invention in the pharmaceutical formulation, the content of each component in prescription is counted by weight percentage.
Amphiphilic anti-cancer drug compounds of the present invention can make following different preparation as required respectively; With 7-ethyl-10-hydroxycamptothecine R-(+)-6-hydroxyl-2,5,7; 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid methoxyl group seven macrogol esters-the 6-succinate is an example, comprising:
A.7-ethyl-10-hydroxycamptothecine R-(+)-6-hydroxyl-2,5,7, the aqueous solution injection liquid of 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid methoxyl group seven macrogol esters-6-succinate
With 7-ethyl-10-hydroxycamptothecine 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 deionized water, and the composition of the injection liquid of being produced after stirring is following:
MXL-004 0.1％
Deionized water 99.9%.
The injection liquid of processing filters through one 0.2 micron strainer, reinstalls in the aseptic vial.
B.7-ethyl-10-hydroxycamptothecine R-(+)-6-hydroxyl-2,5,7, the normal saline solution of 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid methoxyl group seven macrogol esters-6-succinate
With 7-ethyl-10-hydroxycamptothecine 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 saline water, and the composition of the injection liquid of being produced after stirring is following:
MXL-004 1％
Saline water 99%.
The injection liquid of processing filters through one 0.2 micron strainer, reinstalls in the aseptic vial.
C.7-ethyl-10-hydroxycamptothecine R-(+)-6-hydroxyl-2,5,7, the micella liquid of 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid methoxyl group seven macrogol esters-6-succinate
With 7-ethyl-10-hydroxycamptothecine 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 deionized water (DI water) again, stir then, the composition of the micella liquid of being produced is following:
MXL-004 0.1％
Tween 80 2%
Ethanol 10%
PEG200 5％
Deionized water to 100%.
The micella liquid of processing filters through one 0.2 micron strainer, reinstalls aseptic vial.
D.7-ethyl-10-hydroxycamptothecine R-(+)-6-hydroxyl-2,5,7, the micella liquid of 8-tetramethyl-benzo dihydropyrane-2-carboxylic acid methoxyl group seven macrogol esters-6-succinate
With 7-ethyl-10-hydroxycamptothecine 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 deionized water (DI water) again, stir then, the composition of the micella liquid of being produced is following:
MXL-004 1％
TPGS 5％
Ethanol 5%
PEG200 5％
Deionized water to 100%.
The micella liquid of processing filters through one 0.2 micron strainer, reinstalls aseptic vial.
The vitro cytotoxicity experiment of embodiment 9. amphiphilic anti-cancer drug compounds
In the present embodiment, detect amphiphilic PTS compounds of the present invention with the XTT method and suppress HOC (A2780s), colon cancer cell (HT-29), liver cancer HePG 2And the GI50 value of lung carcinoma cell (A549) cell (anticancer 50% growth drug level), and compare with anticarcinogen irinotecan (irinotican), estimate the vitro cytotoxicity of medical compounds.
Experimental result shows that anti-cancer drug compounds of the present invention is to HOC (A2780s) cell, colon cancer cell (HT-29), liver cancer (HePG 2) cell and lung carcinoma cell (A549) have tangible inhibited proliferation, and along with the increase of drug level, the inhibited proliferation of its pair cell strengthens, and is tangible dose-dependent effect.Compare with the positive drug irinotecan (Irinotecan) with concentration, it is more obvious that anti-cancer drug compounds of the present invention suppresses effect to human body ovarian cancer, colorectal carcinoma, liver cancer and lung carcinoma cell.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 one type of medical compounds with potential anti-human ovarian carcinoma, colorectal carcinoma, liver cancer and lung cancer effect.With MXL-004 is 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 the GI50 value of obvious reduction equally.
The mtt assay detection method: the cell in the vegetative period of taking the logarithm, the adjustment cell density is 10 5Individual/mL, be inoculated in 96 well culture plates, nutrient solution is changed in 100 μ L/ holes behind the cell cultures 18h, add the drug sample of different concns respectively, 150 μ L/ holes.The hole that does not add cell only to add the RPMI RPMI-1640 that contains 10% calf serum is blank control group (being used for zeroing), and negative control group adds the RPMI RPMI-1640 of equal-volume 10% calf serum, and positive controls adds equal-volume 13ug/ml positive drug.More than each group establish 3 multiple holes.Cell continues to cultivate 72h, adds MTT (5mg/mL) solution 15 μ L/ holes, continues to cultivate 4h.Supernatant is abandoned in suction, adds DMSO 150 μ L/ holes, vibration mixing 10min, and after the dissolving fully to be crystallized, on ELIASA, detecting wavelength is absorbancy (D) value in each hole, 490nm place.Calculate the growth inhibition ratio of cell by following formula: 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-hydroxycamptothecine R-(+)-6-hydroxyl-2,5,7,8-tetramethyl-benzo dihydropyrane-2-carboxylic acid methoxyl group seven macrogol esters-6-succinate.

Claims (12)

1. the amphiphilic anti-cancer drug compounds of a watermiscible vitamin E derivative modified has the structure of following formula I or II:
Figure FDA0000107473080000011
Wherein:
R is the polyalkylene glycol monoalkyl ether;
R 1Be the link group, be 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 the C1-C6 alkyl;
R 2Be H, C1-C6 alkyl or-Si (CH 3) 2TBu;
R 3Be H, NO 2,-CH 2N (CH 3) 2, NH 2Or
Figure FDA0000107473080000012
R 4Be H, C1-C6 alkyl or
Figure FDA0000107473080000013
2. the amphiphilic anti-cancer drug compounds of watermiscible vitamin E derivative modified according to claim 1 is characterized in that, described polyalkylene glycol monoalkyl ether group R is:
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.
3. the amphiphilic anti-cancer drug compounds of watermiscible vitamin E derivative modified according to claim 1 is characterized in that, has the structure of following formula I or II:
Figure FDA0000107473080000021
Among the formula I, R 2Be H or-CH 2CH 3
4. according to the amphiphilic anti-cancer drug compounds of claim 1,2 or 3 described watermiscible vitamin E derivative modified, it is characterized in that in the described amphiphilic anti-cancer drug compounds, watermiscible vitamin E comprises its optical isomer or racemic modification.
5. the preparation method of the amphiphilic anti-cancer drug compounds of the described watermiscible vitamin E derivative modified of claim 1 may further comprise the steps:
1) watermiscible vitamin E and alkoxyl group polyoxyethylene glycol or 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 and link molecule generation esterification or etherification reaction generate the verivate of watermiscible vitamin E ester or the verivate of watermiscible vitamin E acid amides;
3) the step 2) verivate of the verivate of resulting watermiscible vitamin E ester or watermiscible vitamin E acid amides; Perhaps their chloride product; With NSC 94600 or derivatives thereof generation esterification, generate the amphiphilic anti-cancer drug compounds of watermiscible vitamin E derivative modified;
Described link molecule is one of following molecule that contains two above reactive 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
Figure FDA0000107473080000031
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 an alkyl.
6. the preparation method of the amphiphilic anti-cancer drug compounds of watermiscible vitamin E derivative modified according to claim 5 is characterized in that, described method may further comprise the steps:
1) be catalyzer with 4-Dimethylamino pyridine and 2-chloro-1-picoline iodide, or with N, N '-dicyclohexyl carbodiimide and 4-Dimethylamino pyridine are catalyzer, watermiscible vitamin E and the reaction of alkoxyl group polyoxyethylene glycol generate the watermiscible vitamin E ester; Or with N, N '-dicyclohexyl carbodiimide is a catalyzer, and watermiscible vitamin E and the reaction of alkoxyl group polyoxamide generate the watermiscible vitamin E acid amides;
2) watermiscible vitamin E ester or watermiscible vitamin E acid amides with link molecule generation esterification or etherification reaction, generate the verivate of watermiscible vitamin E ester or the verivate of watermiscible vitamin E acid amides by one of following method:
A) watermiscible vitamin E ester (3) or watermiscible vitamin E acid amides (9) are catalyzer with 2 ethyl hexanoic acid tin (II) or cesium carbonate, with cyclic acid anhydride
Figure FDA0000107473080000032
Or diglycollic acid anhydride reactant; Perhaps with 4-Dimethylamino pyridine and 2-chloro-1-picoline iodide, or N, N '-dicyclohexyl carbodiimide and 4-Dimethylamino pyridine are catalyzer, with excessive di-carboxylic acid (CH 2) n(COOH) 2Or the diglycollic acid reaction, generate the verivate of watermiscible vitamin E ester or the verivate of watermiscible vitamin E acid amides respectively;
B) watermiscible vitamin E ester or watermiscible vitamin E acid amides are catalyzer with alkali, with the verivate of halogenated carboxylic acid water generation reaction soluble vitamin E ester or the verivate of watermiscible vitamin E acid amides; Or with halogenated carboxylic ester reaction, product generates the verivate of watermiscible vitamin E ester or the verivate of watermiscible vitamin E acid amides after taking off alkyl;
C) watermiscible vitamin E ester or watermiscible vitamin E acid amides are catalyzer with alkali, with alkyl phosphonyl dichloride, alkoxyl group phosphonyl dichloride or the reaction of aryl phosphonyl dichloride, generate the verivate of watermiscible vitamin E ester or the verivate of watermiscible vitamin E acid amides;
D) watermiscible vitamin E ester or watermiscible vitamin E acid amides are catalyzer with alkali, with the oxalyl chloride reaction, generate the verivate of watermiscible vitamin E ester or the verivate of watermiscible vitamin E acid amides;
3) step 2) a) or b) verivate of resulting watermiscible vitamin E ester or the verivate of watermiscible vitamin E acid amides and thionyl (two) cl cpd reaction generation chloride product;
4) step 2) a) or b) verivate of resulting watermiscible vitamin E ester or the verivate of watermiscible vitamin E acid amides be with 4-Dimethylamino pyridine and 2-chloro-1-picoline iodide; Or N; N '-dicyclohexyl carbodiimide and 4-Dimethylamino pyridine are catalyzer; With the reaction of NSC 94600 or derivatives thereof, generate the amphiphilic anti-cancer drug compounds of watermiscible vitamin E derivative modified; Or
5) c the resultant chloride product of step 3), or step 2)) or d) verivate of resulting watermiscible vitamin E ester or the verivate of watermiscible vitamin E acid amides are catalyzer with alkali, react with the NSC 94600 or derivatives thereof; Generate the amphiphilic anti-cancer drug compounds of watermiscible vitamin E derivative modified.
7. the preparation method of the amphiphilic anti-cancer drug compounds of watermiscible vitamin E derivative modified according to claim 6 is characterized in that, described alkaline catalysts is selected from triethylamine, pyridine, yellow soda ash, salt of wormwood or cesium carbonate.
8. the amphiphilic anti-cancer drug compounds injection of the described watermiscible vitamin E derivative modified of claim 1 comprises:
1) has the amphiphilic anti-cancer drug compounds of the watermiscible vitamin E derivative modified of formula I or II structure;
2) water or saline water.
9. the amphiphilic anti-cancer drug compounds injection of watermiscible vitamin E derivative modified according to claim 8 is characterized in that, in the described injection, medical compounds weight percentage in prescription is 0.005% to 5.0%.
10. the amphiphilic anti-cancer drug compounds micell formulations of the described watermiscible vitamin E derivative modified of claim 1 comprises:
1) has the amphiphilic anti-cancer drug compounds of the watermiscible vitamin E derivative modified of formula I or II structure;
2) tensio-active agent;
3) solvent;
4) water.
11. the amphiphilic anti-cancer drug compounds micell formulations of watermiscible vitamin E derivative modified according to claim 10 is characterized in that, in the described micell formulations, medical compounds weight percentage in prescription is 0.005% to 5.0%; The weight percentage of tensio-active agent is about 1% to 10%, and solvent accounts for 2% to 20% of formulation weight.
12. the application of the amphiphilic anti-cancer drug compounds of the watermiscible vitamin E derivative modified of claim 1 in the preparation cancer therapy drug.
CN201110356393.6A 2011-11-11 2011-11-11 Amphiphilic anti-cancer drug compound modified by water-soluble vitamin E derivative, preparation, preparation method and application for compound Expired - Fee Related CN102491981B (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104817574A (en) * 2015-05-26 2015-08-05 遵义医学院 Novel camptothecin derivative and antitumor application thereof
CN105315294A (en) * 2014-06-26 2016-02-10 王杭祥 7-ethyl-10-hydroxycamptothecine drug precursor, preparation method and 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
CN105646546A (en) * 2015-12-29 2016-06-08 遵义医学院 Acid-sensitive camptothecin-20-position ester derivative and antineoplastic application thereof
CN105820188A (en) * 2016-02-22 2016-08-03 刘天军 Medicinal preparation containing tenofovir disoproxil fumarate (vitamin E), and use thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102516258B (en) * 2011-11-11 2014-06-25 正大天晴药业集团股份有限公司 Water-soluble vitamin E derivative modified fat-soluble anti-cancer drug compound and preparation, preparation method and application of compound

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002076970A2 (en) * 2001-03-23 2002-10-03 Sonus Pharmaceuticals, Inc. Tocopherol succinate derivatives and compositions
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

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080045559A1 (en) * 2003-10-29 2008-02-21 Sonus Pharmaceuticals, Inc. Tocopherol-modified therapeutic drug compounds
WO2010060098A1 (en) * 2008-11-24 2010-05-27 Cedars-Sinai Medical Center Antioxidant camptothecin derivatives and antioxidant antineoplastic nanospheres thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002076970A2 (en) * 2001-03-23 2002-10-03 Sonus Pharmaceuticals, Inc. Tocopherol succinate derivatives and compositions
CN1875022A (en) * 2003-10-29 2006-12-06 搜讷斯医药股份有限公司 Tocopherol-modified therapeutic drug compounds
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 (1)

* Cited by examiner, † Cited by third party
Title
XINLI LIU,等: "A Versatile Prodrug Approach for Liposomal Core-Loading of Water-Insoluble Camptothecin Anticancer Drugs", 《J.AM.CHEM.SOC.》 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105315294A (en) * 2014-06-26 2016-02-10 王杭祥 7-ethyl-10-hydroxycamptothecine drug precursor, preparation method and application thereof
CN104817574A (en) * 2015-05-26 2015-08-05 遵义医学院 Novel camptothecin derivative and antitumor application thereof
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
CN105646546A (en) * 2015-12-29 2016-06-08 遵义医学院 Acid-sensitive camptothecin-20-position ester derivative and antineoplastic application thereof
CN105820188A (en) * 2016-02-22 2016-08-03 刘天军 Medicinal preparation containing tenofovir disoproxil fumarate (vitamin E), and use thereof

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