CN109384730A - 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil and preparation and application - Google Patents
1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil and preparation and application Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
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Abstract
The invention discloses the antineoplastic compounds with Formulas I structure: 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil and preparation method thereof.5 FU 5 fluorouracil front body structure in medical compounds molecule of the present invention simultaneously containing the double chloride alkanisation group and inhibition deoxythymidine acid enzyme that make DNA base cross link, with two kinds of machining functions in cancer cell, to generate synergistic effect, more effectively inhibit and kill cancer cell, improve curative effect and reduces toxic side effect.Compound of the present invention has good anticancer activity, can be used for preparing the drug of cancer, solid tumor cancer, sarcoma, cutaneum carcinoma or glioma for the treatment of hematological system etc..
Description
Technical field
The present invention relates to a kind of derivatives of Chlorambucil, and in particular to a kind of compound 1- { 3- [p- double-(2- chlorine
Ethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil and preparation method thereof and the application as anti-tumor drug.
Background technique
Tumour is a kind of disease for seriously endangering human life and health, is body under carcinogenic factor effect, local organization
Some cell lose the normal regulation grown to it at the genetic level, lead to its clonal abnormality hyperplasia and formed different
Normal lesion shows as cell hyperproliferation, disdifferentiation.Cancer has become first cause of the death of the mankind at present, constitutes to human survival
The threat of most serious.
Drug therapy acts as important function in terms for the treatment of tumour, and anti-tumor drug is various in style, and the mechanism of action is different.It is more
The mechanism of action of number anti-tumor drug is mainly the conjunction for preventing DNA (DNA), ribonucleic acid (RNA) or protein
At, or directly have an effect to these macromoleculars, to inhibit the division growth of tumour cell, it is allowed to dead.Some drugs
It can inhibit tumour growth by changing hormone in vivo balance.Anti-tumor drug is broadly divided into 6 major class: 1. antimetabolic at present
Medicine；2. alkylating agent；3. cytotoxin class antibiotic；4. plant alkaloid and other crude drugs；5. antitumor steroids；6. platinum class
And other antineoplastics.
Currently, targeted therapy has become the important directions for the treatment of of cancer, the treatment mode of one target spot of a medicine is mostly used, is such as used
The Irinotecan (Irinotecan, CPT-11) of DNA topoisomerase I is acted on and for treating ovum in treatment advanced CRC
Nest cancer and breast cancer act on taxol (Taxol) of intracellular canaliculus etc..But tumour is different from general diseases, its growth
A kind of receptor or a kind of conduction of signal path are depended not only upon with survival, this allows for the strategy for acting on a target spot merely
Tumour cell can not be thoroughly killed, and is easy to produce drug resistance.Then, a variety of combination therapies are treated as cancer clinical
Main means, although expected therapeutic effect can be reached to a certain extent, since a variety of drugs are easy to happen to each other
Interaction, if absorption of drugs and metabolism have an impact, even if not interacting, these drugs generally also cannot be with it
Dosage combination when being used alone, for this purpose, drug research person uses for reference the principle of a variety of combination therapies, spelled using pharmacophore
Two or more pharmacophore is pieced together a molecule by the method for conjunction, makees this molecule itself or its metabolite
For two or more target spots, to generate synergistic effect to improve curative effect.Therefore, design and synthesis are in two or more
Therapeutic effect not only can be improved in the anticancer drug of a target spot, but also caused by being possible to avoid a variety of combination therapies
The side effects such as drug interaction, to reduce toxic side effect.
Nucleoside analog is a kind of anti-tumor drug for belonging to antimetabolite, is using bioisosterism, by DNA
The structure of the units substance such as purine nucleosides, pyrimidine nucleoside needed for duplication is made chemical modification and is obtained, through intracellular triphosphoric acid
Afterwards, cellular replication, competitiveness are interfered in synthesis, incorporation DNA or the RNA molecule by inhibiting deoxynucleoside triphosphate (dNTPs)
The effects of inhibiting archaeal dna polymerase, the metabolism of specific interfering nucleic acid prevents the division and breeding of cell, it is thin to eventually lead to tumour
Born of the same parents are dead.Nucleosides series antineoplastic medicament includes: 1) guanosine analogue, such as guanosint glycoside drug nelarabine
(nelarabine)；2) neplanocin, such as fludarabine (fludarabine), Cladribine (cladribine) and chlorine method
It draws shore (clofarabine)；3) purine analogue, such as mercaptopurine (mercaptopurine, 6-MP), thioguanine
(tioguanine, 6-TG) and imuran (azathioprine)；4) uracil and uridine analogs, such as fluorouracil (5-
FU, fluorouracil), Tegafur (tegafur), capecitabine (capecitabine) and 5-ethinyluracil (5-
ethynyluracil)；5) cytidine analog, such as cytarabine (cytarabine, ara-C), gemcitabine
(gemcitabine), azacitidine (azacitidine, 5-AC) and Decitabine (decitabine).Ucleosides is antitumor
Drug acts as important function in terms for the treatment of tumour.
Nitrogen mustards compound (including mustargen, cyclophosphamide, Chlorambucil) is for clinic and to obtain prominent curative effect
Anti-tumor drug.It is a kind of compound that height is active for dichloro ethamine kind alkylating agent.After nitrogen mustards compound enters in vivo,
By intramolecular condensation, the active aziridine ion of height is formed, is had with a variety of rapidly under the conditions of neutral or weak base
The nucleophilic group (carboxyl of such as protein, amino, sulfydryl, the amino of nucleic acid and hydroxyl, phosphate radical) of machine substance combines, and carries out alkane
Baseization effect.Nitrogen mustards compound it is most important reaction be with the 7th nitrogen covalent bond of guanine, generate in the double-strand of DNA
The cross link of different bases in the same chain of cross link or DNA.
Summary of the invention
The purpose of the present invention is to provide a kind of new antineoplastic compounds, have therapeutic effect to kinds of tumors.
The chemical name of the compound are as follows: 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil, tool
There is the chemical structure of Formulas I:
Another object of the present invention is to provide the synthetic methods of the antineoplastic compounds (I).
The antineoplastic compounds (I, hereinafter referred to as YY-001) can be prepared by the following method:
1) synthesis of 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol based isocyanate.
[bis- (2- chloroethyl) amino] benzenebutanoic acid of method one: 4- and diphenyl phosphate azide (DPPA) progress Azide are anti-
It answers, generates 4- [p- double-(2- chloroethyl) amido] benzene bytyry nitrine, 4- [p- double-(2- chloroethyl) amido] benzene bytyry
Nitrine releases nitrogen, through Ku Ertisi rearrangement reaction (Curtius rearrangement), generates 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol
Based isocyanate.
One preferred embodiment of above-mentioned reaction is under nitrogen protection, and 4- [bis- (2- chloroethyl) amino] benzenebutanoic acid is molten
In toluene, appropriate powdered 4A molecular sieve is added, adds diphenyl phosphate azide (DPPA) and three dry in right amount second
Amine stirs at room temperature, obtains 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol based isocyanate.
Method two: 4- [bis- (2- chloroethyl) amino] benzenebutanoic acid is reacted with chloride reagent, generates 4- [p- double-(2- chlorine
Ethyl) amido] benzene butyl chloride, then with reaction of sodium azide, through Ku Ertisi rearrangement reaction (Curtius rearrangement reaction) generate 3-
[p- double-(2- chloroethyl) amido] phenylpropyl alcohol based isocyanate.Above-mentioned chloride reagent is chloride commonly used in the art
Reagent, preferably SOCl2Or (COCl)2Or POCl3, reaction condition is conventional acyl chloride reaction condition.
One preferred embodiment of above-mentioned reaction is under nitrogen protection, and dry toluene is as solvent, anhydrous DMF catalysis
Under, 4- [bis- (2- chloroethyl) amino] benzenebutanoic acid reacts at room temperature with thionyl chloride and obtains within 2-10 hours 4- [bis- (2- chloroethenes
Base) amino] benzene butyl chloride, then with reaction of sodium azide, through Ku Ertisi rearrangement reaction (Curtius rearrangement reaction) generate 3-
[p- double-(2- chloroethyl) amido] phenylpropyl alcohol based isocyanate.
Method three: 4- [bis- (2- chloroethyl) amino] benzenebutanoic acid is reacted with ethyl chloroformate, generates ethyoxyl formic acid 4-
[p- double-(2- chloroethyl) amido] benzenebutanoic acid acid anhydride, then with reaction of sodium azide, through Ku Ertisi rearrangement reaction (Curtius weight
Row's reaction) generate 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol based isocyanate.
[bis- (2- chloroethyl) amino] the benzenebutanoic acid ester (preferably ethyl ester or methyl esters) of method four: 4- and hydrazine reaction generate 4-
[p- double-(2- chloroethyl) amido] benzene daminozide, then reacted with sodium nitrite, generate 4- [p- double-(2- chloroethyl) amido]
Benzene bytyry nitrine, then through Ku Ertisi rearrangement reaction (Curtius rearrangement reaction), generate 3- [p- double-(2- chloroethyl) amine
Base] phenylpropyl alcohol based isocyanate.
2) 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil synthesis.
3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol based isocyanate is reacted with 5 FU 5 fluorouracil, is given birth in the presence of alkali
At compound 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl } formyl -5-fluor-uracil.
Above-mentioned alkali is preferably organic base, such as triethylamine, pyridine, 4-dimethylaminopyridine (DMAP).
One preferred embodiment is dissolved in dry for 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol based isocyanate
In pyridine, suitable 4-dimethylaminopyridine (DMAP) and 5 FU 5 fluorouracil is added, is heated to 80 DEG C, stirring to reaction is completed,
The method of the invention reaction route is shown below:
Another object of the present invention, which also resides in, provides the antineoplastic compounds 1- { 3- [p- double-(2- chloroethyl)
Amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001) preparing the application in anticancer drug.The medical compounds is used
In preparing anticancer drug, the including but not limited to 1. cancer of hematological system, such as leukaemia, lymthoma, myeloma；2. non-blood cancer
Disease, as solid tumor cancer (such as breast cancer, oophoroma, cancer of pancreas, colon and rectum carcinoma, non-small cell lung cancer, bladder cancer, gastric cancer,
Liver cancer etc.), sarcoma, cutaneum carcinoma and glioma etc..
Further, based on the antineoplastic compounds (YY-001), the present invention provides a kind of anti-tumor drug,
It is characterized in that, the drug includes 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } first of effective therapeutic dose
Acyl -5- fluorouracil and pharmaceutically acceptable excipient substance.
The compound of the present invention 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil molecule
In simultaneously containing can make the double chloride alkanisation group of DNA base cross link and to can inhibit the 5- fluorine of deoxythymidine acid enzyme
Uracil front body structure, it is contemplated that molecule itself or its metabolite can two kinds of machining functions in cancer cell, to generate collaboration
Function and effect inhibit and kill cancer cell, to improve curative effect and reduce toxic side effect.
The anti-tumor drug can be oral preparation, injection or external preparation, including tablet, capsule, lipid
Body agent, emulsion or micro emulsion liquor, micellar and paste etc..Tablet includes neoteric anti-cancer drug compounds and auxiliary material.Capsule
Agent includes neoteric anti-cancer drug compounds and auxiliary material.Liposomal agents include neoteric anti-cancer drug compounds, phosphatide (most
Representative is lecithin, phosphatidyl choline), cholesterol and water phase.Emulsion include neoteric anti-cancer drug compounds,
One or more surfactants, oily phase (lipophilic medium) and water phase.Emulsion can be oil-in-water type or water-in-oil type.Micella
Agent includes neoteric anti-cancer drug compounds, cosolvent and one or more surfactants and water phase.Paste ingredient includes
Neoteric anti-cancer drug compounds and matrix.
Further, a kind of tablet of the anti-cancer drug compounds, ingredient include:
1) anti-cancer drug compounds YY-001；
2) auxiliary material.
Common auxiliary material includes: 1. diluent (Diluents), such as starch, Icing Sugar, dextrin, lactose, pregelatinized starch
(Pregelatinized starch), microcrystalline cellulose (Microcrystalline cellulose, MCC), inorganic calcium salt,
Such as calcium sulfate, calcium monohydrogen phosphate and medicinal calcium carbonate, mannitol；2. adhesive (Adhesives), such as distilled water, ethyl alcohol, starch
Slurry, sodium carboxymethylcellulose (carboxymethylcellulose sodium, CMC-Na), hydroxypropyl cellulose
(hydroxypropylcellulose, HPC), methylcellulose and ethyl cellulose (Methylcellulose, MC；
Ethylcellulose, EC), hydroxypropyl methylcellulose (Hydroxypropylmethyl cellulose, HPMC), other bondings
(5%~20% gelatin solution, 50%~70% sucrose solution, 3%~5% polyethylene adjoin the water of pyrrolidone (PVP) for agent
Solution or alcoholic solution)；3. disintegrating agent (Disintegrants), such as dried starch, sodium carboxymethyl starch (Carboxymethyl
Starch sodium, CMS-Na), low-substituted hydroxypropyl cellulose (L-HPC), cross linked polyvinyl pyrrolidone (Cross-
Linked polyvinyl pyrrolidone, also known as cross-linked pvp), croscarmellose sodium (Croscarmellose
Sodium, CCNa are the carboxymethyl cellulose ether of Cross-linked (about 70% carboxyl is sodium-salt type)；4. lubricant
(Lubricants), as hung magnesium stearate, hydrogenated vegetable oil, polyethylene glycol, the moon alcohol magnesium sulfate, superfine silica gel powder (Aerosil), sliding
Mountain flour；5. colorant；6. corrigent etc..Which kind of auxiliary material no matter is added, should all meet medicinal requirement, cannot all occur with main ingredient
Reaction, should not also interfere the dissolution and absorption of main ingredient.
Wet granule compression tablet, dry granulation tabletting and direct tablet compressing preparation can be used in tablet.
Alternatively, the capsule of anti-cancer drug compounds described in one kind, including hard capsule and soft capsule, ingredient include:
1) anti-cancer drug compounds YY-001；
2) auxiliary material.
The common auxiliary material of hard capsule includes but is not limited to: 1. diluent: for improving the physical characteristic and increasing of content
Add volume, often there is certain compressibility.Common diluent has mannitol, microcrystalline cellulose, lactose, pregelatinized starch
1500, cornstarch etc..2. lubricant: to prevent sticking for powder and metal material.It is common to have magnesium stearate, monostearate sweet
Grease, stearic acid, talcum powder etc..3. glidant: improving the mobility of content.It is common to have superfine silica gel powder and talcum powder etc..④
Disintegrating agent: guarantee the disintegration of content.Common crosslinking cellulose, cornstarch, crospovidone, pregelatinized starch 1500,
Glycyl sodium starch, alginic acid etc..5. wetting agent: increasing the wetability of drug and dissolution medium, guarantee the efficiency of preparation.Often
Seeing has Tween 80, lauryl sodium sulfate etc..
Auxiliary material in soft capsule content include but is not limited to oiliness dispersion or PEG dispersion, content can be solution,
Suspension, emulsion, semisolid etc..Oiliness dispersion (lipophilicity) content auxiliary material includes: 1. oiliness carrier: soybean oil, castor oil,
Medium chain fatty acid etc.；2. including rilanit special, beeswax etc. for adjusting the semisolid of viscosity；3. surfactant such as phosphatide can
To improve the suspension stability of suspension.Other stabilizers such as antioxidant BHT etc. can also be added.PEG disperses (hydrophily) content
Object auxiliary material is usually PEG400 and 600, semisolid to use PEG200, PEG300 of low molecular weight and high molecular simultaneously
PEG4000-10000。
Hard capsule case is similar to soft capsule shell, mainly containing gelatin, Arabic gum, water, (such as glycerol can also add plasticizer
Enter appropriate propylene glycol and polyethylene glycol 200, mannitol or sorbierite can substitute plasticizer of the glycerol as rubber), preservative
(such as potassium sorbate, nipalgin), opacifier and pigment etc., wherein the effect of water is solvent.
Alternatively, the paste of anti-cancer drug compounds described in one kind, ingredient include:
1) anti-cancer drug compounds YY-001；
2) matrix.
Common matrix include: hydro carbons (such as vaseline, solid paraffin, atoleine, silicone), lipoidis (such as lanolin,
Beeswax and spermaceti, dimeticone), grease type (such as animals and plants higher fatty acid rouge and its mixture).
Anti-cancer drug compounds of the invention dissolve in lipophilic medium, and suitable preparation further includes Liposomal agents, cream
Agent or micro emulsion liquor, micellar etc..
Further, a kind of anti-cancer drug compounds Liposomal formulation, ingredient include:
1) anti-cancer drug compounds YY-001；
2) phosphatide；
3) cholesterol or vitamin E and its derivative；
4) water phase.
Alternatively, the emulsion or microemulsion of anti-cancer drug compounds described in one kind, ingredient include:
1) oily phase, comprising:
A) anti-cancer drug compounds YY-001；
B) biocompatible lipophilic medium；
2) surfactant and cosolvent；
3) water phase.
Alternatively, anti-cancer drug compounds micellar, ingredient described in one kind include:
1) anti-cancer drug compounds YY-001；
2) surfactant；
3) cosolvent；
4) water phase.
The lipophilic medium (or carrier) can be any biocompatible lipophilic medium, has and represents
The biocompatible lipophilic medium of property includes:
1) grease that can be used as lipophilic medium, fatty acid and ester including different chain length, they are straight chain mostly, but
It is also possible to branch, such as capric acid, octanoic acid, caproic acid, lauric acid, nutmeg, stearic acid, oleic acid, linoleic acid and other full
And/or unsaturated fatty acid and esters.
2) fat-soluble vitamin E and derivative.Vitamin E refers to natural or artificial synthesized vitamin E series, it
Commonly referred to as tocopherol and tocotrienols (tocopherols and tocotrienols), tocopherol include 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).Tocotrienols is similar to tocopherol in structure, but tocotrienols is on the side chain phytyl (phytyl) of carbon -2
There are three double bonds.Tocotrienols includes alpha-tocotrienol (D type, DL type, L-type), β-tocotrienols (D type, DL type, L
Type), γ-tocotrienols (D type, DL type, L-type) and δ-tocotrienols (D type, DL type, L-type).Vitamin e derivative packet
Include the derivative of all tocopherols and tocotrienols, such as Vitamin E succinate, Vitwas E etc..
3) fatty acid is reacted with glycerine esterification is formed by monoglyceride, diglyceride or triglycerides, and no matter they are
It is synthesis or natural, it all can be used as lipophilic medium, for example, glyceride, such as soya-bean oil, cottonseed oil, rapeseed oil, fish oil, second
Acylated monoglyceride, Monoolein, triacetyl glycerine and diacetyl tartrate ester, monoglyceride, castor oil etc..
4) fatty alcohol, such as benzylalcohol, stearyl alcohol, laruyl alcohol or their ester or ether, such as Ergol.
Representative surfactant includes:
1) polyglycol surfactants, as Emulsifier EL-60 EL (Cremophor EL), TWEEN Series surface are living
Property agent etc..
2) non-phospholipid surfactants (phospholipids), such as lecithin (lecithin), soybean lecithin
(granulesten or soybean lecithin), polyethylene glycol phosphatide (pegylated phospholipids).
3) polyethylene glycol vitamin e derivative, such as Vitamin E succinate polyethylene glycol (d- α-tocopherol
Polyethylene glycol 1000succinate, TPGS).
4) polyoxyethylene polyoxypropylene block copolymer: the block copolymer (H of POLOXAMERS or PLURONICS
(OCH2CH2)a(OCH2CH2CH2)b(OCH2CH2)aOH)。
The representative are co-solvent contents to include:
Ethyl alcohol, polyethylene glycol, propylene glycol, glycerol, N-Methyl pyrrolidone etc..Polyethylene glycol (PEG) is hydrophilic, weight
The chemical structure group of multiple unit becomes-CH2CH2O-, general formula are H- (CH2CH2)n- OH, molecular weight ranges generally from 200 to
10000.For example, polyethylene glycol 200, PEG-300, polyethylene glycol 400 etc..
" emulsion " used herein refers under the action of surfactant, and a phase liquid is scattered in another with drop state
The heterogeneous liquid dispersion formed in phase liquid, such as oil and water are formed by drop, and diameter is generally micro- 0.1 to 3.0
Rice.
The emulsion can form stable microemulsion." micro emulsion " word refers to that two unmixing liquid form one
Thermodynamically stable isotropism, transparent or semitransparent dispersion, such as the micro emulsion dispersion of oil and water are lived by surface
Property agent molecule formed interfacial film stablized.Micro emulsion average droplet size be less than 200nm, general 10 to 50 nanometers.
It include oil phase and water phase in emulsion or microemulsion.Emulsion or microemulsion can be oil-in-water type emulsion or Water-In-Oil
Type.
In the absence of water, it is formed by by the mixing of oily phase, nonionic surface active agent and assistant for emulsifying agent uniform
Solution that is transparent and including drug is referred to as self-emulsifying drug delivery system (self-emulsifying drug delivery
System:SEDDS), spontaneous emulsification forms partial size in the emulsion of 100nm to 500nm, can be used for improving lipophilic drugs solubility
And oral absorbability.
In the embodiment of an emulsion or microemulsion, lipophilic medium includes soya-bean oil, and aqueous media is water.Another
In the embodiment of a emulsion and microemulsion, lipophilic medium includes fat soluble vitamin E.In another emulsion or microemulsion
In embodiment, lipophilic medium includes fat soluble vitamin E derivative.
It can also include pharmaceutical emulsion and micro emulsion in emulsion or micro-emulsion formulation in addition to anti-cancer drug compounds of the invention
Common others ingredient in agent, these ingredients include surfactant and cosolvent.Representative surfactant packet
Nonionic surfactant is included, such as Emulsifier EL-60 EL (Cremophor EL), Tween 80 (Tween 80), polyethylene glycol
Vitamin E derivative surfactant and other surfactant polymers.
Suitable polyethylene glycol vitamin e derivative surface-active 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 include have 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 succinate (such as D- alpha tocopherol cetomacrogol 1000 succinate, TPGS, a kind of non-ionic surfactant
Agent (HLB=16-18)) and vitamin E polyethylene glycol various esters and ether derivant.
It all include the anti-cancer drug compounds and auxiliary material of the invention of effective therapeutic dose in its formula of above-mentioned various preparations.
The tablet of the anti-cancer drug compounds includes anti-cancer drug compounds and auxiliary material of the invention.The anticancer
The content in every of medical compounds can be 1 milligram to 1000 milligrams, and anti-cancer drug compounds are every in preferred scheme
Content in piece is 5 milligrams to 500 milligrams；In preferred scheme, content of the anti-cancer drug compounds in every is 10 millis
Gram to 250 milligrams.
The capsule of the anti-cancer drug compounds includes anti-cancer drug compounds and auxiliary material of the invention.Described is anti-
The content in every capsule of cancer drug compound can be 1 milligram to 1000 milligrams, anticancer drug chemical combination in preferred scheme
Content of the object in every capsule is 5 milligrams to 500 milligrams；In preferred scheme, anti-cancer drug compounds are in every
Content is 10 milligrams to 250 milligrams.
In the emulsion or microemulsion of the anti-cancer drug compounds, anti-cancer drug compounds are shared in pharmaceutical formulation
Weight percent is 0.005% to 5.0%；It is preferred that anti-cancer drug compounds account in pharmaceutical formulation
0.01% to 2.5%；In preferred scheme, anti-cancer drug compounds account in pharmaceutical formulation
0.1% to 1.5%.
In the emulsion or microemulsion, lipophilic medium accounted in pharmaceutical formulation 2% to
20%；It is preferred that lipophilic medium accounts for 4% to 12% in pharmaceutical formulation；In preferred scheme, parent
Lipid medium accounts for 6% to 10% in pharmaceutical formulation.
In the emulsion or microemulsion, the weight percentage of surfactant in formula is about 1 to 10%, preferably
2-6%, more preferable 4-5%.
In the emulsion or microemulsion, cosolvent accounts for about the 0% to 20% of formulation weight.
The micellar preparation of anti-cancer drug compounds as described above includes anti-cancer drug compounds of the invention, Yi Zhonghuo
A variety of surfactants, one or more cosolvents and water phase.
In the micellar of the anti-cancer drug compounds, weight percentage is about medical compounds in formula
0.005% to 3.0%, weight percentage is about 0.01% to 2.5% to preferred agents compound in formula；It is further preferred that medicine
Weight percentage is about 0.1% to 1.0% to compounds in formula.
Suitable weight percentage of the surfactant in micella agent prescription of the invention is about 1 to 10%, preferably
2-6%, more preferable 4-5%.
Micella agent prescription further includes other compositions, cosolvent as mentioned above.In one embodiment, micellar is matched
It include polyethylene glycol and lower alkylol (such as ethyl alcohol) in side.In the micellar, cosolvent accounts for about the 1% of formulation weight
To 20%.
The Liposomal agents of the anti-cancer drug compounds include anti-cancer drug compounds of the invention, one or more phosphorus
Rouge (including PEGylated phosphatide), one or more lipophilic mediums (such as cholesterol) and water phase.
In the Liposomal agents of the anti-cancer drug compounds, weight percentage is about medical compounds in formula
0.005% to 5.0%, the weight percentage of preferred agents compound in formula is about 0.01% to 2.5%；It is further preferred that
Weight percentage is about 0.1% to 1.5% to medical compounds in formula.
Suitable weight percentage of the phosphatide in Liposomal agents formula of the invention is about 1 to 10%, preferably 2-
6%, more preferable 4-5%.
Liposomal agents formula further includes other compositions, lipophilic medium (such as cholesterol) as mentioned above.At one
It include cholesterol or vitamin E in Liposomal agents formula in embodiment.In the Liposomal agents, cholesterol or vitamin E are about
Account for the 0.1% to 20% of formulation weight.
It include water phase in above-mentioned emulsion, microemulsion, micellar and Liposomal agents formula.In one embodiment, water phase packet
Include deionized water.In another embodiment, water phase includes physiological saline.In another embodiment, a kind of acid is contained in water phase
The buffer of (such as succinic acid, citric acid, phosphoric acid).
The paste of the anti-cancer drug compounds includes anti-cancer drug compounds of the invention, one or more matrix.
The weight percentage of YY-001 is about 0.01% to 30% in the paste of the anti-cancer drug compounds, excellent
Selecting the weight percentage of medical compounds in formula is about 0.05% to 20%；It is further preferred that medical compounds is in formula
Weight percentage is about 0.1% to 10%.
The curative effect and toxicity of medical compounds of the invention determine with cell in vitro or interior animal experiment, for example,
ED50 (50%effective dose, effective dose 50: dose when positive reaction occurs in 50% experimental subjects), LD50
(50%lethal dose, median lethal dose kill the dosage of half subjects) and GI50 (concentration of
The anti-cancer drug that inhibits the growth ofcancer cells by 50% inhibits 50%
Experimental subjects growth drug concentration).Usually median lethal dose (LD50)/effective dose 50 (ED50) ratio is known as controlling
Index is treated, to indicate Drug safety.The big drug of the therapeutic index drug small with respect to therapeutic index is safer.
Neoteric anti-cancer drug compounds are intended to improve therapeutic index and Drug safety, while also improving treatment effect
Fruit.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 seldom or at all do not have within the scope of virose ED50.Doses change generally depends on use
Dosage form, the sensibility of patient and administration route etc..Same or like drug usually can be used, it is normal such as Irinotecan and topotecan
Rule dosage makes reference.Such as the routine dose of topotecan is 0.2-1.5mg/m2, Irinotecan routine dose be 100mg-
350mg/m2。
Medical compounds of the invention can be used alone, and can also make together with one or more of the other therapeutic agent
With.For example, these medical compounds can be used together with following therapeutic agent, including but not limited in the treatment of cancer: male
Hormone inhibitors, such as Flutamide (flutamide) and Lu Poruoli get (luprolide)；Antiestrogenic, such as tamoxifen
(tomoxifen)；Antimetabolite and cytotoxic drug, such as daunorubicin (daunorubicin), 5-fluorouracil
(fluorouracil), floxuridine (floxuridine), alpha-interferon (interferon alpha), methotrexate (MTX)
(methotrexate), mithramycin (plicamycin), mercaptopurine (mecaptopurine), thioguanine
(thioguanine), adriamycin (adriamycin), Carmustine (carmustine), lomustine (lomustine), Ah
Sugared cytidine (cytarabine), cyclophosphamide (cyclophosphamide), adriamycin (doxorubicin), Estramustine
(estramustine), hemel (altretamine), hydroxycarbamide (hydroxyurea), ifosfamide
(ifosfamide), procarbazine (procarbazine), mutamycin (mutamycin), busulfan (busulfan), rice
Hold in the palm anthraquinone (mitoxantrone), carboplatin carboplatin), cis-platinum (cisplatin), streptozotocin
(streptozocin), bleomycin (bleomycin), D actinomycin D (dactinomycin) and darubicin
(idamycin)；Hormone, such as medroxyprogesterone acetate (medroxyprogesterone), alkynes estradiol (ethinyl estradiol), female
Glycol (estradiol), Leuprorelin (leuprolide), megestrol acetate (megestrol), Octreotide (octreotide),
Diethylstilbestrol (diethylstilbestrol), Chlorotrianisene (chlorotrianisene), etoposide (etoposide),
Podophyllotoxin (podophyllotoxin) and Goserelin (goserelin)；Nitrogen mustard derivatives, such as phenyalamine mustard
(melphalan), Chlorambucil (chlorambucil) and phosphinothioylidynetrisaziridine (thiotepa)；Steroids, such as betamethasone
(betamethasone)；With other anti-tumor drugs, such as cattle on the hoof mycobacteria (live Mycobacterium bovis), reach
Carbazine (dicarbazine), asparaginase (asparaginase), formyl tetrahydrofolic acid (leucovorin), mitotane
(mitotane), vincristine (vincristine), vincaleukoblastinum (vinblastine) and Docetaxel (taxotere) etc..
The utility model has the advantages that antineoplastic compounds 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } of the invention
Formyl -5-fluor-uracil, the method that pharmacophore split is used in MOLECULE DESIGN, simultaneously containing DNA base being made to intersect in molecule
The double chloride alkanisation group of connection and the 5 FU 5 fluorouracil front body structure that can inhibit deoxythymidine acid enzyme, molecule itself or
Its metabolite can act on two or more target spots, with two kinds of machining functions in cancer cell, to generate synergistic effect, more
Cancer cell is effectively inhibited and killed, curative effect is improved and reduces toxic side effect.Compound of the present invention has good anticancer
Activity can be used for preparing the drug of cancer, solid tumor cancer, sarcoma, cutaneum carcinoma or glioma for the treatment of hematological system etc..
Detailed description of the invention
Fig. 1 is 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001) nuclear-magnetism
Resonate hydrogen spectrogram.
Fig. 2 is 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001) mass spectrum
Figure, wherein A is holotype ESI (Positive Ion mode ESI) mass spectrogram, and B is negative mode ESI (Negtive Ion
Mode ESI) mass spectrogram.
Fig. 3 is the liquid of 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001)
Phase chromatogram.
Specific embodiment
Illustrate synthesis, preparation and the zoopery of new anti-cancer drug compounds etc. of the invention with embodiment below.It is described
Embodiment facilitate the understanding of the present invention and implementation, and be not construed as limiting the scope of this invention limitation, protection scope is wanted by right
It asks and is defined.
1. 1- of embodiment { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001)
Synthesis
(1) synthesis of 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol based isocyanate
Reaction equation is shown below:
Experimental procedure:
Into 100mL round-bottomed flask, the toluene of 1.0g Chlorambucil (3.287mmol) and 10ml drying, stirring is added
It makes it dissolve, the powdered 4A molecular sieve of 0.4g is added, then 1.403g (5.10mmol) nitrine phosphoric acid hexichol is added into solution
The triethylamine of ester (DPPA) and 0.515g (5.10mmol), (about 30 minutes) are completed in stirring to reaction at room temperature, into reaction solution
The saturation NaHCO of about 10ml is added3Aqueous solution stirs 2-3 minutes, and ethyl acetate (30ml × 3) extraction is added three times, will be organic
Mutually merge, with anhydrous Na SO4Dry, chromatography is stationary phase, methylene chloride and petroleum ether mixing with 200-300 mesh silica gel
Liquid is leacheate, obtains colourless liquid 0.64g, yield 64.0%.
1H NMR (400MHz, CDCl3): δ ppm:7.08-7.06 (d, J=8Hz, 2H), 6.65-6.63 (d, J=8Hz,
2H), 3.73-3.69 (m, 4H), 3.65-3.60 (m, 4H), 3.32-3.28 (t, J=8Hz 2H), 2.64-2.61 (t, J=
6Hz, 2H), 1.91-1.84 (m, 2H).
(2) synthesis of 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001)
Reaction equation is shown below:
Into 50mL round-bottomed flask, 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol of 0.300g (0.996mmol) is added
The 4-dimethylaminopyridine of based isocyanate, the dry pyridine of 5ml, the 5 FU 5 fluorouracil of 0.100g (0.769mmol) and 15mg
(DMAP), it stirs, after being heated to 80 DEG C, reaction 5 hours, reaction solution is cooled to room temperature, chromatography, with 100-200 mesh silicon
Glue is stationary phase, and methylene chloride and ethyl acetate mixtures are leacheate, obtains white solid 0.189g, yield 57.1%.Product
Nuclear magnetic resonance spectroscopy and mass spectrogram such as Fig. 1 and Fig. 2.
MS (Positive Ion mode ESI): m/z=431.0961 (M+H)+、453.0862(M+Na)+；MS
(Negtive Ion Mode ESI): m/z=429.0893 (M-H)-。
1H NMR (500MHz, CDCl3): δ 8.9588 (1H, s), 8.5792 (1H, s), 8.4645-8.4509 (1H, d, J=
6.80Hz), 7.0844-7.0673 (2H, d, J=8.55Hz), 6.6678-6.6507 (2H, d, J=8.55Hz), 3.7129-
3.6854 (4H, m), 3.6480-3.6075 (4H, m), 3.4254-3.3862 (2H, m), 2.6239-2.5585 (2H, m),
1.9371-1.5651 (2H, m).
The liquid chromatogram of 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001)
Figure is as shown in figure 3, purity: 98.94%.Chromatographic condition: chromatographic column: C18 column (5 μm, 150mm × 5mm)；Mobile phase: CH3CN∶
Water (contains 0.2%CF3COOH)=55: 45；Detection wavelength: 258nm；Flow velocity: 1.0ml/min；Sample volume: 5 μ L；Column temperature: 40
℃。
2. 1- of embodiment { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001)
Synthesis
(1) synthesis of 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol based isocyanate
Reaction equation is shown below:
Into 100mL round-bottomed flask, 1.0g Chlorambucil (3.287mmol) and 5ml acetone is added, stirring keeps its molten
0.365g (3.616mmol) triethylamine is added in solution, and ice salt bath is cooled to 0 to -5 DEG C, then 0.392g is slowly added dropwise into solution
The solution of the acetone (2ml) of (3.616mmol) ethyl chloroformate after dripping off, continues stirring 30 minutes at 0 to -5 DEG C.Then,
The aqueous solution (1.5ml) of the sodium azide of 0.427g (6.574mmol) is slowly added dropwise into solution, continues to stir at 0 to -5 DEG C
It mixes 30 minutes.Into solution be added 30ml ice water, pour the mixture into separatory funnel, in four times be added 50ml toluene to divide
Reaction product, combining methylbenzene phase are extracted in liquid funnel, toluene extract liquor is dried, filtered with anhydrous magnesium sulfate, is heated to reflux toluene
Solution 1 hour, vacuum distillation removed toluene, and chromatography is stationary phase, methylene chloride and petroleum ether with 200-300 mesh silica gel
Mixed liquor is leacheate, obtains the colourless liquid 0.69g of 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol based isocyanate, produces
Rate 69.0%.
(2) synthesis of 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001)
It is same as Example 1.
3. 1- of embodiment { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001)
Synthesis
(1) synthesis of 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol based isocyanate
Reaction equation is shown below:
1.0g (3.287mmol) Chlorambucil, 30ml chloroform and 2-3 drop DMF are added in the flask of 100ml, stirs,
0.782g (6.616mmol) thionyl chloride (MW:119) is stirred at room temperature 4 hours under nitrogen protection, at back flow reaction 1 hour, subtracts
Pressure removes solvent and superfluous thionyl chloride, obtains 4- [two (2- chloroethyl) amino] benzene butyl chloride (A).
0.321g (4.950mmol) sodium azide, 10ml anhydrous tetrahydro furan are added in the flask of 100ml, heating is stirred
It mixes to reflux.4- obtained above [two (2- chloroethyl) amino] benzene butyl chloride is dissolved in the tetrahydrofuran of 10ml and constant pressure is added
In dropping funel, start that the tetrahydrofuran that 4- [two (2- chloroethyl) amino] benzene butyl chloride is dissolved in 10ml is added dropwise after thering is reflux to occur
Reflux 2h is added dropwise in solution.It being cooled to room temperature, solvent is removed under reduced pressure, chromatography is stationary phase with 200-300 mesh silica gel,
Methylene chloride and petroleum ether mixed liquor are leacheate, obtain the nothing of 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol based isocyanate
Color liquid 0.49g, yield 49.0%.
(2) synthesis of 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001)
It is same as Example 1.
The preparation of 4. anti-cancer drug compounds of embodiment (YY-001), including tablet, capsule, emulsion, micellar, lipid
Body agent and paste ingredient
In the present embodiment, tablet, capsule, emulsion, micellar, liposome including anti-cancer drug compounds (YY-001)
Agent and paste ingredient.
1) 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001) capsule
((wet granulation)
After the YY-001 of recipe quantity is mixed with the sodium starch glycollate of recipe quantity, lactose and magnesium stearate, prescription is added
Wet granulation is carried out after the Tween 80 aqueous solution of amount, wet stock obtained is in fluidized bed, basin or other appropriate driers
It is dry, it is mixed by the particle grinding after drying to suitable particle diameter distribution, then with other components of recipe quantity, finally by mixture
It is fitted into two panels hard gelatin capsule shell.
| Component | The content (mg) of every capsule | The percentage composition (%) of every component |
| YY-001 | 25 | 25 |
| Tween 80 | 2.5 | 2.5 |
| Lactose | 25 | 25 |
| Magnesium stearate | 2.5 | 2.5 |
| Sodium starch glycollate | 45 | 45 |
| Every total capsule weight amount | 100 |
2) 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001) tablet is (wet
Method granulation)
The lauryl sodium sulfate aqueous solution of recipe quantity and YY-001, sodium starch glycollate, the magnesium stearate of recipe quantity
It pelletizes with microcrystalline cellulose, wet stock obtained is dry in fluidized bed, basin or other appropriate driers, after drying
Grain is milled to required particle diameter distribution, then that mixture is tabletted.
| Component | Every content (mg) | The percentage composition (%) of every component |
| YY-001 | 30 | 47.7 |
| Lauryl sodium sulfate | 1.5 | 2.4 |
| Lactose | 4.5 | 7.1 |
| Magnesium stearate | 3 | 4.8 |
| Sodium starch glycollate | 12 | 19.0 |
| Microcrystalline cellulose | 12 | 19.0 |
| Every total capsule weight amount | 63 |
3) 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001) tablet is (dry
Method granulation)
YY-001 raw material is pulverized and sieved first, controls partial size less than 80 μm, then by the YY-001 of recipe quantity and micro mist silicon
Glue mixes, and the starch, sucrose, croscarmellose sodium of recipe quantity is added, and mixes, dry granulation, and after granulation, prescription is added
The magnesium stearate of amount mixes, tabletting, film coating.
| Component | Every content (mg) | The percentage composition (%) of every component |
| YY-001 | 10 | 50 |
| Starch | 5 | 25 |
| Sucrose | 1.5 | 7.5 |
| Croscarmellose sodium | 1.5 | 7.5 |
| Superfine silica gel powder | 1.5 | 7.5 |
| Magnesium stearate | 0.5 | 2.5 |
| Every total capsule weight amount | 20 |
4) 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001) emulsion
YY-001 is dissolved in the mixture of soya-bean oil, Tween 80 and polyethylene glycol PEG (200), adds deionized water (DI
Water), then stirring and ultrasonic emulsification or emulsified with homogenizer, the composition of emulsion produced is as follows:
Manufactured emulsion drug is reloaded into sterile vial by the filter filtering in 0.2 micron of an aperture.
5) 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001) emulsion
YY-001 is dissolved in D- alpha-tocopherol acetate, D- alpha-tocopherol cetomacrogol 1000 succinate (TPGS) and gathers
In the mixture of ethylene glycol PEG (200), deionized water (DI water) is added, then stirring and ultrasonic emulsification or uses homogeneous
Machine emulsification, the composition of emulsion produced are as follows:
Manufactured lotion drug is reloaded into sterile vial by the filter filtering in 0.2 micron of an aperture.
6) micellar of 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001)
YY-001 is dissolved in 1000 succinate of D-d- tocopherol polyethyleneglycol (TPGS), ethyl alcohol and polyethylene glycol PEG
(200) a transparent liquid is obtained in mixture, suitable physiological saline is added before use, and then stirring and ultrasound are stirred
It mixes, obtains a supernatant liquid, the composition of micellar produced is as follows:
Manufactured micellar drug is filtered by the filter in 0.2 micron of an aperture, spare.
7) 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001) micellar
YY-001 is dissolved in the mixed of Emulsifier EL-60 EL (Cremophor EL), ethyl alcohol and polyethylene glycol PEG (200)
It closes in object and obtains transparent liquid, suitable deionized water (DI water) is added before use, then stir and be stirred by ultrasonic,
A supernatant liquid is obtained, the composition of micellar produced is as follows:
Manufactured micellar drug is filtered by the filter in 0.2 micron of an aperture, spare.
8) 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001) micellar
YY-001 is dissolved in the mixed of Emulsifier EL-60 EL (Cremophor EL), ethyl alcohol and polyethylene glycol PEG (200)
It closes in object and obtains transparent liquid, suitable deionized water (DI water) is added before use, then stir and be stirred by ultrasonic,
A supernatant liquid is obtained, the composition of micellar produced is as follows:
Manufactured micellar drug is filtered by the filter in 0.2 micron of an aperture, spare.
9) 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001) micellar
YY-001 be dissolved in the mixture of Tween 80 (Tween 80), ethyl alcohol and polyethylene glycol PEG (200) obtain it is transparent
Liquid, suitable deionized water (DI water) is added before use, then stir and be stirred by ultrasonic, obtain a supernatant liquid,
The composition of micellar produced is as follows:
Manufactured micellar drug is filtered by the filter in 0.2 micron of an aperture, spare
10) 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001) liposome
Agent
In a round-bottomed flask, by 100 milligrams of YY-001,1600 milligrams of phosphatide (lecithin, phosphatidyl choline) and
110 milligrams of cholesterol is dissolved in the chloroform (CHCl of 15mL3), 40 DEG C are slowly heated to, is evaporated under reduced pressure with Rotary Evaporators molten
Agent forms one layer of thin lipid film, is dried in vacuum overnight, and further removes the chloroform in lipid film, 5% sucrose of 50ml is added
Then solution is stirred and is stirred by ultrasonic, gained liposome liquid is reloaded into nothing by the filter filtering in 0.2 micron of an aperture
The vial of bacterium is freezed with dry ice and acetone, is then freeze-dried 24 hours, and 1- { 3- [p- double-(2- chloroethyl) amido] is obtained
Phenylpropyl } formyl -5-fluor-uracil Liposomal agents.
11) 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil (YY-001) paste
It takes appropriate YY-001, stearic acid, glycerin monostearate, atoleine, polyethylene glycol 200 (PEG 200), spit
- 80 heating fusing of temperature；Separately qs glycerin, water is taken to be heated to 70-80 DEG C, is added under stiring into oily phase, continue stirring at
The composition of type, paste produced is as follows:
5. anti-cancer drug compounds YY-001 of embodiment tests the inhibiting effect of animal transplanting tumor H22
1) experimental method
ICR mouse is taken, by transplanted tumor organon, solid type tumor is inoculated with and (takes tumor mass under sterile working, weigh, use
Glass tissue homogenizer grinding, grind it is even after be put into sterile chamber, add normal saline dilution at 1: 3 cell suspension, container sets
On ice cube, aspirated with empty needle, every time mix cell before suction, every mouse right fore armpit inoculates 0.2ml), inoculation
24 hours title mouse weights afterwards, and it is randomly divided into 4 groups.Each administration group (d after inoculation 24 hours1) be administered for the first time.Equal stomach-filling is given
Medicine 1 time/1 day, is administered 7 times altogether.Administered volume is 0.2ml/20g.The 8th day (d after inoculation8) put to death tumor-bearing mice claim
Weight, and tumor mass weighing is separated, the data obtained carries out statistical procedures (t inspection).
2) dosage is arranged
4 groups are set altogether
3) experimental result
1. drug of table is to mice-transplanted tumor H22 inhibiting effect
The * P < 0.01 compared with model control group
4) experiment conclusion
The result shows that compared with model control group, YY-001 62.5mg/kg dosage group, YY-001 31.25mg/kg agent
Amount group, capecitabine group 500mg/kg have extremely significant property growth inhibition effect (P < 0.01) to H22 tumour, and YY-001 is to swollen
The inhibitory effect of tumor growth is apparently higher than positive control drug capecitabine；After administration, YY-001 62.5mg/kg dosage group, YY-
001 31.25mg/kg dosage group has extremely significant property body weight increase inhibiting effect (P < 0.01) to experimental mouse.YY-001 is to experiment
Mouse body weight increase inhibiting effect is bigger than capecitabine.
6. anti-cancer drug compounds YY-001 of embodiment tests the inhibiting effect of animal transplanting tumor S180
1) experimental method
ICR mouse is taken, by transplanted tumor organon, ascites tumor is inoculated with and (takes ascites under sterile working, physiological saline is dilute
It is interpreted into proper proportion, prepares cell suspension, container is set on ice cube, is aspirated with empty needle, every time mixes cell before suction, every small
Mouse right fore armpit inoculates 0.2ml, 24 hours title mouse weights after inoculation, and is randomly divided into 4 groups.Each administration group is small in inoculation 24
When after (d1) be administered for the first time.Equal gastric infusion 1 time/1 day, is administered 9 times altogether.Administered volume is 0.2ml/20g.In inoculation
11st day (d afterwards10) tumor-bearing mice weighing is put to death, and tumor mass weighing is separated, the data obtained carries out statistical procedures (t inspection).
2) dosage is arranged
5 groups are set altogether
3) experimental result
2. drug of table is to mice-transplanted tumor S180 inhibiting effect
The * P < 0.01 compared with model group
4) experiment conclusion
The result shows that positive drug capecitabine has extremely significant property growth inhibition to S180 mouse tumour compared with model group
It acts on (P < 0.01), YY-001 30.00mg/kg dosage group, 15.00mg/kg dosage group, 0.75mg/kg dosage group are to S180
Mouse tumour all has extremely significant property growth inhibition effect (P < 0.01)；Compared with model group, YY-001 30mg/kg dosage group is removed
There is more apparent inhibiting effect (P < 0.05) outside to mouse body weight increase, other groups are to mouse body weight increase without obvious inhibiting effect.
Claims (7)
1. compound 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5- fluorine with formula (I) molecular structure
Urea pyrimidine:
2. a kind of compound 1- described in claim 1 { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5- fluorine
The preparation method of urea pyrimidine, comprising the following steps:
(1) synthesis of 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol based isocyanate
[bis- (2- chloroethyl) amino] benzenebutanoic acid of method one: 4- and diphenyl phosphate azide carry out azido reaction, generate 4-
[p- double-(2- chloroethyl) amido] benzene bytyry nitrine, 4- [p- double-(2- chloroethyl) amido] benzene bytyry nitrine is through Ku Er
This rearrangement reaction is proposed, 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol based isocyanate is generated；
Method two: 4- [bis- (2- chloroethyl) amino] benzenebutanoic acid is reacted with chloride reagent, generates 4- [p- double-(2- chloroethene
Base) amido] benzene butyl chloride, then with reaction of sodium azide, generate 3- [p- double-(2- chloroethyl) amine through Ku Ertisi rearrangement reaction
Base] phenylpropyl alcohol based isocyanate；
Method three: 4- [bis- (2- chloroethyl) amino] benzenebutanoic acid is reacted with ethyl chloroformate, generation ethyoxyl formic acid 4- [p- pair-
(2- chloroethyl) amido] benzenebutanoic acid acid anhydride, then with reaction of sodium azide, generate 3- [p- double-(2- chlorine through Ku Ertisi rearrangement reaction
Ethyl) amido] phenylpropyl alcohol based isocyanate；Or
[bis- (2- chloroethyl) amino] the benzenebutanoic acid ester of method four: 4- and hydrazine reaction generate 4- [p- double-(2- chloroethyl) amido]
Benzene daminozide, then reacted with sodium nitrite, 4- [p- double-(2- chloroethyl) amido] benzene bytyry nitrine is generated, then mention through Ku Er
This rearrangement reaction generates 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol based isocyanate；
(2) 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil synthesis
3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol based isocyanate is reacted with 5 FU 5 fluorouracil, in the presence of alkali generationization
Close object 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil.
3. compound 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5- fluorine according to claim 1
Urea pyrimidine is preparing the application in anticancer drug.
4. application according to claim 3, which is characterized in that the cancer include the cancer of hematological system, solid tumor cancer,
Sarcoma, cutaneum carcinoma or glioma.
5. application according to claim 4, which is characterized in that the cancer includes leukaemia, lymthoma, myeloma, cream
Gland cancer, oophoroma, cancer of pancreas, colon and rectum carcinoma, non-small cell lung cancer, bladder cancer, gastric cancer, liver cancer, sarcoma, cutaneum carcinoma or
Glioma.
6. a kind of antineoplastic pharmaceutical compositions, which is characterized in that the pharmaceutical composition includes the 1- { 3- of effective therapeutic dose
[p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil and pharmaceutically acceptable auxiliary material.
7. antineoplastic pharmaceutical compositions according to claim 6, which is characterized in that described pharmaceutical composition is tablet, glue
Wafer, emulsion, micellar, liposome or paste.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN111825601A (en) * | 2019-04-22 | 2020-10-27 | 杭州珠联医药科技有限公司 | Method for continuously preparing pimavanserin by using microchannel reactor |
| CN113979954A (en) * | 2021-11-12 | 2022-01-28 | 南京友怡医药科技有限公司 | Teninil antitumor drug compound and preparation method and application thereof |
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| CN111040014A (en) * | 2019-12-27 | 2020-04-21 | 苏州络森生物科技有限公司 | Preparation method of CHAPSO |
| CN113979954A (en) * | 2021-11-12 | 2022-01-28 | 南京友怡医药科技有限公司 | Teninil antitumor drug compound and preparation method and application thereof |
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| CN109384730B (en) | 2022-02-18 |
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