CN1306863A - Sulfoamino radical containing paramagnetic metal compound as magnetic resonance imaging contrast agent - Google Patents
Sulfoamino radical containing paramagnetic metal compound as magnetic resonance imaging contrast agent Download PDFInfo
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Abstract
The present invention belongs to the field of chemistry and medical technology. The contrast agent of the present invention consists of open-chain or ring polyamine, polycarboxylic acid ligand and the coordination compound formed by the divalent and trivalent ion of metal elements with atomic number of 21-29, 42, 44 or 57-71. It may be used in the magnetic resonance imaging analysis, X-ray CT supersonic imaging diagnosis for tumor in tissue and organ of human body and other mammal.
Description
The present invention relates to a class and contain sulfa paramagnetic metal complex magnetic resonance imaging contrast, is non-annularity or cyclic many ammonia polycarboxylic acid coordination compound and the tumor-targeting magnetic resonance imaging contrast of paramagnetic metal ion formation and their preparation method thereof that contains sulfanilamide or sulphone amide derivative specifically.The invention belongs to medicine and pharmacology, technical field of chemistry.
Nuclear magnetic resonance is an advanced medical imaging diagnosis technology, utilize the influence of organism different tissues outside magnetic field to produce different resonance signals down and come imaging, the power of magnetic resonance signal depends on the relaxation time of proton in the interior hydrone of tissue, detection to tissue necrosis, ischemia and various malignant change (as tumor) is effective especially, and can carry out early diagnosis, can also monitor the metabolic process of each blood circulation of human body.
Magnetic resonance imaging contrast is to be used for shortening imaging time, that improves image contrast and definition a kind ofly becomes the image intensifying contrast medium, it can change the relaxation rate of water proton in the body interior tissue, improve the image contrast of normal and disease sites, thereby the functional status (Chem.Rev. that shows intracorporeal organ, 1987,87,901).
Be applied to the paramagnetic metal complex contrast agent of clinical diagnosis at present, ionic contrast agent Gd-DTPA (D.H.Carr et al, Cancer are arranged, 1984,1,484) and Gd-DOTA (M.Magerstade et al, Magn.Reson.Med., 1986,3,808), non-ionic contrast agent Gd (DTPA-BMA) (Wedeking P.et al, Magn.Reson.Med., 1988,8,180) and Gd (DO3A-HP) (M.F.Tweedle et al, Drugs Future, 1992,17,187), liver and gall selectivity contrast agent Gd (DTPA-EOB) (H.J.Weinmann et al, Magn.Reson.Med., 1991,22,233), Gd-BOPTA (Friedrich C.et al, Magn.Reson.Imag., 1999,9,704) and Mn-DPDP (Cavagna F.et al, Magn.Reson.Med., 1991,22,329) etc.Studies show that non-ionic contrast agent has the osmotic pressure close with blood plasma, its toxic and side effects is lower than ionic contrast agent.The introducing of targeting group can improve the tissue or the organ selectivity of contrast agent, improves the enrichment concentration of contrast agent at the target tissue position, thereby can strengthen drug effect and reduce dosage.Therefore the design of contrast agent with synthetic in, to a certain tissue or organ have specificity optionally contrast agent be subjected to people's attention.
The objective of the invention is: intend tumor cell being had stronger affinity according to sulfonamides compound (as sulfadiazine, 2-sulfanilamidopyrazine .), can be by the characteristics of tumor uptake, with sulfanilamide and derivant non-annularity or cyclic many ammonia multi-carboxylic acid compounds are carried out structure of modification, thereby introduce the synthetic contrast agent part of sulfanilamide group by the interval base of amido link or other type, expectation is with the molecular structure of tumor-targeting, nonionic, relaxation is forthright preferably unites, and obtains the practical magnetic resonance imaging contrast of new class of low toxicity and tool tumor-targeting.
Magnetic resonance imaging contrast of the present invention and part thereof or coordination compound have the structure of formula 1, formula 2 representatives:
Formula 1
Formula 2 wherein Q is oxygen atom, sulphur atom, NH or N (CR
3R
4) group of X representative;
X is COOM or group B;
Y represents hydrogen atom, alkyl or group-(CR
3R
4)
qCOOM;
Z represents group-(CR
1R
2)
m-,-(SR
1R
2)
m-,-(OR
1R
2)
m-,-(NR
1R
2)
m-;
R
1, R
2, R
3And R
4Represent hydrogen atom, alkyl, aryl respectively or have the alkyl of one or more hydroxyls, alkoxyl, aryl or aryloxy group;
M can be the mark of hydrogen atom, ammonium ion and organic derivative thereof, positive 1 valence metal ion or polyvalent metal ion;
M is 0 to 10 integer, particularly preferably is 0,1 or 2;
Q is 1 or 2;
B is the group of following formula representative or its sodium salt, silver salt;
A wherein
1Represent hydrogen atom, alkyl, hydroxyalkyl, amine alkyl, alkoxyl or have alkyl or the carbonyl of heteroaryl or carboxyl, sodium ion, silver ion;
A
2Representative
A
3Represent hydrogen atom, alkyl, amine alkyl, hydroxyalkyl, alkoxyl or have the carbonyl or the carboxyl of alkyl, aryl or heteroaryl.
According to technical scheme of the present invention, in the part of formula 1 representative, preferred part has the structural formula of formula 3 representatives:
Formula 3
According to technical scheme of the present invention, in the part of formula 1 representative, preferred part has the structural formula of formula 4 representatives:
Formula 4
According to technical scheme of the present invention, in the part of formula 2 representatives, preferred part has the structural formula of formula 5 representatives:
Formula 5 Q here is oxygen atom, sulphur atom, NH or NCHR
4COOM;
R
4Be hydrogen atom or methyl;
D
1, D
2And D
3Be respectively
N is 0,1 or 2;
R is 1 or 2;
M is 0,1,2,3,
M be hydrogen atom, ammonium ion, replacement ammonium ion ,+mark of 1 valence metal ion or polyvalent metal ion.
According to technical scheme of the present invention, in the part of formula 2 representatives, preferred part has the structural formula of formula 6 representatives:
Formula 6 Q here is oxygen atom, sulphur atom, NH or NCHR
4COOM;
R
4Be hydrogen atom or methyl;
D
1, D
2And D
3Be respectively
N is 0,1 or 2;
R is 1 or 2;
M is 0,1,2,3,
M be hydrogen atom, ammonium ion, replacement ammonium ion ,+mark of 1 valence metal ion or polyvalent metal ion.
According to technical scheme of the present invention, in the part of formula 1 representative, preferred part has the structural formula of following formula representative:
According to technical scheme of the present invention, in the part of formula 1 representative, preferred part has the structural formula of following formula representative:
According to technical scheme of the present invention, in the part of formula 1 representative, preferred part has the structural formula of following formula representative:
According to technical scheme of the present invention, in the part of formula 2 representatives, preferred part has the structural formula of following formula representative:
According to technical scheme of the present invention, in the part of formula 2 representatives, preferred part has the structural formula of following formula representative:
Chinese style 1 of the present invention to the chemical compound of formula 6 representatives is preparations like this: with sulfanilamide and derivant thereof is raw material, with corresponding open chain or many ammonia of ring-type multi-carboxylic acid compounds's reactive derivative such as monocycle anhydride, dicyclo anhydride, mixed acid anhydride, active ester, acylbromide or acyl chlorides effect; Another kind method is with alkylating reagent and effects such as corresponding amine or alcohol, again with many ammonia multi-carboxylic acid compounds as 1,4,7,10-four bad dodecanes of azepine-1,4,7-triacetic acid (DO3A) or its salt action.Above-mentioned synthetic reaction is carried out in aqueous solution or organic solvent.Wherein organic solvent has N, dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxine, pyridine, triethylamine, oxolane, dioxane or by any two or the multiple mixed solvent that constitutes in them.Reaction temperature depends on the character of reaction raw materials, is generally in-20 ℃ to the 120 ℃ scopes, and suitable reaction temperature is-5 ℃ to 70 ℃.The protection of noble gas such as nitrogen or argon is to reacting favourable.
Sometimes need protection some group that does not need to react in some compound process in the above-claimed cpd such as hydroxyl, amido, available known method is protected, and sloughs protecting group after the reaction again.These methods have description in " blocking group in the organic chemistry " monographs such as (the medium compiling of Zhao Zhi, Science Press, Beijing 1984).
The chemical compound of above-mentioned formula 1-6 representative can be made the form of cationic salts, such as Na
+, K
+, Ca
2+, Mg
2+, Cu
2+, Zn
2+Or NH
4+And organic derivative, also can make anion salt such as hydrochlorate, sulfate, nitrate or acylate.
As part, is that 21 to 29,42,44 or 57 or 70 transition elements or the bivalence of rare earth element or oxide, carbonate, acetate, hydroxide or the chloride of trivalent ion react in water or polar organic solvent with atomic number with the above-mentioned many ammonia multi-carboxylic acid compounds who contains sulfanilamide and derivant thereof respectively.Reaction temperature can change according to the differential responses thing, and general range of reaction temperature is 〉=20 ℃ to 120 ℃, and suitable temperature is 20 ℃ to 80 ℃.Polar organic solvent can be an alcohols, dimethyl formamide, dimethyl sulfoxine, pyridine.
Water miscible paramagnetic metal complex is made concentration usually and is 〉=0.1 to 0.5M, and pH value is 6.5 to 8.0 aqueous solution.Fat-soluble paramagnetic metal complex is mixed with certain density liposome with biomolecule such as itself and phospholipid usually.For the non-vanishing situation of total electrical charge number behind the formation coordination compound, the cation of available physiological compatibility is Na particularly
+, Ca
2+, Cu
2+, Zn
2+, NH
4+Or organic derivative such as N-methyl glucoside amine, aminoacid, morpholine, hydramine or electrically charged with anion ratio such as its institute of chloride ion, sulfate radical, phosphate radical or organic acid balance of physiological compatibility, the pH value of regulator solution is in 6.5 to 8.0 scopes.Product can be with conventional method such as recrystallization, column chromatography, ion-exchange chromatogram purification.
Contrast agent among the present invention can be made intestinal canal administration preparation or oral agents, also can make non-enteral administration preparation such as injection.Wherein injection can be used sodium chloride injection, glucose injection, it is 0.001 or the solution (wherein suitable concentration is 0.1 to 0.5M) of 5.0M that the carrier that dextrose ﹠ sodium chloride injection or distilled water or other are stipulated on the Pharmacopoeia of the People's Republic of China is mixed with concentration with paramagnetic complex of the present invention or its salt, and (comprises N-methyl glucoside amine with the acid (example hydrochloric acid) of physiological compatibility or the alkali of physiological compatibility, slow blood ammonia, organic base or ammonia such as aminoacid, sodium hydroxide, sodium carbonate, inorganic bases such as sodium bicarbonate) regulate pH value between 6.5 to 8.0.Usually in preparation, add 0.1 to 15% the respective ligand that is equivalent to the coordination compound amount or salt or calcium, magnesium, copper, the coordination compound of zinc or the physiological compatibility salt of these coordination compounds of other physiological compatibilities, to guarantee that paramagnetic metal ion is (as Gd
3+) cooperated fully by part.Also need add antioxidant such as ascorbic acid or its sodium, calcium salt does not in addition influence the additive of preparation, storage and the use of preparation.Another kind of suitable way is with suitably the respective ligand of excessive (be equivalent to said coordination compound amount 0.1% to 15%) or salt, PH regulator, antioxidant or other required composition of its salt or calcium, magnesium, copper, Zn complex or these coordination compounds are mixed with dried solid preparation with the paramagnetic metal of the present invention of effective dose, be powder or injectable powder, be diluted to desired concn with distilled water or the injection of chlorine water sodium before using.
Oral formulations can have many forms, such as tablet, powder, capsule, powder, syrup, water preparation.For example the paramagnetic complex with effective dose is mixed with water preparation, can add stabilizing agent, buffer agent, correctives, antioxidant, surfactant.
Contrast agent of the present invention can use according to a conventional method, this method comprises bestows the paramagnetic metal complex of a kind of above-mentioned formula 1 of diagnosis object such as human body or other mammalian body to formula 6 definition, carry out magnetic resonance imaging analysis then, draw enhanced nuclear magnetic resonance figure.The dosage of contrast agent of the present invention can because of the kind of paramagnetic complex with very big variation is arranged as the tissue of diagnosis object or organ and diagnostic device type different, generally, the injection consumption preferably 0.05 arrives 0.5mmol for the people of diagnosis main body or every kg body weight 0.001 to 5.0mmol of other mammalian body.Oral dose is generally every kg body weight 0.01 to 100mmol, preferably 0.5 arrives 20mmol.
The many ammonia multi-carboxylic acid compounds who contains the sulfanilamide group among the present invention makes part also can form heavy metal complex as lead, bismuth, gold etc. with heavy metal ion, be used for ultrasonic imaging or X-ray CT, or form the contrast agent of radiometal complex as radiotherapy medicine or scintillography with radioactive metal ion.
Compared with the prior art, the technique effect that the present invention has reached: the many ammonia polycarboxylic acid coordination compound contrast agent that contains the sulfanilamide group of present inventor's invention has kept the construction features of corresponding many ammonia polycarboxylic acid coordination compound, thereby has a good stable, water solublity and relaxation rate, simultaneously because sulfanilamide and derivant thereof are a kind of tumor cell is had affinity and can be selected picked-up by tumor cell, and in vivo can biocompatible medicine, therefore this class contrast agent has selectivity or targeting preferably to tumor cell among the present invention, and the early diagnosis level that improves tumor is had effect preferably.Contrast agent great majority of the present invention in addition are nonionics or electroneutral, thereby have also overcome the caused side effect of ionic contrast agent hyperosmosis.
Below in conjunction with specific embodiment, technical scheme of the present invention is further described:
Embodiment 1:
Ethylenediamine-N, N ＇-two (sulfacetamide)-oxalic acid gadolinium (III) coordination compound
A) ethylenediamine-N, the preparation of N ＇-two (sulfacetamide)-oxalic acid:
3.5g sulfanilamide (20mmol) is dissolved in 40ml N, in the dinethylformamide (DMF), ice-water bath cooling, stirring add 2.6g ethylenediaminetetraacetic acid bisgallic acid acid anhydride (10mmol), low-temp reaction 6 hours, stirred overnight at room temperature in batches.Add adequate amount of ethanol, separate out white precipitate.Filter, with ethanol, ether washing, vacuum drying gets white solid, productive rate 95%.
B) ethylenediamine-N, the preparation of N ＇-two (sulfacetamide)-oxalic acid gadolinium (III) coordination compound: 6.0g ethylenediamine-N, N ＇-two (sulfacetamide)-oxalic acid (10mmol) and 1.8g gadolinium sesquioxide (Gd
2O
3, 5mmol) add in the 50ml distilled water, 80 ℃ of stirring reactions 5 hours, remove by filter insoluble matter, concentrated filtrate, respectively with ethanol, ether washing, dry white solid product.
Embodiment 2:
Diethylenetriamine-N, N " two (acetylsulfadiazine)-N, N ＇, N " triacetic acid gadolinium (III) coordination compound;
A) Diethylenetriamine-N, N " two (acetylsulfadiazine)-N, N ＇, the N " preparation of triacetic acid:
5.0g sulfadiazine (20mmol) is dissolved in 40ml N, in the dinethylformamide, the ice-water bath cooling is stirred, and adds 3.6g diethylenetriamine pentaacetic acid dicarboxylic anhydride (10mmol), low-temp reaction 6 hours, stirred overnight at room temperature in batches.Add adequate amount of ethanol, separate out white precipitate, filter, with ethanol, ether washing, vacuum drying gets white solid, productive rate 94%
B) Diethylenetriamine-N, the preparation of N " two (acetylsulfadiazine)-N, N ＇, N " ＇-triacetic acid gadolinium (III):
4.3g Diethylenetriamine-N, N " two (acetylsulfadiazine)-N, N ＇, N " triacetic acid (10mmol) and 1.8g Gd
2O
3(5mmol) add in the 50ml distilled water, 80 ℃ of stirring reactions 5 hours.Remove by filter insoluble matter, concentrated filtrate, with ethanol, ether washing, the dry white solid that gets.
Embodiment 3:
Diethylenetriamine-N, N " two [acetic acid (N-ethoxy sulfanilamide) ester]-N, N ＇, N " ＇-triacetic acid gadolinium (III) coordination compound
A) preparation of 4-amido-N-ethoxy sulfanilamide:
1.6g sodium hydroxide (40mmol) is dissolved in the 20ml distilled water, stirs, and adds 10g sulfanilamide (40mmol), heating for dissolving adds an amount of activated carbon, stirs 1 hour, and filtration, filtrate are concentrated into pulpous state, and is cold slightly; Add an amount of ethanol, stir evenly, crystallisation by cooling 24 hours.Filter, the crystal washing with alcohol, dry below 70 ℃, get white sulfanilamide crystals of sodium salt, yield 90%.
1.9g sulfanilamide sodium salt (10mmol) and 0.8g 2-chloroethyl alcohol (10mmol) add 20ml N, in the dinethylformamide, are heated to 90 ℃, stir 4 hours, cooling is filtered, and is concentrated into pulpous state, add small amount of ethanol and stir evenly, add suitable ether and get white precipitate, placement is spent the night.Filter, precipitation is washed with ether, and vacuum drying gets white solid, productive rate 90%.
B) preparation of 4-benzyloxy carbonyl amide groups-N-ethoxy sulfanilamide:
2.2.g 4-amido-N-ethoxy sulfanilamide (10mmol) is dissolved in 10ml N, in the dinethylformamide, adds 5ml pyrrole heavy stone used as an anchor, under the ice-water bath, drips the benzyl alcohol solution that contains 1.7g benzyloxy dicarbonyl chloride (10mmol), low-temp reaction 4 hours, room temperature reaction 6 hours.Add an amount of ether sedimentation, filter, vacuum drying gets white solid, productive rate 90%.
C) Diethylenetriamine-N, N " two [acetic acid (N-ethoxy sulfanilamide) ester]-N, N ＇, the N " preparation of triacetic acid:
7.0g 4-benzyloxy carbonyl amide groups-N-ethoxy sulfanilamide (20mmol) is dissolved in 50ml N, in the dinethylformamide, adds 3.6g diethylenetriamine pentaacetic acid dicarboxylic anhydride (10mmol), stirs 6 hours cooling at 80 ℃ in batches.Add 1.0g 10%Pd/C catalyst again, room temperature feeding hydrogen 24 hours filters, and adds an amount of ether sedimentation, filters, and with ethanol, ether washing, vacuum drying gets white solid, and productive rate is 75%.
D) Diethylenetriamine-N, N " two [acetic acid (N-ethoxy sulfanilamide) ester]-N, N ＇, the N " preparation of triacetic acid gadolinium (III):
8.0g Diethylenetriamine-N, N " two [acetic acid (N-ethoxy sulfanilamide) ester]-N, N ＇, N " triacetic acid (10mmol) and 1.8g Gd
2O
3(5mmol) in the adding 50ml distilled water, heat 80 ℃ and stirred 5 hours down, remove by filter insoluble matter, concentrated filtrate, with ethanol, ether washing, vacuum drying gets white solid product.
Embodiment 4:
1,4,7,10-tetraazacyclododecanand-N-acetylsulfanilamide pyrazine-N ＇, N ", N " ＇-triacetic acid gadolinium (III) coordination compound
A) 1,4,7,10-tetraazacyclododecanand-N-acetylsulfanilamide pyrazine-N ＇, N ", N " and the preparation of ＇-triacetic acid:
4.76g 1,4,7, (DOTA 10mmol) adds 50ml dimethyl sulfoxine and N with the 8ml triethylamine, in the mixed liquor of dinethylformamide to 10-tetraazacyclododecanand tetraacethyl, add 1.15gN-N-Hydroxysuccinimide (10mmol) again, be cooled to-5 ℃ and stir down, add 10ml dicyclohexylcarbodiimide (DCC, 2.06g, N 10mmol), the solution of dinethylformamide continues reaction 2 hours down at-5 ℃, and room temperature reaction is 12 hours then.Filter, remove the solid of generation, filtrate is standby-5 ℃ of-0 ℃ of placements.
2.5g 2-sulfanilamidopyrazine. (10mmol) is dissolved in 20ml N, in the dinethylformamide, bathes under the cooling at cryosel, stirs, and is added dropwise to above-mentioned filtrate, low-temp reaction 6 hours, room temperature reaction 12 hours.Filter, add an amount of ether in the filtrate, separate out white precipitate, filter, with the ether washing, vacuum drying gets white solid, yield 85%.
B) 1,4,7,10-tetraazacyclododecanand-N-acetylsulfanilamide pyrazine--N, N ", N " and the preparation of ＇-triacetic acid gadolinium (III):
6.4g 1,4,7,10-tetraazacyclododecanand-N-acetylsulfanilamide pyrazine-N, N ", N " ＇-triacetic acid (10mmol) and 1.8g Gd
2O
3(5mmol) add in the 50ml distilled water,, remove by filter insoluble matter 80 ℃ of stirring reactions 5 hours, concentrated filtrate, with ethanol, ether washing, drying, white solid product.
Embodiment 5:
1,4,7,10-tetraazacyclododecanand-N-acyl (ethoxy 2-sulfanilamidopyrazine .) ester-N ＇, N ", N " ＇-triacetic acid gadolinium (III) coordination compound
A) preparation of 4-amido-N-ethoxy 2-sulfanilamidopyrazine.:
5g 2-sulfanilamidopyrazine. (0.02mol) is put in the 100ml ampere bottle unable to make ends meet, and syringe adds 20ml oxirane, and the sealing bottleneck is put into 60 ℃ oil bath reactor 10 days.Reactant is used earlier ether extraction, and the hydroxide of reuse method 0.5N soaks, and filters, and collects pressed powder, and vacuum drying gets 4-amido-N-ethoxy 2-sulfanilamidopyrazine. product.
B) preparation of 4-benzyloxy carbonyl amide groups-N-ethoxy 2-sulfanilamidopyrazine.:
5.9g 4-amido-N-ethoxy 2-sulfanilamidopyrazine. (20mmol) is dissolved in 20ml N, in the dinethylformamide, adds 5ml pyrrole heavy stone used as an anchor, under the ice-water bath, drips the benzyl alcohol solution that contains 3.4g benzyloxy dicarbonyl chloride (20mmol), low-temp reaction 4 hours, room temperature reaction 6 hours.Add an amount of ether sedimentation, filter, vacuum drying gets white solid, productive rate 90%.
C) preparation of 4-benzyloxy carbonyl amide groups-N-chloro-carbonic acid ethyl 2-sulfanilamidopyrazine. ester:
8.4g 4-benzyloxy carbonyl amide groups-N-chloro-carbonic acid ethyl 2-sulfanilamidopyrazine. ester (20mmol) is dissolved in 50ml N, in the dinethylformamide, under the ice-water bath, feeds phosgene 1 hour, stirs 4 hours, feeds drying nitrogen and drives remaining phosgene, low temperature is placed standby.
D) 1,4,7,10-tetraazacyclododecanand-N-acyl (ethoxy 2-sulfanilamidopyrazine .) ester-N ＇, N ", N " and the preparation of ＇-triacetic acid:
6.92g 1,4,7,10-tetraazacyclododecanand-N ＇, N ", " reaction solution slowly is added dropwise in the solution N in ＇-triacetic acid (DO3A 20mmol) is dissolved in 20ml N, in the dinethylformamide, under the room temperature, with c), stirs 4 hours.Add 1.0g 10%Pd/C catalyst again, room temperature feeding hydrogen 24 hours filters, and adds an amount of ether sedimentation, filters, and with ethanol, ether washing, vacuum drying gets white solid, and productive rate is 85%.
E) 1,4,7,10-tetraazacyclododecanand-N-acyl (ethoxy 2-sulfanilamidopyrazine .) ester-N ＇, N ", N " and the preparation of ＇-triacetic acid gadolinium (III) coordination compound:
6.7g 1,4,7,10-tetraazacyclododecanand-N-acyl (ethoxy 2-sulfanilamidopyrazine .) ester-N ＇, N ", N " ＇-triacetic acid (10mmol) and 1.8g Gd
2O
3(5mmol) in the adding 50ml distilled water, heat 80 ℃ and stirred 5 hours down, remove by filter insoluble matter, concentrated filtrate, with ethanol, ether washing, vacuum drying gets white solid product.
Claims (14)
1, a kind of novel tumor targeting magnetic resonance imaging contrast that contains sulfanilamide, it is characterized in that: make part with the non-annularity that contains sulfanilamide and derivant thereof or many ammonia of ring-type polycarboxylic acid derivatives or its salt, respectively with atomic number be 21 to 29,42,44 or 57 or 70 metallic element+divalent or+3 valency ionizations form paramagnetic metal complex, said here part has the chemical structural formula of formula 1 or formula 2 representatives:
Formula 1
Formula 2 wherein Q is oxygen atom, sulphur atom, NH or N (CR
3R
4) group of X representative;
X is COOM or group B;
Y represents hydrogen atom, alkyl or group-(CR
3R
4)
qCOOM;
Z represents group-(CR
1R
2)
m-,-(SR
1R
2)
m-,-(OR
1R
2)
m-or-(NR
1R
2)
m-;
R
1, R
2, R
3And R
4Represent hydrogen atom, alkyl, aryl respectively or have the alkyl of one or more hydroxyls, alkoxyl, aryl or aryloxy group;
M can be the mark of hydrion, ammonium ion and organic derivative thereof, positive 1 valence metal ion or polyvalent metal ion; M is 2,3 or 4, particularly preferably is 2;
N is 0 to 10 integer, particularly preferably is 0,1 or 2;
Q is 1 or 2;
B is the group of following formula representative or its sodium salt, silver salt:
A wherein
1Represent hydrogen atom, alkyl, hydroxyalkyl, amine alkyl, alkoxyl or have the carbonyl of alkyl, aryl or heteroaryl or carboxyl, sodium ion, silver ion;
A
3Represent hydrogen atom, alkyl, amine alkyl, hydroxyalkyl, alkoxyl or have the carbonyl or the carboxyl of alkyl, aryl or heteroaryl.
A
2Representative:
2, tumor-targeting magnetic resonance imaging contrast according to claim 1 is characterized in that: part formula 1 has the structural formula of formula 3 representatives:
Formula 3
3, tumor-targeting magnetic resonance imaging contrast according to claim 1 is characterized in that: part formula 1 has the structural formula of formula 4 representatives:
Formula 4
4, tumor-targeting magnetic resonance imaging contrast according to claim 1 is characterized in that: part formula 2 has the structural formula of formula 5 representatives:
Formula 5 Q here is oxygen atom, sulphur atom, NH or NCHR
4COOM;
R
4Be hydrogen atom or methyl;
D
1, D
2And D
3Be respectively
N is 0,1 or 2;
R is 1 or 2;
M is 0,1,2,3,
M be hydrogen atom, ammonium ion, replacement ammonium ion ,+mark of 1 valence metal ion or polyvalent metal ion.
5, according to the tumor-targeting magnetic resonance imaging contrast described in the claim 1, it is characterized in that: part formula 2 has the structural formula of formula 6 representatives:
Formula 6 Q here is oxygen atom, sulphur atom, NH or NCHR
4COOM;
R
4Be hydrogen atom or methyl;
D
1, D
2And D
3Be respectively
N is 0,1 or 2;
R is 1 or 2;
M is 0,1,2,3,
M be hydrogen atom, ammonium ion, replacement ammonium ion ,+mark of 1 valence metal ion or polyvalent metal ion.
6, tumor-targeting magnetic resonance imaging contrast according to claim 2 is characterized in that: the structural formula of part:
7, tumor-targeting magnetic resonance imaging contrast according to claim 3 is characterized in that: the structural formula of part:
8, tumor-targeting magnetic resonance imaging contrast according to claim 3 is characterized in that: the structural formula of part:
9, tumor-targeting magnetic resonance imaging contrast according to claim 4 is characterized in that: the structural formula of part:
Embodiment 4
10, tumor-targeting magnetic resonance imaging contrast according to claim 5 is characterized in that: the structural formula of part:
11, the method for any described tumor-targeting magnetic resonance imaging contrast among a kind of synthetic claim 1-10, this method comprises: (1) forms many ammonia of chemical compound multi-carboxylic acid compounds of the formula 3-6 definition that contains the sulfanilamide or derivatives thereof by sulfanilamide or derivatives thereof and many ammonia multi-carboxylic acid compounds's activity derivatives reaction; (2) chemical compound of formula 3-6 definition is converted into salt or the salt of the chemical compound of formula 3-6 definition is converted into free acid or alkali; (3) compound or its salt of formula 3-6 definition and paramagnetic metal ion are comprised atomic number be 21 to 29,42,44 or 57 to 71 metallic element+2 or+3 valency ions cooperate, forming mol ratio is 1: 1 the metal complex or the salt of coordination compound, promptly contain sulfa paramagnetic metal complex magnetic resonance imaging contrast, described reactive derivative is monocycle anhydride, dicyclo anhydride, mixed acid anhydride, active ester, acyl chlorides or acylbromide, and metal ion is Gd
3+, Mn
2+, Cr
3+, Fe
3+, Co
2+, N
i 2+, Tc
2+Or Cu
2+
12, the described tumor-targeting magnetic resonance imaging contrast of claim 1-10 is used to make a kind of diagnostic preparation, it is characterized in that: this diagnostic preparation is made of to the paramagnetic metal complex of formula 6 definition and at least a sodium chloride injection, glucose injection, dextrose ﹠ sodium chloride injection, distilled water or other pharmaceutical carrier of stipulating on the Pharmacopoeia of the People's Republic of China or figuration body such as phospholipid, gelatin, starch or syrup the formula 1 of effective dose; Or by the above-mentioned coordination compound of effective dose be equivalent to the coordination compound of said coordination compound amount 〉=0.1 to 15% or its salt and at least a pharmaceutical carrier or figuration body constitute.
13, diagnostic agent preparation according to claim 12, it is characterized in that: said preparation is to be carrier with distilled water, distilled water for injection, sodium chloride injection, glucose injection or sodium chloride-glucose injection pharmaceutical carrier, contain concentration and be 〉=0.001 to 5.0M formula 1 compliance metal complex or its salt to formula 6 definition, contain be equivalent to above-mentioned coordination compound 〉=0.1 to 15% corresponding coordination compound or the injection preparation of its salt and PH regulator, electrolyte, antioxidant, stabilizing agent or other pharmaceutic adjuvant.
14, diagnostic agent preparation according to claim 12, it is characterized in that: said preparation is to contain the paramagnetic metal complex of the formula 1 of effective dose to formula 6 definition, contain be equivalent to above-mentioned coordination compound 〉=0.1 to 15% respective ligand or the sterilized powder for injection of its coordination compound or its salt and PH regulator, antioxidant, electrolyte and other pharmaceutic adjuvant, face the time spent with distilled water for injection, sodium chloride injection, glucose injection, the liquid pharmaceutical carrier desired concn of sodium chloride-glucose injection promptly 〉=0.001 to 5.0M.
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| CN 00114345 CN1306863A (en) | 2000-01-27 | 2000-01-27 | Sulfoamino radical containing paramagnetic metal compound as magnetic resonance imaging contrast agent |
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| CN 00114345 CN1306863A (en) | 2000-01-27 | 2000-01-27 | Sulfoamino radical containing paramagnetic metal compound as magnetic resonance imaging contrast agent |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103432146A (en) * | 2013-08-23 | 2013-12-11 | 辽宁海思科制药有限公司 | Invert sugar injection composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103432146A (en) * | 2013-08-23 | 2013-12-11 | 辽宁海思科制药有限公司 | Invert sugar injection composition |
| CN103432146B (en) * | 2013-08-23 | 2015-02-04 | 辽宁海思科制药有限公司 | Invert sugar injection composition |
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