CN1053910C - Method for synthesizing cyclic poly amino poly carboxylic acid chelate contrast medium - Google Patents
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- CN1053910C CN1053910C CN95119302A CN95119302A CN1053910C CN 1053910 C CN1053910 C CN 1053910C CN 95119302 A CN95119302 A CN 95119302A CN 95119302 A CN95119302 A CN 95119302A CN 1053910 C CN1053910 C CN 1053910C
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Abstract
The present invention relates to a new synthesis method of macrocyclic multiple-ammonia polycarboxylic acid chelating agents or the salt thereof and paramagnetic metal chelate complexes of the chelating agents and the salt thereof, which belongs to the technical field of medicine, pharmacology and chemistry, particularly to a synthesis method of 1, 4, 7, 10-tetrazacyclo dodecane-1, 4, 7, 10-tetraacethyl (DOTA), 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid (DO3A) and an analog thereof. For example, diethyl triamine and diethanolamine are used as raw materials; after sulfonylation is carried out on toluene, solid sodium hydroxide is directly used to make the raw materials cyclized in N, N-dimethyl formamide solutions, and then, protective base removal, carboxyl methylation and chelating reaction are carried out so as to prepare GdDOTA and the salt thereof.
Description
The present invention relates to a kind of method for preparing many ammonia of ring-type multi-carboxylic acid compounds or its salt and their paramagnetic metal ion inner complex contrast medium, belong to chemistry and medicine and pharmacology technical field.
Magnetic resonance imaging (MRI) is the medical diagnosis new technology that development in recent years is got up, and also is present unique a kind of non-invasive diagnostic art.It is compared with other technology that are used for checking human body such as computed tomography (CT) etc. has many superior parts.Do not use ionizing rays such as it, avoided X ray the damage of human body particularly to be brought out the danger of cancer; The parameter that its adopts is many, and the quantity of information that provides is many, can show pathology that many CT can not show etc.
Magnetic resonance imaging mainly is density p and the relaxation time T by the proton of contained humidity in the proton in Different Organs in the human body or tissue, healthy tissues and the pathological tissues and these tissues or the organ at present
1(spin-lattice relaxation time), T
2(spin-spin relaxation time) three parameters are come imaging, and the quality of image also depends primarily on them.Usually, the proton density that changes in human organ and the tissue is very difficult, thus mainly improve picture quality by the relaxation rate of regulating proton, and relaxation rate can be that contrast medium is regulated by adding relaxation reagent.Contrast medium is generally seen with paramagnetic substance more, when approaching tested nuclear of paramagnetic substance such as proton, the local high-intensity magnetic field that it produced has booster action to the relaxation rate of proton, has improved the sharpness and the contrast gradient of image, helps particularly detecting of minimal disease of focus.Simultaneously can also shorten imaging time.
Say that in principle paramagnetic metal ion can both influence the relaxation rate of proton such as transition metal ion and lanthanide metal ion, as gadolinium ion Gd
3+, it has seven unpaired electrons, and a big magnetic moment is arranged, but it can not be ignored the toxicity of human body when using by the desired dosage of clinical diagnosis.The effective ways that address this problem be make these metal ions and organic sequestering agent form stable, water miscible, in human body, be difficult for dissociating, can be by human body by excretory inner complex (Chem.Rev.1987,87,901).
Proof paramagnetic metal chelates contrast medium has many, and the many ammonia multi-carboxylic acid chelating agents of acyclic (or claiming open chain) such as gadolinium (III) inner complex (GdDTPA) (US401,594 of diethylenetriamine pentaacetic acid are arranged preferably; US4,647,447; WO91 079; WO911,335) and many ammonia of cyclic multi-carboxylic acid chelating agents as 1,4,7,10-tetraazacyclododecanand-1,4,7, the gadolinium of 10-tetraacethyl (III) inner complex (Gd-DOTA) (BE898,708; WO86 02,352; DE3,625,417), 1,4,7,10-tetraazacyclododecanand-1,4,7, the gadolinium of 10-tetraacethyl (III) inner complex (Gd-DO3A) (DE3,625,417; EP292,689; EP232,615) or the like.Many ammonia of ring-type multi-carboxylic acid chelating agents such as above-mentioned two kinds have the stronger complex ability than the acyclic ammonia of manying multi-carboxylic acid chelating agents, formed inner complex is more stable, particularly GdDO3A and Virahol derivative GdDO3A-HP thereof belong to the non-ionic type inner complex, the effect of paying of having avoided high osmotic pressure that ionic contrast agent causes to produce, thereby the security when being used for human body nuclear magnetic resonance radiography is better.But these cyclic poly amino poly carboxylic acid chelate's contrast medium synthetic is loaded down with trivial details inconvenience.
Germany Schering A-G company is at belgian patent BE898, and with 1,4,7,10-tetraazacyclododecanand-1,4,7,10-tetraacethyl (DOTA) directly and gadolinium sesquioxide formation GdDOTA but do not relate to the synthetic method of sequestrant DOTA in 708.It is the method for raw material through synthetic GdDOTA of six steps such as tosylation, sodium alkoxide salify, pass ring, deprotection base, carboxymethylation and integration by three second tetramines and ethylene glycol that Sherry has proposed a kind of in world patent WO86 02,352; Tweedle etc. are in U.S. Pat 4,885, have described three kinds of routes that prepare DO3A in 363: the one, by 1,4,7,10-tetraazacyclododecanand (encircling stupefied amine) and three mol-chloric acetate effects, through separate DOTA and DO3A; The 2nd, prepare DO3A by the stupefied amine of ring through single formylation, carboxymethylation and hydrolysis reaction; The 3rd, by N, N-two (aminoethyl) benzylamine and diethanolamine go benzyl to synthesize DO3A through tosylation, sodium hydride salify, pass ring, sodium amide deprotection base, carboxymethylation, hydrogenolysis.The another kind of synthetic method of DO3A is that ScheringA-G company proposes; by Diethylenetriamine and N; N-two (hydroxyethyl) benzylamine is sulfonated through toluoyl, sodium saltization, close ring, deprotection base, carboxymethylation (using ethyl bromoacetate); hydrogenolysis goes benzyl to get the DO3A triethyl, the direct and Gd (OAc) of DO3A triethyl
3Act on GdDO3A (DE3,625,417; EP255,471).Utilize the secondary amine in the DO3A molecule can synthesize various DO3A derivatives easily, the 10-2-hydroxyl typically arranged) propyl group-1,4,7,10-tetraazacyclododecanand-1,4,7-nitrilotriacetic (DO3A-HP) (EP299,795).
Some non-patent literatures are (as J.Am.Chem.Soc.1974; 96; 2268) synthetic method of the stupefied amine of precursor compound ring of DOTA has been described, promptly by Diethylenetriamine and diethanolamine through to toluene, sulfonylation, sodium alkoxide sodium saltization, close that steps such as ring, deprotection base are synthetic encircles stupefied amine.
From research in the past, the synthetic of DOTA and analogue thereof is good with linear amine and di-alcohols compound such as Diethylenetriamine and diethanolamine or three second tetramines and ethylene glycol through tosylation, sodium saltization, the route that closes steps formations such as ring, deprotection base, carboxymethylation usually.But this route steps is many, especially anhydrous the and/or high prices such as oxygen free condition and highly basic such as sodium hydride, sodium ethylate of the Chloramine salinization reaction needed strictness of linear amine, the difficult raw material that obtains.
The purpose of this invention is to provide the particularly economic and easy novel method of the paramagnetic metal chelates contrast medium of DOTA, DO3A and derivative thereof of a kind of many ammonia of synthesis of cyclic multi-carboxylic acid compounds.
The method of many ammonia of synthesis of cyclic poly carboxylic acid inner complex contrast medium provided by the invention is: with linear amine and di-alcohols compound is raw material, takes off many ammonia of step synthesis of cyclic multi-carboxylic acid compounds such as sulfonylation, (4) carboxymethylation reaction and (5) chelatropic reaction (four steps) and inner complex contrast medium (five steps) thereof through the reaction of (1) tosylation, (2) ring closure reaction, (3).
Many ammonia of the ring-type multi-carboxylic acid chelating agents that the present invention sets up and the synthetic route of paramagnetic metal chelates thereof are the available following graphic explanation of example with DOTA:
Be suitable for having the general structure of formula 1 representative with sequestrant in the aforesaid method synthetic cyclic poly amino poly carboxylic acid chelate contrast medium of the present invention or part:
Wherein Y is Sauerstoffatom, sulphur atom or NR;
R is hydrogen atom, alkyl, aryl, benzyl, have the alkyl of one or more carboxyls,
Perhaps-CH
2COOH;
N is 1 or 2;
M is arbitrary integer of 0 to 3; Metal ion in the above-mentioned inner complex contrast medium is that ordination number is 21 to 29,42,44 or 57 to 70 paramagnetic metal ion.
Starting raw material neutral line polyamines and dibasic alcohol have the general formula of formula 2 and formula 3 representatives respectively:
In formula 2 and the formula 3, R
1Be hydrogen atom, alkyl, aryl, benzyl;
Q is Sauerstoffatom, sulphur atom or NR
1
N is 1 or 2;
P and q are respectively the arbitrary integers between 0 to 4;
X is that hydroxyl can prepare identical product with different starting raw materials, also can prepare different products, such as: by three second tetramines and ethylene glycol is starting raw material, also can make DOTA and paramagnetic metal chelates contrast medium thereof through same method and step;
With Diethylenetriamine and ethylene glycol is that starting raw material can make 1,4 through same method and step, 7-7-triazacyclononane-1,4,7-nitrilotriacetic (NOTA);
With dipropanetriamine and 1, ammediol is that starting raw material can make 1,5 through same method and step, 9-three heterocycle dodecanes-1,5,9-nitrilotriacetic (DOTRA);
Replace diethanolamine such as N-benzyl diethanolamine (being N, N-two (hydroxyethyl) benzylamine) can make DO3A (increasing hydrogenolysis one goes on foot) and derivative thereof for starting raw material with Diethylenetriamine and N-;
With Diethylenetriamine and tirethylene glycol is that raw material can make 1-oxa-4-4,7, the 10-nitrilotriacetic;
With Diethylenetriamine and 3-thia-1, the 5-pentanediol is that raw material can make 1-thia-4,7,10-three azo-cycle dodecanes-4,7,10-nitrilotriacetic;
In addition, with Diethylenetriamine and 2, the 6-disubstituted pyridines (
, X=OTs herein, Br or Cl) and for can making, starting raw material contains 3,6,9 of pyridine ring, 15-four azabicyclos [9,3,1] pentadecane-1 (15), 11,13-triolefin-3,6,9-nitrilotriacetic (PCTA):
Committed step of the present invention is a ring closure reaction, the careful result who explores shows: under common highly basic such as NaOH effect cheap and easy to get, ring closure reaction between two p-toluenesulfonic esters of the para toluene sulfonamide of linear amine and alkylating agent dibasic alcohol can directly be finished in aprotic polar solvent, and productive rate is good.In addition, the present invention also improves other step, and these improvement will be illustrated in an embodiment.
Here said alkali is meant that alkali metal hydroxide comprises as LiOH, NaOH, KOH, CsOH or C
1-C
10Quaternary ammonium hydroxide
(R is C
1-C
10Alkyl) in a kind of, or several mixture.Above-mentioned alkali can use separately also can with alkaline carbonate such as Li
2CO
3, Na
2CO
3, K
2CO
3, Cs
2CO
3In any or several merging use.NaOH because it is cheap, reaction effect good than the composition of other alkali or alkali and alkali for well.The usage quantity of alkali is 2-20 a times of linear amine para toluene sulfonamide.
Reaction solvent is meant general common aprotic polar solvent such as acetonitrile, acetone, N, dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone, methyl-sulphoxide, hexametapol etc.
The feed ratio of two p-toluenesulfonic esters of the para toluene sulfonamide of linear amine and alkylating agent dibasic alcohol can change between 1: 0.1 to 1: 10.Alkylating agent also can be that benzene sulfonate, methane sulfonate or dichloro-, two bromos or the diiodo compound of dibasic alcohol (is X=PhSO in the formula 3 except that two p-toluenesulfonic esters of dibasic alcohol
3, CH
3SO
3, Cl, Br or I).The concentration range of starting raw material can be 0.001M-1M when feeding intake.Temperature of reaction can be between room temperature to 140 ℃, perhaps in room temperature between the reaction solvent ebullient temperature.
Compare with existing technology, the technique effect that the present invention has reached is: because the present invention makes the para toluene sulfonamide of linear amine and two p-toluenesulfonic esters step in aprotic polar solvent of alkylating agent such as dibasic alcohol close ring with alkali metal hydroxide or quaternary ammonium hydroxide, sodium hydride or the sodium alkoxide and the strict anhydrous and/or oxygen free condition of the costliness used in the relevant technologies have in the past been avoided, and original in the prior art one step of two reactions carried out of step is finished, simplified reactions steps and operation.And because sodium alkoxide need be used expensive and dangerous sodium Metal 99.5 and prepared fresh such as anhydrous methyl alcohol or ethanol, these unsafe factors have not existed in the present invention yet.In a word, economic, easy, safety is the conspicuous advantage of the present invention.
The invention will be further described below in conjunction with embodiment.
Embodiment 1 DOTA's is synthetic
1, the tosylation of Diethylenetriamine:
57.3g (0.3mol) Tosyl chloride is dissolved in the 150ml toluene.Under ice bath cooling and high degree of agitation, this solution splashed in the mixture by the sodium hydroxide solution of 10.3g (0.1mol) Diethylenetriamine, 100ml 12% and 200ml toluene formation.Dropwising the back continues to stir 5 hours.Suction filtration, filter cake wash with water to not having alkalescence, oven dry.Boil 2h altogether with ethanol.Filtration, drying get the white powder solid.Productive rate 86%, fusing point: 173-5 ℃
2, the tosylation of diethanolamine:
57.3g (0.3mol) Tosyl chloride is dissolved in the 200ml methylene dichloride, cooling and stir the sodium hydroxide solution that splashes into 10.5g (0.1mol) diethanolamine, 0.8g Tetrabutyl amonium bromide, 100ml 15% down and the mixing solutions of 200ml methylene dichloride in, reaction 4-6h.In reaction mixture impouring 200ml water, branch vibration layer, organic layer wash with water to neutrality, anhydrous Na
2SO
4Dry.Use ethyl alcohol recrystallization after removing solvent, get the white powder crystal.Yield 90%, mp 98-100 ℃.
3,1,4,7,10-four (p-toluenesulfonyl)-1,4,7,10-tetraazacyclododecanand synthetic
56.5g (0.1mol) N, " three (p-toluenesulfonyl) Diethylenetriamine, 10g sodium hydroxide fine powder is added on 1500ml exsiccant N, in the dinethylformamide, is warming up to 110 ℃ under stirring for N ', N.Dropwise 5 6.7g (0.1mol) N then, N-two (tolysulfonyl oxygen ethyl) para toluene sulfonamide is dissolved in 1000ml N, the solution of dinethylformamide.Stirring reaction 9h.Remove solvent, in the impouring water.The greyish white precipitation suction filtration of viscosity, washing, drying, recrystallization.Productive rate 75-83%, mp 270-90 ℃.4,1,4,7,10-tetraazacyclododecanand four hydrosulfates synthetic:
15g 1,4,7, and 10-four tolysulfonyl-1,4,7,10-tetraazacyclododecanand dissolve in the dense H of 100ml
2SO
4In, heating is chilled to room temperature behind the stirring 10h, with alcohol-ether solution precipitation is separated out.Filtration, washing, drying get greyish white solid, productive rate 90%, fusing point 104-9 ℃.5,1,4,7,10-tetraazacyclododecanand-1,4,7, the preparation and the purifying of 10-tetraacethyl (DOTA)
38.6g above-mentioned product is water-soluble, with the sodium hydroxide solution neutralization, and keeps 60-70 ℃ in hot water bath.Splash into the chloroacetic aqueous solution of 37.8g under stirring, keep pH ~ 9.In room temperature reaction 2h, remove solvent again, residue water-ethyl alcohol recrystallization, and change resin column (H+ type) in the highly acidic cation effect and go up purifying.Get the white powder crystal of high-purity DOTA, yield 80-90%, 250 ℃ of mp.
The preparation of embodiment 2 GdDOTA sodium salts
40.4g (0.1mol) DOTA dissolves with suitable quantity of water, adds 18.2g (0.05mol) gadolinium sesquioxide powder, stirring, backflow 24h carefully transfer pH=7.0 with sodium hydroxide solution, remove solvent, get white solid GdDOTANa, and productive rate is near theoretical amount.
Synthesizing of embodiment 3 GdDOTA N-meglumin salt
40.4g (0.1mol) DOTA is dissolved in suitable quantity of water, adds 18.2g (0.05mol) gadolinium sesquioxide powder.Stirring, backflow 24h, (NMG) carefully transfers pH=7.0 with the N-meglumin.Remove solvent.To get the GdDOTANMG white solid near the theoretical amount productive rate.
Claims (6)
1, a kind of method of many ammonia of synthesis of cyclic poly carboxylic acid inner complex contrast medium, it is characterized in that: with linear amine and dibasic alcohol is starting raw material, via tosylation, ring closure reaction, take off sulfonylation, carboxymethylation reaction and many ammonia of chelatropic reaction synthesis of cyclic poly carboxylic acid inner complex contrast medium, here in the said inner complex contrast medium, metal ion be meant ordination number be respectively 〉=21 to 29,42,44 or 〉=57 to 70 paramagnetic metal ion; Sequestrant is the compound with general formula of formula 1 representative:
Wherein: Y is Sauerstoffatom, sulphur atom or NR;
R is hydrogen atom, alkyl, aryl, benzyl, with the alkyl of one or more hydroxyls
Perhaps-CH
2COOH;
N is 1 or 2;
M is 〉=arbitrary integer of 0 to 3.
2, by the method for the described synthetic contrast medium of claim 1, it is characterized in that: make the tosic acid amine of linear amine and two p-toluenesulfonic esters of alkylating agent such as dibasic alcohol in polar aprotic solvent, directly carry out ring closure reaction with common highly basic.
3, by the method for the described synthetic contrast medium of claim 1, it is characterized in that: linear amine in the starting raw material and di-alcohols compound have the general formula of formula 2 and formula 3 representatives:
Wherein: R
1Be hydrogen atom, alkyl, aryl, benzyl;
Q is Sauerstoffatom, sulphur atom or NR
1
N is 1 or 2;
P and q are respectively the arbitrary integers between 0 to 4;
X is a hydroxyl.
4, press the method for the described synthetic contrast medium of claim 1, it is characterized in that: the alkylating agent in the ring closure reaction is the p-toluenesulfonic esters of the dibasic alcohol of above-mentioned formula 3 representatives, also can be corresponding benzene sulfonate, methane sulfonate or corresponding dihalo compound.
5, by the method for the described synthetic contrast medium of claim 1, it is characterized in that: the alkali that uses in ring closure reaction is that alkali metal hydroxide comprises LiOH, NaOH, KOH, CsOH or C
1-C
10Quaternary ammonium hydroxide
In one or more mixture; Also can be that above-mentioned alkali and alkaline carbonate comprise Li
2CO
3, Na
2CO
3, K
2CO
3, Cs
2CO
3In the mixture of one or more formations.
6, by the method for the described synthetic contrast medium of claim 1, it is characterized in that: the sequestrant of contrast medium is 3,6,9,15-four azabicyclos [9,3,1] pentadecane-1 (15), 11, and 13-triolefin-3,6,9-nitrilotriacetic, i.e. PCTA:
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|---|---|---|---|
| CN95119302A CN1053910C (en) | 1995-11-14 | 1995-11-14 | Method for synthesizing cyclic poly amino poly carboxylic acid chelate contrast medium |
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| CN95119302A CN1053910C (en) | 1995-11-14 | 1995-11-14 | Method for synthesizing cyclic poly amino poly carboxylic acid chelate contrast medium |
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| CN1130189A CN1130189A (en) | 1996-09-04 |
| CN1053910C true CN1053910C (en) | 2000-06-28 |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552941B (en) * | 2011-12-28 | 2013-06-05 | 中国科学院长春应用化学研究所 | Two-nuclear magnetic resonance imaging contrast agent taking 2,5-dimethylpyrazine as connector and preparation method of two-nuclear magnetic resonance imaging contrast agent |
| CN102659702B (en) * | 2012-04-09 | 2014-12-03 | 武汉工程大学 | Purifying process of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid (DOTA) |
| WO2014114664A1 (en) * | 2013-01-28 | 2014-07-31 | Agfa Healthcare | Process for producing 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid and complexes thereof |
| EP2786768A1 (en) * | 2013-04-04 | 2014-10-08 | Agfa Healthcare | Process for preparing a material comprising a macrocyclic ligand and for producing a pharmaceutical formulation comprising said ligand with a lanthanide |
| CN106220580B (en) * | 2016-08-10 | 2019-07-12 | 上海万巷制药有限公司 | The method of purification of gadoterlc acid meglumine saltlniection |
| CN110407887A (en) * | 2019-04-25 | 2019-11-05 | 上海大学 | Complex, preparation method and its application containing positive quadrivalent iron or manganese complex ion |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1986002352A1 (en) * | 1984-10-18 | 1986-04-24 | Board Of Regents, The University Of Texas System | Gadolinium chelates as nmr contrast agents |
| DE3633243A1 (en) * | 1986-09-26 | 1988-03-31 | Diagnostikforschung Inst | Phosphonate complexes |
| EP0292689A2 (en) * | 1987-04-24 | 1988-11-30 | Bracco International B.V. | Substituted 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclo-dodecane and analogs |
| US4923985A (en) * | 1988-05-25 | 1990-05-08 | The United States Of America As Represented By The Department Of Health & Human Services | Process for synthesizing macrocyclic chelates |
-
1995
- 1995-11-14 CN CN95119302A patent/CN1053910C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1986002352A1 (en) * | 1984-10-18 | 1986-04-24 | Board Of Regents, The University Of Texas System | Gadolinium chelates as nmr contrast agents |
| DE3633243A1 (en) * | 1986-09-26 | 1988-03-31 | Diagnostikforschung Inst | Phosphonate complexes |
| EP0292689A2 (en) * | 1987-04-24 | 1988-11-30 | Bracco International B.V. | Substituted 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclo-dodecane and analogs |
| US4923985A (en) * | 1988-05-25 | 1990-05-08 | The United States Of America As Represented By The Department Of Health & Human Services | Process for synthesizing macrocyclic chelates |
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