CN109384776A - A kind of 5-fluor-uracil derivative and its preparation method and application - Google Patents
A kind of 5-fluor-uracil derivative and its preparation method and application Download PDFInfo
- Publication number
- CN109384776A CN109384776A CN201710680247.6A CN201710680247A CN109384776A CN 109384776 A CN109384776 A CN 109384776A CN 201710680247 A CN201710680247 A CN 201710680247A CN 109384776 A CN109384776 A CN 109384776A
- Authority
- CN
- China
- Prior art keywords
- dithiolane
- cancer
- formyl
- fluor
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of antineoplastic compounds with Formulas I structure: 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil and preparation method thereof.Contain the lipoic acid structure to cell with stronger penetrating power in medical compounds molecule of the present invention, simultaneously containing the 5 FU 5 fluorouracil front body structure that can inhibit deoxythymidine acid enzyme, molecule metabolite 5 FU 5 fluorouracil can inhibit and kill cancer cell, with good anticancer activity, it 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 5-fluor-uracil derivatives, more particularly to a kind of compound 1- { 4- [3- (1,2- bis- sulphur
Heterocycle pentane)]-butylamine base } formyl -5-fluor-uracil and preparation method thereof, and as the application of 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 the exception that is formed
Lesion shows as cell hyperproliferation, disdifferentiation.Cancer has become first cause of the death of the mankind at present, constitutes most to human survival
Serious threat.
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.
Nucleoside analog is a kind of antimetabolite anti-tumor drug, is to utilize bioisosterism, will be in DNA replication dna
The structure of the units substance such as required purine nucleosides, pyrimidine nucleoside is made chemical modification and is obtained, and after intracellular triphosphoric acid, passes through
Inhibit to interfere cellular replication, Reverse transcriptase DNA in synthesis, incorporation DNA or the RNA molecule of deoxynucleoside triphosphate (dNTPs)
The effects of polymerase, the metabolism of specific interfering nucleic acid prevent the division and breeding of cell, eventually lead to death of neoplastic cells.
Nucleosides series antineoplastic medicament includes: 1. guanosine analogue, such as guanosint glycoside drug nelarabine (nelarabine)；2. adenosine
Analog, such as fludarabine (fludarabine), Cladribine (cladribine) and clofarabine (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 is similar
Object, such as cytarabine (cytarabine, ara-C), gemcitabine (gemcitabine), azacitidine (azacitidine, 5-
) and Decitabine (decitabine) AC.Nucleosides series antineoplastic medicament acts as important function in terms for the treatment of tumour.
According to the literature, many cancer treatment drugs unsatisfactory curative effects, one of reason are that these drugs can not seep
Enter the hyperbaric environment inside solid tumor, it is to lead to cancer that hyaluronic acid, which can lead to inside tumor and form gluey liquid pressure environment,
Major reason that drug can not penetrate into (Christopher C.DuFort et al, Biophysical Journal 110,
2106-2119, May 10,2016.).Lipoic acid (alpha lipoic acid) is a kind of enzyme for being present in mitochondria, similar
Vitamin, lipoic acid contain double sulphur five-membered ring structures, and electron density is very high, it is easy to carry out redox reaction, lipoic acid exists
Enter cell after intestinal absorption in vivo, have both fat-soluble and water-soluble characteristic, therefore can go everywhere without any hindrance here in whole body, reaches
Any one cell area.
Summary of the invention
The purpose of the present invention is to provide a kind of 5-fluor-uracil derivatives, by lipoic acid and medicine with anti-tumor activity
A kind of new medical compounds molecule is made in object molecule, improves drug molecule to the penetrating power of cancer cell, to improve to cancer
The inhibiting effect of cell.The chemical name of the compound are as follows: 1- { 4- [3- (1,2- dithiolane)]-butylamine base } first
Acyl -5-fluor-uracil, the chemical structure with Formulas I:
The antineoplastic compounds (Formulas I, hereinafter referred to as compound YY-003) can be prepared by the following method:
1) synthesis of 4- [3- (1,2- dithiolane)]-butyl isocyanate.
Method one: (±) -5- [3- (1,2- dithiolane)]-valeric acid (lipoic acid) and diphenyl phosphate azide
(DPPA) azido reaction is carried out, (±) -5- [3- (1,2- dithiolane)]-valeryl nitrine, (±) -5- [3- are generated
(1,2- dithiolane)]-valeryl nitrine releasing nitrogen, through Ku Ertisi rearrangement reaction (Curtius rearrangement), generation 4-
[3- (1,2- dithiolane)]-butyl isocyanate.
One preferred embodiment of above-mentioned reaction is (±) -5- [3- (1,2- dithia ring penta under nitrogen protection
Alkane)]-valeric acid is dissolved in toluene, appropriate powdered 4A molecular sieve is added, add diphenyl phosphate azide (DPPA) and in right amount
Dry triethylamine, is stirred at room temperature, obtains 4- [3- (1,2- dithiolane)]-butyl isocyanate.
Method two: (±) -5- [3- (1,2- dithiolane)]-valeric acid is reacted with chloride reagent, generates (±) -5-
[3- (1,2- dithiolane)]-valeric chloride, then with reaction of sodium azide, through Ku Ertisi rearrangement reaction (Curtius reset
Reaction) generate 4- [3- (1,2- dithiolane)]-butyl isocyanate.Above-mentioned chloride reagent is commonly used in the art
Chloride 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, (±) -5- [3- (1,2- dithiolane)]-valeric acid reacts 2-10 hours at room temperature with thionyl chloride and obtains (±) -
5- [3- (1,2- dithiolane)]-valeric chloride, then with reaction of sodium azide, through Ku Ertisi rearrangement reaction (Curtius weight
Row's reaction) generate 4- [3- (1,2- dithiolane)]-butyl isocyanate.
Method three: (±) -5- [3- (1,2- dithiolane)]-valeric acid is reacted with ethyl chloroformate, generates ethyoxyl
Formic acid (±) -5- [3- (1,2- dithiolane)]-valeric anhydride, then with reaction of sodium azide, through Ku Ertisi rearrangement reaction
(Curtius rearrangement reaction) generates 4- [3- (1,2- dithiolane)]-butyl isocyanate.
Method four: (±) -5- [3- (1,2- dithiolane)]-valerate (preferably ethyl ester or methyl esters) and hydrazine reaction,
(±) -5- [3- (1,2- dithiolane)]-valeryl hydrazine is generated, then is reacted with sodium nitrite, (±) -5- [3- (1,2- is generated
Dithiolane)]-valeryl nitrine, then through Ku Ertisi rearrangement reaction (Curtius rearrangement reaction), generate 4- [3- (1,
2- dithiolane)]-butyl isocyanate.
2) 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil synthesis
4- [3- (1,2- dithiolane)]-butyl isocyanate is reacted with 5 FU 5 fluorouracil, is given birth in the presence of alkali
At compound 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil.
Above-mentioned alkali is preferably organic base, such as triethylamine, pyridine, 4-dimethylaminopyridine (DMAP).
One preferred embodiment is that 4- [3- (1,2- dithiolane)]-butyl isocyanate is dissolved in dry pyrrole
In pyridine, suitable 4-dimethylaminopyridine (DMAP) and 5 FU 5 fluorouracil is added, heats, stirring to reaction is completed.
The reaction route schematic diagram of the method for the invention is shown below:
Another object of the present invention, which also resides in, provides antineoplastic compounds 1- { 4- [3- (1, the 2- dithia ring penta
Alkane)]-butylamine base } formyl -5-fluor-uracil (YY-003) preparing the application in anticancer drug.The medical compounds is used for
Anticancer drug is prepared, cancer includes but is not limited to the cancer of 1. hematological system, such as leukaemia, lymthoma, myeloma；2. non-blood
Cancer, such as solid tumor cancer (such as breast cancer, oophoroma, cancer of pancreas, colon and rectum carcinoma, non-small cell lung cancer, bladder cancer, stomach
Cancer, liver cancer etc.), sarcoma, cutaneum carcinoma and glioma etc..
Further, based on the antineoplastic compounds (YY-003), the present invention provides a kind of anti-tumor drug,
It is characterized in that, the drug includes 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl-of effective therapeutic dose
5-fluor-uracil and pharmaceutically acceptable auxiliary material.
The compound of the present invention 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil molecule
In containing the lipoic acid structure to cell with stronger penetrating power, simultaneously containing can inhibit the 5- fluorine of deoxythymidine acid enzyme
Uracil front body structure, molecule metabolite 5 FU 5 fluorouracil can inhibit and kill cancer cell, antitumor action with higher.
The anti-tumor drug can be oral preparation, injection or external preparation, including tablet, capsule, lipid
The formula such as body agent, emulsion or micro emulsion liquor, micellar and paste.Tablet includes neoteric anti-cancer drug compounds and auxiliary material.
Capsule includes neoteric anti-cancer drug compounds and auxiliary material.Liposomal agents include neoteric anti-cancer drug compounds, phosphorus
Rouge (most representational is lecithin, soybean lecithin), cholesterol and water phase.Emulsion includes neoteric anticarcinogen materialization
Close object, one or more surfactants, oily phase (lipophilic medium) and water phase.Emulsion can be oil-in-water type or Water-In-Oil
Type.Micellar includes neoteric anti-cancer drug compounds, cosolvent and one or more surfactants and water phase.Paste is matched
Side 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-003；
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-003；
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-003；
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-003；
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-003；
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-003；
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 includes
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), polyethylene glycol phosphatide
(pegylated phospholipids)。
3) polyethylene glycol vitamin e derivative, such as Vitamin E succinate polyethylene glycol (d- α-tocopherol
Polyethylene glycol 1000 succinate, 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..
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 YY-003 and auxiliary material of the invention.It is described
The contents in every of anti-cancer drug compounds can be 1 milligram to 1000 milligrams, anticancer drug chemical combination in preferred scheme
Content of the object in every is 5 milligrams to 500 milligrams；In preferred scheme, content of the anti-cancer drug compounds in every
It is 10 milligrams to 250 milligrams.
The capsule of the anti-cancer drug compounds includes anti-cancer drug compounds of the invention (YY-003) and auxiliary material.
The content in every capsule of the anti-cancer drug compounds can be 1 milligram to 1000 milligrams, anticancer in preferred scheme
Content of the medical compounds in every capsule is 5 milligrams to 500 milligrams；In preferred scheme, anti-cancer drug compounds exist
Content in every is 10 milligrams to 250 milligrams.
In the emulsion or microemulsion of the anti-cancer drug compounds (YY-003), anti-cancer drug compounds are in pharmaceutical formulation
In account for 0.005% to 5.0%；It is preferred that the weight hundred that anti-cancer drug compounds are shared in pharmaceutical formulation
Divide than being 0.01% to 2.5%；In preferred scheme, anti-cancer drug compounds weight percent shared in pharmaceutical formulation
It is 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.
" 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.
The micellar preparation of the anti-cancer drug compounds includes anti-cancer drug compounds YY-003, Yi Zhonghuo of the invention
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 0% of formulation weight
To 20%.
The Liposomal agents of the anti-cancer drug compounds include anti-cancer drug compounds YY-003, Yi Zhonghuo of the invention
A variety of phosphatide (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, water phase includes that sucrose is molten
Liquid；In another embodiment, water phase includes glucose solution；In another embodiment, containing a kind of sour (such as amber in water phase
Acid, citric acid, phosphoric acid) buffer.
The paste of the anti-cancer drug compounds includes anti-cancer drug compounds of the invention, one or more matrix.
The weight percentage of medical compounds YY-003 is about in the paste of the anti-cancer drug compounds
0.01% to 30%, the weight percentage of preferred agents compound in formula is about 0.05% to 20%；It is further preferred that drug
Weight percentage is about 0.1% to 10% to compound in formula.
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 of cancer cells by 50% inhibits
The drug concentration of 50% experimental subjects growth).Usually median lethal dose (LD50)/effective dose 50 (ED50) ratio is claimed
For therapeutic index, 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.
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), meter Tuo
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), estradiol (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), benzene
Butyric acid mustargen (chlorambucil) and phosphinothioylidynetrisaziridine (thiotepa)；Steroids, such as betamethasone (betamethasone)；With
Other anti-tumor drugs, such as cattle on the hoof mycobacteria (live Mycobacterium bovis), Dacarbazine
(dicarbazine), asparaginase (asparaginase), formyl tetrahydrofolic acid (leucovorin), mitotane
(mitotane), vincristine (vincristine), vincaleukoblastinum (vinblastine) and Docetaxel (taxotere) etc..
The present invention will be described in detail combined with specific embodiments below.Protection scope of the present invention is not with specific implementation
Mode is limited, but is defined in the claims.
Detailed description of the invention
Fig. 1 is that 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003) nuclear-magnetism is total
Shake hydrogen spectrogram.
Fig. 2 is 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003) 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 phase of 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003)
Chromatogram.
Influence of Fig. 4 YY-003 to human liver cancer cell Huh7 nude mouse xenograft tumor relative tumour volume.
Influence of Fig. 5 YY-003 to human liver cancer cell Huh7 nude mouse xenograft tumor knurl weight.
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 { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003)
Synthesis
(1) synthesis of 4- [3- (1,2- dithiolane)]-butyl isocyanate
Reaction equation is shown below:
Experimental procedure:
Into 100mL round-bottomed flask, the toluene of 1.0g (4.85mmol) lipoic acid and 10ml drying is added, stirring keeps its molten
Solution is added the powdered 4A molecular sieve of 0.4g, then 2.105g (7.65mmol) diphenyl phosphate azide is added into solution
(DPPA) (about 2 hours) are completed, are added into reaction solution with the triethylamine of 0.773g (7.65mmol), at room temperature stirring extremely reaction
The saturation NaHCO of about 30ml3Aqueous solution stirs 2-3 minutes, and ethyl acetate (30ml × 3) extraction is added and three times, is harmonious organic
And use anhydrous Na2SO4Dry, chromatography is stationary phase with 200-300 mesh silica gel, and methylene chloride and petroleum ether mixed liquor are
Leacheate obtains colourless liquid 0.60g, yield 60.8%.
1H NMR (400MHz, CDCl3): δ ppm:3.60-3.56 (m, 1H), 3.34-3.31 (t, J=6Hz, 2H), 3.23-
3.10 (m, 2H), 2.52-2.44 (m, 1H), 1.97-1.90 (m, 1H), 1.72-1.52 (m, 6H).
(2) synthesis of 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003)
Reaction equation is shown below:
Into 50mL round-bottomed flask, 4- [3- (1,2- dithiolane)]-butyl of 0.300g (1.476mmol) is added
The 4-dimethylaminopyridine of isocyanates, the dry pyridine of 5ml, the 5 FU 5 fluorouracil of 0.192g (1.476mmol) 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 0.30g, yield 73.2%.Product
Nuclear magnetic resonance spectroscopy and mass spectrogram such as Fig. 1 and Fig. 2.
MS (Positive Ion mode ESI): m/z=356.0494 (M+Na)+；MS(Negative Ion mode
ESI): m/z=332.0600 (M-H)-。
1H NMR (500MHz, CDCl3): δ 9.0027 (1H, s), 8.6326 (1H, s), 8.4795-8.4751 (1H, d, J=
6.72Hz), 3.6160-3.5254 (1H, m), 3.4424-3.3775 (2H, m), 3.2288-3.0752 (2H, m), 2.5201-
2.4157 (1H, m), 1.9734-1.8624 (1H, m), 1.7634-1.4485 (6H, m).
The liquid chromatogram of 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003)
Figure is as shown in figure 3, purity: 99.431%.Chromatographic condition: chromatographic column: C18 column (5 μm, 150mm × 5mm)；Mobile phase: CH3CN:
Water (containing 0.1%CF3COOH)=40:60；Detection wavelength: 220nm；Flow velocity: 1.0ml/min；Sample volume: 5 μ L；Column temperature: 40 DEG C.
2. 1- of embodiment { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003)
Synthesis
(1) synthesis of 4- [3- (1,2- dithiolane)]-butyl isocyanate
Reaction equation is shown below:
Into 100mL round-bottomed flask, 1.0g (4.85mmol) lipoic acid and 5ml acetone is added, stirs to dissolve, is added
0.539g (5.335mmol) triethylamine, ice salt bath is cooled to 0 to -5 DEG C, then 0.578g 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 (2ml) of the sodium azide of 0.630g (9.70mmol) is slowly added dropwise into solution, continues stirring 30 at 0 to -5 DEG C
Minute.30ml ice water is added into solution, pours the mixture into separatory funnel, 50ml toluene is added in four times to separatory funnel
Middle extraction reaction product, combining methylbenzene phase, toluene extract liquor are dried, filtered with anhydrous magnesium sulfate, and it is small to be heated to reflux toluene solution 1
When, vacuum distillation removes toluene, and chromatography is stationary phase with 200-300 mesh silica gel, and methylene chloride and petroleum ether mixed liquor are
Leacheate obtains 4- [3- (1,2- dithiolane)]-butyl isocyanate colourless liquid 0.56g, yield 57.01%.
(2) synthesis of 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003)
It is same as Example 1.
3. 1- of embodiment { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003)
Synthesis
(1) synthesis of 4- [3- (1,2- dithiolane)]-butyl isocyanate
Reaction equation is shown below:
1.0g (4.85mmol) lipoic acid, 30ml chloroform and 2-3 drop DMF are added in the flask of 100ml, stirs,
1.150g (9.7mmol) thionyl chloride (MW:119) is stirred at room temperature 4 hours under nitrogen protection, at back flow reaction 1 hour, decompression
Solvent and superfluous thionyl chloride are removed, 4- [3- (1,2- dithiolane)]-valeric chloride is obtained.
It is added in the flask of 100ml plus 0.630g (9.70mmol) sodium azide, 10ml anhydrous tetrahydro furan, heating is stirred
It mixes to reflux.4- obtained above [3- (1,2- dithiolane)]-valeric chloride is dissolved in tetrahydrofuran and the addition of 10ml
In constant pressure funnel, starts dropwise addition 4- [3- (1,2- dithiolane)]-valeric chloride after thering is reflux to occur and be dissolved in 10ml's
Reflux 2h is added dropwise in tetrahydrofuran solution.It is cooled to room temperature, depressurizes away solvent, chromatography, with 200-300 mesh silica gel
For stationary phase, methylene chloride and petroleum ether mixed liquor are leacheate, obtain 4- [3- (1,2- dithiolane)]-butyl isocyanide
Acid esters colourless liquid 0.52g, yield 53.0%.
(2) synthesis of 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003)
It is same as Example 1.
The preparation of 4. anti-cancer drug compounds of embodiment (YY-003), including tablet, capsule, emulsion, micellar, lipid
Body agent and paste ingredient
In the present embodiment, tablet, capsule, emulsion, micellar, Liposomal agents and paste including anti-cancer drug compounds
Formula.Contain anti-cancer drug compounds of the invention in tablet, capsule, emulsion, micellar, Liposomal agents and paste ingredient
YY-003。
1) 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003) capsule
((wet granulation)
After the YY-003 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.
2) 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003) tablet (wet process
Granulation)
The lauryl sodium sulfate aqueous solution of recipe quantity and YY-003, 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-003 | 300 | 50 |
| Lauryl sodium sulfate | 12 | 2 |
| Lactose | 42 | 7 |
| Magnesium stearate | 6 | 1 |
| Sodium starch glycollate | 120 | 20 |
| Microcrystalline cellulose | 120 | 20 |
| Every total capsule weight amount | 600 |
3) 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003) tablet (dry method
Granulation)
YY-003 raw material is pulverized and sieved first, controls partial size less than 80 μm, then by the YY-003 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-003 | 100 | 50 |
| Starch | 52 | 26 |
| Sucrose | 15 | 7.5 |
| Croscarmellose sodium | 15 | 7.5 |
| Superfine silica gel powder | 15 | 7.5 |
| Magnesium stearate | 3 | 1.5 |
| Every total capsule weight amount | 200 |
4) 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003) emulsion
YY-003 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- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003) emulsion
YY-003 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- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003)
YY-003 is dissolved in D- alpha-tocopherol cetomacrogol 1000 succinate (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- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003) micellar
YY-003 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- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003) micellar
YY-003 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 5% glucose injection is added before use, then stir and be stirred by ultrasonic, obtain
The composition of one supernatant liquid, micellar produced is as follows:
Manufactured micellar drug is filtered by the filter in 0.2 micron of an aperture, spare.
9) 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003) micellar
YY-003 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- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003) Liposomal agents
In a round-bottomed flask, by 100 milligrams of YY-003,1600 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, obtain 1- 4- " 3- (1,2- dithiolane)]-
Butylamine base } formyl -5-fluor-uracil Liposomal agents.
11) 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil (YY-003) paste
It takes appropriate YY-003, 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-003 of embodiment is to human liver cancer cell Huh7 nude mouse xenograft tumor growth inhibition
Act on pharmacodynamic experiment
1) experimental method
The human liver cancer Huh7 cell strain of logarithmic growth phase, is aseptically prepared into 5 × 10 afterwards6/ ml cell suspension,
It is subcutaneous that armpit on the right side of nude mouse is inoculated in 0.1ml.Nude Mice vernier caliper measurement transplantable tumor diameter, it is raw to tumour
It grows to 100~300mm3Animal is grouped at random afterwards.Using the method for measurement knurl footpath, dynamic observation is tested the effect of drugs against tumor
It answers.Diameter of tumor is measured as surveying 1 time for every 2 days.Administered volume is 0.2ml/20g.After 12 days, mouse is put to death, and operation strips tumor
Block weighing.
The calculation formula of gross tumor volume (tumor volume, TV) are as follows:
TV=1/2 × a × b2
Wherein a, b respectively indicate length and width.
Relative tumour volume (relative tumor volume, RTV), calculation formula are calculated according to the result of measurement
Are as follows:
RTV=Vt/V0
Wherein V0(d when for sub-cage administration0) measurement gained gross tumor volume, VtGross tumor volume when to measure each time.
The evaluation index of anti-tumor activity is Relative tumor proliferation rate T/C (%), and calculation formula is as follows:
TRTV: treatment group RTV；CRTV: negative control group RTV.
Tumour inhibiting rate calculation formula is as follows:
Tweight: treatment group's average knurl weight；Cweight: negative control group average knurl weight.
2) experimental result
Drug YY-003 the results are shown in Table 1 and Fig. 4 to the experimental treatment of human liver cancer cell Huh7 Nude Mice.Experiment
As a result as follows, YY-003 was administered once with 278mg/kg gastric infusion, every 2 days, naked to human liver cancer cell Huh7 after being administered 6 times altogether
The T/C of mice-transplanted tumor is 16.63%, inhibitory rate 83.49%.Capecitabine is administered for every 2 days with 600mg/kg gastric infusion
1 time, after being administered 6 times altogether, the T/C to human liver cancer cell Huh7 Nude Mice is 50.48%, inhibitory rate 57.55%,
YY-003 is obviously stronger than capecitabine to the inhibiting effect of human liver cancer cell Huh7.
Capecitabine 600mg/kg and drug YY-003278mg/kg group are poor without statistics to experimental animals ghost image sound
It is different.
The inhibiting effect (X ± SD) that table 1.YY-003 grows human liver cancer cell Huh7 nude mouse xenograft tumor
Compared with blank control group, * P < 0.05, * * P < 0.01.
Claims (7)
1. compound 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5- that one kind has formula (I) molecular structure
Fluorouracil:
2. a kind of compound 1- described in claim 1 { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5- fluorine urea
The preparation method of pyrimidine, comprising the following steps:
(1) synthesis of 4- [3- (1,2- dithiolane)]-butyl isocyanate
Method one: (±) -5- [3- (1,2- dithiolane)]-valeric acid (lipoic acid) and diphenyl phosphate azide carry out nitrine
Change reaction, generates (±) -5- [3- (1,2- dithiolane)]-valeryl nitrine, (±) -5- [3- (1,2- dithia ring penta
Alkane)]-valeryl nitrine through Ku Ertisi rearrangement reaction, generates 4- [3- (1,2- dithiolane)]-butyl isocyanate；
Method two: (±) -5- [3- (1,2- dithiolane)]-valeric acid is reacted with chloride reagent, generates (±) -5- [3-
(1,2- dithiolane)]-valeric chloride, then with reaction of sodium azide, through Ku Ertisi rearrangement reaction generate 4- [3- (1,2-
Dithiolane)]-butyl isocyanate；
Method three: (±) -5- [3- (1,2- dithiolane)]-valeric acid is reacted with ethyl chloroformate, generates ethyoxyl formic acid
(±) -5- [3- (1,2- dithiolane)]-valeric anhydride, then with reaction of sodium azide, generated through Ku Ertisi rearrangement reaction
4- [3- (1,2- dithiolane)]-butyl isocyanate；Or
Method four: (±) -5- [3- (1,2- dithiolane)]-valerate and hydrazine reaction generate (±) -5- [3- (1,2- bis-
Tiacyclopentane)]-valeryl hydrazine, then reacted with sodium nitrite, generate (±) -5- [3- (1,2- dithiolane)]-valeryl
Nitrine, then through Ku Ertisi rearrangement reaction, generate 4- [3- (1,2- dithiolane)]-butyl isocyanate；
(2) 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil synthesis
4- [3- (1,2- dithiolane)]-butyl isocyanate is reacted with 5 FU 5 fluorouracil, in the presence of alkali generationization
Close object 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5-fluor-uracil.
3. compound 1- { 4- [3- (1,2- dithiolane)]-butylamine base } formyl -5- fluorine urea according to claim 1
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 described pharmaceutical composition includes the compound 1- of effective therapeutic dose
{ 4- [3- (1,2- dithiolane)]-butylamine base } 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710680247.6A CN109384776A (en) | 2017-08-10 | 2017-08-10 | A kind of 5-fluor-uracil derivative and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710680247.6A CN109384776A (en) | 2017-08-10 | 2017-08-10 | A kind of 5-fluor-uracil derivative and its preparation method and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109384776A true CN109384776A (en) | 2019-02-26 |
Family
ID=65414339
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710680247.6A Pending CN109384776A (en) | 2017-08-10 | 2017-08-10 | A kind of 5-fluor-uracil derivative and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109384776A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111040014A (en) * | 2019-12-27 | 2020-04-21 | 苏州络森生物科技有限公司 | Preparation method of CHAPSO |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4349552A (en) * | 1978-10-30 | 1982-09-14 | Fujisawa Pharmaceutical Company, Ltd. | 5-Fluorouracil derivatives, and their pharmaceutical compositions |
| CN103012165A (en) * | 2011-09-28 | 2013-04-03 | 李兰心 | Process for synthesizing an aminopropanol |
-
2017
- 2017-08-10 CN CN201710680247.6A patent/CN109384776A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4349552A (en) * | 1978-10-30 | 1982-09-14 | Fujisawa Pharmaceutical Company, Ltd. | 5-Fluorouracil derivatives, and their pharmaceutical compositions |
| CN103012165A (en) * | 2011-09-28 | 2013-04-03 | 李兰心 | Process for synthesizing an aminopropanol |
Non-Patent Citations (1)
| Title |
|---|
| MARCO MOR，等: "Synthesis and Quantitative Structure-Activity Relationship of Fatty Acid Amide Hydrolase Inhibitors: Modulation at the N-Portion of Biphenyl-3-yl Alkylcarbamates", 《J. MED. CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111040014A (en) * | 2019-12-27 | 2020-04-21 | 苏州络森生物科技有限公司 | Preparation method of CHAPSO |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0956854B1 (en) | Pharmaceutical composition comprising coenzyme q 10 | |
| KR20210055042A (en) | “Solid self-emulsifying pharmaceutical composition” | |
| CN101138550B (en) | Mixed glue bundle pharmaceutical preparations produced in combination use of multiple surfactant and processes for their preparation | |
| MXPA06005565A (en) | Composition and dosage form comprising an amphiphilic molecule as a suspension vehicle. | |
| CN104427976A (en) | Depot formulations of a hydrophobic active ingredient and methods for preparation thereof | |
| CN106798725A (en) | A kind of cordycepin nano liposomes and preparation method thereof and antitumor activity application | |
| CN109384730A (en) | 1- { 3- [p- double-(2- chloroethyl) amido] phenylpropyl alcohol amido } formyl -5-fluor-uracil and preparation and application | |
| CN106139151A (en) | Ascorbic acid palmityl ester and the synergistic pharmaceutical composition of antitumor drug | |
| CN113979954B (en) | Tinich antitumor drug compound and preparation method and application thereof | |
| CN104826122A (en) | Lipid-modified substance of chlorogenic acid and derivative thereof, preparation method and purification method of the lipid-modified substance | |
| CN104710433B (en) | Chlorambucil derivative, preparation method and application | |
| CN104826118A (en) | Application of lipid-modified substance of chlorogenic acid and derivative thereof | |
| CN101524329A (en) | Bicyclo-ethanol submicron emulsion and preparation method thereof | |
| CN104710489B (en) | The fluorine N of 5 ' deoxidation 5 4-[double（2 chloroethyls）Amino] benzene bytyry } cytidine and its preparation method and application | |
| CN111481640B (en) | Anti-liver cancer microemulsion nano composition and application thereof | |
| CN109384776A (en) | A kind of 5-fluor-uracil derivative and its preparation method and application | |
| CN115850248B (en) | Tinich antitumor drug compound and preparation method and application thereof | |
| US20120101057A1 (en) | Combined therapy of colorectal carcinoma | |
| US20090186835A1 (en) | Treatment and prophylaxis of cancer | |
| CN103096877A (en) | New formulations of 14-epi-analogues of vitamin D | |
| CN108434101A (en) | A kind of novel Tivozanib liposomes for anticancer, preparation and its preparation method and application | |
| CN112741828B (en) | Drug combination and preparation method and application thereof | |
| CN101450039A (en) | Long-acting preparation containing amphotericin B | |
| CN101120926B (en) | Freezing-dried preparation containing voriconazole and its preparation method | |
| CN102836437B (en) | Docetaxelpolyoxyethelene-polyoxypropylene-polyoxyethelene compound capable of self-assembling into micelle |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190226 |