CN103965208B - Lipophilic camptothecin kind anti-cancer drugs compounds that lipophilic alcohol or phenol are modified and preparation, the preparation method and application of this compound - Google Patents

Abstract

The invention discloses the lipophilic camptothecin kind anti-cancer drugs compounds that a kind of lipophilic alcohol or phenol are modified for linking group with diethylene glycol acyl group, there is the structure of following formula I or II.The active part of described anti-cancer drug compounds is camptothecine or camptothecin derivative, forms described lipophilic camptothecin kind anti-cancer drugs compounds with lipophilic moieties R by linking group covalent bond.The invention still further relates to the preparation of described medical compounds, preparation method and application.

Description

Lipophilic camptothecin kind anti-cancer drugs compounds that lipophilic alcohol or phenol are modified and system Agent, the preparation method and application of this compound

Technical field

The present invention relates to a kind of new anti-cancer drug compounds and its preparation method and application, particularly relate to a kind of liposoluble Property camptothecin anti-cancer drug compounds, comprises the preparation of this compound, preparation method and the application as cancer therapy drug.

Background technology

Many has the compound of active anticancer due to water insoluble and other biocompatible solvent, or at water and biology In compatible solvent, poor stability 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 the existing medicine of 30 percent is slightly solubility.Few techniques is currently had to grind Among studying carefully and developing, to solve the problem of medical compounds poor solubility, these technology include the complexant skill increasing dissolubility Art, nano particle technology, microemulsion technology, the preparation technique of enhancing dissolubility, fat-soluble and water-soluble prodrug technology, and novel Polymer drug-carried technology etc..

Camptothecine (20 (s)-camptothecin, formula 1,1) and derivant thereof have good anti-tumor activity, are classes Important DNA topoisomerase I (Top I) inhibitor, they can be combined with Top I-DNA cleavable complex, is formed CPT-Top I-DNA ternary complexes, thus stablize cleavable complex, cause cell death.But because it is in water and other lifes The problem that dissolubility in thing compatible solvent is poor and toxicity is big, 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.But, only derivant topotecan (Topotecan, formula 1,2) and irinotecan (Irinotrcan, formula 1,3) are faced by FDA's approval entrance Bed has listed, and is respectively used to treat ovarian cancer, pulmonary carcinoma and rectal cancer.But, topotecan and irinotecan have significantly Shortcoming, is included in that Half-life in vivo is short and toxic and side effects is big etc..At present, multiple camptothecin derivative is had to be in clinical research rank Section.

Additionally, the E lactonic ring in camptothecin molecule is function base necessary to camptothecin analogues active anticancer, Understand rapid open loop under alkalescence or physiological condition and cause the disappearance (formula 2) of activity.It is demonstrated experimentally that in blood plasma lactonic 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 this compounds.Further study card

1,20 (S)-camptothecin, R=R₁=R₂=H

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

3.irinotecan, R₁=H, R₂=Et,

Formula 1 camptothecine, topotecan (topotecan) and the chemical constitution of irinotecan (irinotecan).

Real, open loop structure thing is the root causing untoward reaction, as caused bone marrow depression, vomits and diarrhoea etc..

The balance of lactonic ring structure and open loop structure is there is in formula 2 camptothecine under alkalescence or physiological condition.

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 a kind of preparation technique is not the most also had to go for Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae) Alkali, because its dissolubility extreme difference in water and organic solvent.Thus it still remains a need develop new existing higher active anticancer Justice has the camptothecin derivative of preferable dissolubility and stability.

The invention provides a series of new lipophilic camptothecin derivative, they are at the fat-soluble solvent of biocompatibility In have preferable dissolubility, the medicine agent such as emulsion, microemulsion, micelle, liposome, nanoparticle can be made by new formulation technology Type.The new medical compounds of the present invention is expected to improve medicine persistent period (half-life) in vivo and curative effect, and reduces Its side effect.

Summary of the invention

It is an object of the invention to provide a kind of new lipophilic camptothecin kind anti-cancer drugs compounds, be lipophilic alcohol Or the camptothecine modified for linking group with diethylene glycol acyl group of phenol or camptothecin derivative, this kind of chemical combination with active anticancer Thing is dissolvable in water in the fat-soluble solvent of biocompatibility.

Another object of the present invention is to provide the synthetic method of described lipophilic camptothecin kind anti-cancer drugs compounds.

Another object of the present invention also resides in provides the system comprising described lipophilic camptothecin kind anti-cancer drugs compounds Agent, including emulsion, micellar preparation and Liposomal formulation.

Meanwhile, another object of the present invention also resides in the lipophilic camptothecin kind anti-cancer drugs compounds described in offer in system Application in standby cancer therapy drug.

In short, the lipophilic camptothecin kind anti-cancer drugs compounds of the present invention, it is that lipophilic alcohol or phenol are with diethylene glycol Acyl group be connect chain modify camptothecine or camptothecin derivative, camptothecine or camptothecin derivative there is active anticancer, Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae) Alkali or camptothecin derivative molecule pass through linking group diethylene glycol acyl group with lipophilic compound molecule (alcohol or phenol) (oxydiacetyl, diglycoloyl, diglycolyl) covalent bond forms the lipophilic camptothecin kind anti-cancer drugs of the present invention Compounds.

Realize the object of the invention by the following technical solutions: the lipophilic camptothecin class that a kind of lipophilic alcohol or phenol are modified Anti-cancer drug compounds, has general formula I or II such as and represents represented structure:

In said structure formula,

R is a kind of lipophilic group, for 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-(C=O) CH₂-O-CH₂(C=O)-；

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 lipophilic camptothecin kind anti-cancer drugs compounds of the present invention is to have the lipophilic compound (alcohol of lipophilic group R Or phenol) formed by a diethylene glycol acyl linkage covalent bond with camptothecine or camptothecin derivative molecule.

Lipophilic compound can be fatty alcohol, such as saturated, undersaturated, straight chain, side chain, ring-type fatty alcohol And fat enol etc..The alcohol compound of preferably C atomic number >=6, includes but not limited to, 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), pentadecyl alcohol (pentadecyl alcohol, 1-pentadecanol, pentadecanol), cetyl alcohol (cetyl alcohol, 1- Hexadecanol), cis-9-hexadecylene 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 alcohol (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), nonadecyl 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-docosene 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), three Ten alkylols (myricyl alcohol, melissyl alcohol, 1-triacontanol), tetratriacontane base alcohol (geddyl Alcohol, 1-tetratriacontanol) etc..Or in above-mentioned fatty alcohol carbochain multiple hydrogen atom by halogen, nitro, The derivant that the group such as amido, sulfonic group generates after replacing.Can also is that other alcohol compound, such as benzylalcohol, phenethanol etc. Aromatic alcohol compounds.

Lipophilic compound also includes phenolic compound, such as phenol, alkylphenol, alkoxy phenol, amino-phenol, halo Phenol, polysubstituted phenol, or 1-naphthols, beta naphthal, alkyl naphthol, alkoxynaphthols, halo naphthols, polysubstituted naphthols etc..

Cancer therapy drug active part in the lipophilic camptothecin kind anti-cancer drugs compounds molecule of the present invention is known There is camptothecine or the camptothecin derivative of active anticancer, its structural formula as shown in Equation 3, 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

Formula 3 camptothecine and the chemical constitution of camptothecin derivative molecule.

In the lipophilic camptothecin kind anti-cancer drugs compounds molecule of the present invention, the preferred camptothecine of active anticancer part (1, Camptothecin), 10-hydroxycamptothecine (2,10-hydroxycamptothecin) and SN38 (3,7-ethyl-10-hydroxycamptothecin), its molecular structure is as shown in Equation 4.They can pass through a diethylene glycol acyl Base linking group generates the lipophilic camptothecin kind anti-cancer drugs materialization of the present invention with lipophilic compound alcohol or phenol covalent bond Compound.

1,20 (S)-camptothecin:R₁=R₂=H

2,10-hydroxycamptothecin:R₁=OH, R₂=H

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

Formula 4 camptothecine and the preferred chemical constitution of camptothecin derivative.

The molecule of the fat-soluble anti-camptothecin cancer drug compound of the present invention comprises cancer therapy drug active part and lipophilic Part, the two part generates new fat-soluble cancer therapy drug chemical combination by a diethylene glycol acyl linkage covalent bond Thing.Cancer therapy drug active part is that camptothecine or camptothecin derivative, camptothecine or camptothecin derivative contain on lactonic ring Hydroxyl or phenolic hydroxyl group, this hydroxyl can form ester bond with anhydride diethylene glycol or diglycolic acid, generate the fat-soluble anticancer of the present invention Medical compounds.Such as, lipophilic alcohol or phenol are by a diethylene glycol acyl linkage and anti-cancer drug compounds Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae) Alkali (camptothecin), 10-hydroxycamptothecine (10-hydroxycamptothecin) or SN38 (7-ethyl-10-hydroxycamptothecin, SN-38) covalent bond forms new fat-soluble anti-cancer drug compounds.

(camptothecine or the derivant of camptothecine, such as 10-hydroxycamptothecine and 7-with the parent compound with active anticancer Ethyl-10-hydroxycamptothecin) to compare, the new anti-cancer drug compounds of the present invention comprises a cancer therapy drug parent compound Part and lipophilic group, cancer therapy drug parent molecule and lipophilic molecules (alcohol or phenol) are by a diethylene glycol acyl group linker Group becomes the new anti-cancer drug compounds of the present invention with covalently bonded symphysis, therefore has more preferable lipotropy (lipophile).

The lipophilic camptothecin kind anti-cancer drugs materialization that the invention still further relates to a kind of described lipophilic alcohol or phenol modification is closed The preparation method of thing, comprises the following steps:

1) lipophilic alcohol or phenol ROH be connected molecule anhydride diethylene glycol or diglycolic acid generation esterification, generate fat Soluble derivatives；

2) step 1) obtained by fat-soluble derivant, or its chloride product, occur with camptothecine or derivatives thereof Esterification, generates lipophilic alcohol or the lipophilic camptothecin kind anti-cancer drugs compounds of phenol modification；

In described lipophilic alcohol or phenol ROH, R is a kind of lipophilic group, for one of following radicals:

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

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

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

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

M) undersaturated cyclic hydrocarbon radical (unsaturated cycloalkyl)；

N) undersaturated branched hydrocarbyl (unsaturated branched alkyl)；

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

P) replace and non-substituted aralkyl (substituted and unsubstituted aralkyl).

More specifically and optimally, described method comprises the following steps:

1) lipophilic alcohol or phenol ROH (1) are one of by the following method, and are connected molecule generation esterification, generate liposoluble Property derivant (2):

A) lipophilic alcohol or phenol ROH (1) with lewis acid (such as 2 ethyl hexanoic acid stannum (II), aluminum chloride) or alkali (as Cesium carbonate, triethylamine, pyridine, sodium carbonate) it is catalyst, generate fat-soluble derivant (2) with diglycolic acid anhydride reactant；

B) lipophilic alcohol or phenol ROH (1) are with DMAP (DMAP) and 2-chloro-1-methyl pyridinium iodide (CMPI), or N, N '-dicyclohexyl carbodiimide (DCC) and DMAP (DMAP) are catalyst, with excess Diglycolic acid reacts, and generates fat-soluble derivant (2).

2) step 1) in a) or b) obtained by fat-soluble derivant (2) react generation acyl with thionyl (two) chlorine compound Chlorizate (3).

3) step 1) in a) or b) obtained by fat-soluble derivant (2) chloro-with DMAP (DMAP) and 2- 1-methyl pyridinium iodide (CMPI), or N, N '-dicyclohexyl carbodiimide (DCC) and DMAP (DMAP) For catalyst, directly react with camptothecine or derivatives thereof, generate lipophilic camptothecin kind anti-cancer drugs compounds (4,5).

4) step 2) obtained by chloride product (3) with alkali (such as triethylamine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate) be Catalyst, directly reacts with camptothecine or derivatives thereof；Generate lipophilic camptothecin kind anti-cancer drugs compounds (4,5).

Formula 5 illustrates a kind of synthetic route, lipophilic alcohol or phenol ROH (1) and diglycolic acid anhydride reactant, with 2-ethyl hexyl Acid stannum (II) (or cesium carbonate) is catalyst, generates fat-soluble derivant (2).Lipophilic alcohol or phenol ROH (1) also can be with excess Have difunctional diglycolic acid reaction, with DMAP (DMAP) and 2-chloro-1-methyl pyridinium iodide (CMPI), or N, N '-dicyclohexyl carbodiimide (DCC) and DMAP (DMAP) are catalyst, generate liposoluble Property derivant (2).This compound (2) then generates the chloride derivative (3) of fat-soluble derivant (2) with thionyl (two) chlorine, Then the acid chloride functional groups of compound (3) and the hydroxyl of camptothecine or optionally with 10-hydroxyl substituted camptothecin or 7-ethyl- The phenolic hydroxyl group reaction of 10-hydroxycamptothecine, with alkali as catalyst (such as triethylamine, pyridine, DMAP, sodium carbonate, carbon Acid potassium, cesium carbonate etc.), generate the lipophilic camptothecin kind anti-cancer drugs compounds (4,5) of the present invention respectively.

As shown in Equation 6, fat-soluble derivant (2) also can directly and camptothecine, 10-hydroxycamptothecine, 7-ethyl-10-hydroxyl Base camptothecine reacts, with DMAP (DMAP) and 2-chloro-1-methyl pyridinium iodide (CMPI), or N, N '-two Cyclohexylcarbodiimide (DCC) and DMAP (DMAP) are catalyst, generate the lipophilic camptothecin of the present invention Kind anti-cancer drugs compounds (4,5).

R: alkyl (alkyl), branched alkyl (branched alkyl) or cycloalkyl (cyclic alkyl), it is also possible to be Undersaturated alkyl, undersaturated branched hydrocarbyl, undersaturated cyclic hydrocarbon radical, aryl or aralkyl etc.；R₁: H ,-CH₂CH₃Deng.

The synthetic route 1 of formula 5 lipophilic camptothecin kind anti-cancer drugs compounds.

The synthetic route 2 of formula 6 lipophilic camptothecin kind anti-cancer drugs compounds.

The invention still further relates to the preparation of described new lipophilic camptothecin kind anti-cancer drugs compounds, including emulsion, glue Bundle and Liposomal formulation formula, common feature is that, comprise described lipophilic camptothecin kind anti-cancer drugs in described preparation Compounds.Wherein, emulsion formulations includes neoteric anti-cancer drug compounds, one or more surfactants, oil phase (parent Lipid medium) and aqueous phase.Emulsion can be oil-in-water type or water-in-oil type.Micellar preparation includes neoteric cancer therapy drug chemical combination Thing, cosolvent and one or more surfactants and aqueous phase.Liposomal formulation includes neoteric anti-cancer drug compounds, phosphorus Fat (the most representational is lecithin, phosphatidylcholine), cholesterol and aqueous phase.Above-mentioned preparation includes its freeze-dried formulation.

Specifically, the technical scheme of employing is, a kind of described lipophilic camptothecin kind anti-cancer drugs compounds emulsion or Microemulsion preparation, its composition includes:

1) oil phase, including:

A) there is the lipophilic camptothecin kind anti-cancer drugs compounds of Formulas I or II structure；

B) biocompatible lipophilic medium；

2) surfactant and cosolvent；

3) aqueous phase.

Or, a kind of described lipophilic camptothecin kind anti-cancer drugs compounds micellar preparation, its composition includes:

1) there is the lipophilic camptothecin kind anti-cancer drugs compounds of Formulas I or II structure；

2) surfactant；

3) cosolvent；

4) aqueous phase.

Or, a kind of described lipophilic camptothecin kind anti-cancer drugs compounds Liposomal formulation, its composition includes:

1) there is the lipophilic camptothecin kind anti-cancer drugs compounds of Formulas I or II structure；

2) phospholipid；

3) aqueous phase；

4) add or be not added with lipophilic medium.

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

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 type, L-type), betatocopherol (D type, DL type, L-type), Gamma-Tocopherol (D type, DL type, L-type) and Delta-Tocopherol (D type, DL Type, L-type).Tocotrienol is structurally similar to tocopherol, but tocotrienol is at the side chain phytyl (phytyl) of carbon-2 On have three double bonds.Tocotrienol includes alpha-tocotrienol (D type, DL type, L-type), β-tocotrienol (D type, DL type, L Type), γ-tocotrienol (D type, DL type, L-type) and δ-tocotrienol (D type, DL type, 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 fats of lipophilic medium, including fatty acid and the 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 satisfy With or unsaturated fatty acid and esters.

C) fatty acid and glycerine esterification react formed monoglyceride, diglyceride or triglyceride, and no matter they are Synthesis or natural, all can be as lipophilic medium, such as, glyceride, such as Oleum Glycines, Oleum Gossypii semen, Oleum Brassicae campestris, 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) polyglycol surfactants, such as polyoxyethylene castor oil EL (CremophorEL), TWEEN Series surface activity 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).

Block copolymer (the H of d) polyoxyethylene polyoxypropylene block copolymer: 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 is H-(CH₂CH₂)_n-OH, molecular weight ranges typically from 200 to 10000.Such as, polyethylene glycol 200, PEG-300, PEG400 etc..

Emulsion, microemulsion, micelle and Liposomal formulation formula according to the present invention all comprises the fat-soluble happiness of the present invention Tree bases anti-cancer drug compounds.

" emulsion " used herein refers under the effect of surfactant, and a phase liquid is scattered in another with drop state The heterogeneous liquid dispersion formed in phase liquid, the drop formed such as oil and water, its diameter is 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 such as oil and water is lived by surface Property agent molecule formed interfacial film stablized.Microemulsion average droplet size is less than 200nm, general 10 to 50 nanometers.

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

In the absence of water, oil phase, nonionic surfactant and co-emulsifier formed homogeneous is mixed Solution that is transparent and that comprise medicine is referred to as self-emulsifying drug delivery system (self-emulsifying drug delivery System:SEDDS), spontaneous emulsification forms the particle diameter Emulsion at 100nm to 500nm, can be used for improving lipophilic drugs dissolubility And oral absorbability.

In described emulsion or microemulsion preparation, anti-cancer drug compounds accounts in pharmaceutical formulation 0.005% to 5.0%；Preferably anti-cancer drug compounds accounts for 0.01% to 2.5% in pharmaceutical formulation； In preferred scheme, anti-cancer drug compounds accounts for 0.1% to 1.5% in pharmaceutical formulation.

In described emulsion or microemulsion preparation, lipophilic medium accounts for 1% in pharmaceutical formulation To 20%；Preferably 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 that Oleum Glycines, aqueous media are water.At another In the embodiment of individual emulsion and microemulsion, lipophilic medium includes fat soluble vitamin E.At another emulsion or microemulsion In embodiment, lipophilic medium includes fat soluble vitamin E derivant.

Except the anti-cancer drug compounds of the present invention, emulsion or microemulsion formula can also include medicine emulsion and microemulsion Other composition conventional in liquid formulation, these compositions include surfactant and cosolvent.Representative surface activity Agent includes nonionic surfactant, as polyoxyethylene castor oil EL (Cremophor EL), Tween 80 (Tween80), phospholipid, Polyethylene Glycol vitamin e derivative surfactant and other surfactant polymer.

Suitably 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 includes having various molecular weight (example As, 200,300,400,600,1000 etc.) Polyethylene Glycol." vitamin E polyethylene glycol succinic acid ester " herein includes that dimension is raw Element E polyethanediol succinate is (such as D-alpha tocopherol cetomacrogol 1000 succinate, TPGS, a kind of non-ionic surfactant Agent (HLB=16-18)) and the various esters of vitamin E polyethylene glycol and ether derivant.

In described emulsion or microemulsion preparation, surfactant weight percentage in formula is about 1 to 10%, Preferably 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 the glue of a kind of described lipophilic camptothecin kind anti-cancer drugs compounds Bundle preparation and freeze-dried formulation thereof, including the anti-cancer drug compounds of the present invention, one or more surfactants, one or more Cosolvent and aqueous phase.

In the micellar preparation of described lipophilic camptothecin kind anti-cancer drugs compounds, medical compounds is weight in formula Amount percentage composition be about 0.005% to 5.0%, preferred agents compound weight percentage in formula be about 0.01% to 2.5%；It is further preferred that medical compounds weight percentage in formula is about 0.1% to 1.0%.

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

Micellar preparation formula also includes other composition, cosolvent as mentioned above.In one embodiment, micelle system Agent prescription comprises Polyethylene Glycol and relatively low alkylol (such as ethanol).In described micellar preparation, cosolvent accounts for formula weight The 1% to 20% of amount.

In yet another aspect, present invention also offers the fat of a kind of described lipophilic camptothecin kind anti-cancer drugs compounds Liposome preparation and freeze-dried formulation thereof, including anti-cancer drug compounds, one or more phospholipid, optionally one or many of the present invention Plant lipophilic medium (such as cholesterol) and aqueous phase.

In the Liposomal formulation of described lipophilic camptothecin kind anti-cancer drugs compounds, medical compounds is in formula Weight percentage is about 0.005% to 5.0%, preferred agents compound weight percentage in formula be about 0.01% to 2.5%；It is further preferred that medical compounds weight percentage in formula is about 0.1% to 1.5%.

Suitably phospholipid weight percentage in the Liposomal formulation formula of the present invention is about 1 to 10%, preferably 2- 6%, more preferably 4-5%.

Liposomal formulation formula also includes other composition, lipophilic medium as mentioned above (such as cholesterol).One In individual embodiment, Liposomal formulation formula comprises cholesterol or vitamin E.In described Liposomal formulation, lipophilic medium As cholesterol or vitamin E account for the 0% to 20% of formulation weight.

Emulsion, microemulsion, micelle and Liposomal formulation formula comprise aqueous phase.In one embodiment, aqueous phase includes Ionized water.In another embodiment, aqueous phase includes normal saline.In another embodiment, containing a kind of organic acid in aqueous phase (such as succinic acid, citric acid) buffer.

Present invention also offers the fat that the application of neoteric medical compounds, i.e. described lipophilic alcohol or phenol are modified The application in preparing cancer therapy drug of the soluble camptothecin kind anti-cancer drugs compounds.

Such as, the medical compounds of the present invention is for preparing the medicine for the treatment of cancer.The medical compounds of the present invention can be used The cancer of blood system is included, such as leukemia, lymphoma, myeloma in treatment；With non-blood cancer, if solid tumor cancer is (such as breast Adenocarcinoma, ovarian cancer, cancer of pancreas, colon and rectum carcinoma, nonsmall-cell lung cancer, bladder cancer, gastric cancer etc.), sarcoma and glioma etc..

The curative effect of the medical compounds of the present invention and toxicity cell in vitro or interior animal experiment determine, such as, ED50 (50%effective dose, median effective dose: dose during positive reaction occurs 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%, suppresses 50% Experimental subject growth drug level).Generally it is referred to as controlling by the ratio of median lethal dose(LD 50) (LD50)/median effective dose (ED50) Treat index, in order to represent Drug safety.The medicine that medicine that therapeutic index is big is little relative to therapeutic index is safer.

Neoteric anti-cancer drug compounds is intended to improve therapeutic index and Drug safety, the most also improves treatment 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 not preferably in the range of seldom or at all having virose ED50.Doses change generally depends on employing Dosage form, the sensitivity of patient and route of administration etc..Generally available same or like medicine, normal such as topotecan and irinotecan Rule dosage makes reference.The routine dose of such as topotecan is 0.2-1.5mg/m², the routine dose of irinotecan be 100mg- 350mg/m²。

The medical compounds of the present invention can be used alone, it is possible to makes together with other medicines one or more With.Such as, when the treatment of cancer, these medical compoundss can be used together with following medicine, includes 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 Sugar 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 derivatives, 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 have the medical compounds molecule camptothecine of active anticancer or camptothecin derivative and lipophilic alcohol Or phenol is by linking group diethylene glycol acyl group covalent bond, obtains fat-soluble camptothecin anti-cancer drug compounds, described Compound contains cancer therapy drug active part and lipophilic portion, can be dissolved in the lipophilic solvent of biocompatibility.The present invention's New anti-cancer drug compounds has higher active anticancer, has preferable dissolubility and stability simultaneously, it is possible to increase happiness Continuous action time (half-life) under tree alkali or derivatives thereof physiological condition in vivo and curative effect, reduce its toxic and side effects.Institute The medical compounds stated can make Emulsion, micelle or Liposomal formulation and corresponding lyophilized preparation, is widely used in blood system Treatment with non-blood gastric cancers.Various camptothecin analogues can be modified by the present invention, widen camptothecine and The application of derivant, the clinical practice for camptothecin analogues provides a kind of new method and approach.

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

Accompanying drawing explanation

The hydrogen nuclear magnetic resonance spectrogram of Fig. 1 hexadecanol diglycolic acid monoesters.

Fig. 2 hexadecanol diglycolic acid monoesters mass spectrum.

Fig. 3 camptothecine hexadecanol diethylene glycol acid esters proton nmr spectra figure.

Fig. 4 camptothecine hexadecanol diethylene glycol acid esters mass spectrum.

Fig. 5 10-Hydroxycamptothecin hexadecanol diethylene glycol acid esters proton nmr spectra figure.

Fig. 6 10-hydroxycamptothecine hexadecanol diethylene glycol acid esters mass spectrum.

Fig. 7 SN38 hexadecanol diethylene glycol acid esters proton nmr spectra figure.

Fig. 8 SN38 hexadecanol diethylene glycol acid esters mass spectrum.

Fig. 9 camptothecine hexadecanol diethylene glycol acid esters high-efficient liquid high-efficient liquid phase chromatogram.

Detailed description of the invention

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

The synthesis of embodiment 1 camptothecine hexadecanol diethylene glycol acid esters

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

1) synthesis of hexadecanol diglycolic acid monoesters

Reaction equation is shown below:

Experimental procedure:

In the round-bottomed flask of 250mL add 0.970g (4mmol) hexadecanol, 0.696g (6mmol) anhydride diethylene glycol and 75mL anhydrous dimethyl benzene, stirring, make solid dissolve, drip 100 μ g2-thylhexoic acid stannum (II).It is heated to reflux 4 under nitrogen protection Hour.Decompression rotary evaporation falls dimethylbenzene, chromatography, and 100-200 mesh silica gel is fixing phase, petroleum ether: ethyl acetate=1: 3 The mixed liquor of (volume ratio) is leacheate, obtains 1.200g white solid hexadecanol diglycolic acid monoesters, and productivity is 80%.

Obtained its proton nmr spectra of compound and mass spectrum are shown in Fig. 1 and Fig. 2.

MS (Positive ESI): m/z=359.9 (M+H)⁺。

¹H NMR (300MHz, CDCl₃): δ ppm:4.2573 (s, 4H), 4.2265-4.1814 (t, J=6.77Hz, 2H), 1.6834-1.6373 (m, 2H), 1.3055-1.2581 (m, 24H), 0.9014-0.8575 (t, J=6.59Hz, 3H).

2) synthesis of camptothecine hexadecanol diethylene glycol acid esters

Reaction equation is shown below:

Experimental procedure:

In the round-bottomed flask of 100mL, add 0.360g (1mmol) hexadecanol diglycolic acid monoesters, 20mL dry toluene, Stirring, then add people 300 μ L (4mmol) thionyl chloride and 10 μ LN, dinethylformamide.It is stirred at room temperature 4 little under nitrogen protection Time.Decompression rotary distillation, removes thionyl chloride and the toluene of excess, obtains a thick white liquid hexadecanol diglycolic acid monoesters acyl Chlorine, adds 10mL dichloromethane and obtains solution A.

In another 100mL round-bottomed flask, add 0.260g (0.75mmol) camptothecine, the N of 30mL, N-dimethyl methyl Amide, adds 0.122g (1mmol) DMAP, obtains a clear solution.The solution A of 7.5mL is slowly added dropwise to In this clear solution, stirred overnight at room temperature.Tlc analysis, if still there being a small amount of camptothecine unreacted complete, adds appropriate Solution A and DMAP are to reacting complete.Chromatography, 100-200 mesh silica gel is fixing phase, dichloromethane: acetic acid Ethyl ester=3: the mixed liquor of 1 (volume ratio) is leacheate, obtain 0.350g faint yellow solid camptothecine hexadecanol diethylene glycol acid esters, Productivity is 67.7%, its high-efficient liquid phase chromatogram such as Fig. 9.

Its proton nmr spectra of target compound and mass spectrum that synthesis obtains are shown in Fig. 3 and Fig. 4.

MS (Positive ESI): m/z=689.5 (M+H)⁺。

¹H NMR (300MHz, CDCl₃): δ ppm:8.4220 (s, 1H), 8.2747-8.2465 (d, J=8.46Hz, 1H), 7.9700-7.9429 (d, J=8.13Hz, 1H), 7.8800-7.8287 (t, J=7.70Hz, 1H), 7.2936 (s, 1H), 5.7332-5.6755 (d, J=17.31Hz, 1H), 5.4494-5.3917 (d, J=17.31Hz, 1H), 4.532-4.389 (m, 2H), 4.2998-4.1626 (m, 2H), 4.1514-4.1061 (t, J=6.80Hz, 2H), 2.3395-2.1113 (m, 2H), 1.6280-1.5828 (m, 2H), 1.2516 (s, 25H), 1.0160-0.9663 (t, J=7.50Hz, 3H), 0.8986-0.8549 (m, 6H).

The synthesis of embodiment 210-hydroxy camptothecin hexadecanol diethylene glycol acid esters

The synthesis of hexadecanol diglycolic acid monoesters is with embodiment 1.Synthesis 10-hydroxycamptothecine hexadecanol two by the following method Glycolate.

Reaction equation is shown below:

Experimental procedure:

In the round-bottomed flask of 100mL, add 0.300g (0.83mmol) hexadecanol diglycolic acid monoesters and 20mL is anhydrous Toluene, 300 μ L (4mmol) thionyl chlorides, 10 μ LN, dinethylformamide.It is stirred at room temperature 4 hours under nitrogen protection.Decompression rotation Turn distillation, remove thionyl chloride and the toluene of excess, obtain a thick white liquid and obtain a thick white liquid hexadecanol diglycolic acid list Ester acyl chlorides, adds 10mL dichloromethane and obtains solution A.

In another 100mL round-bottomed flask, add 0.182g (0.5mmol) 10-hydroxycamptothecine and the N of 20mL, N- Dimethylformamide, stirring, obtain a solution, add 150 μ L (1.1mmol) triethylamines.The solution A of 6mL is slowly added dropwise to In this solution, stirred overnight at room temperature.Tlc analysis, if still there being a small amount of 10-hydroxycamptothecine unreacted complete, adds appropriate Solution A and triethylamine are to reacting complete.Chromatography, 100-200 mesh silica gel is fixing phase, dichloromethane: ethyl acetate=1: 1 The mixed liquor of (volume ratio) is leacheate, obtains 0.100g faint yellow solid 10-hydroxycamptothecine hexadecanol diethylene glycol acid esters, produces Rate is 28.3%.

Its proton nmr spectra of target compound and mass spectrum that synthesis obtains are shown in Fig. 5 and Fig. 6.

MS (Positive ESI): m/z=705.5 (M+H)⁺。

¹H NMR (300MHz, CDCl₃): δ ppm:8.3569 (s, 1H), 8.2817-8.2516 (d, J=9.03Hz, 1H), 7.7536 (s, 1H), 7.6857 (s, 1H), 7.6193-7.5884 (d, J=9.27Hz, 1H), 5.7797-5.7250 (d, J= 16.41Hz, 1H), 5.3375-5.2832 (d, J=16.29Hz, 1H), 5.3068 (s, 2H), 4.5986 (s, 2H), 4.3494 (s, 2H), 4.2262-4.1811 (t, J=6.77Hz, 2H), 3.7321 (s, 1H), 1.9520-1.8570 (m, 2H), 1.6756- 1.6531 (m, 2H), 1.2549 (s, 26H), 1.0726-1.0237 (t, J=7.34Hz, 3H), 0.8971-0.8548 (t, J= 6.35Hz, 3H).

The synthesis of embodiment 37-ethyl-10-hydroxycamptothecin hexadecanol diethylene glycol acid esters

The synthesis of hexadecanol diglycolic acid monoesters is with embodiment 1.Synthesize SN38 by the following method Hexadecanol diethylene glycol acid esters.

Reaction equation is shown below:

Experimental procedure:

In the round-bottomed flask of 100mL, add 0.360g (1mmol) hexadecanol diglycolic acid monoesters, be dissolved in 20mL anhydrous In toluene, 300 μ L (4mmol) thionyl chlorides, 10 μ LN, dinethylformamide, it is stirred at room temperature 4 hours under nitrogen protection.Decompression Rotary distillation, removes thionyl chloride and the toluene of excess, obtains a thick white liquid hexadecanol diglycolic acid monoesters acyl chlorides, add 10mL dichloromethane obtains solution A.

In another 100mL round-bottomed flask, add 0.196g (0.5mmol) SN38 (SN- 38) and 20mLN, dinethylformamide, stirring, obtain a solution, add 250 μ L (1.8mmol) triethylamines.Molten by 5mL Liquid A is added dropwise in this solution, stirred overnight at room temperature.Tlc analysis, if still there being a small amount of SN38 the most anti- Should be complete, add appropriate solution A and triethylamine to reacting complete.Chromatography, 100-200 mesh silica gel is fixing phase, dichloro Methane: ethyl acetate=1: the mixed liquor of 1 (volume ratio) is leacheate, obtains 0.240g faint yellow solid 7-ethyl-10-hydroxyl Camptothecine hexadecanol diethylene glycol acid esters, productivity is 64.0%.

Its proton nmr spectra of target compound and mass spectrum that synthesis obtains are shown in Fig. 7 and Fig. 8.

MS (Positive ESI): m/z=733.5 (M+H)⁺。

¹H NMR (300MHz, CDCl₃): δ ppm:8.3523-8.3218 (d, J=9.15Hz, 1H), 7.9197 (s, 1H), 7.7678 (s, 1H), 7.6224-7.5915 (d, J=9.27Hz, 1H), 5.7803-5.7255 (d, J=16.44Hz, 1H), 5.3374-5.2834 (m, 3H), 4.6133 (s, 2H), 4.3592 (s, 2H), 4.2296-4.1844 (t, J=6.78Hz, 2H), 3.7359 (s, 1H), 3.2170-3.1414 (q, J=7.56Hz, 2H), 1.9723-1.8266 (m, 2H), 1.7018-1.6325 (m, 2H), 1.4386-1.2537 (m, 29H), 1.0683-1.0193 (t, J=7.35Hz, 3H), 0.8975-0.8535 (m, 3H)。

The preparation of embodiment 4 lipophilic camptothecin kind anti-cancer drugs compounds, including emulsion, micelle and liposome formula

In the present embodiment, including emulsion, micelle and the liposome formula of lipophilic camptothecin kind anti-cancer drugs compounds.Breast Containing the lipophilic camptothecin kind anti-cancer drugs compounds of the present invention in liquid, micelle and liposome formula, each component is at formula In content count by weight percentage.Medical compounds in formula can be resisted by other lipophilic camptothecin class of the present invention Cancer drug compound is replaced.

A. the emulsion of camptothecine hexadecanol diethylene glycol acid esters

Camptothecine hexadecanol diethylene glycol acid esters (MXN-006) is dissolved in Oleum Glycines, D-alpha-tocopherol cetomacrogol 1000 amber In the mixture of amber acid esters (TPGS) and Polyethylene Glycol PEG (200), add deionized water (DI water), then stirring and Ultrasonic emulsification, the composition of the emulsion produced is as follows:

MXN-006 1%

Oleum Glycines 10%

TPGS 5%

PEG (200) 3%

Deionized water is to 100%

The emulsion medicine made is filtered by the filter in 0.2 micron of an aperture, reinstalls aseptic vial.

B. the emulsion of camptothecine hexadecanol diethylene glycol acid esters

Camptothecine hexadecanol diethylene glycol acid esters (MXN-006) is dissolved in D-alpha-tocopherol acetate, D-alpha-tocopherol gathers In the mixture of ethylene glycol 1000 succinate (TPGS) and Polyethylene Glycol PEG (200), add normal saline, then stir And ultrasonic emulsification, the composition of the emulsion produced is as follows:

The emulsion medicine made is filtered by the filter in 0.2 micron of an aperture, reinstalls aseptic vial.

C. the Micellar Solution Which Is of camptothecine hexadecanol diethylene glycol acid esters

Camptothecine hexadecanol diethylene glycol acid esters (MXN-006) is dissolved in Tween 80 (Tween80), ethanol and Polyethylene Glycol The mixture of PEG (200) obtains transparent liquid, adds deionized water (DI water), then stir, the glue produced The composition of bundle liquid is as follows:

The emulsion medicine made is filtered by the filter in 0.2 micron of an aperture, reinstalls aseptic vial.

D. the Micellar Solution Which Is of camptothecine hexadecanol diethylene glycol acid esters

Camptothecine hexadecanol diethylene glycol acid esters (MXN-006) is dissolved in D-alpha-tocopherol cetomacrogol 1000 succinate (TPGS), the mixture of ethanol and Polyethylene Glycol PEG (200) obtains a transparent liquid, add normal saline, then stir Mixing, the composition of the Micellar Solution Which Is produced is as follows:

The emulsion medicine made is filtered by the filter in 0.2 micron of an aperture, reinstalls aseptic vial.

E. the liposome of camptothecine hexadecanol diethylene glycol acid esters

In a round-bottomed flask, by 0.01mmol camptothecine hexadecanol diethylene glycol acid esters (MXN-006) and 0.5mmol phosphorus Fat (lecithin, phosphatidylcholine) is dissolved in the chloroform (CHCl of 15mL₃), slowly it is heated to 40 DEG C, reduces pressure with Rotary Evaporators Evaporation solvent, forms one layer of thin lipid film, dried in vacuum overnight, removes the chloroform in lipid film further, add 10mL and steam Distilled water, then stirring and ultrasonic agitation, gained liposome liquid is filtered by the filter in 0.2 micron of an aperture, reinstalls nothing The vial of bacterium, freezing with dry ice and acetone, then lyophilization 24 hours, obtain the lipid of camptothecine hexadecanol diethylene glycol acid esters Body product.

F. the liposome of camptothecine hexadecanol diethylene glycol acid esters

In a round-bottomed flask, by 0.01mmol camptothecine hexadecanol diethylene glycol acid esters (MXN-006), 0.01mmol gallbladder Sterin (or 0.01mmol vitamin E) and 0.5mmol phospholipid (lecithin, phosphatidylcholine) are dissolved in the chloroform of 15mL (CHCl₃), slowly it is heated to 40 DEG C, solvent is evaporated under reduced pressure with Rotary Evaporators, form one layer of thin lipid film, be vacuum dried At night, removing the chloroform in lipid film further, add 10mL distilled water, then stirring and ultrasonic agitation, gained liposome liquid leads to The filter crossing 0.2 micron of an aperture filters, and reinstalls aseptic vial, and freezing with dry ice and acetone, then vacuum is cold Dry 24 hours of lyophilizing, obtains the liposome product of camptothecine hexadecanol diethylene glycol acid esters.

The vitro cytotoxicity experiment of embodiment 8 lipophilic camptothecin kind anti-cancer drugs compounds

In the present embodiment, detect PTS compounds suppression human ovarian cancer (A2780s) of the present invention by CCK8 method With the GI50 value of lung carcinoma cell (A549) cell (drug level of anticancer 50% growth), and with anticarcinogen irinotecan (irinotican) contrast, evaluate the vitro cytotoxicity of medical compounds.

The representative value of GI50 is as shown in table 1, and other anti-cancer drug compounds of the present invention has similar result, has equally The GI50 value substantially reduced.Result shows, the anti-cancer drug compounds of the present invention is to human ovarian cancer (A2780s) and lung carcinoma cell (A549) cell has obvious inhibited proliferation, and along with the increase of drug level, its inhibited proliferation to cell Strengthen, in obvious dose-dependent effect.With compared with the positive drug irinotecan (Irinotecan) of concentration, the present invention's Human ovarian cancer and lung carcinoma cell inhibition are become apparent from by anti-cancer drug compounds.

Test result indicate that, the anti-cancer drug compounds of the present invention has suppression Proliferation of Human Ovarian Cell (A2780s) colon cancer Cell (HT-29), hepatocarcinoma (HePG₂) cell and the proliferation function of lung carcinoma cell (A549), it is that a class has potential anti-human ovary Cancer, colon cancer, hepatocarcinoma and the medical compounds of pulmonary carcinoma effect.

CCK8 method detection method: trophophase cell of taking the logarithm, adjustment cell density is 3*10⁴Individual/mL, is inoculated in 96 hole trainings Support in plate, 100 μ L/ holes, change culture fluid after cell cultivation 24h, be separately added into the drug sample 150 μ L/ hole of variable concentrations, with Only adding culture fluid and being not added with the hole of cell is blank group (being used for returning to zero), and negative control group adds equal-volume culture fluid.Often group sets 3 Individual multiple hole.Cell continues to cultivate 72h, adds CCK8 solution 10 μ L/ hole, continues to cultivate 3h, detects wavelength and be in microplate reader Absorbance (D) value in each hole at 450nm.Calculate the growth inhibition ratio of cell as follows.Cell grows

Suppression ratio=(1-experimental group average D value/matched group average D value) × 100%.

Table 1. new anti-cancer drug thing GI50

MXN-006: camptothecine hexadecanol diethylene glycol acid esters.

MXN-008:7-ethyl-10-hydroxycamptothecin hexadecanol diethylene glycol acid esters.

Claims (8)

1. the lipophilic camptothecin kind anti-cancer drugs compounds that a lipophilic alcohol or phenol are modified, it is characterised in that under having Formulas I or the structure of II:

In Formulas I and II, R is cetyl, R₂It is H or-CH₂CH₃, R₃It is H, R₄It is H.

2. the emulsion of the lipophilic camptothecin kind anti-cancer drugs compounds described in claim 1 or a microemulsion preparation, it becomes Divide and include:

1) oil phase, including:

A) there is the lipophilic camptothecin kind anti-cancer drugs compounds of Formulas I or II structure；

B) biocompatible lipophilic medium；

2) surfactant and cosolvent；

3) aqueous phase.

The emulsion of lipophilic camptothecin kind anti-cancer drugs compounds the most according to claim 2 or microemulsion preparation, it is special Levying and be, in described emulsion or microemulsion preparation, lipophilic camptothecin kind anti-cancer drugs compounds is shared in pharmaceutical formulation Percentage by weight be 0.005% to 5%, lipophilic medium accounts for 1% to 20% in pharmaceutical formulation, Surfactant weight percentage in pharmaceutical formulation is 1% to 10%.

4. a micellar preparation for the lipophilic camptothecin kind anti-cancer drugs compounds described in claim 1, its composition includes:

1) there is the lipophilic camptothecin kind anti-cancer drugs compounds of Formulas I or II structure；

2) surfactant；

3) cosolvent；

4) aqueous phase.

The micellar preparation of lipophilic camptothecin kind anti-cancer drugs compounds the most according to claim 4, it is characterised in that institute In the micellar preparation of the lipophilic camptothecin kind anti-cancer drugs compounds stated, lipophilic camptothecin kind anti-cancer drugs compounds is being joined In side, weight percentage is 0.005% to 5.0%, and surfactant weight percentage in formula is 1 to 10%, helps Solvent weight percentage in formula is 2% to 20%.

6. a Liposomal formulation for the lipophilic camptothecin kind anti-cancer drugs compounds described in claim 1, its composition includes:

1) there is the lipophilic camptothecin kind anti-cancer drugs compounds of Formulas I or II structure；

2) phospholipid；

3) aqueous phase；

4) add or be not added with lipophilic medium.

The Liposomal formulation of lipophilic camptothecin kind anti-cancer drugs compounds the most according to claim 6, it is characterised in that In described Liposomal formulation, lipophilic camptothecin kind anti-cancer drugs compounds weight percentage in formula is 0.005% To 5.0%, phospholipid weight percentage in formula is 1 to 10%, lipophilic medium weight percentage in formula Be 0% to 20%.

8. the application in preparing cancer therapy drug of the lipophilic camptothecin kind anti-cancer drugs compounds described in claim 1.