CN1962656A - Indomethacin 5-fluorouracil methyl ester pharmaceutical compound and its formulation and preparation method - Google Patents
Indomethacin 5-fluorouracil methyl ester pharmaceutical compound and its formulation and preparation method Download PDFInfo
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- CN1962656A CN1962656A CNA2006101344153A CN200610134415A CN1962656A CN 1962656 A CN1962656 A CN 1962656A CN A2006101344153 A CNA2006101344153 A CN A2006101344153A CN 200610134415 A CN200610134415 A CN 200610134415A CN 1962656 A CN1962656 A CN 1962656A
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- indomethacin
- fluorouracil
- methyl ester
- idm
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Abstract
The invention discloses a new compound indomethacin 5-efudix methyl ester and agent and preparing method, whose chemical names is 1-(4-chlorobenzene formyl)-5-methoxyl-2-methyl indole-3-acetate (5-fluorine-3, 4-dihydrogen-2, 4-dioxo-1 (2H)-pyrimidinyl) methyl ester, wherein the compound is reacted by 5-FU and formaldehyde to produce intermediate 1,3-dimethylol-5-FU, which combines IDM to form the product as tablet or capsule with acceptable medical carrier or excipient.
Description
Technical field:
The invention belongs to medical technical field, disclose a kind of Indomethacin 5-fluorouracil methyl ester pharmaceutical compound and preparation thereof and preparation method.
Background technology:
Attract much attention very early about the relation between inflammation and the cancer, the loyal professor of the meter will of Shenyang Pharmaceutical University just delivered the article that is entitled as " cancer and inflammation and new drug research " as far back as 1986.Point out on the one hand PGs synthetic of propagation capable of inhibiting cell of indomethacin (IDM), help antitumous effect because increase lipoxidase product suppresses other effects (as anti-inflammatory action) of tumor growth and indomethacin on the other hand.Because inflammation can be impelled the formation and the growth of tumour.Healthy net points out in the article of " scientist's current research is opened the mystery of inflammation and cancer relation " on November 16th, 2004, and it is to be developed by chronic inflammatory diseases to form that 15% cancer is arranged.The IDM that is used as anti-inflammatory rheumatism and antipyretic effect for many years clinically that studies show that in recent years has certain antitumous effect.Epidemiological study shows that the cancered possibility of people of regularly taking NSAID (non-steroidal anti-inflammatory drug) such as acetylsalicylic acid, IDM is lower.Experiment shows that IDM has positive effect to patients' such as kinds of tumors such as cancer of the stomach, colorectal carcinoma, liver cancer immunologic function; Can reduce the pair infringement of chemotherapy, strengthen chemotherapy effect body; Tumor remission heating pain etc.Pharmacokinetic points out that IDM can delay 5 FU 5 fluorouracil (5-FU) in the intravital elimination of rat, has certain synergistic effect.Yet, because the toxicity of 5-FU and IDM is all bigger, individually dosed produce often make most patients have to stop medication even lose valuable life as toxic side effect such as gastrointestinal reaction, heatings.Say that in some sense the cancer patients dies from cancer itself, but die from the toxic side effect of medicine.
Although IDM and 5 FU 5 fluorouracil (5-FU) have certain synergistic effect, because of both separately or to unite the toxicity of use all bigger, therefore limited both uses.For bring into play IDM treatment on the tumour remarkable effect and reduce 5-FU and IDM reaches the caused serious toxic side effect of physical mixed administration separately, seeks a kind of toxic side effect that can reduce both, thereby the method for raising curative effect is very important.
Summary of the invention
For bring into play IDM treatment on the tumour remarkable effect and reduce 5-FU and IDM reaches the caused serious toxic side effect of physical mixed administration separately, the invention provides following technical scheme:
This compound is that 5-FU and formaldehyde reaction are generated intermediate product 1; behind 3-dihydroxymethyl-5-FU; being combined into ester with IDM again prepares; chemistry 1-(4-chlorobenzene formacyl) by name-5-methoxyl group-2 methyl indole-3-acetate (5-fluoro-3; 4-dihydro-2,4-dioxo-1 (2H)-pyrimidyl) methyl esters.
Compound of the present invention has following structure:
This compound can be made various formulations such as tablet, capsule with other pharmaceutically acceptable carrier or mixed with excipients, in anticancer, also has anti-inflammatory and analgesic activity concurrently.
Compare with IDM, 5-FU and the physical mixture of the two [1/1 (mol/mol)], the toxic side effect of Indomethacin 5-fluorouracil methyl ester (IFM) reduces greatly, and has tangible anti-inflammatory and analgesic activity, and this will be significant to the treatment of cancer patient.
Embodiment:
Synthesizing of embodiment 1 Indomethacin 5-fluorouracil methyl ester
With 1.30g (10mmol) 5-FU and 1.78g (22mmol) formalin (37%) after heated and stirred to solid dissolves fully in 60 ℃ of water-baths, continue reaction 50min, underpressure distillation removes anhydrates and excessive formaldehyde, gets water white intermediate product 1,3-dihydroxymethyl-5-FU.To wherein adding the 100mL anhydrous acetonitrile, 4.3g (12mmol) IDM, 2.47g (14mmol) N, N-dicyclohexyl carbimide (DCC), 0.08gN, N-dimethyl aminopyridine (DMAP), stirring at room was reacted more than 72 hours, the degree that thin-layer chromatography (TLC) monitoring reaction carries out.Question response removes by filter precipitation after finishing, and acetonitrile is reclaimed in the filtrate decompression distillation, and resistates is dissolved in an amount of ethyl acetate, uses rare HCl, saturated sodium bicarbonate aqueous solution, distilled water wash successively.Organic layer is with anhydrous sodium sulfate drying, organic layer concentrate thick product, separate crude product with silica gel column chromatography, eluent is methylene dichloride-acetone, collects primary product.Obtain the crystallization of yellow powder powder.Productive rate is 30-70%.
m.p.217-220℃
High resolution mass spectrum: M
+=499
1H-NMR(300MHz DMSO-d
6)
δ：2.20(s，3H)，3.75(s，3H)，3.85(s，2H)，5.62(s.2H)，6.73(dd，1H)，6.93(d，1H)，7.01(d，1H)，7.66(m，4H)，8.11(d，1H)，12.02(s，1H)
IR(KBr)：3067，2831，1661，1503，1449，1430，1349，1247，1182，995，947，879，815，752，642，552，469.
The anti-tumor activity of embodiment 2 indomethacins-5 FU 5 fluorouracil methyl esters
Select murine sarcoma S for use
180Knurl strain, liver cancer H
22Three kinds of knurl strains of knurl strain and Lewis lung cancer solid tumor are index, and the antitumor activity of IFM is investigated.
The external recovery murine sarcoma S of difference
180Knurl strain, liver cancer H
22Knurl strain and the strain of Lewis lung cancer knurl are at the collecting cell exponential phase of growth of cell, 1000rmin
-1Centrifugal, PBS washing 2 times is inhaled and is removed supernatant, with the stroke-physiological saline solution dilution, adjusts to 2 * 10
7Individual mL
-1The picked at random healthy mice, every the above-mentioned cell suspension 0.2mL of usefulness abdominal injection, note observing the ascites growing state of inoculation mouse, about week back inoculation mouse web portion obviously rises greatly, protrudes, extract ascites, ascites is creamy white, and [it was 2 (S that oncocyte is counted concentration with dilution in 1: 2 with stroke-physiological saline solution in sterile test tube
180, H
22) or 4 (Lewis lung cancer) * 10
7Individual mL
-1], obtain the ascites diluent.With above-mentioned ascites diluent animal is inoculated, every subcutaneous vaccination 0.2mL behind armpit place sterilization skin sets up liver cancer H
22Knurl strain armpit subcutaneous vaccination model, murine sarcoma S
180Armpit subcutaneous vaccination model and Lewis lung cancer armpit subcutaneous vaccination model.Every kind of knurl strain experimentation on animals triplicate calculates tumour inhibiting rate respectively.
Lotus knurl Kunming mouse or C57BL/6 mouse are divided into 7 groups at random, 12 every group, numbering in the group.Be respectively lotus knurl model control group, the basic, normal, high dosage group of IFM, dosage is respectively 38,77,115mgkg
-1(being equivalent to and dosage such as 5-FU), the basic, normal, high dosage group of 5-FU, dosage is respectively 10,20,40mgkg
-1, modeling began to irritate stomach on the 2nd day and gives relative medicine, every day 1 time, successive administration 7d; Model control group gives suitable volumetrical 1% carboxymethylcellulose sodium solution every day, writes down every group every mouse body weight before the administration and after the drug withdrawal.
Behind the last administration 24h, the cervical vertebra dislocation method is put to death animal, dissects and peels off the knurl piece, and electronic balance claims knurl heavy.Calculate tumour inhibiting rate according to following formula:
Experimental data all adopts three experimental results
Expression, the t check analysis meets the requirements between group.Press down knurl and the results are shown in Table 1.
Table 1.IFM and 5-FU are to the restraining effect of mouse S180, H22 and three kinds of solid tumors of lewis
| Group | Dosage (mg/kg/d) | Number of animals (only) | Tumour inhibiting rate (%) | |||
| Beginning | The end | S180 | H22 | Leiws | ||
| Control group | 0.2mL/d | 12 | 12 | --- | --- | --- |
| 5-FU | 10 | 12 | 12 | 60.01 | 52.34 | 48.21 |
| 20 | 12 | 12 | 66.25 | 54.85 | 50.14 | |
| 40 | 12 | 12 | 69.85 | 55.54 | 52.34 | |
| IFM | 38 | 12 | 12 | 58.86 | 56.94 | 54.43 |
| 77 | 12 | 12 | 64.73 | 58.87 | 57.11 | |
| 115 | 12 | 12 | 72.28 | 65.96 | 60.47 | |
The acute toxicity of embodiment 3 indomethacins-5 FU 5 fluorouracil methyl esters.
The precision weighing appropriate amount of drug is dissolved into 15mL with 1%CMC-Na, gets 6mL as first group of medicine, and residual drug is diluted to 15mL, gets 6mL as second group of administration, by that analogy.50 mouse evenly are divided into 5 groups by sex, body weight, and 10 every group, by design dosage gastric infusion, the administration volume is 20mL/kg.Observed 14 days after the administration.Write down each treated animal death condition.Gross necropsy does not see that the mouse main organs has obvious pathology.
The Bliss method is calculated, the medium lethal dose (LD of 5-FU, IDM, 5-FU and IDM physical mixture 1: 1 (mol/mol) and IFM
50) be respectively 82.28mg/kg, 260.09mg/kg, 200.34mg/kg and 1929.57mg/kg.
The result shows, compares with the physical mixture of two kinds of former medicines and two kinds of former medicines, and the acute toxicity of Indomethacin 5-fluorouracil methyl ester reduces greatly.
The anti-inflammatory action of embodiment 4 Indomethacin 5-fluorouracil methyl esters.
Take by weighing 70 of the Kunming mouses of body weight 18～22g, male and female half and half are divided into 7 groups by the equilibrium of body weight sex, 10 every group.Be solvent control group (1% carboxymethylcellulose sodium solution); The high, medium and low dosage group of IFM (dosage be respectively 28,14,7mg/kg), the high, medium and low dosage group of IDM (dosage be respectively 20,10,5mg/kg).Route of administration is for irritating stomach, and the administration volume is 20mL/kg.Continuous use 3d behind the last administration 1h, is coated with dimethylbenzene 0.1mL/ and only causes swollenly once a day in the mouse right ear two sides, left ear is not painted with normal ear, takes off cervical vertebra behind the 1h and puts to death, and the disk that diameter 10mm punch tool is laid left ear and the same position of auris dextra is weighed on the analytical balance.Swelling degree=auris dextra weight-left ear is heavy.The experimental data employing (
) expression, the t check analysis meets the requirements between group.The results are shown in Table 2.
Table 2.IFM, IDM gastric infusion to the mouse dimethylbenzene ear expanding influence (
, n=10)
| Group | Dosage (mg/kg) | Swelling degree (mg) | Inhibiting rate (%) |
| Solvent group IFM IFM IFM IDM IDM | - 28 14 7 20 10 | 0.017±0.025 0.015±0.005 0.015±0.006 0.017±0.006 0.012±0.004 * 0.015±0.003 | - 11.8 11.8 0 29.4 11.8 |
| IDM | 5 | 0.016±0.003 | 5.9 |
Each administration group and solvent group be P＜0.05 relatively
The result shows that IFM has the dimethylbenzene of inhibition inductive mice ear trend
The analgesic activity of embodiment 5 Indomethacin 5-fluorouracil methyl esters
Get 70 of the Kunming mouses of body weight 18～22g, male and female half and half are divided into 7 groups by body weight, sex equilibrium, 10 every group.Grouping and medication are the same.Behind the last administration 1h, each mouse abdominal injection 0.6% acetum 10mL/kg (acetum face use preceding preparation), observe behind the 5min and record injection acetum after in the 15min animal writhing response occurs (belly shrink indent, stretches hind leg; Buttocks is raised, crawling) number of times, be calculated as follows IFM, the analgesia percentage of IDM.The results are shown in Table 3.
Table 3.IFM, IDM gastric infusion Dichlorodiphenyl Acetate cause the pain mouse analgesic activity (
N=10)
| Group | Dosage (mg/kg) | Turn round the body number of times | Analgesia rate (%) |
| Among the low high IDM of IDM of the high IFM IFM of solvent group IFM | - 28 14 7 20 10 | 23.6±17.0 3.4 ±4.2 ** 5.7±7.2 * 7.4±11.9 * 4.2±8.5 ** 6.1±7.8 ** | -- 85.5 75.8 68.6 82.2 74.1 |
| IDM is low | 5 | 8.4±9.3 * | 64.4 |
Each administration group and solvent group are relatively
*P＜0.05,
*P＜0.01
The result shows each administration group of IFM, IDM and solvent group relatively, can be significantly or the minimizing acetic acid induced mice of highly significant turn round the body number of times, the analgesia rate can reach 60-80%.
The preparation of embodiment 6 Indomethacin 5-fluorouracil methyl ester capsules
Activeconstituents
Oral phosphatide
Micropowder silica gel
Microcrystalline cellulose
The preparation method: add about 40mL tetrahydrofuran (THF) in the mixing of the oral phosphatide of 1.0g and 0.25g activeconstituents, stirring at room to solution is clarified, and 40 ℃ of decompression rotary evaporations obtain the mixture of activeconstituents and phosphatide except that desolvating.Phospholipid complex is transferred in the mortar, and adds 0.5gTween-80 and 2mL water, grind evenly.After adding 1.0g micropowder silica gel blots water in above-mentioned mixed system, add 0.2g Microcrystalline Cellulose (MCC) again and grind even.Cross 30 mesh sieves, granulate, 60 ℃ are drying to obtain.The heavy 295mg of each capsule, active component content 25mg.
The preparation of embodiment 7 Indomethacin 5-fluorouracil methyl ester tablets:
Activeconstituents 25mg
Lactose 180mg
W-Gum 40mg
Magnesium Stearate 5mg
The preparation method: activeconstituents, lactose and starch are mixed, and water is evenly wetting, the mixture after wetting is sieved and drying, after sieve, adds Magnesium Stearate, and then with the mixture compressing tablet, every heavy 250mg contains activeconstituents 25mg.
Claims (5)
1, Indomethacin 5-fluorouracil methyl ester is characterized in that: this structural formula of compound is as follows:
2, the application of the described compound of claim 1 in preparation antitumour drug, anti-inflammation analgesis medicament.
3, Indomethacin 5-fluorouracil methyl ester according to claim 1 is characterized in that: this compound can be used as activeconstituents, makes various formulations with pharmaceutically acceptable carrier and/or mixed with excipients.
4, a kind of preparation method of Indomethacin 5-fluorouracil methyl ester according to claim 1 is characterized in that: by methylene radical 5-FU and IDM are combined into Indomethacin 5-fluorouracil methyl ester.
5, according to the preparation method of the described Indomethacin 5-fluorouracil methyl ester of claim 4, it is characterized in that: the process that 5-FU and IDM are combined into Indomethacin 5-fluorouracil methyl ester is as follows by methylene radical, 5-FU and formalin are after heated and stirred to solid dissolves fully in 60 ℃ of water-baths, continue reaction 50min, underpressure distillation removes anhydrates and excessive formaldehyde, get water white intermediate product 1,3-dihydroxymethyl-5-FU; To wherein adding anhydrous acetonitrile, IDM, N, N-dicyclohexyl carbimide, N, N-dimethyl aminopyridine, stirring at room reacted more than 72 hours, the degree that the thin-layer chromatography monitoring reaction carries out, after question response finishes, remove by filter precipitation, acetonitrile is reclaimed in the filtrate decompression distillation, resistates is dissolved in an amount of ethyl acetate, use dilute hydrochloric acid successively, saturated sodium bicarbonate aqueous solution, distilled water wash, organic layer is with anhydrous sodium sulfate drying, organic layer concentrate thick product, separate crude product with silica gel column chromatography, eluent is methylene dichloride-acetone, collect primary product, obtain the crystallization of yellow powder powder, productive rate is 30-70%.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7884124B2 (en) | 2006-06-30 | 2011-02-08 | Sepracor Inc. | Fluoro-substituted inhibitors of D-amino acid oxidase |
| US7893098B2 (en) | 2003-12-29 | 2011-02-22 | Sepracor Inc. | Pyrrole and pyrazole DAAO inhibitors |
| US7902252B2 (en) | 2007-01-18 | 2011-03-08 | Sepracor, Inc. | Inhibitors of D-amino acid oxidase |
| US8053603B2 (en) | 2006-01-06 | 2011-11-08 | Sunovion Pharmaceuticals Inc. | Tetralone-based monoamine reuptake inhibitors |
| US8097760B2 (en) | 2006-03-31 | 2012-01-17 | Sunovion Pharmacuticals Inc. | Preparation of chiral amides and amines |
| US8329950B2 (en) | 2005-07-06 | 2012-12-11 | Sunovion Pharmaceuticals Inc. | Process for preparation of trans 4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-1Napthalenamine |
| US8669291B2 (en) | 2007-05-31 | 2014-03-11 | Sunovion Pharmaceuticals Inc. | Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors |
| US8877975B2 (en) | 2006-01-06 | 2014-11-04 | Sunovion Pharmaceuticals Inc. | Cycloalkylamines as monoamine reuptake inhibitors |
| CN105777609A (en) * | 2016-04-13 | 2016-07-20 | 南京工业大学 | Preparation method of 7-benzoyl-1,3-indoline-2-ketone |
| CN110467574A (en) * | 2019-07-17 | 2019-11-19 | 蒋周倩 | Compound adamantane acid -5 FU 5 fluorouracil methyl esters synthesis and application |
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2006
- 2006-11-29 CN CNA2006101344153A patent/CN1962656A/en active Pending
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7893098B2 (en) | 2003-12-29 | 2011-02-22 | Sepracor Inc. | Pyrrole and pyrazole DAAO inhibitors |
| US8329950B2 (en) | 2005-07-06 | 2012-12-11 | Sunovion Pharmaceuticals Inc. | Process for preparation of trans 4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-1Napthalenamine |
| US8877975B2 (en) | 2006-01-06 | 2014-11-04 | Sunovion Pharmaceuticals Inc. | Cycloalkylamines as monoamine reuptake inhibitors |
| US10562878B2 (en) | 2006-01-06 | 2020-02-18 | Sunovion Pharamceuticals Inc. | Cycloalkylamines as monoamine reuptake inhibitors |
| US8053603B2 (en) | 2006-01-06 | 2011-11-08 | Sunovion Pharmaceuticals Inc. | Tetralone-based monoamine reuptake inhibitors |
| US9868718B2 (en) | 2006-01-06 | 2018-01-16 | Sunovion Pharmaceuticals Inc. | Cycloalkylamines as monoamine reuptake inhibitors |
| US8524950B2 (en) | 2006-03-31 | 2013-09-03 | Sunovion Pharmaceuticals Inc. | Preparation of chiral amides and amines |
| US8097760B2 (en) | 2006-03-31 | 2012-01-17 | Sunovion Pharmacuticals Inc. | Preparation of chiral amides and amines |
| US7884124B2 (en) | 2006-06-30 | 2011-02-08 | Sepracor Inc. | Fluoro-substituted inhibitors of D-amino acid oxidase |
| US7902252B2 (en) | 2007-01-18 | 2011-03-08 | Sepracor, Inc. | Inhibitors of D-amino acid oxidase |
| US8669291B2 (en) | 2007-05-31 | 2014-03-11 | Sunovion Pharmaceuticals Inc. | Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors |
| US9586888B2 (en) | 2007-05-31 | 2017-03-07 | Sunovion Pharmaceuticals Inc. | Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors |
| CN105777609A (en) * | 2016-04-13 | 2016-07-20 | 南京工业大学 | Preparation method of 7-benzoyl-1,3-indoline-2-ketone |
| CN110467574A (en) * | 2019-07-17 | 2019-11-19 | 蒋周倩 | Compound adamantane acid -5 FU 5 fluorouracil methyl esters synthesis and application |
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Application publication date: 20070516 |