CN104003996B

CN104003996B - The fat-soluble anti-cancer drug compounds of watermiscible vitamin E Derivatives Modified and preparation, the preparation method and application of the compound

Info

Publication number: CN104003996B
Application number: CN201410229587.3A
Authority: CN
Inventors: 张跃华
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2011-11-11
Filing date: 2011-11-11
Publication date: 2017-03-15
Anticipated expiration: 2031-11-11
Also published as: CN104003996A

Abstract

The invention discloses a kind of fat-soluble anti-cancer drug compounds of watermiscible vitamin E Derivatives Modified, the structure with following formula I or II.Cancer therapy drug active part camptothecine or camptothecin derivative, and lipophilic moieties watermiscible vitamin E ester or amide, form described fat-soluble anti-cancer drug compounds by linking group covalent bond.The invention further relates to the preparation of the medical compoundss, preparation method and application.

Description

The fat-soluble anti-cancer drug compounds of watermiscible vitamin E Derivatives Modified and preparation, The preparation method and application of the compound

The application is Application No. 201110355747.5, and the applying date is on November 11st, 2011, entitled " water-soluble Property vitamin e derivative modification fat-soluble anti-cancer drug compounds and preparation, the preparation method and application of the compound " point Case application.

Technical field

The present invention relates to a kind of new anti-cancer drug compounds and its preparation method and application, more particularly to a kind of water-soluble Property vitamin e derivative modification fat-soluble anti-cancer drug compounds, preparation, preparation method and conduct comprising the compound The application of cancer therapy drug.

Background technology

Many has the compounds of active anticancer due to water insoluble and other biocompatible solvents, or in water and biology In compatible solvent, stability difference has become an obstacle of drug development, often leads to drug development time delay.According to estimates, Up to 40 percent candidate drug compounds with potential value through filtering out be rejected due to its poorly water-soluble into Enter preparation research and development phase, and 30 percent existing medicine is slightly solubility.Currently there are few techniques to grind Among studying carefully and developing, to solve the problems, such as medical compoundss poor solubility, these technology include the complexant skill for increasing dissolubility Art, nano particle technology, microemulsion technology, the preparation technique of enhancing dissolubility, fat-soluble and water-soluble prodrug technology, and new Polymer drug-carried technology etc..

1) and its derivant has good anti-tumor activity (20 (s)-camptothecin, formula 1, are classes to camptothecine Important DNA topoisomerase Is (Top I) inhibitor, they can be combined with Top I-DNA cleavable complex, formed CPT-Top I-DNA ternary complexes, so as to stablize cleavable complex, cause cell death.But because which is in water and other lifes Dissolubility difference and the big problem of toxicity in thing compatible solvent, ultimately fails to enter clinic.In order to improve the water solublity of medicine And retain the antitumor properties of parent compound, synthesize many camptothecin derivatives.However, only derivant topotecan (2) (3) Irinotrcan, formula 1 are faced by FDA's approval entrance with irinotecan for Topotecan, formula 1 Bed has been listed, and is respectively used to treat ovarian cancer, pulmonary carcinoma and rectal cancer.But, topotecan and irinotecan have significantly Shortcoming, is included in Half-life in vivo is short and toxic and side effects are big etc..At present, multiple camptothecin derivatives are in clinical research rank Section.

Additionally, the E lactonic rings in camptothecin molecule are function bases necessary to camptothecin analogues active anticancer, Rapid open loop is understood under alkalescence or physiological condition and cause the disappearance (formula 2) of activity.It is demonstrated experimentally that in blood plasma lactone ring structure and There is balance in open loop structure, and human plasma protein is preferentially combined with open loop structure molecule, promotes to balance and shifts to open loop form, Cause medicine valid density in blood plasma to reduce, and then reduce the anti-tumor activity of such compound.Further research card

1,20 (S)-camptothecin, R=R₁=R₂=H

2, topotecan, R=OH, R₁=(CH₃)₂NCH₂-,R₂=H

3.irinotecan,R₁=H,R₂=Et,

The chemical constitution of 1. camptothecine of formula, topotecan (topotecan) and irinotecan (irinotecan).Real, open Ring structure thing is the root for causing untoward reaction, such as causes bone marrow depression, vomiting and diarrhoea etc..

There is the balance of lactone ring structure and open loop structure under alkalescence or physiological condition in 2. camptothecine of formula.

In order to improve the dissolubility of medicine, the technology such as Emulsion (Emulsion) and micelle (micelle) is widely used in water In the preparation of the poor or water-fast medicine of dissolubility, but up to the present also do not have a kind of preparation technique to go for Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae) Alkali, because its dissolubility extreme difference in water and organic solvent.Therefore, there is still a need for the new existing higher active anticancer of exploitation There is the camptothecin derivative of preferable dissolubility and stability again.

The invention provides a series of new lipophilic camptothecin derivatives, their fat-soluble solvents in biocompatibility In have preferable dissolubility, the medicine agent such as emulsion, microemulsion, micelle, liposome, nanoparticle can be made with new formulation technology Type.The new medical compoundss of the present invention are expected to improve medicine persistent period (half-life) in vivo and curative effect, and reduce Its side effect.

Content of the invention

It is an object of the invention to provide a kind of new fat-soluble anti-cancer drug compounds, this kind of change with active anticancer Compound is dissolvable in water in the fat-soluble solvent of biocompatibility, is the ester (trolox of lipophilic watermiscible vitamin E Ester) or lipophilic watermiscible vitamin E the camptothecine modified of amide (trolox amide) or camptothecin derivative.

Another object of the present invention is to providing the synthetic method of described fat-soluble anti-cancer drug compounds.

Another object of the present invention is also resided in and provides the preparation comprising described fat-soluble cancer therapy drug, i.e. emulsion and micelle Pharmaceutical formulation, emulsion formulations include described anti-cancer drug compounds, (lipotropy is situated between for one or more surfactant, oil phase Matter) and water phase；Micellar preparation includes described anti-cancer drug compounds, cosolvent and one or more surfactant and water Phase.

Meanwhile, another object of the present invention is also resided in and provides described fat-soluble cancer therapy drug in cancer therapy drug is prepared Application.

The fat-soluble anti-cancer drug compounds of the present invention, are the ester (trolox of lipophilic watermiscible vitamin E Ester) or lipophilic watermiscible vitamin E the camptothecine modified of amide (trolox amide) or camptothecin derivative, There is active anticancer, camptothecine or camptothecin derivative molecule to be given birth to lipophilic water soluble vitamin for camptothecine or camptothecin derivative Plain E esters (or amide) molecule is by linking group (such as amber base：succinyl；Glutaryl：glutaryl；Diethylene glycol acyl group： Oxydiacetyl, diglycoloyl, diglycolyl；Methylene carbonyl：Methylene carbonyl, methyl phosphono, Methylphosphono etc.) covalent bond formed the present invention fat-soluble anti-cancer drug compounds.

Realize that the object of the invention is employed the following technical solutions：A kind of the fat-soluble of watermiscible vitamin E Derivatives Modified resists Cancer drug compound, represents represented structure with such as general formula I or II：

In said structure formula,

R is a kind of lipophilic group, is one of following radicals：

A) replace and non-substituted straight chained alkyl (substituted and unsubstituted alkyl)；

B) replace and non-substituted cycloalkyl (substituted and unsubstituted cycloalkyl)；

C) replace and non-substituted branched alkyl (substituted and unsubstituted branched alkyl)；

D) undersaturated straight-chain alkyl (unsaturated alkyl)；

E) undersaturated cyclic hydrocarbon radical (unsaturated cycloalkyl)；

F) undersaturated branched hydrocarbyl (unsaturated branched alkyl)；

G) replace and non-substituted aryl (substituted and unsubstituted aryl)；

H) replace and non-substituted aralkyl (substituted and unsubstituted aralkyl)；

R₁It is link group, is one of following radicals：

A)-(C=O)-；

B)-P (=O) (R ')-, wherein R ' is C1-C6 alkyl, C1-C6 alkoxyls or aryl；

C)-(C=O) (CH₂)_n(C=O)-, wherein n=1-10；

D)-(C=O) CH₂-O-CH₂(C=O)-；

e)-(CH₂)_n(C=O)-, wherein n=1-10；

X is-O- ,-NH- or-NR '-, wherein R ' is C1-C6 alkyl；

R₂It is H, C1-C6 alkyl or-Si (CH₃)₂tBu；

R₃It is H, NO₂、-CH₂N(CH₃)₂、NH₂Or

R₄Be H, C1-C6 alkyl or

The fat-soluble anti-cancer drug compounds of the present invention, lipophilic moieties are the water soluble vitamins with lipophilic group R E, selected from the ester or amide compound of watermiscible vitamin E.

Watermiscible vitamin E (trolox) is the soluble derivative of vitamin E, and chemical name is:6- hydroxyl -2,5,7, 8- tetramethyl benzodihydropyran -2- carboxylic acid (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic Acid), it is a kind of antioxidant as vitamin E, its structure is as shown in Equation 3.Trolox has two kinds of optical isomer structures, I.e. R- (+)-trolox (chemical entitled R- (+)-Trolox, R- (+)- 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) and S- (-)-trolox (chemical names For S- (-)-Trolox, S- (-) -6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxylic acid)；Its racemic modification is (±)-trolox (entitled (±) -6- of chemistry Hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acids, (±) -6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxylic acid).

The chemical constitution of 3. watermiscible vitamin E of formula (trolox), wherein A：R-(+)-trolox；B:S-(-)- trolox；C:(±)-trolox.

Watermiscible vitamin E in the fat-soluble anti-cancer drug compounds of the present invention includes its optical isomer or raceme Body.

Watermiscible vitamin E ester (trolox ester) is watermiscible vitamin E (trolox) and alcohols or phenols chemical combination The ester type compound that thing reaction is generated, they can be spread out with the camptothecine with active anticancer or camptothecine by a linking group Biomolecule covalent bond generates the new anti-cancer drug compounds of the present invention.The chemical constitution of watermiscible vitamin E ester such as Fig. 4 Shown, equally there are two kinds of optical isomers, i.e. R- (+)-trolox ester (chemical entitled R- (+) -6- hydroxyl -2,5,7,8- Tetramethyl benzodihydropyran -2- carboxylates, R- (+) -6-hydroxy-2,5,7,8-tetramethylchroman-2- Carboxylic acid ester) and S- (-)-trolox ester (chemical entitled S- (-) -6- hydroxyls -2,5,7,8- tetramethyls Base benzodihydropyran -2- carboxylates, S- (-) -6-hydroxy-2,5,7,8-tetramethylchroman-2- carboxylic acid ester)；Its racemic modification be (±)-trolox ester (entitled (±) -6- hydroxyl -2,5 of chemistry, 7,8- tetramethyl benzodihydropyran -2- carboxylates, (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2- carboxylic acid ester).Lipotropy functional group R in molecular structure can be alkyl (alkyl), branched alkyl (branched alkyl) and cycloalkyl (cyclic alkyl), or unsaturated alkyl (unsaturated alkyl), Undersaturated branched hydrocarbyl (unsaturated branched alkyl), undersaturated cyclic hydrocarbon radical (unsaturated Cycloalkyl), replace and non-substituted aryl (substituted and unsubstituted aryl), replace and non-take The aralkyl (substituted and unsubstituted aralkyl) in generation etc..

The chemical constitution of 4. watermiscible vitamin E ester of formula (trolox ester), wherein A:R-(+)-trolox ester； B:S-(-)-trolox ester；C:(±)-trolox ester.

With watermiscible vitamin E formed watermiscible vitamin E ester alcohol can be fatty alcohol, such as saturation, undersaturated, Straight chain, side chain, ring-type fatty alcohol and fatty enol etc..It is preferred that the alcohol compound of C atomic number >=6, including but do not limit In hexanol, capryl alcohol (capryl alcohol, 1-octanol), 2-Ethylhexyl Alcohol (2-ethyl hexanol), nonyl alcohol (pelargonic alcohol, 1-nonanol), decanol (capric alcohol, 1-decanol, decyl alcohol), Undecyl alcohol (undecyl alcohol, 1-undecanol, undecanol, hendecanol), lauryl alcohol (lauryl Alcohol, dodecanol, 1-dodecanol), tridecyl alcohol (tridecyl alcohol, 1-tridecanol, Tridecanol, isotridecanol), myristyl alcohol (myristyl alcohol, 1-tetradecanol), pentadecane Base alcohol (pentadecyl alcohol, 1-pentadecanol, pentadecanol), cetyl alcohol (cetyl Alcohol, 1-hexadecanol), cis- 9- hexadecylenes alcohol (palmitoleyl alcohol, cis-9-hexadecen-1- Ol), heptadecyl alcohol (heptadecyl alcohol), stearyl alcohol (stearyl alcohol, 1-octadecanol), Different octadecyl alcohol (isostearyl alcohol, 16-methylheptadecan-1-ol), trans -9- oleic alcohols (elaidyl alcohol, 9E-octadecen-1-ol), oleyl alcohol (oleyl alcohol, cis-9-octadecen-1- Ol), cis- 9, cis- 12- core of Caulis et Folium Lini oleyl alcohol (linoleyl alcohol, 9Z, 12Z-octadecadien-1-ol), trans- 9, trans- 12- core of Caulis et Folium Lini oleyl alcohol (elaidolinoleyl alcohol, 9E, 12E-octadecadien-1-ol), cis- 9, cis- 12, cis- 15- core of Caulis et Folium Lini oleyl alcohol (linolenyl alcohol, 9Z, 12Z, 15Z-octadecatrien-1-ol), trans- 9, trans- 12, trans- 15- core of Caulis et Folium Lini oleyl alcohol (elaidolinolenyl alcohol, 9E, 12E, 15-E-octadecatrien-1-ol), nonadecane Base alcohol (nonadecyl alcohol, 1-nonadecanol), eicosyl alcohol (arachidyl alcohol, 1- Eicosanol), heneicosyl alcohol (eneicosyl alcohol, 1-heneicosanol), docosyl alcohol (behenyl alcohol, 1-docosanol), cis- 13- docosenes alcohol (erucyl alcohol, cis-13-docosen- 1-ol), tetracosyl alcohol (lignoceryl alcohol, 1-tetracosanol), cerul alcohol (ceryl Alcohol, 1-hexacosanol), octacosyl alcohol (montanyl alcohol, cluytyl alcohol, 1- Octacosanol), melissyl alcohol (myricyl alcohol, melissyl alcohol, 1-triacontanol), 30 Tetraalkyl alcohol (geddyl alcohol, 1-tetratriacontanol) etc..Can also be other alcohol compounds, such as benzyl The aromatic alcohol compounds such as alcohol, phenethanol.

The compound that watermiscible vitamin E ester is formed with watermiscible vitamin E also includes phenolic compound, such as phenol, alkane Base phenol, alkoxy phenol, amino-phenol, halogenated phenols, polysubstituted phenol, or 1- naphthols, beta naphthal, alkyl naphthol, alcoxyl Base naphthols, halo naphthols, polysubstituted naphthols etc..

Watermiscible vitamin E amide (trolox amide) is watermiscible vitamin E (trolox) and aminated compoundss (primary Amine or secondary amine) amides compound for generating is reacted, they can pass through a linking group with the camptothecine with active anticancer Or camptothecin derivative molecule covalent combines the new anti-cancer drug compounds for generating the present invention.Watermiscible vitamin E amide Chemical constitution as shown in Equation 5, has two kinds of optical isomers, i.e. R- (+)-trolox amide (chemical entitled R- (+) -6- hydroxyls - 2,5,7,8- tetramethyl benzodihydropyran -2- Methanamides, R- (+) -6-hydroxy-2,5,7,8- Tetramethylchroman-2-carboxamide) and S- (-)-trolox amide (chemical entitled S- (-) -6- hydroxyl -2, 5,7,8- tetramethyl benzodihydropyran -2- Methanamides, S- (-) -6-hydroxy-2,5,7,8-tetramethylchroman- 2-carboxamide)；Its racemic modification is (±)-trolox ester (entitled (±) -6- hydroxyls -2,5,7,8- tetramethyls of chemistry Base benzodihydropyran -2- Methanamides, (±) -6-hydroxy-2,5,7,8-tetramethylchroman-2- carboxamide).Functional group R in molecular structure can be alkyl (alkyl), branched alkyl (branched alkyl) and Cycloalkyl (cyclic alkyl), or unsaturated alkyl (unsaturated alkyl), unsaturated side chain alkyl (unsaturated branched alkyl), undersaturated cyclic hydrocarbon radical (unsaturated cycloalkyl), replace and non- Substituted aryl (substituted and unsubstituted aryl), replace and non-substituted aralkyl (substituted and unsubstituted aralkyl) etc., preferred C atomic number >=6 of substituent R.In molecular structure Substituent R₁It is preferred that H ,-CH₃、-CH₂CH₃、-CH₂CH₂CH₃、-CH₂CH₂CH₂CH₃、-CH₂CH₂CH₂CH₂CH₃With- CH₂CH₂CH₂CH₂CH₂CH₃.

The aminated compoundss for forming watermiscible vitamin E amide with watermiscible vitamin E can be primary amine or secondary amine, including The fatty amine, or arylamine of fatty amine or aromatic amine, such as saturation, undersaturated, straight chain, side chain, ring-type and virtue Alkylamine etc..

The chemical constitution of 5. watermiscible vitamin E amide of formula (trolox amide), wherein A:R-(+)-trolox amide；B:S-(-)-trolox amide；C:(±)-trolox amide.

Cancer therapy drug active part in the fat-soluble anti-cancer drug compounds molecule of the present invention is known with anticancer The camptothecine or camptothecin derivative of activity, its structural formula are as shown in Equation 6, wherein R₂It is H, C1-C6 alkyl or-Si (CH₃)₂tBu；R₃It is H, NO₂、-CH₂N(CH₃)₂、NH₂OrR₄Be H, OH, C1-C6 alkyl or

6 camptothecine of formula and the chemical constitution of camptothecin derivative molecule.

In the fat-soluble anti-cancer drug compounds molecule of the present invention, the preferred camptothecine in active anticancer part (1, Camptothecin), 10-hydroxycamptothecine (2,10-hydroxycamptothecin) and SN38 (3,7-ethyl-10-hydroxycamptothecin), its molecular structure are as shown in Equation 7.They can pass through a linking group The fat-soluble anti-cancer drug compounds of the present invention are generated with watermiscible vitamin E ester (or amide) covalent bond.

1,20(S)-camptothecin∶R₁=R₂=H

2,10-hydroxycamptothecin∶R₁=OH,R₂=H

3.7-ethyl-10-hydroxycamptothecin∶R₁=OH,R₂=Et

7. camptothecine of formula and the preferred chemical constitution of camptothecin derivative.

The molecule of the fat-soluble anti-cancer drug compounds of the present invention includes cancer therapy drug active part and lipophilic portion, and this two Fat-soluble anti-cancer drug compounds of the individual part by linking group covalent bond Cheng Xin.Cancer therapy drug active part is happiness Tree alkali or camptothecin derivative, camptothecine or camptothecin derivative contain phenolic hydroxyl group or the hydroxyl on lactonic ring, and the hydroxyl can be with Ester bond is formed with carboxyl, chlorine acyl group or phosphine (phosphorus) acyl group.Lipophilic portion is watermiscible vitamin E ester (or amide), water soluble vitamin Raw element E esters (or amide) is fat-soluble compound and carries a phenolic hydroxyl group, and the phenolic hydroxyl group can be with carboxyl or phosphine (phosphorus) acyl group Form ester bond or react to form ehter bond with halides.Therefore, camptothecine or camptothecin derivative can pass through a difunctional Linking group and lipophilic watermiscible vitamin E ester (or amide) covalent bond generate the new anticarcinogen materialization of the present invention The molecule of compound.For example, watermiscible vitamin E ester (or amide) by linking group (as amber base, glutaryl, two Glycol acyl group or methylene carbonyl) and anti-cancer drug compounds camptothecine (camptothecin), 10-hydroxycamptothecine (10- ) or SN38 (7-ethyl-10-hydroxycamptothecin, SN- hydroxycamptothecin 38) covalent bond forms new fat-soluble anti-cancer drug compounds.

Described linking group is provided by the connection molecule containing two or more active groups, for example：Second two Acyl chlorides (O=CCl₂) offer carbonyl-(C=O)-, phosphinylidyne dichloro ester (O=POR ' Cl₂)-P (=O) (OR ')-group, halo are provided Carboxylic acid or halogenated carboxylic ester provide alkylenecarbonyl (- (CH₂)_nCO-), different dicarboxylic acids (CH₂)_n(COOH)₂Or ring-type acid Acid anhydrideAmber base (succinyl), glutaryl (glutaryl), diethylene glycol acyl group can be provided (oxydiacetyl, diglycoloyl, diglycolyl) etc..

With parent compound (derivant of camptothecine or camptothecine, such as 10-hydroxycamptothecine and 7- with active anticancer Ethyl-10-hydroxycamptothecin) to compare, the new anti-cancer drug compounds of the present invention have more preferable lipotropy (lipophile).Newly The compound of invention includes a cancer therapy drug parent compound part and lipophilic group part.Cancer therapy drug parent molecule with Lipophilic molecules synthesize the new anti-cancer drug compounds of the present invention by a linking group with covalently bonded.

The invention further relates to a kind of fat-soluble anti-cancer drug compounds of described watermiscible vitamin E Derivatives Modified Preparation method, comprises the following steps：

1) there is esterification or amidation process in watermiscible vitamin E and alcohol, phenol or amine, generate watermiscible vitamin E ester or Watermiscible vitamin E amide；

2) there is esterification with connection molecule or be etherified in the phenolic hydroxyl group of watermiscible vitamin E ester or watermiscible vitamin E amide Reaction, generates the derivant of watermiscible vitamin E ester or the derivant of watermiscible vitamin E amide；

3) step 2) obtained by watermiscible vitamin E ester derivant or the derivant of watermiscible vitamin E amide, or , there is esterification with camptothecine or derivatives thereof, generate watermiscible vitamin E Derivatives Modified in person their chloride product Fat-soluble anti-cancer drug compounds；

Described connection molecule is one of following molecule containing two or more active group：

(1) ethanedioly chloride O=CCl₂；

(2) phosphinylidyne dichloro Arrcostab, alkoxy ester or aryl ester O=POR ' Cl₂, wherein R ' is C1-C6 alkyl, C1-C6 Alkoxyl or aryl；

(3) dicarboxylic acids (CH₂)_n(COOH)₂Or cyclic acid anhydrideWherein n=1-10；

(4) diglycolic acid or anhydride diethylene glycol；

(5) halogenated carboxylic acid or halogenated carboxylic ester Z- (CH₂)_nCOOR ', wherein n=1-10, Z are Cl, Br or I, and R ' is alkyl.

More specifically and optimally, described method is comprised the following steps：

1) with DMAP (DMAP) and 2- chloro- 1- methyl pyridinium iodides (CMPI) as catalyst, or with N, N '-dicyclohexyl carbodiimide (DCC) and DMAP (DMAP) are catalyst, watermiscible vitamin E (1) with Alcohol or phenol (2) reaction, generate watermiscible vitamin E ester (3)；Or with N, N '-dicyclohexyl carbodiimide (DCC) is catalysis Agent, watermiscible vitamin E (1) are reacted with amine (8), generate watermiscible vitamin E amide (9).

2) watermiscible vitamin E ester (3) or watermiscible vitamin E amide (9) respectively one of by the following method, and are connected point There is esterification or etherification reaction in son, generate the derivant of watermiscible vitamin E ester or the derivant of watermiscible vitamin E amide：

A) watermiscible vitamin E ester (3) or watermiscible vitamin E amide (9) are with 2 ethyl hexanoic acid stannum (II) or cesium carbonate For catalyst, with cyclic acid anhydrideOr diglycolic acid anhydride reactant；Or with DMAP (DMAP) and 2- Chloro- 1- methyl pyridinium iodides (CMPI) or N, N '-dicyclohexyl carbodiimide (DCC) and DMAP (DMAP) it is catalyst, with excessive dicarboxylic acids (CH₂)_n(COOH)₂Or diglycolic acid reaction, generate water soluble vitamin life respectively The derivant (4) of plain E esters or the derivant (10) of watermiscible vitamin E amide；

B) watermiscible vitamin E ester (3) or watermiscible vitamin E amide (9) with alkali (such as triethylamine, pyridine, sodium carbonate, Potassium carbonate, cesium carbonate) be catalyst, react with halogenated carboxylic acid the derivant (15a, R '=H) that generates watermiscible vitamin E ester or The derivant (15a) of watermiscible vitamin E amide, or react with halogenated carboxylic ester, after the de- alkyl of product (15b, R '=alkyl) Generate the derivant (15a) of watermiscible vitamin E ester or the derivant (15a) of watermiscible vitamin E amide；

C) watermiscible vitamin E ester (3) or watermiscible vitamin E amide (9) with alkali (such as triethylamine, pyridine, sodium carbonate, Potassium carbonate, cesium carbonate) it is catalyst, with alkylphosphines (phosphorus) acyl dichloro, alkoxyl phosphine (phosphorus) acyl dichloro or aryl phosphine (phosphorus) acyl two Chlorine reacts, and generates the derivant (19) of watermiscible vitamin E ester or the derivant (19) of watermiscible vitamin E amide；

D) watermiscible vitamin E ester (3) or watermiscible vitamin E amide (9) are with alkali (such as triethylamine or pyridine) as catalysis Agent, is reacted with ethanedioly chloride, generates the derivant of watermiscible vitamin E ester or the derivant of watermiscible vitamin E amide.

3) step 2) in a) or b) obtained by watermiscible vitamin E ester derivant (4,15a) or watermiscible vitamin E The derivant (10,15a) of amide generates chloride product (5,11 or 16) respectively with the reaction of thionyl (two) chlorine compound.

4) step 2) in a) or b) obtained by watermiscible vitamin E ester derivant (4,15a) or watermiscible vitamin E The derivant (10,15a) of amide with DMAP (DMAP) and 2- chloro- 1- methyl pyridinium iodides (CMPI) or N, N '-dicyclohexyl carbodiimide (DCC) and DMAP (DMAP) are catalyst, directly with camptothecine or which is derivative Thing reacts, and generates the fat-soluble anti-cancer drug compounds (6,12,13,14,17 or 18) of watermiscible vitamin E Derivatives Modified； Or

5) step 3) obtained by chloride product (5,11 or 16), or step 2) in c) or d) obtained by water soluble vitamin life The derivant (19) of plain E esters or the derivant (19) of watermiscible vitamin E amide, with alkali (such as triethylamine, pyridine, sodium carbonate, carbon Sour potassium, cesium carbonate) it is catalyst, directly with camptothecine or derivatives thereof reaction；Generate watermiscible vitamin E Derivatives Modified Fat-soluble anti-cancer drug compounds (6,12,13,14,17,18,20 or 21).

Formula 8 illustrates a kind of synthetic route, and watermiscible vitamin E (trolox) (1) is reacted with alcohol or phenol (2), with 4- bis- Methylamino pyridine (DMAP) and 2- chloro- 1- methyl pyridinium iodides (CMPI) they are catalyst, or with N, N '-dicyclohexyl carbonization Diimine (DCC) and DMAP (DMAP) are catalyst, generate watermiscible vitamin E ester (3), water soluble vitamins E esters (3) are reacted with cyclic acid anhydride (such as succinic anhydrides, glutaric anhydride, anhydride diethylene glycol etc.) again, with 2 ethyl hexanoic acid stannum (II) (or cesium carbonate) is catalyst, generates the derivant (4) of watermiscible vitamin E ester.Watermiscible vitamin E ester (3) also can be with mistake Dicarboxylic acids (the such as dicarboxylic acids such as succinic acid, the 1,3-propanedicarboxylic acid, diglycolic acid) reaction with difunctional of amount, with 4- diformazan ammonia Yl pyridines (DMAP) and 2- chloro- 1- methyl pyridinium iodides (CMPI) or N, N '-dicyclohexyl carbodiimide (DCC) and 4- Dimethylamino naphthyridine (DMAP) is catalyst, generates the derivant (4) of watermiscible vitamin E ester.Compound (4) then with sulfurous The reaction of acyl (two) chlorine compound generates the chloride derivative (5) of watermiscible vitamin E ester, then the acyl chlorides sense of compound (5) Group optionally with 10- hydroxyl substituted camptothecins, the phenolic hydroxyl group of such as 10-hydroxycamptothecine or SN38 is anti- Should, with alkali as catalyst (such as triethylamine), generate the fat-soluble anti-cancer drug compounds (6) of the present invention.Watermiscible vitamin E ester The camptothecine that also directly can replace with 10- hydroxyls of derivant (4), such as 10-hydroxycamptothecine or 7- ethyl -10- hydroxy-camptothecins Alkali reaction, with DMAP (DMAP) and 2- chloro- 1- methyl pyridinium iodides (CMPI) or N, N '-dicyclohexyl carbon It is catalyst to change diimine (DCC) and DMAP (DMAP), generates the fat-soluble anti-cancer drug compounds of the present invention (6).

R:Alkyl (alkyl), branched alkyl (branched alkyl) and cycloalkyl (cyclic alkyl), or Undersaturated alkyl, undersaturated branched hydrocarbyl, undersaturated cyclic hydrocarbon radical, aryl and aralkyl etc.；R₁:-CH₂CH₂-,- CH₂CH₂CH₂-,-CH₂OCH₂- etc.；R₂:H,-CH₂CH₃Deng.

The synthetic route 1 of 8. new anti-cancer drug compounds of formula.

As shown in Equation 9, be the present invention fat-soluble anti-cancer drug compounds another kind of synthetic method, water soluble vitamins The chloride derivative (5) of E esters in the presence of alkali (such as triethylamine) with camptothecine (or derivatives thereof) lactonic ring on hydroxyl Reaction, generates the new anti-cancer drug compounds (7) of the present invention.The derivant (4) of watermiscible vitamin E ester also can directly and Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae) Alkali (or derivatives thereof) reaction, with DMAP (DMAP) and 2- chloro- 1- methyl pyridinium iodides (CMPI) or N, N '-dicyclohexyl carbodiimide (DCC) and DMAP (DMAP) are catalyst, generate the new anti-cancer drug of the present invention Compounds (7).

R:Alkyl (alkyl), branched alkyl (branched alkyl) and cycloalkyl (cyclic alkyl), or Undersaturated alkyl, undersaturated branched hydrocarbyl, undersaturated cyclic hydrocarbon radical, aryl and aralkyl etc.；R₁:-CH₂CH₂-,- CH₂CH₂CH₂-,-CH₂OCH₂- etc.；

The synthetic route 2 of 9. new anti-cancer drug compounds of formula.

Another synthetic method of the fat-soluble anti-cancer drug compounds of the present invention is as shown in Equation 10, watermiscible vitamin E (trolox) (1) is reacted with amine (8), and with N, N '-dicyclohexyl carbodiimide (DCC) is coupling agent, generates water soluble vitamin life Plain E amide (9), watermiscible vitamin E amide (9) again with cyclic acid anhydride (such as succinic anhydrides, glutaric anhydride, anhydride diethylene glycol etc.) Reaction, with 2 ethyl hexanoic acid stannum (II) or cesium carbonate as catalyst, generates the derivant (10) of watermiscible vitamin E amide, so Compound (10) and the reactions such as camptothecine, 10-hydroxycamptothecine or SN38 afterwards, with 4- dimethylamino pyrroles Pyridine (DMAP) and 2- chloro- 1- methyl pyridinium iodides (CMPI) or N, N '-dicyclohexyl carbodiimide (DCC) and 4- diformazans Aminopyridine (DMAP) is catalyst, generates the new anti-cancer drug compounds (12) of the present invention, (13), (14) respectively.Compound (10) chloride derivative (11) for generating watermiscible vitamin E ester also can be reacted with thionyl (two) chlorine, then compound (11) Acid chloride functional groups optionally with 10- hydroxyl substituted camptothecins, such as 10-hydroxycamptothecine or SN38 Phenolic hydroxyl group reaction, or with camptothecine (or derivatives thereof) lactonic ring on hydroxyl reaction, with alkali as catalyst (such as three second Amine), generate the fat-soluble anti-cancer drug compounds (12), (13) and (14) of the present invention.

R:Alkyl (alkyl), branched alkyl (branched alkyl) and cycloalkyl (cyclic alkyl), or Undersaturated alkane thiazolinyl, undersaturated branched alkane thiazolinyl, undersaturated cycloalkenyl, aryl and aralkyl etc.；R₁:- CH₂CH₂-,-CH₂CH₂CH₂-,-CH₂OCH₂- etc.；R₂:H,-CH₂CH₃Deng.

The synthetic route 3 of 10. new anti-cancer drug compounds of formula.

The present invention fat-soluble anti-cancer drug compounds still another synthetic method as shown in formula 11 and formula 12, with alkali (such as triethylamine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate) is catalyst, watermiscible vitamin E ester (3) or water soluble vitamins E amide (9) reacts the derivant (15a) for generating watermiscible vitamin E ester with halogen (iodine, bromine, chlorine) for carboxylic acid (such as monobromo-acetic acid), Or (15b) is generated with halogenated carboxylic ester (such as bromoethyl acetate) reaction, given birth to acid treatment after (15b) reacting with Lithium hydrate again Into (15a).(15a) chloride derivative (16) is generated with the reaction of thionyl (two) chlorine, then the acid chloride functional groups of compound (16) Optionally with 10- hydroxyl substituted camptothecins, the phenolic hydroxyl group of such as 10-hydroxycamptothecine or SN38 is anti- Should, or with camptothecine (or derivatives thereof) lactonic ring on hydroxyl reaction, with alkali as catalyst (such as triethylamine), generate this Bright fat-soluble anti-cancer drug compounds (17) and (18).The derivant (15a) of watermiscible vitamin E ester also can directly and 10- Camptothecine (such as 10-hydroxycamptothecine or SN38) or Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae) alkali reaction that hydroxyl replaces, with 4- diformazans Aminopyridine (DMAP) and 2- chloro- 1- methyl pyridinium iodides (CMPI) or N, N '-dicyclohexyl carbodiimide (DCC) and DMAP (DMAP) is catalyst, generates fat-soluble anti-cancer drug compounds (17) and (18) of the present invention respectively.

Formula 13 describes another synthetic method of the fat-soluble anti-cancer drug compounds of the present invention, with alkali (such as triethylamine, Pyridine, sodium carbonate, potassium carbonate, cesium carbonate) be catalyst, watermiscible vitamin E ester (3) or watermiscible vitamin E amide (9) with Alkane (oxygen) base phosphine (phosphorus) acyl dichloro (such as first (oxygen) base phosphine (phosphorus) acyl dichloro) or fragrant (oxygen) base phosphine (phosphorus) acyl dichloro are (such as benzene (oxygen) base Phosphine (phosphorus) acyl dichloro) react the derivant (19) for generating watermiscible vitamin E ester.Compound (19) directly with camptothecine or its spread out Biological respinse, generates fat-soluble anti-cancer drug compounds (20) and (21) of watermiscible vitamin E Derivatives Modified.

R:Alkyl (alkyl), branched alkyl (branched alkyl) and cycloalkyl (cyclic alkyl), or Undersaturated straight-chain alkyl, undersaturated branched hydrocarbyl, undersaturated cyclic hydrocarbon radical, aryl and aralkyl etc.；X is-O- ,-NH- Or-NR '-, wherein R ' is C1-C6 alkyl；M=1-10；R₂:H,-CH₂CH₃Deng.

The synthetic route 4 of 11. new anti-cancer drug compounds of formula.

R:Alkyl (alkyl), branched alkyl (branched alkyl) and cycloalkyl (cyclic alkyl), or Undersaturated straight-chain alkyl, undersaturated branched hydrocarbyl, undersaturated cyclic hydrocarbon radical, aryl and aralkyl etc.；X is-O- ,-NH- Or-NR '-, wherein R ' is C1-C6 alkyl；M=1-10.

The synthetic route 5 of 12. new anti-cancer drug compounds of formula.

R:Alkyl (alkyl), branched alkyl (branched alkyl) and cycloalkyl (cyclic alkyl), or Undersaturated straight-chain alkyl, undersaturated branched hydrocarbyl, undersaturated cyclic hydrocarbon radical, aryl and aralkyl etc.；X is-O- ,-NH- Or-NR '-, wherein R ' is C1-C6 alkyl；R1:C1-C6alkyl,phenyl and substituted phenyl,R'O-, R':C1-C6alkyl,phenyl and substituted phenyl；R₂:H,-CH₂CH₃.

The synthetic route 6 of 13. new anti-cancer drug compounds of formula.

The invention further relates to the pharmaceutical formulation of described new fat-soluble cancer therapy drug, matches somebody with somebody including emulsion and micellar preparation Side, emulsion formulations include neoteric anti-cancer drug compounds, one or more surfactant, oil phase (lipophilic medium) and Water phase.Emulsion can be oil-in-water type or water-in-oil type.Micellar preparation include neoteric anti-cancer drug compounds, cosolvent and One or more surfactant and water phase.

The technical scheme for adopting is a kind of, described fat-soluble anti-cancer drug compounds emulsion or microemulsion preparation, its into Dividing includes：

1) oil phase, including：

A) there are the fat-soluble anti-cancer drug compounds of the watermiscible vitamin E Derivatives Modified of formula I or II structure；

B) biocompatible lipophilic medium；

2) surfactant and cosolvent；

3) water phase.

Or, a kind of described fat-soluble anti-cancer drug compounds micellar preparation, its composition include：

1) there are the fat-soluble anti-cancer drug compounds of the watermiscible vitamin E Derivatives Modified of formula I or II structure；

2) surfactant；

3) cosolvent；

4) water phase.

The anti-cancer drug compounds of the present invention are dissolved in lipophilic medium.Lipophilic medium (or carrier) can be any A kind of biocompatible lipophilic medium, representative biocompatible lipophilic medium include：

A) fat-soluble vitamin E and derivant.Vitamin E refers to the vitamin E series with natural or synthetic, it Commonly referred to tocopherol and tocotrienol (tocopherols and tocotrienols), tocopherol includes alpha-tocopherol (D Type, DL types, L-type), betatocopherol (D types, DL types, L-type), Gamma-Tocopherol (D types, DL types, L-type) and Delta-Tocopherol (D types, DL Type, L-type).Tocotrienol is similar to tocopherol in structure, but tocotrienol is on the side chain phytyl (phytyl) of carbon -2 There are three double bonds.Tocotrienol includes alpha-tocotrienol (D types, DL types, L-type), β-tocotrienol (D types, DL types, L Type), γ-tocotrienol (D types, DL types, L-type) and δ-tocotrienol (D types, DL types, L-type).Vitamin e derivative includes All tocopherols and the derivant of tocotrienol, such as vitamin e succinate, Vitamin E acetate etc..

B) can be as the oils and fatss of lipophilic medium, including the fatty acid and ester of different chain length, they are straight chain mostly, but Can also be side chain, such as capric acid, octanoic acid, caproic acid, lauric acid, Semen Myristicae, stearic acid, Oleic acid, linoleic acid and other are full And/or unsaturated fatty acid and esters.

C) the fatty acid monoglyceride formed with glycerine esterification reaction, diglyceride or triglyceride, no matter they are Synthesis or natural, all can be as lipophilic medium, for example, glyceride, such as Oleum Glycines, Oleum Gossypii semen, Oleum Brassicae campestriss, fish oil, second Acylated monoglyceride, glycerin mono-fatty acid ester, triacetyl glycerine, and diacetyltartaric acid ester, monoglyceride, Oleum Ricini etc..

D) fatty alcohol, such as benzylalcohol, stearyl alcohol, lauryl alcohol etc., or their ester or ether, such as benzyl benzoate.

Representative surfactant includes：

A) live in polyglycol surfactants, such as polyoxyethylene castor oil EL (Cremophor EL), TWEEN Series surface Property agent.

B) non-phospholipid surfactants (phospholipids), such as lecithin (lecithin), Polyethylene Glycol phospholipid (pegylated phospholipids).

C) Polyethylene Glycol vitamin e derivative, such as vitamin e succinate Polyethylene Glycol (d- α-tocopherol polyethylene glycol1000succinate,TPGS).

D) polyoxyethylene polyoxypropylene block copolymer：Block copolymer (the H of POLOXAMERS or PLURONICS (OCH₂CH₂)_a(OCH₂CH₂CH₂)_b(OCH₂CH₂)_aOH).

Representative organic cosolvent includes：

Ethanol, Polyethylene Glycol, Propylene Glycol, glycerol, N-Methyl pyrrolidone etc..Polyethylene Glycol (PEG) is hydrophilic, weight The chemical constitution of multiple unit consists of-CH₂CH₂O-, formula are H- (CH₂CH₂)_n- OH, molecular weight ranges typically from 200 to 10000.For example, polyethylene glycol 200, PEG-300, PEG400 etc..

All include the fat-soluble anticarcinogen materialization of the present invention in emulsion, microemulsion and micellar preparation formula according to the present invention Compound.

" emulsion " used herein is referred in the presence of surfactant, and a phase liquid is scattered in another with drop state The heterogeneous liquid dispersion formed in phase liquid, the such as drop formed by oil and water, its diameter are typically micro- 0.1 to 3.0 Rice.

Described emulsion can form stable microemulsion." microemulsion " word refers to that two immiscible liquid form one Thermodynamically stable isotropism, transparent or semitransparent dispersion, the microemulsion dispersion of such as oil and water is lived by surface Property agent molecule formed interfacial film stablized.Microemulsion average droplet size be less than 200nm, general 10 to 50 nanometers.

Emulsion or microemulsion include oil phase and water phase.Emulsion or microemulsion can be oil-in-water type emulsion or Water-In-Oil Type.

In the absence of water, by oil phase, nonionic surfactant and co-emulsifier mixing formed homogeneous Transparent and comprising medicine solution is referred to as self-emulsifying drug delivery system (self-emulsifying drug delivery system：SEDDS), spontaneous emulsification forms Emulsion of the particle diameter in 100nm to 500nm, can be used to improve lipophilic drugs dissolubility And oral absorbability.

In described emulsion or microemulsion preparation, anti-cancer drug compounds are accounted in pharmaceutical formulation 0.005% to 5.0%；It is preferred that anti-cancer drug compounds account for 0.01% to 2.5% in pharmaceutical formulation； In preferred scheme, anti-cancer drug compounds account for 0.1% to 1.5% in pharmaceutical formulation.

In described emulsion or microemulsion preparation, lipophilic medium accounts for 2% in pharmaceutical formulation To 20%；It is preferred that lipophilic medium accounts for 4% to 12% in pharmaceutical formulation；In preferred scheme, Lipophilic medium accounts for 6% to 10% in pharmaceutical formulation.

In the embodiment of an emulsion or microemulsion, lipophilic medium includes Oleum Glycines, and aqueous media is water.Another In the embodiment of individual emulsion and microemulsion, lipophilic medium includes fat soluble vitamin E.In another emulsion or microemulsion In embodiment, lipophilic medium includes fat soluble vitamin E derivants.

Except the anti-cancer drug compounds of the present invention, medicine emulsion and microemulsion in emulsion or microemulsion formula of liquid, can also be included The other compositions that commonly uses in liquid formulation, these compositions include surfactant and cosolvent.Representative surface activity Agent includes nonionic surfactant, such as polyoxyethylene castor oil EL (Cremophor EL), Tween 80 (Tween80), poly- second Glycol vitamin e derivative surfactant and other surfactant polymers.

Suitable Polyethylene Glycol vitamin e derivative surface activity includes VE succinic acid polyethyleneglycol derivative (example Such as vitamin E polyethylene glycol succinic acid ester), in vitamin e derivative molecule, Polyethylene Glycol is by succinic acid and vitamin E Hydroxyl be formed by connecting, the Polyethylene Glycol in the polyethyleneglycol derivative of these vitamin Es is included with various molecular weight (examples Such as, Polyethylene Glycol 200,300,400,600,1000 etc.)." vitamin E polyethylene glycol succinic acid ester " herein includes dimension life Plain E polyethanediol succinates are (such as D- alpha tocopherol cetomacrogol 1000 succinates, TPGS, a kind of non-ionic surfactant Agent (HLB=16-18)) and vitamin E polyethylene glycol various esters and ether derivant.

In described emulsion or microemulsion preparation, weight percentage of the surfactant in formula about 1 to 10%, It is preferred that 2-6%, more preferably 4-5%.

In described emulsion or microemulsion preparation, cosolvent accounts for the 0% to 20% of formulation weight.

In yet another aspect, present invention also offers a kind of micellar preparation bag of described fat-soluble anti-cancer drug compounds Include anti-cancer drug compounds, one or more surfactants, one or more cosolvents and the water phase of the present invention.

In the micellar preparation of described fat-soluble anti-cancer drug compounds, medical compoundss weight percent in formula contains Amount about 0.005% to 3.0%, preferred agents compound weight percentage about 0.01% to 2.5% in formula；More excellent Choosing, medical compoundss weight percentage about 0.1% to 1.0% in formula.

Weight percentage of the suitable surfactant in the micellar preparation formula of the present invention about 1 to 10%, excellent Select 2-6%, more preferably 4-5%.

Micellar preparation formula also includes other compositions, cosolvent as mentioned above.In one embodiment, micelle system Comprising Polyethylene Glycol and relatively low alkylol (such as ethanol) in agent prescription.In described micellar preparation, cosolvent accounts for formula weight The 2% to 20% of amount.

Bag aqueous phase in emulsion, microemulsion and micellar preparation formula.In one embodiment, water mutually includes deionized water. In another embodiment, water mutually includes normal saline.In another embodiment, contain a kind of organic acid in water phase (such as succinum Acid, citric acid) buffer.

Present invention also offers the application of neoteric medical compoundss, i.e., described watermiscible vitamin E derivant is repaiied Application of the fat-soluble anti-cancer drug compounds of decorations in cancer therapy drug is prepared.

For example, medical compoundss of the invention are used for the medicine for preparing treating cancer.The medical compoundss of the present invention can use In the cancer that treatment includes blood system, such as leukemia, lymphoma, myeloma；With non-blood cancer, such as solid tumor cancer is (such as breast Adenocarcinoma, ovarian cancer, cancer of pancreas, colon and rectum carcinoma, nonsmall-cell lung cancer, bladder cancer), sarcoma and glioma etc..

The present invention medical compoundss curative effect and toxicity determined with cell in vitro or interior animal experiment, for example, ED50 (50%effective dose, median effective dose：There is dose during positive reaction in 50% experimental subject), LD50 (50%lethal dose, median lethal dose(LD 50) kill the dosage of half subjects) and GI50 (concentration of The anti-cancer drug that inhibits the growth of cancer cells by50%, suppress 50% Experimental subject growth drug level).Generally the ratio of median lethal dose(LD 50) (LD50)/median effective dose (ED50) is referred to as controlling Index is treated, in order to represent Drug safety.The big medicine of the therapeutic index medicine little with respect to therapeutic index is safer.

Neoteric anti-cancer drug compounds are intended to improve therapeutic index and Drug safety, while also improve controlling curative effect Really.The drug dose obtained from In vitro cell experiment and interior animal experiment can be used to formulate the dosage range for human body. The dosage of this compound is preferably little or do not have in the range of virose ED50 at all.Doses change generally depends on employing Dosage form, the sensitivity of patient and route of administration etc..Same or like medicine generally can use, and such as topotecan and irinotecan is normal Rule dosage makes reference.The routine dose of such as topotecan is 0.2-1.5mg/m², irinotecan routine dose be 100mg- 350mg/m².

The medical compoundss of the present invention can be used alone, and also can make together with one or more of the other medicine With.For example, in the treatment of cancer, these medical compoundss can be used together with following medicine, including but not limited to：Male Hormone inhibitors, such as flutamide (flutamide) and Lu Poruoli get (luprolide)；Estrogen antagonist, such as tamoxifen (tomoxifen)；Antimetabolite and cytotoxic drug, such as daunorubicin (daunorubicin), 5-fluorouracil (fluorouracil), floxuridine (floxuridine), alpha-interferon (interferon alpha), methotrexate (methotrexate), mithramycin (plicamycin), mercaptopurine (mecaptopurine), thioguanine (thioguanine), amycin (adriamycin), carmustine (carmustine), lomustine (lomustine), Ah Sugared cytidine (cytarabine), cyclophosphamide (cyclophosphamide), amycin (doxorubicin), estramustine (estramustine), altretamine (altretamine), hydroxyurea (hydroxyurea), ifosfamide (ifosfamide), procarbazine (procarbazine), mutamycin (mutamycin), busulfan (busulfan), meter Tuo Anthraquinone (mitoxantrone), carboplatin carboplatin), cisplatin (cisplatin), streptozotocin (streptozocin), Bleomycin (bleomycin), D actinomycin D (dactinomycin) and darubicin (idamycin)；Hormone, such as medroxyprogesterone (medroxyprogesterone), alkynes estradiol (ethinyl estradiol), estradiol (estradiol), leuprorelin (leuprolide), megestrol (megestrol), octreotide (octreotide), diethylstilbestrol (diethylstilbestrol), chlorotrianisene (chlorotrianisene), etoposide (etoposide), podophyllotoxin And goserelin (goserelin) (podophyllotoxin)；Nitrogen mustard derivativeses, such as phenyalamine mustard (melphalan), benzene Butanoic acid chlormethine (chlorambucil) and phosphinothioylidynetrisaziridine (thiotepa)；Steroid, such as betamethasone (betamethasone)；With Other antitumor drug, such as cattle on the hoof mycobacteria (live Mycobacterium bovis), dacarbazine (dicarbazine), asparaginase (asparaginase), formyl tetrahydrofolic acid (leucovorin), mitotane (mitotane), vincristine (vincristine), vinblastine (vinblastine) and Docetaxel (taxotere) etc..

The present invention will be water-soluble with lipotropy for the medical compoundss molecule camptothecine or camptothecin derivative with active anticancer Property vitamin-e ester or amide by linking group covalent bond, obtain the fat-soluble anticancer of watermiscible vitamin E Derivatives Modified Medical compoundss, described compound contain cancer therapy drug active part and lipophilic portion, can be dissolved in the parent of biocompatibility Ester solvent.The present invention new anti-cancer drug compounds have higher active anticancer, while have preferable dissolubility and Stability, it is possible to increase camptothecine or derivatives thereof continuous action time (half-life) in vivo under physiological condition and curative effect, Reduce its toxic and side effects.Described medical compoundss can make Emulsion or micellar preparation, be widely used in blood system and non- The treatment of hematological cancer.The present invention can be modified to various camptothecin analogues, widened camptothecine and its derived The application of thing, the clinical practice for camptothecin analogues provide a kind of new method and approach.

Describe the present invention with reference to specific embodiment.Protection scope of the present invention is not being embodied as Mode is limited, but is defined in the claims.

Description of the drawings

The mass spectrum of Fig. 1 R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acid hexadecanol esters.

The nuclear magnetic resonance, NMR of Fig. 2 R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acid hexadecanol esters Hydrogen spectrogram.

Fig. 3 R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acid hexadecanol ester -6- mono succinates The mass spectrum of ester.

Fig. 4 R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acid hexadecanol ester -6- mono succinates The hydrogen nuclear magnetic resonance spectrogram of ester.

Fig. 5 SN38 R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylics The mass spectrum of sour hexadecanol ester -6- succinates.

Fig. 6 SN38 R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylics The hydrogen nuclear magnetic resonance spectrogram of sour hexadecanol ester -6- succinates.

Fig. 7 SN38 R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylics The mass spectrum of sour hexanol ester -6- succinates.

Fig. 8 SN38 R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylics The hydrogen nuclear magnetic resonance spectrogram of sour hexanol ester -6- succinates.

Fig. 9 SN38 R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylics The mass spectrum of sour lauryl alcohol ester -6- succinates.

Figure 10 SN38 R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylics The hydrogen nuclear magnetic resonance spectrogram of sour lauryl alcohol ester -6- succinates.

Figure 11 SN38 (±) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylicsAcidThe mass spectrum of hexadecanol ester -6- succinates.

Figure 12 SN38 (±) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylicsAcidThe hydrogen nuclear magnetic resonance spectrogram of hexadecanol ester -6- succinates.

Specific embodiment

The following examples are used for synthesis, preparation and the In vitro cell experiment of the new anti-cancer drug compounds that the present invention is described Deng.Described embodiment contributes to the understanding of the present invention and enforcement, does not constitute for the restriction of the present invention.

Embodiment 1.7- ethyl-10-hydroxycamptothecin R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyrans - The synthesis of 2- carboxylic acid hexadecanol ester -6- succinates

The synthesis of described fat-soluble anti-cancer drug compounds is comprised the following steps：

1) synthesis of R- (+) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- carboxylic acid hexadecanol esters

Reaction equation is shown below：

Experimental procedure：

In the reaction bulb of 50mL, add 727mg (3mmol) hexadecanol, 733mg (6mmol) DMAP, The chloro- 1- methyl pyridinium iodides of 766mg (3mmol) 2- and 15mL DMFs, electromagnetic agitation, slowly to anti- Deca 750mg in liquid (3mmol) R- (+) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- carboxylic acids and 10mL N is answered, The solution of dinethylformamide.12h is reacted under room temperature and nitrogen protection.With Rotary Evaporators by solvent (N, N- dimethyl Methanamide) remove, and 50 milliliters of ether is added, 2h is stirred, and by overanxious for precipitate removing, then 10mL, post is concentrated into by liquid is considered Layer separate (230-400mesh silica gel be fixing phase, hexane：Ethyl acetate (volume ratio)=10：1 is leacheate), obtain 1026mg R- (+)-Trolox hexadecanol ester, yield 72.0%.

Its mass spectrum of obtained compound and proton nmr spectra are shown in Fig. 1 and Fig. 2.

MS(Positive ESI):M/z=475.3 (M+H)⁺,497.3(M+Na)⁺, 971.6 (2M+Na)⁺.

¹H NMR(400MHz,CDCl₃):δppm:4.173(s,1H),4.079-3.690(m,2H),2.648-2.384(m, 3H),2.161(s,3H),2.136(s,3H),2.038(s,3H),1.879-1.802(m,1H),1.577(s,3H),1.538- 1.475 (m, 2H), 1.302-1.176 (m, 26H), 0.880-0.846 (t, J=6.6Hz, 3H).

2) R- (+) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- carboxylic acids hexadecanol ester -6- monomester succinates Synthesis

Reaction equation is as follows：

Experimental procedure：

In the reaction bulb of 50mL, 949mg (2mmol) R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzo dihydros are added Pyrans -2- carboxylic acid hexadecanol esters, 300mg (3mmol) succinic anhydrides, 815mg (2.5mmol) cesium carbonates and 20mL N, N- diformazan Base Methanamide, electromagnetic agitation react 12h under the protection of room temperature and nitrogen.The ethyl acetate that reactant liquor is added to 100mL In, stirring, with being washed three times with 50mL respectively, organic faciess are dried the mixed liquor with anhydrous magnesium sulfate, overanxious removing magnesium sulfate, then Liquid will be considered and be concentrated into 10mL, (230-400mesh silica gel is drip washing for the mixed liquor of fixing phase, hexane and acetone to chromatography Liquid), obtain 908mg R- (+)-Trolox hexadecanol ester -6- mono succinates Ester, yield 79.0%.

Its mass spectrum of compound and proton nmr spectra that synthesis is obtained is shown in Fig. 3 and Fig. 4.

MS(Positive ESI):M/z=597.5 (M+Na)⁺, 1194.0 (2M+2Na)⁺.

¹H NMR(400MHz,CDCl₃):δppm:4.084-4.002 (m, 2H), 2.911-2.879 (t, J=6.4Hz, 2H), 2.809-2.776 (t, J=6.6Hz, 2H), 2.633-2.363 (m, 3H), 2.137 (s, 3H), 1.995 (s, 3H), 1.903(s,3H),1.867-1.791(m,1H),1.580(s,3H),1.514-1.499(m,2H),1.330-1.240(m, 26H), 0.878-0.844 (t, J=6.8Hz, 3H).

3) SN38 R- (+) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- carboxylic acids The synthesis of hexadecanol ester -6- succinates

Reaction equation is as follows：

Experimental procedure：

In the reaction bulb of 50mL, 519mg (1mmol) R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzo dihydros are added Pyrans -2- carboxylic acid hexadecanol ester -6- monomester succinates, 238mg (2mmol) thionyl chloride, 10 μ L N,N-dimethylformamides and 20mL dry toluenes, electromagnetic agitation react 4h under the protection of room temperature and nitrogen.Vacuum distillation removes the sulfurous of toluene and excess Acyl chlorides, obtains a thick liquid, adds 10mL anhydrous chloroforms, obtains solution A.

In the reaction bulb of 50mL, 196mg (0.5mmol) SN38,61mg (0.6mmol) is added Anhydrous triethylamine and the anhydrous N,N-dimethylacetamide of 20mL, stirring, are slowly added into 6mL solution As, in the protection of room temperature and nitrogen Lower reaction 4h, tlc analysis, if still there is a small amount of SN38 unreacted complete, add appropriate solution A Finish to reaction with triethylamine.Reactant liquor is added in the ethyl acetate of 100mL, the mixed liquor washes three with 50mL respectively Secondary, organic faciess are dried with anhydrous magnesium sulfate, overanxious removing magnesium sulfate, then are concentrated into 10mL, chromatography (230- by liquid is considered 400mesh silica gel is leacheate for the mixed liquor of fixing phase, hexane and acetone), obtain 340mg7- ethyl-10-hydroxycamptothecin R- (+)-Trolox hexadecanol ester -6- succinates, yield 76.2%.

Its mass spectrum of compound and proton nmr spectra that synthesis is obtained is shown in Fig. 5 and Fig. 6.

MS(Positive ESI):M/z=949.7 (M+H)⁺,971.7(M+Na)⁺.

¹H NMR(400MHz,CDCl₃):δppm:8.223-8.200 (d, J=9.2Hz, 1H), 7.796 (s, 1H), 7.624 (s, 1H), 7.554-7.532 (d, J=8.8Hz, 1H), 5.757-5.717 (d, J=16Hz, 1H), 5.312-5.271 (d, J= 16.4Hz,1H),5.240(s,2H),4.092-4.021(m,2H),3.714(s,1H),3.142-3.081(m,6H),2.632- 2.389(m,3H),2.146(s,3H),2.020(s,3H),1.929(s,3H),1.903-1.802(m,1H),1.589-1.545 (m, 7H), 1.374-1.335 (t, J=7.8Hz, 3H), 1.229 (m, 26H), 1.042-1.005 (t, J=7.4Hz, 3H), 0.869-0.836 (t, J=6.6Hz, 3H).

Embodiment 2.7- ethyl-10-hydroxycamptothecin R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyrans - The synthesis of 2- carboxylic acid hexanol ester -6- succinates

1) synthesis of R- (+) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- carboxylic acid hexanol esters

Reaction equation is as follows：

Experimental procedure：

In the reaction bulb of 50mL, 978mg (8mmol) DMAP, the chloro- 1- of 1022mg (4mmol) 2- is added Methyl pyridinium iodide and 20mL hexanol, electromagnetic agitation, slowly to Deca 751mg in reactant liquor (3mmol) R- (+) -6- The solution of hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acids and 10mL DMFs, in room temperature and 12h is reacted under the protection of nitrogen.Overanxious removing solid matter, is concentrated into 10mL, chromatography with Rotary Evaporators by liquid is considered (230-400mesh silica gel is leacheate for the mixed liquor of fixing phase, hexane and acetone), obtains 856mg R- (+) -6- hydroxyl -2, 5,7,8- tetramethyl benzodihydropyran -2- carboxylic acid hexanol esters, yield 85.0%.

MS(Positive ESI):M/z=335.3 (M+H)⁺,357.2(M+Na)⁺,691.5(2M+Na)⁺.

¹H NMR(400MHz,CDCl₃):δppm:4.081-3.959(m,2H),2.674-2.392(m,3H),2.159(s, 3H),2.134(s,3H),1.991(s,3H),1.877-1.737(m,1H),1.578(s,3H),1.534-1.471(m,2H), 1.294-1.165 (m, 6H), 0.876-0.839 (t, J=7.4Hz, 3H).

2) R- (+) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- carboxylic acids hexanol ester -6- monomester succinates Synthesis

Reaction equation is as follows：

Experimental procedure：

In the reaction bulb of 50mL, 836mg (2.5mmol) R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzos two are added Hydrogen pyrans -2- carboxylic acid hexanol esters, 300mg (3mmol) succinic anhydrides, 815mg (2.5mmol) cesium carbonates and 20mL N, N- bis- Methylformamide, electromagnetic agitation react 12h under the protection of room temperature and nitrogen.The ethyl acetate that reactant liquor is added to 100mL In, stirring, the mixed liquor are washed three times with the 0.1N HCl solutions of 50mL respectively, then are washed three times with 50mL respectively, and organic faciess are used Anhydrous magnesium sulfate is dried, overanxious removing magnesium sulfate, then is concentrated into 10mL by liquid is considered, and (230-400mesh silica gel is solid to chromatography The mixed liquor for determining phase, hexane and acetone is leacheate), obtain 865mg R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzo dihydros Pyrans -2- carboxylic acid hexanol ester -6- monomester succinates, yield 79.0%.

MS(Positive ESI):M/z=457.3 (M+Na)⁺,891.6(2M+Na)⁺.

¹H NMR(400MHz,CDCl₃):δppm:4.086-3.974 (m, 2H), 2.915-2.883 (t, J=6.4Hz, 2H), 2.809-2.777 (t, J=6.4Hz, 2H), 2.667-2.373 (m, 3H), 2.135 (s, 3H), 1.992 (s, 3H), 1.901(s,3H),1.864-1.788(m,1H),1.580(s,3H),1.491(s,2H),1.281-1.189(m,6H), 0.857-0.822 (t, J=7Hz, 3H).

3) SN38 R- (+) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- carboxylic acids The synthesis of hexanol ester -6- succinates

Reaction equation is

Experimental procedure：

In the reaction bulb of 50mL, 439mg (1mmol) R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzo dihydros are added Pyrans -2- carboxylic acid hexanol ester -6- monomester succinates, 238mg (2mmol) thionyl chloride, 10 μ L N,N-dimethylformamides and 20mL dry toluenes, electromagnetic agitation react 4h under the protection of room temperature and nitrogen.Vacuum distillation removes the sulfurous of toluene and excess Acyl chlorides, obtains a thick liquid, adds 10mL anhydrous chloroforms, obtains solution A.

In the reaction bulb of 50mL, 196mg (0.5mmol) SN38,61mg (0.6mmol) is added Anhydrous triethylamine and the anhydrous N,N-dimethylacetamide of 20mL, stirring, are slowly added into 6mL solution As, in the protection of room temperature and nitrogen Lower reaction 4h.Tlc analysis, if still there is a small amount of SN38 unreacted complete, add appropriate solution A Finish to reaction with triethylamine.Reactant liquor is added in the ethyl acetate of 100mL, the mixed liquor is with respectively with 50mL washings three Secondary, organic faciess are dried with anhydrous magnesium sulfate, overanxious removing magnesium sulfate, then are concentrated into 10mL, chromatography (230- by liquid is considered 400mesh silica gel is leacheate for the mixed liquor of fixing phase, hexane and acetone), obtain 358mg7- ethyl-10-hydroxycamptothecin R- (+)-Trolox hexanol ester -6- succinates, yield 90.0%.

Its mass spectrum of fat-soluble anti-cancer drug compounds and proton nmr spectra that synthesis is obtained is shown in Fig. 7 and Fig. 8.

MS(Positive ESI):M/z=809.5 (M+H)⁺,831.5(M+Na)⁺.

¹H NMR(400MHz,CDCl₃):δppm:8.223-8.200 (d, J=9.2Hz, 1H), 7.795 (s, 1H), 7.625 (s, 1H), 7.555-7.532 (d, J=9.2Hz, 1H), 5.759-5.718 (d, J=16.4Hz, 1H), 5.313-5.273 (d, J =16Hz, 1H), 5.241 (s, 2H), 4.066-4.020 (m, 2H), 3.705 (s, 1H), 3.142-3.083 (6H), 2.632- 2.382(m,3H),2.144(s,3H),2.018(s,3H),1.927(s,3H),1.901-1.799(m,1H),1.590-1.512 (m, 7H), 1.372-1.334 (t, J=7.6Hz, 3H), 1.232-1.170 (m, 6H), 1.041-1.005 (t, J=7.2Hz, 3H), 0.857-0.822 (t, J=7Hz, 3H).

Embodiment 3.7- ethyl-10-hydroxycamptothecin R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyrans - The synthesis of 2- carboxylic acid lauryl alcohol ester -6- succinates

1) R- (+) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- carboxylic acid lauryl alcohol esters

Reaction equation such as following formula：

Experimental procedure：

In the reaction bulb of 50mL, add 373mg (2mmol) lauryl alcohol, 489mg (4mmol) DMAP, The chloro- 1- methyl pyridinium iodides of 511mg (2mmol) 2- and 10mL DMFs, electromagnetic agitation, slowly to anti- Deca 500mg in liquid (2mmol) R- (+) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- carboxylic acids and 10mL N is answered, The solution of dinethylformamide, reacts 12h under room temperature and nitrogen protection.Overanxious removing solid matter, uses Rotary Evaporators Liquid will be considered and be concentrated into 10mL, (230-400mesh silica gel will be pouring for the mixed liquor of fixing phase, hexane and ethyl acetate to chromatography Washing liquid), obtain 365mg R- (+)-Trolox lauryl alcohol ester, yield 43.6%.

MS(Positive ESI):M/z=419.4 (M+H)⁺,441.4(M+Na)⁺,859.7(2M+Na)⁺.

¹H NMR(400MHz,CDCl₃):δppm:4.183(s,1H),4.079-3.961(m,2H),2.655-2.383(m, 3H),2.161(s,3H),2.135(s,3H),2.037(s,3H),1.879-1.803(m,1H),1.578(s,3H),1.525- 1.459 (m, 2H), 1.304-1.178 (m, 18H), 0.884-0.849 (t, J=7.0Hz, 3H).

2) R- (+) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- carboxylic acids lauryl alcohol ester -6- monomester succinates Synthesis

Reaction equation is

Experimental procedure：

In the reaction bulb of 50mL, 837mg (2mmol) R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzo dihydros are added Pyrans -2- carboxylic acid lauryl alcohol esters, 300mg (3mmol) succinic anhydrides, 815mg (2.5mmol) cesium carbonates and 20mL N, N- diformazan Base Methanamide, electromagnetic agitation react 12h under the protection of room temperature and nitrogen.The ethyl acetate that reactant liquor is added to 100mL In, stirring, the mixed liquor are washed three times with the 0.1N HCl solutions of 50mL respectively, then are washed three times with 50mL respectively, and organic faciess are used Anhydrous magnesium sulfate is dried, overanxious removing magnesium sulfate, then is concentrated into 10mL by liquid is considered, and (230-400mesh silica gel is solid to chromatography The mixed liquor for determining phase, hexane and acetone is leacheate), obtain 908mg R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzo dihydros Pyrans -2- carboxylic acid lauryl alcohol ester -6- monomester succinates, yield 86.0%.

MS(Positive ESI):M/z=541.4 (M+Na)⁺.

¹H NMR(400MHz,CDCl₃):δppm:4.089-3.999 (m, 2H), 2.911-2.879 (t, J=6.4Hz, 2H), 2.807-2.774 (t, J=6.6Hz, 2H), 2.664-2.363 (m, 3H), 2.136 (s, 3H), 1.994 (s, 3H), 1.902(s,3H),1.866-1.790(m,1H),1.579(s,3H),1.496(m,2H),1.299-1.192(m,18H), 0.878-0.844 (t, J=6.8Hz, 3H).

3) SN38 R- (+) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- carboxylic acids The synthesis of lauryl alcohol ester -6- succinates

Reaction equation is

Experimental procedure：

In the reaction bulb of 50mL, 519mg (1mmol) R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzo dihydros are added Pyrans -2- carboxylic acid lauryl alcohol ester -6- monomester succinates, 238mg (2mmol) thionyl chloride, 10 μ L N,N-dimethylformamides and 20mL dry toluenes, electromagnetic agitation react 4h under the protection of room temperature and nitrogen.Vacuum distillation removes the sulfurous of toluene and excess Acyl chlorides, obtains a thick liquid, adds 10mL anhydrous chloroforms, obtains solution A.

In the reaction bulb of 50mL, 196mg (0.5mmol) SN38,61mg (0.6mmol) is added Anhydrous triethylamine and the anhydrous N,N-dimethylacetamide of 20mL, stirring, are slowly added into 6mL solution As, in the protection of room temperature and nitrogen Lower reaction 4h, tlc analysis, if still there is a small amount of SN38 unreacted complete, add appropriate solution A Finish to reaction with triethylamine.Reactant liquor is added in the ethyl acetate of 100mL, the mixed liquor is with respectively with 50mL washings three Secondary, organic faciess are dried with anhydrous magnesium sulfate, overanxious removing magnesium sulfate, then are concentrated into 10mL, chromatography (230- by liquid is considered 400mesh silica gel is leacheate for the mixed liquor of fixing phase, hexane and acetone), obtain 340mg7- ethyl-10-hydroxycamptothecin R- (+)-Trolox lauryl alcohol ester -6- succinates, yield 76.2%.

Its mass spectrum of fat-soluble anti-cancer drug compounds and proton nmr spectra that synthesis is obtained is shown in Fig. 9 and Figure 10.

MS(Positive ESI):M/z=893.7 (M+H)⁺,915.7(M+Na)⁺.

¹H NMR(400MHz,CDCl₃):δppm:8.220-8.197 (d, J=9.2Hz, 1H), 7.794 (s, 1H), 7.623 (s, 1H), 7.552-7.529 (d, J=9.2Hz, 1H), 5.755-5.714 (d, J=16.4Hz, 1H), 5.310-5.269 (d, J =16.4Hz, 1H), 5.238 (s, 2H), 4.075-4.108 (m, 2H), 3.739 (s, 1H), 3.140-3.081 (m, 6H), 2.633-2.397(t,3H),2.145(s,3H),2.020(s,3H),1.929(s,3H),1.902-1.801(m,1H), 1.589-1.506 (s, 7H), 1.373-1.335 (t, J=7.6Hz, 3H), 1.272-1.223 (m, 18), 1.041-1.004 (t, J=7.4Hz, 3H), 0.869-0.835 (t, J=6.8Hz, 3H).

Embodiment 4.7- ethyl-10-hydroxycamptothecin (±) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- The synthesis of carboxylic acid hexadecanol ester -6- succinates

1) synthesis of (±) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- carboxylic acid hexadecanol esters

Reaction equation is shown below：

Experimental procedure：

In the reaction bulb of 100mL, add 970mg (4mmol) hexadecanol, 1466mg (12mmol) DMAP, The chloro- 1- methyl pyridinium iodides of 1533mg (6mmol) 2- and 20mL dioxanes, electromagnetic agitation, slowly to reactant liquor Middle Deca 1001mg (4mmol) (±) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- carboxylic acids and 20mL dioxas The solution of thiacyclohexane, reacts 12h under room temperature and nitrogen protection.Solvent (dioxane) is removed with Rotary Evaporators, And 50 milliliters of ether is added, 2h is stirred, and by overanxious for precipitate removing, then 10mL, chromatography (230- is concentrated into by liquid is considered 400mesh silica gel be fixing phase, hexane：Ethyl acetate=10：1 is leacheate), obtain 1242mg (±) -6- hydroxyl -2,5,7,8- Tetramethyl benzodihydropyran -2- carboxylic acid hexadecanol esters, yield 65.4%.

MS(Positive ESI):M/z=475.3 (M+H)⁺,497.3(M+Na)⁺,971.5(2M+Na)⁺.

¹H NMR(400MHz,CDCl₃):δppm:4.167(s,1H),4.077-3.974(m,2H),2.647-2.383(m, 3H),2.160(s,3H),2.135(s,3H),2.037(s,3H),1.878-1.801(m,1H),1.577(s,3H),1.535- 1.471 (m, 2H), 1.282-1.174 (m, 26H), 0.879-0.844 (t, J=7.0Hz, 3H).

2) (±) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- carboxylic acids hexadecanol ester -6- monomester succinates Synthesis

Reaction equation is as follows：

Experimental procedure：

In the reaction bulb of 100mL, 949mg (2mmol) (±) -6- hydroxyl -2,5,7,8- tetramethyl benzo dihydros are added Pyrans -2- carboxylic acid hexadecanol esters, 300mg (3mmol) succinic anhydrides, 100 μ g2- thylhexoic acid stannum (II) and 50mL anhydrous dimethyls Benzene, is heated to reflux 8h under the protection of nitrogen.Solvent (N, N- dimethylbenzene) is removed by overanxious removing solid matter with Rotary Evaporators Go, chromatography (230-400mesh silica gel for fixing phase, hexane and acetone mixed liquor be leacheate), obtain 1002mg (±)- Trolox hexadecanol ester -6- monomester succinates, yield 87.2%.

MS(Positive ESI):M/z=597.3 (M+Na)⁺.

¹H NMR(400MHz,CDCl₃):δppm:4.066-3.999 (m, 2H), 2.916-2.884 (t, J=6.4Hz, 2H), 2.811-2.778 (t, J=6.6Hz, 2H), 2.625-2.363 (m, 3H), 2.136 (s, 3H), 1.994 (s, 3H), 1.903(s,3H),1.866-1.790(m,1H),1.579(s,3H),1.512-1.496(m,2H),1.298-1.193(m, 26H), 0.876-0.842 (t, J=6.8Hz, 3H).

3) SN38 (±) -6- hydroxyls -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acids ten The synthesis of six alcohol ester -6- succinates

Reaction equation is

Experimental procedure：

In the reaction bulb of 50mL, 862mg (1.5mmol) (±) -6- hydroxyl -2,5,7,8- tetramethyl benzo dihydros are added Pyrans -2- carboxylic acid hexadecanol ester -6- monomester succinates, 357mg (3mmol) thionyl chloride, 10 μ L N,N-dimethylformamides and 30mL dry toluenes, electromagnetic agitation react 4h under the protection of room temperature and nitrogen, and vacuum distillation removes the sulfurous of toluene and excess Acyl chlorides, obtains a thick liquid, adds 10mL anhydrous chloroforms, obtains solution A.

In the reaction bulb of 50mL, 392mg (1mmol) SN38,121mg (1.2mmol) is added Anhydrous triethylamine and the anhydrous N,N-dimethylacetamide of 20mL, stirring, are slowly added into 6mL solution As, in the protection of room temperature and nitrogen Lower reaction 4h.Tlc analysis, if still there is a small amount of SN38 unreacted complete, add appropriate solution A Finish to reaction with triethylamine.Reactant liquor is added in the ethyl acetate of 100mL, the mixed liquor is with respectively with 50mL washings three Secondary, organic faciess are dried with anhydrous magnesium sulfate, overanxious removing magnesium sulfate, then are concentrated into 10mL, chromatography (230- by liquid is considered 400mesh silica gel is leacheate for the mixed liquor of fixing phase, hexane and acetone), obtain 475mg7- ethyl-10-hydroxycamptothecins (±)-Trolox hexadecanol ester -6- succinates, yield 50.0%.

Its mass spectrum of fat-soluble anti-cancer drug compounds and proton nmr spectra that synthesis is obtained is shown in Figure 11 and Figure 12.

MS(Positive ESI):M/z=949.4 (M+H)⁺,1898.8(2M+H)⁺.

¹H NMR(400MHz,CDCl₃):δppm:8.238-8.215 (d, J=4.6Hz, 1H), 7.798 (s, 1H), 7.645 (s, 1H), 7.645-7.529 (m, 1H), 5.758-5.718 (d, J=8Hz, 1H), 5.313-5.272 (d, J=8Hz, 1H), 5.243(s,2H),4.075-4.017(m,2H),3.709(s,1H),3.144-3.082(m,6H),2.597-2.382(m, 3H),2.145(s,3H),2.020(s,3H),1.928(s,3H),1.902-1.801(m,1H),1.598-1.507(m,5H), 1.374-1.336 (t, J=7.6Hz), 1.289-1.187 (m, 26H), 1.024-1.005 (t, J=7.4Hz), 0.869- 0.835 (t, J=6.8Hz, 3H).

Embodiment 5.7- ethyl-10-hydroxycamptothecin N- cetylamine base R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzos The synthesis of dihydropyran -2- Methanamide -6- succinates

The synthesis of the fat-soluble anti-cancer drug compounds is comprised the following steps：

1) synthesis of N- cetylamines base R- (+) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- Methanamides

Reaction equation is shown below：

Experimental procedure：

In the reaction bulb of 50mL, 825mg (4mmol) N, N '-dicyclohexyl carbodiimide (DCC), 724mg is added (3mmol) cetylamine, 751mg (3mmol) R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acids and 20mL N,N-dimethylformamides.Electromagnetic agitation, reaction 12h under the protection of room temperature and nitrogen, overanxious removing solid matter, The DMF that considers in liquid is removed with Rotary Evaporators, 10mL ethyl acetate is added, and stirs chromatography (230- 400mesh silica gel is leacheate for the mixed liquor of fixing phase, hexane and acetone), obtain 1074mg N- cetylamine base R- (+) -6- hydroxyls Base -2,5,7,8- tetramethyl benzodihydropyran -2- Methanamides, yield 75.6%.

2) N- cetylamines base R- (+) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- Methanamide -6- succinic acid The synthesis of monoesters

Reaction equation is as follows：

Experimental procedure：

In the reaction bulb of 50mL, 947mg (2mmol) N- cetylamine base R- (+) -6- hydroxyl -2,5,7,8- tetramethyls are added Base benzodihydropyran -2- Methanamides, 300mg (3mmol) succinic anhydrides, 100mg2- thylhexoic acid stannum (II) and 50mL are anhydrous Dimethylbenzene, is heated to reflux 8h under the protection of nitrogen, overanxious removing solid matter, and (230-400mesh silica gel is solid to chromatography The mixed liquor for determining phase, hexane and acetone is leacheate) obtain 943mg N- cetylamine base R- (+) -6- hydroxyl -2,5,7,8- tetramethyls Benzodihydropyran -2- Methanamide -6- monomester succinates, yield 82.2%.

3) SN38 N- cetylamines base R- (+) -6- hydroxyls -2,5,7,8- tetramethyl benzo dihydro pyrroles Mutter the synthesis of -2- Methanamide -6- succinates

Reaction equation is as follows：

Experimental procedure：

In the reaction bulb of 50mL, 574mg (1mmol) N- cetylamine base R- (+) -6- hydroxyl -2,5,7,8- tetramethyls are added Base benzodihydropyran -2- Methanamide -6- monomester succinates, 238mg (2mmol) thionyl chloride, 10 μ L N, N- dimethyl formyls Amine and 20mL dry toluenes, electromagnetic agitation react 4h under the protection of room temperature and nitrogen.Vacuum distillation removes toluene with excess Thionyl chloride, obtains thick liquid, adds 10mL anhydrous chloroforms to obtain solution A.

In the reaction bulb of 50mL, 196mg (0.5mmol) SN38,61mg (0.6mmol) is added Anhydrous triethylamine and the anhydrous N,N-dimethylacetamide of 20mL, electromagnetic agitation, are slowly added into 6mL solution As, in room temperature and nitrogen The lower reaction 4h of protection, tlc analysis, if still there is a small amount of SN38 unreacted complete, are added appropriate molten Liquid A and triethylamine are finished to reaction.Reactant liquor is added in the ethyl acetate of 100mL, overanxious removing solid matter, then will be considered Liquid is concentrated into 10mL, and chromatography (230-400mesh silica gel is leacheate for the mixed liquor of fixing phase, hexane and acetone) is obtained 645mg7- ethyl-10-hydroxycamptothecin N- cetylamine base R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- Methanamide -6- succinates, yield 68.0%.

6. camptothecine N- cetylamine base R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- first of embodiment The synthesis of amide -6- succinates

Reaction equation is as follows：

Experimental procedure：

In the reaction bulb of 50mL, 174mg (0.5mmol) camptothecine, 287mg (0.5mmol) N- cetylamine base R- is added (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- formyl -6- monomester succinates, 147mg (1.2mmol) 4- bis- Methylamino pyridine, the chloro- 1- methyl pyridinium iodides of 153mg (0.6mmol) 2- and the anhydrous N,N-dimethylacetamide of 20mL, electricity Magnetic is stirred, and reacts 4h under the protection of room temperature and nitrogen.Reactant liquor is added in the ethyl acetate of 100mL, overanxious removing is solid Body material, then worry liquid is concentrated into 10mL, chromatography (mixed liquor of the 230-400mesh silica gel for fixing phase, hexane and acetone For leacheate) obtain 316mg camptothecine N- cetylamine base R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- first Amide -6- succinates, yield 70.0%.

Embodiment 7.7- ethyl-10-hydroxycamptothecin (±) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- The synthesis of carboxylic acid hexadecanol ester -6- oxoacetate esters

1) (±) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- carboxylic acids hexadecanol ester -6- fluoroacetic acid ethyl esters Synthesis

Reaction equation is as follows：

Experimental procedure：

In the reaction bulb of 50mL, 948mg (2mmol) (±) -6- hydroxyl -2,5,7,8- tetramethyl benzo dihydro pyrroles are added Mutter -2- carboxylic hexadecanol esters, 501mg (3mmol) bromoacetate, 652mg (2mmol) cesium carbonates and the anhydrous N of 20mL, N- dimethyl Methanamide, electromagnetic agitation react 12h under the protection of room temperature and nitrogen.Vacuum distillation removing DMF, then plus Enter the ethyl acetate of 100mL, stir, overanxious removing solid matter, then 10mL, chromatography (230- is concentrated into by liquid is considered 400mesh silica gel for fixing phase, hexane and acetone mixed liquor be leacheate) 864mg (±) -6- hydroxyl -2,5,7,8- tetra- Methyl benzodihydropyran -2- carboxylic acid hexadecanol ester -6- fluoroacetic acid ethyl esters, yield 77.0%.

2) conjunction of (±) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- carboxylic acids hexadecanol ester -6- fluoroacetic acid Into

Reaction equation is as follows：

Experimental procedure：

In the reaction bulb of 50mL, 1122mg (2mmol) (±) -6- hydroxyl -2,5,7,8- tetramethyl benzo dihydros are added Pyrans -2- carboxylic acids hexadecanol ester -6- fluoroacetic acid ethyl ester and 20mL methanol, electromagnetic agitation, are subsequently adding 48mg (2mmol) hydroxide Lithium and the solution of 5mL water, electromagnetic agitation react about 1h to (±) -6- hydroxyl -2 under the protection of room temperature and nitrogen, and 5,7,8- tetra- Methyl benzodihydropyran -2- carboxylic acid hexadecanol ester -6- fluoroacetic acid ethyl esters react completely.Vacuum distillation removes methanol, Deca The pH value of 0.1NHCl to solution is 3-4, and lyophilization adds the ethyl acetate of 10mL, stirs, overanxious removing solid matter, Chromatography (230-400mesh silica gel is leacheate for the mixed liquor of fixing phase, hexane and acetone) obtains 938mg (±) -6- hydroxyls Base -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acid hexadecanol ester -6- fluoroacetic acid, yield 88%.

3) SN38 (±) -6- hydroxyls -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acids ten The synthesis of six alcohol ester -6- fluoroacetic acid esters.

Reaction equation is as follows：

Experimental procedure：

In the reaction bulb of 50mL, 533mg (1mmol) (±) -6- hydroxyl -2,5,7,8- tetramethyl benzo dihydro pyrroles are added Mutter -2- carboxylic acid hexadecanol ester -6- fluoroacetic acid, 238mg (2mmol) thionyl chloride, 10 μ L N,N-dimethylformamides and 20mL without Water-toluene, electromagnetic agitation react 4h under the protection of room temperature and nitrogen.Vacuum distillation removes the thionyl chloride of toluene and excess, Thick liquid is obtained, adds 10mL anhydrous chloroforms to obtain solution A.

In the reaction bulb of 50mL, 196mg (0.5mmol) SN38,61mg (0.6mmol) is added Anhydrous triethylamine and the anhydrous N,N-dimethylacetamide of 20mL, electromagnetic agitation, are slowly added into 6mL solution As, in room temperature and nitrogen The lower reaction 4h of protection, tlc analysis, if still there is a small amount of SN38 unreacted complete, are added appropriate molten Liquid A and triethylamine are finished to reaction.Reactant liquor is added in the ethyl acetate of 100mL, overanxious removing solid matter, then will be considered Liquid is concentrated into 10mL, and chromatography (230-400mesh silica gel is leacheate for the mixed liquor of fixing phase, hexane and acetone) is obtained 259mg7- ethyl-10-hydroxycamptothecin (±) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acid hexadecanol Ester -6- fluoroacetic acid esters, yield 57.0%.

8. camptothecine (±) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acid hexadecanol esters of embodiment - The synthesis of 6- fluoroacetic acid esters

Reaction equation is as follows：

Experimental procedure：

In the reaction bulb of 50mL, add 348mg (1mmol) camptothecine, 244mg (2mmol) DMAP, The chloro- 1- methyl pyridinium iodides of 255mg (1mmol) 2-, 533mg (1mmol) (±) -6- hydroxyl -2,5,7,8- durols And dihydropyran -2- carboxylic acid hexadecanol ester -6- fluoroacetic acid and the anhydrous N,N-dimethylacetamide of 20mL, electromagnetic agitation, in room temperature With reaction 4h under the protection of nitrogen.Overanxious removing solid matter, then 10mL, chromatography (230- is evaporated to by liquid is considered 400mesh silica gel for fixing phase, hexane and acetone mixed liquor be leacheate) 630mg camptothecine (±) -6- hydroxyl -2,5, 7,8- tetramethyl benzodihydropyran -2- carboxylic acid hexadecanol ester -6- fluoroacetic acid esters, yield 73.0%.

9. camptothecine (±) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acid hexadecanol esters of embodiment - The synthesis of 6- methyl phosphonic esters.

Reaction equation is as follows：

Experimental procedure：

In the reaction bulb of 100mL, 293mg (2.2mmol) methyl phosphonyl dichlorides and 20mL absolute ethers, electromagnetism is added to stir Mix, then slowly Deca 949mg (2mmol) (±)-Trolox hexadecanol Ester, the solution of 202mg (2mmol) triethylamines and 20mL absolute ethers, room temperature reaction 8h under the protection of nitrogen, vacuum distillation are removed Remove ether, be vacuum dried 1096mg (±)-Trolox hexadecanol ester- 6- methyl phosphonic chloride esters, yield 96.0%.

In the reaction bulb of 50mL, 348mg (1mmol) camptothecine, 111mg (1.1mmol) triethylamine, 628mg is added (1.1mmol) (±) -6- hydroxyls -2,5,7,8- tetramethyls benzodihydropyran -2- carboxylic acids hexadecanol ester -6- methyl phosphonic chloride esters With the anhydrous N,N-dimethylacetamide of 20mL, electromagnetic agitation, 4h is reacted under the protection of room temperature and nitrogen.Overanxious removing solidss Matter, then worry liquid is evaporated to 10mL, chromatography (mixed liquor of the 230-400mesh silica gel for fixing phase, hexane and acetone For leacheate) 732mg camptothecine (±) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acid hexadecanol esters - 6- methyl phosphonic esters, yield 83.0%.

The preparation of 10. fat-soluble anti-cancer drug compounds of embodiment, including emulsion and micellar formulation

Emulsion and micellar formulation in the present embodiment, including fat-soluble anti-cancer drug compounds.In emulsion and micellar formulation The fat-soluble anti-cancer drug compounds of the present invention can be contained, content of each component in formula is count by weight percentage.Match somebody with somebody Medical compoundss in side can be replaced with the fat-soluble anti-cancer drug compounds of other of the present invention.

A：SN38 R (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acids ten The emulsion of six alcohol ester -6- succinates

By SN38 R (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acids ten Six alcohol esters -6- succinates (MXL-003) are dissolved in Oleum Glycines, D- alpha-tocopherols cetomacrogol 1000 succinate (TPGS) and gather In the mixture of ethylene glycol PEG (200), deionized water (DI water) is added, then stirring and ultrasonic emulsification, are produced The composition of emulsion is as follows：

MXL-003 1%

Oleum Glycines 10%

TPGS 5%

PEG (200) 3%

Deionized water is to 100%

The emulsion medicine that makes passes through the filter in 0.2 micron of an aperture and filters, and reinstalls aseptic vial.

B：SN38 R (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acids ten The emulsion of diol ester -6- succinates

By SN38 R (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acids ten Diol ester -6- succinates (MXL-002) is dissolved in D- alpha-tocopherol acetates, D- alpha-tocopherol cetomacrogol 1000 succinic acid In the mixture of ester (TPGS) and Polyethylene Glycol PEG (200), deionized water (DI water) is added, then stirring and ultrasound Emulsifying, the composition of the emulsion for being produced are as follows：

MXL-002 0.1%

D- alpha-tocopherol acetates 6%

TPGS 4%

PEG (200) 10%

Normal saline is to 100%

C.7- ethyl-10-hydroxycamptothecin R (+) -6- hydroxyls -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acids ten The Micellar Solution Which Is of six alcohol ester -6- succinates

By SN38 R (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acids 16 Alcohol ester -6- succinates (MXL-003) is dissolved in the mixture of Tween 80 (Tween80), ethanol and Polyethylene Glycol PEG (200) In obtain transparent liquid, add deionized water (DI water), then stir, the composition of the Micellar Solution Which Is for being produced is as follows：

MXL-003 0.05%

Tween 80 5%

Ethanol 5%

PEG200 5%

Deionized water is to 100%

D.7- ethyl-10-hydroxycamptothecin R (+) -6- hydroxyls -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acids ten The Micellar Solution Which Is of diol ester -6- succinates

By SN38 R (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyran -2- carboxylic acids ten Diol ester -6- succinates (MXL-002) is dissolved in D- alpha-tocopherols cetomacrogol 1000 succinate (TPGS), ethanol and gathers A transparent liquid is obtained in the mixture of ethylene glycol PEG (200), is added normal saline, is then stirred, the micelle for being produced The composition of liquid is as follows：

MXL-002 1.0%

TPGS 4%

Ethanol 10%

PEG200 5%

Normal saline is to 100%

The vitro cytotoxicity experiment of 11. fat-soluble anti-cancer drug compounds of embodiment

In the present embodiment, detected with XTT methods the present invention PTS compounds suppress human ovarian cancer (A2780s), Colon cancer cell (HT-29), hepatocarcinoma HePG₂(anticancer 50% grows with the GI50 values of lung carcinoma cell (A549) cell Drug level), and contrasted with anticarcinogen irinotecan (irinotican), evaluate the cell in vitro poison of medical compoundss Property.

As shown in table 1, other anti-cancer drug compounds of the present invention have similar result to GI50 values, and same have substantially drop Low GI50 values.Test result indicate that, the anti-cancer drug compounds of the present invention are to human ovarian cancer (A2780s), colon cancer cell (HT-29), hepatocarcinoma HePG₂There is obvious inhibited proliferation with lung carcinoma cell (A549) cell, and with drug level Increase, its inhibited proliferation to cell strengthens, in obvious dose-dependent effect.Replace with the positive drug Yi Li of same concentration Health (Irinotecan) is compared, and the anti-cancer drug compounds of the present invention press down to human ovarian cancer, colon cancer, hepatocarcinoma and lung carcinoma cell Effect processed becomes apparent from.The anti-cancer drug compounds of the present invention have suppression Proliferation of Human Ovarian Cell (A2780s) colon cancer cell (HT- 29), hepatocarcinoma (HePG₂) cell and lung carcinoma cell (A549) proliferation function, be that a class has potential anti-human ovarian carcinoma, colon The medical compoundss of cancer, hepatocarcinoma and pulmonary carcinoma effect.

Mtt assay detection method：Take the logarithm the cell of trophophase, adjustment cell density is 10⁵Individual/mL, is inoculated in the training of 96 holes In foster plate, 100 μ L/ holes are changed culture fluid after cell culture 18h, are separately added into the drug sample of variable concentrations, 150 μ L/ holes. The hole of cell is not added with as blank group (for returning to zero) only to add the RPMI1640 culture fluid containing 10% calf serum, negative control Group adds the RPMI1640 culture fluid of 10% calf serum of equal-volume, positive controls to add equal-volume 13ug/ml positive drugs. Above each group sets 3 multiple holes.Cell continues culture 72h, adds 15 μ L/ holes of MTT (5mg/mL) solution, continues culture 4h.Suction is abandoned Supernatant, adds DMSO150 μ L/ holes, and vibration mixes 10min, to be crystallized be completely dissolved after, in microplate reader, Detection wavelength is Absorbance (D) value in each hole at 490nm.The growth inhibition ratio of cell is calculated as follows：Inhibitory rate of cell growth=(1- The average D values of the average D values/matched group of experimental group) × 100%.

1. new anti-cancer drug thing of table and the contrast of anticarcinogen irinotecan GI50

NP：Do not detect.

MXL-001：SN38 R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyrans - 2- carboxylic acid hexanol ester -6- succinates.

MXL-002：SN38 R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyrans - 2- carboxylic acid lauryl alcohol ester -6- succinates.

MXL-003：SN38 R- (+) -6- hydroxyl -2,5,7,8- tetramethyl benzodihydropyrans - 2- carboxylic acid hexadecanol ester -6- succinates.

Claims

1. a kind of fat-soluble anti-cancer drug compounds of watermiscible vitamin E Derivatives Modified, the structure with following formula I：

Wherein：

R is C_6-15Non-substituted straight chained alkyl；

R₁It is-(C=O) (CH₂)₂(C=O)-；

X is-O-；

R₂It is-CH₂CH₃；

R₃It is H.

2. fat-soluble anti-cancer drug compounds of watermiscible vitamin E Derivatives Modified according to claim 1, its feature It is, R is selected from C_6-12Non-substituted straight chained alkyl.

3. fat-soluble anti-cancer drug compounds of watermiscible vitamin E Derivatives Modified according to claim 2, its feature It is, R is selected from C₆Or C₁₂Non-substituted straight chained alkyl.

4. the fat-soluble anticancer of the watermiscible vitamin E Derivatives Modified according to claims 1 to 3 any one claim Medical compoundss, it is characterised in that in described fat-soluble anti-cancer drug compounds, watermiscible vitamin E are its optical siomerism Body.

5. the emulsion or microemulsion preparation of the fat-soluble anti-cancer drug compounds described in a kind of claim 1, its composition include：

1) oil phase, including：

A) there is the fat-soluble cancer therapy drug chemical combination of the watermiscible vitamin E Derivatives Modified of structure shown in formula I described in claim 1 Thing；

B) biocompatible lipophilic medium；

2) surfactant and cosolvent；

3) water phase.

6. the compound emulsion of fat-soluble cancer therapy drug according to claim 5 or microemulsion preparation, it is characterised in that institute In the emulsion that states or microemulsion preparation, anti-cancer drug compounds account in pharmaceutical formulation 0.005% to 5.0%, lipophilic medium accounts for 2% to 20% in pharmaceutical formulation, and surfactant is in pharmaceutical formulation In weight percentage be 1 to 10%.

7. the micellar preparation of the fat-soluble anti-cancer drug compounds described in a kind of claim 1, its composition include：

1) there is the fat-soluble cancer therapy drug chemical combination of the watermiscible vitamin E Derivatives Modified of structure shown in formula I described in claim 1 Thing；

2) surfactant；

3) cosolvent；

4) water phase.

8. the micellar preparation of fat-soluble anti-cancer drug compounds according to claim 7, it is characterised in that described liposoluble Property anti-cancer drug compounds micellar preparation in, anti-cancer drug compounds in formula weight percentage be 0.005% to 5.0%, weight percentage of the surfactant in formula is 1 to 10%, weight percentage of the cosolvent in formula For 2% to 20%.

9. the fat-soluble anti-cancer drug compounds of the watermiscible vitamin E Derivatives Modified described in claim 1 are preparing anticancer Application in medicine.