CN108774264A - Phosphocholine analogs, Preparation method and use - Google Patents
Phosphocholine analogs, Preparation method and use Download PDFInfo
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- CN108774264A CN108774264A CN201810479128.9A CN201810479128A CN108774264A CN 108774264 A CN108774264 A CN 108774264A CN 201810479128 A CN201810479128 A CN 201810479128A CN 108774264 A CN108774264 A CN 108774264A
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- phosphocholines
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- 0 CCC(C1=C(CO2)C3OC3*(Cc3cc(cc(*)cc4)c4nc33)C3=C1)(C2=O)OC(*C(OC(CI)=COP(O)(O)=O)=O)=O Chemical compound CCC(C1=C(CO2)C3OC3*(Cc3cc(cc(*)cc4)c4nc33)C3=C1)(C2=O)OC(*C(OC(CI)=COP(O)(O)=O)=O)=O 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention provides phosphocholine analogs, the purposes the present invention also provides the preparation method of such phosphocholine analogs and on preparing antitumor drug shown in formula (1).
Description
Technical field
The present invention relates to pharmaceutical chemistry and therapeutic field, and in particular to phosphocholine analogs, preparation method and its conduct
The purposes of antitumor drug.
Background technology
Lecithin (i.e. phosphatidyl choline) is one of main component of phosphatide, and lecithin transmits rapidly the instruction of brain,
Information transmission speed is faster, and memory is stronger, is brain tonic food.It can enhance infant intelligence, improve learning efficiency.Especially tire
Youngster, it is very big to the demand of lecithin in growth and development.In addition, lecithin can also resist fatty liver and alcoholic liver, effective protection
Liver health.The amphipathic of lecithin makes it have emulsification function, can be sufficiently mixed internal moisture and grease, avoid water
Divide and be largely lost, prevents pachylosis aging；Can extra fat be turned to smaller emulsion droplet to excrete, help puerpera or fertilizer
Fat person restores the bodily form as early as possible.Lecithin can also by blood cholesterol and fatty acid be superfine particle, arranged from blood vessel
Go out, to improve hdl concentration, so that blood vessel is restored elasticity, blood flow is unimpeded, is known as " blood vessel scavenger ".
Cancer chemotherapy refers to the method with drug therapy cancer, can eliminate have spread to each position of whole body cancer it is thin
Born of the same parents, but the effect of chemotherapy is often associated with serious toxic side effect, and the nanometer formulation of self assembly can effectively improve chemotherapeutics, drop
Hypotoxicity.Lecithin is a kind of amphiphatic molecule, is made of hydrophilic head and hydrophobic tail portion, can be self-assembled into nano-particle.
Single acylglycerol lecithin is set to be combined with the compound molecule with antitumaous effect by chemical bonding effect, it can be formed
Treat drug-lecithin.The compound can be made up corresponding liposome medicament transmission system and be had of self assembly
Effect reduces drug toxicity.
Camptothecine (Camptothecin, CPT) is the alkaloid extracted from China endemic plant camplotheca acuminata, camptothecine
And its derivative has formed a kind of important anticancer drug.The Alpha-hydroxy lactonic ring being closed in camptothecine E ring structures is its holding
The required structure of antitumor activity, but the facile hydrolysis open loop in human body of this Alpha-hydroxy lactonic ring forms carboxylate structure, it is this to open
Loop type easily with human albumin in conjunction with and make its lose antitumor activity.More seriously, the sodium salt of open loop form is through kidney
There is great toxic side effect to urinary system and digestive system after dirty metabolism.In addition, most camptothecine reactive derivatives are insoluble in
Water seriously hampers popularization and application of the camptothecin derivative in clinic.
The preparation method research of camptothecin derivative is more, and part document is given below as reference.
United States Patent (USP) 104894, No. 1990-3-1
PCT Patent Application 2001009139, No. 2001-2-8
PCT Patent Application 9602546, No. 1996-7-12
J Biol Chem, 1985,260,14873-14878
J Med Chem, 1991,34 (1), 98-107
J Med Chem, 1998,41 (1), 31-37
Bioorg Med Chem Lett, 2002,12 (9), 1241-1244
Bioorg Med Chem Lett, 2003,13 (21), 3739-3741
Bioorg Med Chem, 2004,12 (15), 4003-4008
Bioorg Med Chem, 2004,12 (13), 3657-3662
Chem Pharm Bull, 1991,39,3183-3188
Cancer Res, 1993,53,1577-1582
Cancer Res, 1995,55,753-760
N Y Acada Sci, 1996,803,231-246
Arch Pharm Res, 1998,21,581-590
J Med Chem, 1995,38 (3), 395-401
Invention content
It is an object of the present invention to provide the phosphocholine analogs that one kind is combined with anticancer drug, be conducive to improve drug
Active anticancer and bioavilability.
It is a further object to provide the preparation methods of such phosphocholine analogs.
Application it is also another object of the present invention to provide such phosphocholine analogs as antitumor drug.
To achieve the goals above, the present invention is to provide with phosphocholine analogs shown in formula (1).
Wherein, R is selected from：
-CH2CH2-S-S-CH2CH2-、-CH2-S-S-CH2-、
R1 is selected from：-OCOCH2(CH2)15CH3、-OCOCH2(CH2)6CH=CH (CH2)7CH3、-OCOCH2(CH2)13CH3；
R2 is selected from：-H,-OH,-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OCH3。
The present invention provides the method for preparing and having phosphocholine analogs shown in (1), includes the following steps：
(1) in dry organic solvent, camptothecine or derivatives thereof and corresponding carboxylic acid are in coupling agent and catalyst
Effect is lower to carry out esterification, obtains the intermediate a with formula (2) structure；
Wherein, R is selected from：
-CH2-CH2-S-S-CH2-CH2-、-CH2-S-S-CH2-、
R2 is selected from：-H,-OH,-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OCH3；
(2) intermediate a under the action of coupling agent and catalyst with corresponding 1- fatty acyls-Sn- glycerine -3- phosphoric acid courages
Alkali reacts, and corresponding phosphocholine analogs are made；The carboxylic acid is selected from 3,3'- dithiodipropionic acids, dithioglycollic acid, Guang
Propylhomoserin；1- fatty acyl-Sn- glycerine -3- the phosphocholines are selected from 1- stearoyl-Sn- glycerine -3- phosphocholines, 1-
Oleoyl-Sn- glycerine -3- phosphocholines, 1- palmityl-Sn- glycerine -3- phosphocholines.
Wherein, it is dichloromethane, dimethyl sulfoxide (DMSO) and N to prepare the organic solvent described in the method for phosphocholine analogs,
Dinethylformamide；The coupling agent is N, N- dicyclohexylcarbodiimides (DCC), N, N- carbonyl dimidazoles (CDI) and
1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDC.HCl)；The catalyst is pyridine and 4- diformazan ammonia
Yl pyridines (DMAP).
The invention further relates to various containing the compounds of this invention as active constituent and acceptable carriers in pharmacodynamics
Preparation.
" acceptable carriers in pharmacodynamics " refer to：One or more biocompatible solids or liquid filler or gelatinous mass,
They are suitable for people's use, and have enough purity and sufficiently low toxicity.It is each in " compatibility " referred to herein as composition
Component energy and the compound of the present invention and they between mutually blend, and significantly reduce the drug effect of compound.In pharmacodynamics
Acceptable carrier part example has sugared (such as glucose, sucrose, lactose), starch (such as cornstarch, potato starch),
Cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate), gelatin, talcum, solid
Lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as oily beans, sesame oil, peanut oil, olive oil), polyalcohol
(such as propylene glycol, glycerine, mannitol, sorbierite), emulsifier (such as tween), lubricant (such as lauryl sodium sulfate), coloring
Agent, flavoring agent, stabilizer, antioxidant, preservative, apirogen water etc..
The application in antitumor drug is prepared the invention further relates to compound of the present invention.
External activity screening experiment shows that the phosphocholine analogs have apparent antitumor action and good dose
Measure dependence.Using abortion syndrome HXB1309H as subject cell strain, the half for determining phosphocholine analogs inhibits
Concentration (IC50), the experimental result of which part sample are shown in Table 1：
Table 1：Half-inhibition concentration of the phosphocholine analogs to XB1309
Specific implementation mode
Elaboration is further retouched in detail to present invention work with reference to embodiment：
With phosphocholine analogs shown in formula (1).
Wherein, R is selected from：
-CH2-CH2-S-S-CH2-CH2-、-CH2-S-S-CH2-、
R1 is selected from：-OCOCH2(CH2)15CH3、-OCOCH2(CH2)6CH=CH (CH2)7CH3、-OCOCH2(CH2)13CH3；
R2 is selected from：-H,-OH,-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OCH3。
The present invention provides the method for preparing and having phosphocholine analogs shown in (1), includes the following steps：
(1) in dry organic solvent, camptothecine or derivatives thereof with corresponding carboxylic acid in coupling agent and catalyst
Under the action of carry out esterification, obtain the intermediate a with formula (2) structure；
Wherein, R is selected from：
-CH2-CH2-S-S-CH2-CH2-、-CH2-S-S-CH2-
R2 is selected from：-H,-OH,-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OCH3；
(2) intermediate a under the action of coupling agent and catalyst with corresponding 1- fatty acyls-Sn- glycerine -3- phosphoric acid courages
Alkali reacts, and corresponding phosphocholine analogs are made；The carboxylic acid is selected from 3,3'- dithiodipropionic acids, dithioglycollic acid, Guang
Propylhomoserin；1- fatty acyl-Sn- glycerine -3- the phosphocholines are selected from 1- stearoyl-Sn- glycerine -3- phosphocholines, 1-
Oleoyl-Sn- glycerine -3- phosphocholines, 1- palmityl-Sn- glycerine -3- phosphocholines.
Wherein, it is dichloromethane, dimethyl sulfoxide (DMSO) and N to prepare the organic solvent described in the method for phosphocholine analogs,
Dinethylformamide；The coupling agent is N, N- dicyclohexylcarbodiimides (DCC), N, N- carbonyl dimidazoles (CDI) and
1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDC.HCl)；The catalyst is pyridine and 4- diformazan ammonia
Yl pyridines (DMAP).
The invention further relates to various containing the compounds of this invention as active constituent and acceptable carriers in pharmacodynamics
Preparation.
" acceptable carriers in pharmacodynamics " refer to：One or more biocompatible solids or liquid filler or gelatinous mass,
They are suitable for people's use, and have enough purity and sufficiently low toxicity.It is each in " compatibility " referred to herein as composition
Component energy and the compound of the present invention and they between mutually blend, and significantly reduce the drug effect of compound.In pharmacodynamics
Acceptable carrier part example has sugared (such as glucose, sucrose, lactose), starch (such as cornstarch, potato starch),
Cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate), gelatin, talcum, solid
Lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil is (such as oily beans, sesame oil, peanut oil, olive oil
Deng), polyalcohol (such as propylene glycol, glycerine, mannitol, sorbierite), emulsifier (such as tween), lubricant (such as dodecane
Base sodium sulphate), colorant, flavoring agent, stabilizer, antioxidant, preservative, apirogen water etc..
The application in antitumor drug is prepared the invention further relates to compound of the present invention.
The phosphocholine analogs and preparation method of the present invention describe in more detail in the following example, but embodiment not structure
At limitation of the present invention.
Embodiment 1 prepares camptothecine -20-O- (3,3'- dithio dipropyls acyl) monoesters
2.1 grams of (0.01 mole) 3,3'- dithiodipropionic acids are dissolved in 300 milliliters of dichloromethane, sequentially add 1 gram two
Methylamino pyridine, 3.5 grams of (0.01 mole) camptothecines, 3 grams of N, N'- Dicyclohexylcarbodiimides are stirred at room temperature 24 hours,
It is filtered to remove precipitation, filtrate decompression concentration removes solvent, by condensate residue silica gel column chromatography (dichloromethane：Methanol=20：
1) light yellow camptothecine -20-O- (3,3'- dithio dipropyl acyl) 3.35 grams of monoesters, yield 62%, are obtained.
1HNMR (300MHz, DMSO-d6, ppm)：δ 0.96 (3H, t, H-19), 2.10 (2H, m, H-18), 2.58-2.72
(4H, m ,-OOCCH 2CH2S-), 2.87-2.99 (4H, m ,-OOCCH2CH 2S-), 5.11 (2H, s, H-5), 5.50 (2H, s, H-
17), 6.89 (1H, d, N-H), 7.14 (H, s, H-14), 7.72 (1H, q, H-10), 7.87 (H, t, H-11), 8.00 (1H, d, H-
12), 8.14 (1H, d, H-9), 8.42 (1H, t, N-H), 8.65 (1H, s, H-7).
ESIMS m/z：539.3(M-1)-
Embodiment 2 prepares 1- stearoyls -2- (camptothecine -20-O- (3,3'- dithio dipropyls acyl) monoesters) glycerine -3- phosphoric acid
Choline (phosphocholine analogs)
0.540 gram of (0.001 mole) camptothecine -20-O- (3,3'- dithio dipropyls acyl) monoesters is dissolved in 50 milliliters of diformazans
In base sulfoxide, 0.5 gram of 1- ethyl-(3- dimethylaminopropyls) carbodiimide hydrochloride, 0.1 gram of 4- dimethylamino pyrrole is added
0.523 gram of (0.001 mole) 1- stearoyl-Sn- glycerine -3- phosphocholine, room temperature is added after 3 hours in pyridine, at room temperature, stirring
Under, it stirs 72 hours, reaction solution is poured into 500 milliliters of ice water, filter, at 50 DEG C, Vacuum dry filter cake, by filter cake silicon
Plastic column chromatography (methanol：Chloroform：Water=25：65:2) yellow 1- stearoyls -2- (camptothecine -20-O- (3,3'- bis- thio two, are obtained
Propionyl) monoesters) glycerine -3- phosphocholines 0.21 gram (i.e. phosphocholine analogs), yield 20%.
1HNMR (300MHz, DMSO-d6, ppm)：2.58-2.72 (4H, m ,-OOCCH2 CH2S-), 2.87-2.99 (4H,
M ,-OOCCH2CH2 S-),3.23(12H,m,-NCH3,-CH2-N-),3.56-4.17(4H m,-OC2H4N-), 5.13 (2H, s,
H-5), 5.55 (2H, s, H-17), 6.89 (1H, d, N-H), 7.14 (H, s, H-14), 7.72 (1H, q, H-10), 7.87 (H, t,
H-11), 8.00 (1H, d, H-12), 8.14 (1H, d, H-9), 8.42 (1H, t, N-H), 8.65 (1H, s, H-7).
Example 3 prepares phosphocholine analogs self assembly liposome
By 0.05 gram of 1- stearoyls -2- (camptothecine -20-O- (3,3'- dithio dipropyls acyl) monoesters) glycerine -3- phosphoric acid
Choline is dissolved in 5 ml methanols, under ul-trasonic irradiation, is added at one time 25 milliliters of distilled water, ultrasound after ten minutes, is quickly blown down
Methanol, residue obtained by freeze drying Nano grade particle (grain size≤200nm), the as fat of self assembly containing phosphocholine analogs
Plastid.
Claims (6)
1. phosphocholine analogs shown in formula (1)
Wherein, R-It is selected from：
-CH2-CH2-S-S-CH2-CH2-、-CH2-S-S-CH2-、
R-1-It is selected from：-OCOCH2(CH2)15CH3、-OCOCH2(CH2)6CH=CH (CH2)7CH3、-OCOCH2(CH2)13CH3；
R-2-It is selected from：-H,-OH,-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OCH3。
2. the method for preparing phosphocholine analogs described in claim 1, includes the following steps：
(1) in dry organic solvent, the effect of camptothecine or derivatives thereof and corresponding carboxylic acid in coupling agent and catalyst
Lower carry out esterification, obtains the intermediate a with formula (2) structure；
Wherein, R-It is selected from：
-CH2-CH2-S-S-CH2-CH2-、-CH2-S-S-CH2-、
R-2-It is selected from：-H,-OH,-OCH3、-OCH2CH3、-OCH2CH2OCH3、-OCH2CH2OCH3；
(2) intermediate a is anti-with corresponding 1- fatty acyls-Sn- glycerine -3- phosphocholines under the action of coupling agent and catalyst
It answers, corresponding phosphocholine analogs is made；The carboxylic acid is selected from 3,3'- dithiodipropionic acids, dithioglycollic acid, Guang ammonia
Acid；1- fatty acyl-Sn- glycerine -3- the phosphocholines are selected from 1- stearoyl-Sn- glycerine -3- phosphocholines, 1- oil
Acyl-Sn- glycerine -3- phosphocholines, 1- palmityl-Sn- glycerine -3- phosphocholines.
3. the method for preparing phosphocholine analogs according to claim 2, it is characterised in that the organic solvent is two
Chloromethanes, dimethyl sulfoxide (DMSO) and n,N-Dimethylformamide；The coupling agent is N, N- dicyclohexylcarbodiimides (DCC),
N, N- carbonyl dimidazoles (CDI) and 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDC.HCl)；Described
Catalyst is pyridine and 4-dimethylaminopyridine (DMAP).
4. a kind of pharmaceutical composition contains acceptable carrier in any compound described in claim 1 and pharmacodynamics.
5. pharmaceutical composition according to claim 4, it is characterised in that the pharmaceutical composition can be tablet, capsule, ball
Agent, injection, sustained release preparation.
6. phosphocholine analogs application in preparation of anti-tumor drugs described in claim 1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110025789A (en) * | 2019-04-01 | 2019-07-19 | 东南大学 | A kind of drug phosphatide cpd and its pharmaceutical composition and application |
| CN113788839A (en) * | 2020-08-21 | 2021-12-14 | 诺茗(北京)生物医药有限公司 | Water-soluble anti-tumor prodrug, and pharmaceutical composition and application thereof |
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| WO2017201528A1 (en) * | 2016-05-20 | 2017-11-23 | The University Of Chicago | Nanoparticles for chemotherapy, targeted therapy, photodynamic therapy, immunotherapy, and any combination thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110025789A (en) * | 2019-04-01 | 2019-07-19 | 东南大学 | A kind of drug phosphatide cpd and its pharmaceutical composition and application |
| CN113788839A (en) * | 2020-08-21 | 2021-12-14 | 诺茗(北京)生物医药有限公司 | Water-soluble anti-tumor prodrug, and pharmaceutical composition and application thereof |
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Application publication date: 20181109 |