CN1214264A - Sulfanilamide derivative for diagnosis and treatment of tumor and its preparation - Google Patents

Sulfanilamide derivative for diagnosis and treatment of tumor and its preparation Download PDF

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CN1214264A
CN1214264A CN97106657A CN97106657A CN1214264A CN 1214264 A CN1214264 A CN 1214264A CN 97106657 A CN97106657 A CN 97106657A CN 97106657 A CN97106657 A CN 97106657A CN 1214264 A CN1214264 A CN 1214264A
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sulfadiazine
peg
formula
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tumor
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谈立松
厉立斌
粟波
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Shanghai No1 Pulmonary Department Hospital
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Shanghai No1 Pulmonary Department Hospital
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Abstract

The present invention relates to a kind of sulfadiazine derivative with antineoplastic effect. The derivative can gather selectively at the tumor part so that it has high cure effect and less side effect. It may become developer for tumor diagnosis. The present invention also provides its preparation process.

Description

The sulphone amide derivative and the preparation method that are used for diagnosing tumor and treatment
The present invention relates to sulphone amide derivative and preparation method.Specifically relate to sulphone amide derivative and preparation method that a class has diagnosing tumor and treatment using value.
As far back as the fifties in this century, people have found that sulfonamide can concentrate at the tumor locus selectivity, and for example SD.Stevens has reported that at Science 112,561 (1950) the concentration ratio liver of 2-sulfanilamidopyrazine. in rat Walker tumor tumor is high four times.The sixties, people such as N.Calvert are at Europ.J.Cancer 4,627 (1968) have reported that sulfadiazine also has similar close tumor distribution character, and the concentrate effect of sulfanilamide in tumor is than 10 times of common drug object heights, and tumor after deliberation also has S180 sarcoma, NK lymphoma, PC plasmocytoma etc.People such as the seventies G.Abel are at Europ.J.Cancer 9,49 (1973) have narrated the aniline aminoterminal of attempting at sulfadiazine introduces chlormethine, the anticarcinogen that preparation is concentrated at tumor locus, but show through isotopic tracing, do not obtain expected results, tumor/liver ratio is 0.3.
The objective of the invention is to develop a kind of can concentrating, isotope or cancer therapy drug are carried to tumor locus, be used for diagnosing tumor and treatment at tumor locus.
It is characterized in that sulfanilamide and radiosiotope or cancer therapy drug are crosslinked by intermediate arm, become a kind of dual-function compound.
Innovation part of the present invention is to introduce linking arm at the sulfonamido end of sulfanilamide.Connect metal isotope chelating agent at the end of linking arm and be used for the chelating radioactive metal ion, or connect cancer therapy drug.Animal test results proves that this process does not influence sulfanilamide and concentrates characteristic and isotope or antitumor drug are carried into tumor locus in tumor.
Utilize sulfanilamide in the tumor locus characteristic that concentrates, to diagnose with isotope enrichment in tumor locus, can use γ-camera technique diagnosing tumour: lethal isotope is carried to tumor locus, can be used for the tumor internal radiotherapy: cancer therapy drug is carried to tumor locus, can improve chemotherapeutics in tumor locus concentration, improve curative effect, reduce side effect.
Sulphonamide derivatives of the present invention has following general formula: In the formula: R 1Be NH 2, CH 3, CH 3Groups such as CONH.R 2For pyrimidine, pyrazine and other are used to prepare each heterocyclic compounds of sulfonamide.L is Polyethylene Glycol (PEG), methylene formyl hexamethylene diamine, methylene formamido group caproic acid etc.R 3Be the energy chelating 111In, 99mTc, 188Re, 186Re, 90Y, 67Isotopic chelating agent of metals such as Cu or cancer therapy drug.
Chemical compound of the present invention has R 1For acetylamino, L are Polyethylene Glycol (PEG), R 3Be the sulfadiazine derivant of diethylamino five acetic acid (DTPA), its chemical structural formula is as follows:
Figure A9710665700072
The animal test results of this chemical compound of N-acetylsulfanilamide pyrimidine-PEG-DTPA (formula II) is as follows: one. materials and methods (1) isotopic labeling:
99mTc reduces with stannous chloride-vitamin C restoring system.After the reduction 99mTc joins in the SD-PEG-DTPA aqueous solution that concentration is 1mg/ml.After room temperature is placed half an hour, identify with common filter paper chromatography in normal saline. 111The labelling of In is with 1ml 111InCl 3Be added in the dissolved SD-PEG-DTA solution of pH3.5 acetate buffer solution (1mg/ml).Room temperature is identified with above-mentioned identical tomographic system after placing half an hour.(2) animal experiment:
Lotus has S 180The Kunming mouse of sarcoma is provided by Shanghai institute of Pharmaceutical Industry pharmacological room.Lotus has the nude mice of people source tumor to be provided by medicine institute of the Chinese Academy of Sciences and Shanghai City tumor institute Animal House.Isotope-labeled sulphone amide derivative is all through lumbar injection.Through different time, pluck the eyeball blood-letting, disconnected neck is put to death mice, dissects the weighing respectively of each internal organs and tumor mass, measures radioactive intensity simultaneously.The specific activity of each tissue is: cpm/ gram tissue two. the CONCENTRATION DISTRIBUTION of experimental result (1) N-acetyl-sulfadiazine-PEG-DTPA label isotope in mice S180 sarcoma model the results are shown in Table 1.: table 1. isotopic labeling N-acetyl-sulfadiazine-PEG-DTPA is at mice S 180The ratio of specific activity and normal internal organs in the tumor
Isotope Number of mice Time (h) T/NT ratio (x ± s)
The heart Lung Liver Spleen Kidney Bone Flesh Blood
153Sm ?1 ?1 ??6 ?12 ?3.59 ?2.3 ?2.8 ?0.24 ?3.98 ?6.18 ?2.19 ?11.2
99mTc ?4 ?3 ??6 ?12 ?5.4±3.2 ?12.1±2.3 2.8±1.3 1.7±0.13 ?5.7±0.9 ?5.4±0.7 ?0.7±0.3 ?0.67±0.06 ?12.3±6.1 ?3.7±2.2 ?6.5±1.1
99mTc ?4 ?12 ?3.8±1.9 2.8±1.3 0.8±0.3 ?1.5±0.7 ?0.07±0.03 2.3±0.6 ?5.6±0.4 ?5.7±2.0
111In ?4 ?4 ?24 ?48 6.1±2.0 8.0±2.9 3.4±0.8 6.7±3.1 0.8±0.3 2.1±0.1 ?1.8±0.7 ?2.1±1.4 ?0.1±0.01 ?0.15±0.08 3.0±1.0 3.5±1.5 ?4.1±0.4 ?6.0±2.0 ?9.6±6.6 ?23.2±10
Table 1. result shows the specific activity of sulfadiazine derivant at tumor locus, except that kidney, all than normal internal organs height, and prolongs in time and further raising is arranged, and shows that The compounds of this invention can concentrate at the tumor locus selectivity.(2) the N-acetyl-sulfadiazine-CONCENTRATION DISTRIBUTION of PEG-DTPA label isotope in the nude mice tumor model the results are shown in Table 2.: table 2. isotopic labeling N-acetyl-sulfadiazine-PEG-DTPA is in the distribution of nude mice tumor tissues and normal structure
Tumor type The Mus number T/NT ratio (x ± s)
The heart Lung Liver Spleen Kidney Bone Flesh Blood
????LAX ????H139 ?HO-8910 ????H128 ????1 ????3 ????3 ????4 ??????2.06 ??3.0±1.2 ?5.95±2.8 ?2.6±0.08 ???????2.09 ???1.3±0.3 ??3.76±2.4 ?1.07±0.05 ???????0.4 0.07±0.18 ?0.8±0.11 ?0.76±0.4 ???????1.27 ?0.95±0.19 ??1.9±0.65 ?1.86±0.17 ???????0.08 ?0.08±0.03 ??0.28±0.1 ?0.15±0.07 ????????0.9 ?0.74±0.28 ???2.2±0.8 ??3.1±0.65 ??????1.7 ?4.3±1.6 ?8.1±2.8 ?4.56±23 ???????4.8 ?1.9±0.56 ?3.3±0.56 ?1.7±0.17
LAX adenocarcinoma of lung H139 hepatocarcinoma HO-8910 ovarian cancer H128 small cell lung cancer
Table 2 result is presented at the sulfonamido end of sulfadiazine and introduces linking arm, connect functional group DTPA after, the characteristic that has still kept sulfanilamide parent tumor to distribute.In the nude mice that has inoculated people source tumor cell line, obtained the result similar to animal tumor.
Behind the sulfadiazine derivant label isotope of the present invention, become the SPECT hypersensitivity of a new generation, the tumor diagnosing developing agent of broad spectrum activity.Be applicable to polytype diagnosing tumor, will provide powerful foundation for video picture, the location of tumor.
If use 133Re, 186Re, 67Cu, 90Y etc. have the metal isotope of beta rays to replace 99mTc and 111In can be used for the internal radiotherapy of tumor.
If connect cancer therapy drug then the portability cancer therapy drug can improve chemotherapeutics in tumor locus concentration to tumor locus, improve curative effect, the reduction side effect.
Chemical compound of the present invention has R 1For acetylamino, L are methylene formyl hexamethylene diamine, R 3Be the sulfadiazine derivant of diethylamino triamine five acetic acid (DTPA), its chemical structural formula is as follows:
Figure A9710665700101
N-acetylsulfanilamide pyrimidine-methylene formyl hexamethylene diamine-DTPA (formula III)
The characteristics of this chemical compound are sulfadiazines by molecular weight is that 158 micromolecule is mutually crosslinked with DTPA.This chemical compound is because structure clearly is expected to become diagnosis or medicine for treatment product.Its animal test results is as follows:
One. materials and methods
(1) label isotope is identical with preceding experiment
(2) animal test method is identical with preceding experiment.
Two. result of the test
Obtain the result similar, see Table 3., table 4 to first chemical compound.
The ratio of table 3. isotopic labeling N-acetylsulfanilamide pyrimidine methylene carbonyl hexamethylene diamine DTPA specific activity and normal internal organs in mice S180 tumor
Isotope Number of mice Time (h) T/NT ratio (x ± s)
The heart Lung Liver Swollen Kidney Bone Flesh Blood
???? 99mTc ????3 ????3 ????6 ????12 ?5.32±1.1 ?11.3±2.2 2.7±0.8 4.26±0.4 0.45±0.1 0.33±0.1 ?4.35±1.5 ?4.02±1.3 0.35±0.08 0.24±0.08 0.85±0.1 0.97±0.1 2.11±0.4 3.47±0.3 ?5.53±1.4 ?9.95±1.8
??? 111In ????4 ????24 ?10.53.4 6.231.8 0.730.3 ?2.0±0.6 0.5±0.08 2.40.3 5.71.2 ?13.7±2.2
Table 4. isotopic labeling N-acetylsulfanilamide pyrimidine methylene formyl diamidogen DTPA in the distribution of nude mice tumor and normal structure
Tumor type The Mus number T8NT ratio (x ± s)
The heart Lung Liver Spleen Kidney Bone Flesh Blood
?LAX ?HO-8910 ?H128 ?1 ?3 ?3 4.270.3 ?6.88±1.3 ?5.02±0.74 2.500.2 3.92±0.4 2.3±0.25 ?0.380.12 ?0.94±0.21 ?0.83±0.2 ?3.501.10 ?3.75±0.54 ?2.76±0.15 0.110.02 0.45±0.1 0.23±0.01 ?1.090.24 ?3.48±1.6 ?3.62±0.48 ?3.700.4 ?5.73±1.2 ?4.44±1.2 6.100.46 5.95±0.56 4.21±0.37
The LAX adenocarcinoma of lung, HO-8910 ovarian cancer, H128 small cell lung cancer
Sulfadiazine methylene carbonyl hexamethylene diamine derivant of the present invention as a kind of close tumor carrier indicium isotope after, will become the hypersensitivity, the tumor γ-photographic diagnostics developer of broad spectrum activity of a new generation.Be applicable to polytype diagnosing tumor, will provide powerful foundation for video picture, the location of tumor.
If complexation 188Re, 186Re, 67Cu, 90Y etc. have the metal isotope of beta rays, can be used for the internal radiotherapy of tumor.
If connect cancer therapy drug then the portability cancer therapy drug can improve chemotherapeutics in tumor locus concentration to tumor locus, improve curative effect, the reduction side effect.
Chemical compound of the present invention has R 1For amino, L are Polyethylene Glycol (PEG), R 3Be the sulfadiazine derivant of methotrexate (MTX), its chemical structural formula is as follows:
Figure A9710665700111
The result is as follows for its zoopery of sulfadiazine-PEG-MTX (formula IV): one. material and method: the preparation of (1) medicament
Sulfadiazine-PEG-MTX is made into normal saline and contains MTX 0.4mg/ml concentration, and filtering with microporous membrane sterilization back is stand-by.MTX is made into normal saline and contains MTX 0.4mg/ml concentration, with molar concentration such as sulfadiazine-PEG-MTX, to do the contrast treatment.(2) treatment of animals test:
Lotus has S 180The Kunming mouse of sarcoma is provided by Shanghai institute of Pharmaceutical Industry pharmacological room.Be divided into two groups of experimental group and matched groups, 10 every group.Experimental group is through lumbar injection sulfadiazine-PEG-MTX medicament 200 μ l, and matched group is through lumbar injection MTX medicament 200 μ l, and equal conditions is raised down.With tumor block size, survival rate is the index evaluation curative effect of medication.Two. test of cure result such as table 5.:
The therapeutic evaluation of table 5.N-acetylsulfadiazine-PEG-MTX treatment mice S180 sarcoma
The example number Survival volume after 30 days (only) Average tumor heavy (gram)
The matched group experimental group ????10 ????10 ????4 ????7 ????1.56±0.36 ????0.54±0.11
The result shows that the effect of isomolar sulfadiazine-PEG-MTX treatment mice S180 sarcoma is better than MTX itself, is a kind of new close tumor chemotherapeutic drug.
Chemical compound of the present invention has R 1For acetylamino, L are methylene formyl hexamethylene diamine, R 3Be the sulfadiazine derivant of ametycin (MMC), its chemical structural formula is as follows:
Figure A9710665700121
The N-acetylsulfanilamide pyrimidine-result is as follows for its zoopery of methylene formyl hexamethylene diamine-MMC (formula VI):
One. material and method:
(1) medicament preparation
N-acetylsulfanilamide pyrimidine-methylene carbonyl-hexamethylene diamine-MMC is made into normal saline and contains MMC 0.2mg/ml concentration, and filtering with microporous membrane sterilization back is stand-by.Medicinal MMC is made into the solution that concentration is 0.2mg/ml with normal saline, with N-acetylsulfanilamide pyrimidine-methylene carbonyl-hexamethylene diamine-molar concentration such as MMC, to do the contrast treatment.
(2) treatment of animals test:
Lotus has S 180The Kunming mouse of sarcoma is provided by Shanghai institute of Pharmaceutical Industry pharmacological room.Be divided into two groups of experimental group and matched groups, 20 every group.Experimental group is through intravenous injection N-acetylsulfanilamide pyrimidine-methylene formyl hexamethylene diamine-MMC medicament 200 μ l, and matched group is through lumbar injection MMC medicament 200 μ l, and equal conditions is raised down.With tumor block size and survival rate is the index evaluation curative effect of medication.
Two. the test of cure result
The results are shown in Table 6.:
The therapeutic evaluation of table 6.N-acetylsulfadiazine-methylene formyl hexamethylene diamine-MMC treatment mice S180 sarcoma
The example number Survival volume after 30 days (only) Average tumor heavy (gram)
The matched group experimental group ????20 ????20 ????9 ????16 ????1.15±0.23 ????0.47±0.16
The result shows that the effect of isomolar N-acetylsulfanilamide pyrimidine-methylene formyl hexamethylene diamine-MMC treatment mice S180 sarcoma is better than MMC itself, is a kind of new close tumor chemotherapeutic drug.
Another object of the present invention has provided the preparation method of above-mentioned all kinds of sulphone amide derivatives, and this method comprises the following steps: respectively
One. the L with formula (formula I) is PEG, R 1Preparation for the sulfadiazine-PEG-isopropyl alcohol-butanediamine of acetylamino
(1) preparation sulfadiazine sodium:
Sulfadiazine is dissolved in NaOH solution, transfers pH to 10-11 with acid, adds 10 times of amount ethanol, and collecting precipitation gets the sulfadiazine sodium crystallization;
(2) preparation sulfadiazine-PEG
Sulfadiazine sodium and oxirane place withstand voltage ampoule bottle, and at 85 ℃ of stirring reaction 3-5 days, adding methanol cessation reaction was dissolved in chloroform with reactant, produced precipitation with 5 amount ethyl acetate, filtered, and got sulfadiazine-PEG after the drying;
(3) preparation N-acetyl-sulfadiazine-PEG
Sulfadiazine-PEG is dissolved in sodium bicarbonate buffer liquid, drips acetic anhydride, and regulates pH9.0-10.0 with NaOH, uses the TNBS endpoint detection, makes N-acetyl-sulfadiazine-PEG;
(4) preparation N-acetyl-sulfadiazine-PEG-isopropyl alcohol-butanediamine
The epoxychloropropane that in sulfadiazine-PEG solution, adds capacity, in 50 ℃, stirring reaction 3 hours, cooling obtains precipitation.Be dissolved in the distilled water, add carbodiimide and excessive butanediamine, stirring reaction spends the night, and adds chloroform solubilizing reaction product after the solution concentration, and the elimination insoluble matter makes N-acetylsulfanilamide pyrimidine-PEG-isopropyl alcohol-butanediamine;
This preparation method makes, and respectively to go on foot the Product Validation result as follows:
(1) sulfadiazine-PEG:
The chemical compound that makes behind sulfadiazine sodium salt and the reacting ethylene oxide has the absworption peak of sulfadiazine at the 280nm place, can measure aniline amino with DMAB.Also can record amino existence with the TNBS method.Diazo reaction then shows atypical yellow.Absorb calculating molar concentration according to OD280, infer that its molecular weight is about 2500 dalton;
(2) N-acetylsulfanilamide pyrimidine-PEG:
Reactant no longer detects free amine group with the existence that DMAB and TNBS are measured to free amine group through the sulfadiazine-PEG of acetic anhydride processing;
(3) N-acetylsulfanilamide pyrimidine-PEG-isopropyl alcohol-butanediamine
To prepare one (4) part solution by Sephadex G10 (1.0 * 20cm).Detect amino with TNBS, can record two amino colour developing peaks.First peak is the contained amino of high molecular polymer, and second peak is unreacted butanediamine.Provable thus polymer C-terminal has connected butanediamine.With the content of OD280 calculating sulfadiazine, with TNBS mensuration amino content, with molecular weight is 2500 calculating, has N-acetyl-sulfadiazine-PEG of 70% to connect butanediamine approximately.
Two. the L with formula (formula I) is methylene formyl hexamethylene diamine, R 1Preparation for the N-acetyl-sulfadiazine-methylene formyl hexamethylene diamine of acetylamino
(1) sulfadiazine adds 2 times of excessive acetic anhydride, and 30 minutes postcooling of slow fire reacting by heating are to room temperature.The filtration of bleeding, distilled water drip washing obtains the acetylation sulfadiazine after the drying;
(2) acetylsulfadiazine is dissolved in the NaOH solution of 4 times of amounts, and pH10-11 is dissolved among the NaOH etc. the gram-molecular weight iodoacetic acid, and pH10-11, the two mixing are placed on 55 ℃ of heating magnetic agitation reaction 5 hours.Behind the reactant readjustment solution pH value to 8.0, low temperature crystallization, collecting precipitation get acetylsulfadiazine acetic acid white crystals;
(3) acetylsulfadiazine acetic acid and DCC, hexamethylene diamine are dissolved among the THF by mole ratio at 1: 1.2: 5,4 ℃ of magnetic agitation 2 days.Centrifugal removing in the distilled water that adds 8 times of amounts behind the insoluble matter, supernatant be with the n-butanol extraction extracting of 1/2 amount, and extract must the crystallization of sulfadiazine methylene carbonyl hexamethylene diamine behind vacuum drying and recrystallization;
This preparation method respectively to go on foot the Product Validation result as follows:
(1) acetylsulfadiazine:
Product has the 280nm characteristic absorption peak, and the amino chromogenic reaction feminine gender of TNBS, DMAB shows that former free amine group protected by acetyl group:
(2) acetylsulfadiazine acetic acid:
Show that through silica gel thin-layer chromatography two kinds of acidic materials are arranged in the reactant liquor, wherein a kind of is unreacted iodoacetic acid, and another kind of acidic materials are measured the sulfanilamide characteristic absorption peak that 280nm is arranged after recrystallization separates, and the amino colour developing of TNBS is negative.Show that this product is an acetylsulfadiazine acetic acid;
(3) acetylsulfadiazine methylene carbonyl hexamethylene diamine:
The reactant liquor sampling is with two main amino colour developing peaks are arranged after the Sephadex LH20 column chromatography for separation; the former is unreacted hexamethylene diamine; the latter has 280nm sulfanilamide characteristic absorption peak, and the chromatography behavior also is different from hexamethylene diamine, sulfadiazine, acetylsulfadiazine acetic acid in polyamide thin layer chromatography system.Show that hexamethylene diamine has been connected on the end of acetylsulfadiazine acetic acid;
Three. have the R of the parent nucleus of formula (formula I) 1Base is modified:
(1) acetylation: precursors such as sulfadiazine, 2-sulfanilamidopyrazine., sulfadiazine-PEG or sulfadiazine acetic acid add 2 times of excessive acetic anhydride, and 30 minutes postcooling of slow fire reacting by heating are to room temperature.The filtration of bleeding, distilled water drip washing obtains acetylation sulfadiazine class material after the drying.Carry out the synthetic work of back as raw material, can obtain R 1Base is the sulphonamide derivatives of acetylation modification:
(2) benzaldehydeization: precursor compounds such as sulfadiazine, 2-sulfanilamidopyrazine., sulfadiazine-PEG or sulfadiazine acetic acid are dissolved in sodium bicarbonate buffer liquid, drip benzaldehyde, and regulate pH9.0-10.0 with NaOH, and use the TNBS endpoint detection, make benzaldehyde sulfadiazine class material through recrystallization.Carry out the synthetic work of back as raw material, can obtain R 1Base is the sulphonamide derivatives of benzaldehyde modification or amido protecting:
(3) go benzaldehydeization: benzaldehyde sulfadiazine derivant is dissolved in 50% glacial acetic acid/methanol solution, places after 5 hours for 50 ℃, and the vacuum concentration drying must be sloughed the sulfadiazine derivant that the benzaldehyde base is protected behind chloroform/ether recrystallization.
(4) has the R of formula (formula I) parent nucleus 3Group connects: with connecting of functional group metal chelating agent or cancer therapy drug
(1) with the connecting of metal chelating agent DTPA
Synthetic band PEG linking arm sulphonamide derivatives is dissolved in an amount of chloroformic solution, add excessive ring DTPA, stirring reaction 24 hours is removed insoluble matter, adding ethyl acetate must precipitate, and will precipitate with chloroform, re-crystallizing in ethyl acetate to obtain dual-function compound: sulfanilamide-PEG-DTPA.The sulphone amide derivative of band methylene formyl hexamethylene diamine linking arm and the reaction condition of DTPA are to above-mentioned similar, and solvent is an aqueous solution, pH9.0, and product is passed through the SephadexG-10 chromatography purification, obtains: sulfanilamide-methylene formyl hexamethylene diamine-DTPA:
(2) with the connecting of cancer therapy drug
With activated carboxylic reagent the ametycin (MMC) of methotrexate (MTX), 1,3-propanedicarboxylic acid modification, the amycin (ADM) of 1,3-propanedicarboxylic acid modification are made the N-hydroxyl butanimide Acibenzolar of tool reactivity, stand-by:
Synthetic band linking arm sulphonamide derivatives parent nucleus is dissolved in an amount of NaHCO 3In the buffer, mix with suitably excessive cancer therapy drug Acibenzolar, transfer to pH9.0, oscillating reactions 30 minutes, with Sephadex G10 or Sephadex LH20 column chromatography or corresponding separation method separation end-product, promptly make dual-function compound sulfanilamide-linking arm-cancer therapy drug.
This preparation method respectively to go on foot the Product Validation result as follows:
(1) connecting of sulfanilamide parent nucleus and DTPA:
Crystallized product has 280nm sulfadiazine characteristic absorption peak, the amino chromogenic reaction feminine gender of TNBS, tool acidity, the chromatography behavior is different from DPTA in polyamide thin layer chromatography system, show that DTPA has been connected on the terminal amino group, its complexation function is by being confirmed with the isotopic complexing of metal.
(2) sulphonamide derivatives parent nucleus and cancer therapy drug connects
The cross-linking agent of MTX, MMC, ADM and sulphonamide derivatives is confirmed by silica gel thin-layer chromatography system and polyamide thin layer chromatography system and characteristic absorption peak thereof respectively.
(5) isotopic labeling has the sulfanilamide-linking arm-DTPA dual-function compound of logical formula I structure
99mThe Tc labelling adopts SnCl 2-Vit.C restoring system carries out.1mg/ml sulfanilamide-linking arm-DTPA solution 200 μ l adds pH4.0 and contains 0.5mg/ml SnCl 2, 0.1mg/mlVit.C reducing solution 200 μ l, add the TcO of 1-30mCi again 4-Leacheate.Room temperature was placed 30 minutes.With the normal saline is developing solvent, and ascending paper chromatography proof and this medicine are in complex status 99mTc accounts for 90%:
111The labelling of In is with 1ml 111InCl 3Be added in the dissolved sulfanilamide-linking arm of pH3.5 acetate buffer solution-DTPA solution (1mg/ml).Room temperature is identified with above-mentioned identical tomographic system after placing half an hour.The proof complexation 111The In ratio is about 95%:
Example one .N-acetylsulfadiazine-PEG-isopropyl alcohol-butanediamine-DTPA preparation
Medicinal sulfadiazine 5 grams are dissolved in 30ml, the 1M NaOH aqueous solution, transfer pH to 11 with the hydrochloric acid of 1M.Add 10 times of volume of ethanol precipitations, place centrifugal collection sulfadiazine sodium crystallization after a hour in the cryogenic refrigerator.Dry back productive rate is about 80%.
3 gram sulfadiazine sodium salts place withstand voltage 100ml glass ampoule bottles, add through the oxirane 20ml of overweight steaming and after adding magnetic stir bar to seal.Place in 85 ℃ of water-baths, reaction is after 3 days under the magnetic agitation, and Kaifeng adds 2ml methanol cessation reaction.Product is dissolved in the 5ml chloroform, and the centrifugal insoluble matter of removing adds 5 times of excessive ethyl acetate and makes the SD-PEG precipitation.Yield is about 90% behind the vacuum drying.
Take by weighing 2 gram SD-PEG and be dissolved in the carbonic acid buffer of 10m1 0.2mol/L pH9.0, oscillating condition drips acetic anhydride down, and keep pH about 9.0.Detect amino to reaching reaction end with TNBS.Add 100 microlitre epoxychloropropane.50 ℃, magnetic agitation reaction 3 hours.Add 200 microlitre butanediamine again, continue stirring reaction spend the night (about 12 hours).Solution is drained with centrifugal and vacuum drier vacuum.
With 2ml chloroform solubilizing reaction product, remove insoluble matter.Be dissolved in again in the chloroform with the ethyl acetate post precipitation, add excessive CDTPA 100mg.Stirring reaction is 24 hours under the room temperature.Centrifugal removing do not dissolved part, with 10 times of excessive ethyl acetate precipitated products.Behind recrystallization, derive from the packetize compound again, the preparation of about 0.5 gram example, two .N-acetylsulfadiazine-methylene carbonyl-hexamethylene diamine-DTPA
Medicinal sulfadiazine 6 grams add acetic anhydride 15ml, and slow fire refluxes 30 minutes postcooling to room temperature.The buchner funnel pumping rate, distilled water drip washing, dried acetylsulfadiazine crystallization, productive rate is about 90%.
5 gram acetylsulfadiazines are dissolved in the 20ml 2M NaOH solution, and 3.5 gram iodoacetic acid are dissolved in the 5ml 4M NaOH solution, and adjust pH is 10-11.Behind the two mixing, 55 ℃ of heating magnetic agitation reaction 5 hours.Reactant is through low-temperature precipitation, and with behind chloroform/ether recrystallization white sulfadiazine acetic acid crystallization.Productive rate is about 85%.
4 gram sulfadiazine acetic acid are dissolved among the 20ml THF, add 3.6 milliliters of the THF solution of the recrystallization DCC of 1g/ml concentration, stir slowly to add hexamethylene diamine 5.4 grams down 0 ℃ of lower magnetic force stirring reaction two days.The centrifugal post precipitation that goes of reactant is concentrated into 5 milliliters; reuse 30 ml distilled waters dissolving behind the acetonitrile precipitation; the centrifugal post precipitation NaOH adjust pH to 11 that goes; add 20 milliliters of n-butyl alcohol extractings at twice; extract with 5 ml distilled water washed twice after; the vacuum concentration drying is collected product acetylsulfadiazine methylene formyl hexamethylene diamine.Productive rate is about 75%.
Get 0.2 gram acetylsulfadiazine methylene carbonyl hexamethylene diamine and be dissolved in 1ml 2M NaHCO 3In; add excessive CDTPA under the vigorous stirring, to the amino colour developing of TNBS feminine gender, stop, adding 1 milliliter of n-butanol extraction extracting; extract obtains end-product N-acetylsulfanilamide pyrimidine-methylene carbonyl-hexamethylene diamine-DTPA after using chloroform/ether recrystallization once after the vacuum concentration drying.Weigh about 0.16 the gram.Example three. sulfadiazine-PEG-isopropyl alcohol-butanediamine-DTPA preparation
Compare with the preparation method of N-acetylsulfanilamide pyrimidine-PEG-isopropyl alcohol-butanediamine-DTPA, increased amido protecting and de-protected process.
Medicinal sulfadiazine 5 grams are dissolved in 30ml, the 1M NaOH aqueous solution, transfer pH to 11 with the hydrochloric acid of 1M.Add 10 times of volume of ethanol precipitations, place centrifugal collection sulfadiazine sodium crystallization after a hour in the cryogenic refrigerator.Dry back productive rate is about 80%.
3 gram sulfadiazine sodium salts place withstand voltage 100ml glass ampoule bottles, add through the oxirane 20ml of overweight steaming and after adding magnetic stir bar to seal.Place in 85 ℃ of water-baths, reaction is after 3 days under the magnetic agitation, and Kaifeng adds 2ml methanol cessation reaction.Product is dissolved in the 5ml chloroform, and the centrifugal insoluble matter of removing adds 5 times of excessive ethyl acetate and makes the SD-PEG precipitation.Yield is about 90% behind the vacuum drying.
Take by weighing 2 gram SD-PEG and be dissolved in the carbonic acid buffer of 10ml 0.2mol/L pH9.0, oscillating condition drips benzaldehyde down, and keep pH about 9.0.Detect amino to reaching reaction end with TNBS.Add 100 microlitre epoxychloropropane.50 ℃, magnetic agitation reaction 3 hours.Add 200 microlitre butanediamine again, continue stirring reaction spend the night (about 12 hours).Solution is drained with centrifugal and vacuum drier vacuum.
With 2ml chloroform solubilizing reaction product, remove insoluble matter.Add excessive CDTPA100mg.Stirring reaction is 24 hours under the room temperature.Centrifugal removing do not dissolved part, with 10 times of excessive ethyl acetate precipitated products.Behind recrystallization, get the whitening compound again, about 1.0 grams
Benzaldehyde sulfadiazine-PEG-isopropyl alcohol-butanediamine-DTPA is dissolved in 50% glacial acetic acid/methanol solution; place after 5 hours for 50 ℃; the vacuum concentration drying must be sloughed the sulfadiazine-PEG-isopropyl alcohol-butanediamine-DTPA of benzaldehyde base protection behind chloroform/ether recrystallization.Example four. the preparation of sulfadiazine-methylene carbonyl-hexamethylene diamine-DTPA
Medicinal sulfadiazine 6 grams are dissolved in the carbonic acid buffer of 20ml 0.2mol/L pH9.0, and oscillating condition drips benzaldehyde down, and keep pH about 9.0.Detect amino to reaching reaction end with TNBS.Add 10 times of excessive ether sedimentations, obtain benzaldehyde-sulfadiazine after the vacuum concentration drying, productive rate is about 90%.
5 gram benzaldehyde-sulfadiazines are dissolved in the 15ml 2M NaOH solution, and 3.5 gram iodoacetic acid are dissolved in the 5ml 4M NaOH solution, and adjust pH is 10-11.Behind the two mixing, 55 ℃ of heating magnetic agitation reaction 5 hours.Reactant is through low-temperature precipitation, and with behind the chloroform % ether recrystallization white benzaldehyde-sulfadiazine acetic acid crystallization.Productive rate is about 85%.
4 gram benzaldehyde-sulfadiazine acetic acid are dissolved among the 20ml 2M THF, add 3.6 milliliters of the THF solution of the recrystallization DCC of 1g/ml concentration, stir slowly to add hexamethylene diamine 5.4 grams down 0 ℃ of lower magnetic force stirring reaction two days.The centrifugal post precipitation that goes of reactant is concentrated into 5 milliliters, reuse 30 ml distilled waters dissolving behind the acetonitrile precipitation, the centrifugal post precipitation NaOH adjust pH to 11 that goes, add 20 milliliters of n-butyl alcohol extractings at twice, extract with 5 ml distilled water washed twice after, the vacuum concentration drying is collected product benzaldehyde-sulfadiazine methylene carbonyl hexamethylene diamine.Productive rate is about 75%.
Get 0.2 gram sulfadiazine methylene formyl hexamethylene diamine and be dissolved in 1ml 2M NaHCO 3In; add excessive CDTPA under the vigorous stirring, to the amino colour developing of TNBS feminine gender, stop, adding 1 milliliter of n-butanol extraction extracting; extract obtains end-product N-acetylsulfanilamide pyrimidine-methylene formyl hexamethylene diamine-DTPA after using chloroform/ether recrystallization once after the vacuum concentration drying.Weigh about 0.6 the gram.
Benzaldehyde-sulfadiazine-methylene formyl diamidogen-DTPA is dissolved in 50% glacial acetic acid/methanol solution; place after 5 hours for 50 ℃; the vacuum concentration drying must be sloughed the sulfadiazine-methylene formyl hexamethylene diamine-DTPA of benzaldehyde base protection behind chloroform/ether recrystallization.Example five. have the dual-function compound sulfanilamide-linking arm-DTPA of logical formula I structure
Isotopic labeling
N-acetylsulfanilamide pyrimidine-methylene formyl diamidogen-DTPA, sulfadiazine-PEG-isopropyl alcohol-butanediamine-DTPA, N-acetylsulfanilamide pyrimidine-methylene carbonyl-hexamethylene diamine-DTPA, sulfadiazine-methylene carbonyl-hexamethylene diamine-DTPA etc. sulfonamides dual-function compound of containing metal chelating agent is made into 1mg/ml concentration with distilled water or pH3.5 acetate buffer solution.
Concentration is 0.5mg/ml SnCl 20.03N HCl solution 2ml and the Vit.C solution 2ml mixing of 0.1mg/ml after with HCl/NaOH adjust pH to 4.0, stand-by as reducing solution.
99mThe Tc labelling adopts SnCl 2-Vit.C restoring system carries out.Above-mentioned 1mg/ml sulfanilamide-linking arm-DTPA solution 200 μ l adds reducing solution 200 μ l, adds the TcO of 1-30mCi again 4-Leacheate.Room temperature was placed 30 minutes.With the normal saline is developing solvent, and ascending paper chromatography proof and this medicine are in complex status 99mTc accounts for 90%.
111The labelling of In is with 1ml 111InCl 3Be added in the dissolved sulfanilamide-linking arm of pH3.5 acetate buffer solution-DTPA solution (1mg/ml).Room temperature is identified with above-mentioned identical tomographic system after placing half an hour.The proof complexation 111The In ratio is about the preparation of 95% example, six .N-acetyl-sulfadiazine-PEG-MTX
Take by weighing MTX 50mg, be dissolved in 3 ml methanol, add the 50mg N-hydroxy-succinamide, carbodiimide 100mg, 20 ℃ were reacted 6 hours, removed excessive N-hydroxy-succinamide through the SephadexLH20 column chromatography for separation again, the dry MTX Acibenzolar that gets of vacuum concentration.
Take by weighing N-acetyl-sulfadiazine-PEG-isopropyl alcohol-butanediamine 30mg, be dissolved in 1ml 0.2M Na 2CO 3In the solution.MTX Acibenzolar 10mg is dissolved among the 150 microlitre DMF, drips in the Na of N-acetyl-sulfadiazine-methylene carbonyl-hexamethylene diamine 2CO 3In the solution, with Na 2CO 3Solution is kept pH9.0, oscillating reactions 30 minutes.Remove unreacted MMC Acibenzolar through the SephadaxG10 separation, collect end-product N-acetyl-sulfadiazine-PEG-isopropyl alcohol-butanediamine-MTX, the vacuum concentration drying.The preparation of example seven .N-acetyl-sulfadiazines-methylene carbonyl-hexamethylene diamine-MMC
20mg MMC is dissolved in 5 milliliters of THF, adds the 21mg glutaric anhydride, and 20 ℃ were reacted 3 hours, and used dissolve with methanol behind the vacuum drying.Remove excessive glutaric anhydride through Scphadex LH20 column chromatography for separation; The chromatography product adds 20 mgN-N-Hydroxysuccinimide, carbodiimide 50mg, and 20 ℃ were reacted 6 hours, removed excessive N through Sephadex LH20 column chromatography for separation again ,-N-Hydroxysuccinimide, the dry MMC Acibenzolar that gets of vacuum concentration.
Take by weighing N-acetyl-sulfadiazine-methylene methyl ether hexamethylene diamine 30mg, be dissolved in 1ml0.2M Na 2CO 3In the solution.MMC Acibenzolar 5mg is dissolved among the 150 microlitre DMF, drips in the Na of N-acetyl-sulfadiazine-methylene formyl hexamethylene diamine 2CO 3In the solution, with Na 2CO 3Solution is kept pH49.0, oscillating reactions 30 minutes.Separate with SephadexLH20 through Sephadax G10 and to remove unreacted MMC Acibenzolar, collect end-product N-acetyl-sulfadiazine-methylene formyl hexamethylene diamine-MMC, the vacuum concentration drying.

Claims (3)

1. sulphone amide derivative with general formula (formula I) of diagnosing tumor and therapeutical effect:
Figure A9710665700021
R in the formula 1Be NH 2, CH 3, CH 3CONH etc. do not influence sulfanilamide in concentrate characteristic or have of tumor locus
Be beneficial to the group that sulfanilamide concentrates at tumor locus.R 2For pyrimidine, pyrazine and other are used to prepare each heterocyclic compounds of sulfonamide.L is Polyethylene Glycol (PEG), methylene formyl hexamethylene diamine, methylene formamido group caproic acid etc.R 3Close for stinging 111In, 99mTc, 188Re, 186Re, 90Y, 67Isotopic chelating agent of metals such as Cu or cancer therapy drug.
2. the preparation method of the capable biology of general formula as claimed in claim 1 (formula I) sulfonamides,
It is characterized in that this method comprises the following steps:
One. the L with formula (formula I) is PEG, R 1Preparation for the sulfadiazine-PEG-isopropyl alcohol-butanediamine of acetylamino
(1) preparation sulfadiazine sodium:
Sulfadiazine is dissolved in NaOH solution, transfers pH to 10-11 with acid, adds 10 times of amount ethanol, and collecting precipitation gets the sulfadiazine sodium crystallization.
(2) preparation sulfadiazine-PEG
Sulfadiazine sodium and oxirane place withstand voltage ampoule bottle, and at 85 ℃ of stirring reaction 3-5 days, adding methanol cessation reaction was dissolved in chloroform with reactant, produced precipitation with 5 times of amount ethyl acetate, filtered, and got sulfadiazine-PEG after the drying.
(3) preparation N-acetyl-sulfadiazine-PEG
Sulfadiazine-PEG is dissolved in sodium bicarbonate buffer liquid, drips acetic anhydride, and regulates pH9.0-10.0 with NaOH, uses the TNBS endpoint detection, makes N-acetyl-sulfadiazine-PEG.
(4) preparation N-acetyl-sulfadiazine-PEG-isopropyl alcohol-butanediamine adds the epoxychloropropane of capacity in sulfadiazine-PEG solution, in 50 ℃, and stirring reaction 3 hours, cooling obtains precipitation.Be dissolved in the distilled water, add carbodiimide and excessive butanediamine, stirring reaction spends the night, and adds chloroform solubilizing reaction product after the solution concentration, and the elimination insoluble matter makes N-acetylsulfanilamide pyrimidine-PEG-isopropyl alcohol-butanediamine.
Two. the L with formula (formula I) is that methylene formyl hexamethylene diamine, R1 are the preparation of the N-acetyl-sulfadiazine-methylene formyl hexamethylene diamine of acetylamino
(1) sulfadiazine adds 2 times of excessive acetic anhydride, and 30 minutes postcooling of slow fire reacting by heating are to room temperature.The filtration of bleeding, distilled water drip washing obtains the acetylation sulfadiazine after the drying.
(2) acetylsulfadiazine is dissolved in the NaOH solution of 4 times of amounts, and pH10-11 is dissolved among the NaOH etc. the gram-molecular weight iodoacetic acid, and pH10-11, the two mixing are placed on 55 ℃ of heating magnetic agitation reaction 5 hours.Behind the reactant readjustment solution pH value to 8.0, low temperature crystallization, collecting precipitation get acetylsulfadiazine acetic acid white crystals.
(3) acetylsulfadiazine acetic acid and DCC, hexamethylene diamine are dissolved among the THF by mole ratio at 1: 1.2: 5,4 ℃ of magnetic agitation 2 days.Centrifugal removing in the distilled water that adds 8 times of amounts behind the insoluble matter, supernatant are with the n-butanol extraction extracting of 1/2 amount, and extract must the crystallization of sulfadiazine methylene carbonyl hexamethylene diamine behind vacuum drying and recrystallization.
Three. have the R of the parent nucleus of formula (formula I) 1Base is modified:
(1) acetylation: precursors such as sulfadiazine, 2-sulfanilamidopyrazine., sulfadiazine-PEG or sulfadiazine acetic acid add 2 times of excessive acetic anhydride, and 30 minutes postcooling of slow fire reacting by heating are to room temperature.The filtration of bleeding, distilled water drip washing obtains acetylation sulfadiazine class material after the drying.Carry out the synthetic work of back as raw material, can obtain R 1Base is the sulphonamide derivatives of acetylation modification.
(2) benzaldehydeization: precursor compounds such as sulfadiazine, 2-sulfanilamidopyrazine., sulfadiazine-PEG or sulfadiazine acetic acid are dissolved in sodium bicarbonate buffer liquid, drip benzaldehyde, and regulate pH9.0-10.0 with NaOH, and use the TNBS endpoint detection, make benzaldehyde sulfadiazine class material through recrystallization.Carry out the synthetic work of back as raw material, can obtain R 1Base is the sulphonamide derivatives of benzaldehyde modification or amido protecting.
(3) go benzaldehydeization: benzaldehyde sulfadiazine derivant is dissolved in 50% glacial acetic acid/methanol solution, places after 5 hours for 50 ℃, and the vacuum concentration drying must be sloughed the sulfadiazine derivant that the benzaldehyde base is protected behind chloroform/ether recrystallization.
(4) has the R of formula (formula I) parent nucleus 3Group connects: with connecting of functional group metal chelating agent or cancer therapy drug
(1) with the connecting of metallic bond DTPA
The molten dried an amount of chloroformic solution of synthetic band PEG linking arm sulphonamide derivatives, add excessive ring DTPA, stirring reaction 24 hours is removed insoluble matter, adding ethyl acetate must precipitate, and will precipitate with chloroform, re-crystallizing in ethyl acetate to obtain dual-function compound: sulfanilamide-PEG-DTPA.The sulphone amide derivative of band methylene formyl hexamethylene diamine linking arm and the reaction condition of DTPA are to above-mentioned similar, and solvent is an aqueous solution, pH9.0, and product is passed through Sephadex G-10 chromatography purification, obtains: sulfanilamide-methylene formyl hexamethylene diamine-DTPA.
(2) with the connecting of cancer therapy drug
With activated carboxylic reagent the ametycin (MMC) of methotrexate (MTX), 1,3-propanedicarboxylic acid modification, the amycin (ADM) of 1,3-propanedicarboxylic acid modification are made the N-hydroxyl butanimide Acibenzolar of tool reactivity, stand-by.
Synthetic band linking arm sulphonamide derivatives parent nucleus is dissolved in an amount of NaHCO 3In the buffer, mix with suitably excessive cancer therapy drug Acibenzolar, transfer to pH9.0, oscillating reactions 30 minutes, with SephadexG10 or SephadexLH20 column chromatography or corresponding separation method separation end-product, promptly make dual-function compound sulfanilamide-linking arm-cancer therapy drug.
3. the purposes of the diagnosis that the sulfadiazine derivant of formula according to claim 1 (formula I) is had clinically, treatment function of tumor.
CN97106657A 1997-10-15 1997-10-15 Sulfanilamide derivative for diagnosis and treatment of tumor and its preparation Pending CN1214264A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106083662A (en) * 2016-05-21 2016-11-09 魏东 Sulfabenz formaldehyde derivatives preparation method
CN111407767A (en) * 2020-03-28 2020-07-14 中山大学 Application of sulfamonomethoxine derivative in preparation of antitumor drugs

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106083662A (en) * 2016-05-21 2016-11-09 魏东 Sulfabenz formaldehyde derivatives preparation method
CN111407767A (en) * 2020-03-28 2020-07-14 中山大学 Application of sulfamonomethoxine derivative in preparation of antitumor drugs

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