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CN1164225A - Iodinated X-ray-contrast media - Google Patents

Iodinated X-ray-contrast media Download PDF

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CN1164225A
CN1164225A CN 95196327 CN95196327A CN1164225A CN 1164225 A CN1164225 A CN 1164225A CN 95196327 CN95196327 CN 95196327 CN 95196327 A CN95196327 A CN 95196327A CN 1164225 A CN1164225 A CN 1164225A
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milliliters
aminocarboxyl
alkyl
phenyl
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A·赖得贝克
T·阿尔曼
M·塞恩宁
S·安德森
L·G·维斯特兰德
K·高尔曼
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GE Healthcare AS
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Nycomed Imaging AS
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Abstract

The invention provides iodinated bis phenyl compounds and isomers, especially stereoisomers and rotamers thereof in formula (I), wherein each C6R5 moiety may be the same or different; each R denotes a hydrogen or iodine atom or a group M, two or three non-adjacent R groups on each C6R5 moiety denoting iodine atoms and one, two or three R groups on each C6R5 moiety denoting M groups; X denotes a group providing a 1, 2 or 3 atom chain linking the two C6R5 groups, preferably where X is or contains in the bridging chain a carbonyloxy group each C6R5 group being a triodophenyl group or a group in which each R is other than hydrogen; and each M is independently a non-ionic hydrophilic moiety, M preferably being a non-ionic hydrophilic moiety comprising a monohydroxy- or polyhydroxy-alkyl group.

Description

Iodinated X-ray-contrast media
The present invention relates to contrast medium and, relate in particular to the x-ray contrast agent of iodo the improvement of contrast medium.
Contrast medium can administration in imaging of medical operational example such as X-ray, mr and ultra sonic imaging, to strengthen the contrast gradient of object (normally human or animal body) image.The enhanced contrast gradient of gained can so that different organs, tissue or body cavity observe more significantly or distinguish.In the X-ray contrast, contrast medium is distributed with the body part of contrast medium by change X-gamma absorption characteristic works.
Yet contrast agent material depends on its toxicity, diagnosis capability, its complexity to administration host's other side effect and complexity of depositing and administration that may have significantly to a great extent as the use of contrast medium.
Because such medicament is generally used for diagnostic purpose rather than obtains direct result of treatment, when developing new contrast medium, general hope can be developed the as far as possible little contrast medium of influence to the living organism of various cells, makes their general lower animal toxicity and lower clinical side effects of producing.
The toxicity of contrast medium and biological side effect are because the composition of medicament causes, i.e. solvent or carrier and radiography medicine and composition thereof (when it for example is an ion when be ionic) and meta-bolites.
Verified as follows to the main contribution factor of contrast medium toxicity and side effect: the chemical toxicity of-radiography medicine, the osmolality of-contrast medium and-the ionic composition (or not having this composition) of contrast medium.
For example, in coronary angiography, contrast-medium injection can be caused multiple seriously influencing to vascular function in the recycle system.The seriousness of these influences is enough to that the use in vasography is construed as limiting to contrast medium.
In the method, in the short period of time, contrast medium agglomerate rather than blood flow are passed through the recycle system, the physical and chemical performance of contrast medium is variant, the interim blood that replaces can produce ill effect, for example heart disorder, QT-prolong the especially generation of the reduction of cardiac contractile force and ventricular fibrillation.Have many about during visualization for example with contrast agent perfusion to the recycle system to the research aspect the side effect of heart function, people are in the method for seeking to reduce or eliminate these effects widely.
The early stage ionic x-ray contrast agent of the injectable based on Triiodobenzoic acid salt is because the hypertonicity of the contrast medium of injection produces the infiltration toxic action especially.
This hypertonicity causes osmosis, and for example water is discharged from red blood cell, endotheliocyte and heart and vascular muscle cell.Dehydration makes red blood cell stiff, and hypertonicity, chemical toxicity and non-best ion can reduce the convergent force of muscle cell separately or together, cause little vasodilation, cause the reduction of blood pressure.
The infiltration toxicity problem is improved by the exploitation of nonionic triiodophenyl monomer (for example iodine is pure), and this monomer can be so that the infiltration toxic action significantly reduce under identical radiography available iodine concentration.
The reduction infiltration is toxic need to have caused for example exploitation of iodixanol of nonionic two (triiodophenyl) dimer in time.It has further reduced and the relevant problem of infiltration toxicity, the feasible iodine concentration that also can obtain the radiography significant quantity with hypotonic solution.
This same weight-molality of oozing that will solution is brought up to flat (the about 300mOsm/kg H of isotonic water 2O) ability that reaches the iodine concentration of radiography significant quantity also makes the unbalanced toxicity of ion be reduced (referring to WO-90/01194 and the WO-91/13636 of for example NycomedImaging AS) by the cationic existence of various plasma bodys.
Yet the iodine concentration of commercially available x-ray contrast agent has higher viscosity up to about 300mgI/ml, is about 15-60mPas at ambient temperature, and the dimer reagent generally viscosity than monomer reagent is bigger.Such viscosity is brought problem to the doctor, when administration, need use the macropore syringe needle or apply high pressure, in the paediatrics radiography and needs rapidly, the radiography of agglomerate administration for example in the vasography this problem obvious especially.
This viscosity problem is that highly muddy X-ray contrast medicine has particularly been constituted serious obstacle to the development of high iodine number compound, its solution provides to produce than the high radiography drug solns of conventional iodine concentration or provide has a conventional iodine concentration but the possibility of the lower radiography drug solns of viscosity, the easier injection of these solution, and can use in the diagnosis research widely.
The present invention has overcome the viscosity problem that the prior art material occurs, thereby from one side, the invention provides formula I iodine aromatic compounds and isomer thereof, especially steric isomer and the rotational isomer that can be used as X-ray contrast medicine:
Figure A9519632700081
In the formula, each C 6R 5Part can be identical or different; Each R represents hydrogen or iodine atom or group M, at each C 6R 5The non-adjacent R group of on the part two or three is represented the iodine atom, at each C 6R 5Part is last one, two or three R groups are represented the M group; The X representative provides and connects two C 6R 5The group of 1,2 or 3 atomchains of group; When being preferably in X and being the ketonic oxygen base or in connection chain, containing the ketonic oxygen base, C 6R 5Group is that triiodophenyl or R are not hydrogen; M is the nonionic hydrophilic parts independently of one another, and M is the nonionic hydrophilic parts preferably, comprises monohydroxy alkyl or polyhydroxy alkyl group.
We find that short chain dimer compound of the present invention shows required low viscosity under aqueous solution state.
Formula I compound is preferably asymmetric.This can be by using asymmetric 2 or polyatom chain formation radicals X and/or select C inequality more 6R 5Group, i.e. replacement inequality by the iodophenyl end group realizes.Unsymmetric molecule is preferred, has better water solubility because find them.
Phenyl end group (C 6R 5Part) such replacement inequality can replace by the iodine with different numbers or position and/or the M by different numbers, position or character replaces and realizes.For making iodine load maximum, preferred triiodophenyl end group, i.e. following formula group: Wherein two R groups can be identical or different, though preferably the both represents the M group.
When the phenyl end group was replaced by iodine, its structural formula was preferably as follows: (M can be identical or different in the formula).
In general, diiodo-phenyl-diiodo-phenyl dimer is good not as diiodo-phenyl-triiodophenyl or triiodophenyl-triiodophenyl dimer, at this moment mainly is that promptly each molecule has 4 rather than 5 or 6 iodine because they have reduced the iodine load.Because triiodophenyl-triiodophenyl dimer has higher iodine load, general really preferred triiodophenyl-triiodophenyl dimer.
Solvation group M can be any water miscible nonionic group that is commonly used to strengthen.Suitable group comprises the C of side chain for example or side chain 1-10Alkyl, preferred C 1-5Alkyl, wherein one or more CH 2Or CH part replaces with oxygen or nitrogen-atoms alternatively and be selected from oxygen base, hydroxyl, amino, carboxy derivatives and oxo sulphur atom and the oxo phosphorus atom replaces by one or more alternatively.Special example comprises polyhydroxy alkyl, hydroxy alkoxy alkyl and hydroxyl multi-alkoxy alkyl, such group is connected on the phenyl by amido linkage, for example hydroxyalkyl aminocarboxyl, N-alkyl hydroxy alkyl aminocarboxyl and dihydroxyl alkyl amino-carbonyl group.Wherein preferably contain 1,2,3,4,5 or 6 compounds of 1,2 or 3 hydroxyl especially, for example :-CONH-CH 2CH 2OH-CONH-CH 2CHOHCH 2OH-CONH-CH (CH 2OH) 2-CON (CH 2CH 2OH) 2And other group, for example-CONH 2-CONHCH 3-OCOCH 3-N (COCH 3) H-N (COCH 3) C 1-3-alkyl-N (COCH 3) one, two and trihydroxy-C 1-4Alkyl-N (COCH 2OH) one, two and trihydroxy-C 1-4Alkyl-N (COCH 3) (one, two and trihydroxy-C 1-4Alkyl) 2-N-(COCH 2OH) 2-CON (CH 2CHOHCH 2OH) (CH 2CH 2OH)-CONH-C (CH 2OH) 3With-CONH-CH (CH 2OH) (CHOHCH 2OH).
In general, the M group preferably comprises poly-hydroxy C separately 1-4Alkyl, for example 1,3-dihydroxyl third-2-base or 2,3-dihydroxyl third-1-base.
Also can use the conventional group in other triiodophenyl x-ray contrast agent field, and the introducing of M group in the iodophenyl structure can realize also by routine techniques.
In dimer compound of the present invention, linking group X conventionally is a key or 1,2 or 3 yuan the chain that comprises carbon, nitrogen, oxygen or sulphur atom, for example an O, S, the atomchain of N or C, NN, NC, NS, CC or CO two atomchains, perhaps NCN, OCN, CNC, OCO, NSN, CSN, COC, OCC or CCC three atomchains, for example: Sauerstoffatom or group NR 1, CO, SO 2Or CR 2 1Group COCO, CONR 1, COCR 2 1, SOCR 2 1, SO 2NR 1, CR 2 1CR 2 1, CR 2 1NR 1Or R 2 1O;
Group NR 1CONR 1, OCONR 1, CONR 1CO, CONR 1CR 1 2, OCOO, CR 1 2OCR 1 2, OCR 1 2CO, CR 1 2CONR 1, CR 1 2CR 1 2CR 1 2, COCR 1R 1CO, CR 1 2NR 1CR 1 2, CR 1 2SO 2NR 1, CR 1 2OCO, or NR 1SO 2NR 1Wherein, R 1Be hydrogen or C 1-6Alkyl or alkoxy base are alternatively by hydroxyl, alkoxyl group replacement, oxa-or oxo (for example polyhydroxy alkyl, formyl radical, ethanoyl, hydroxyl, alkoxyl group or hydroxy alkoxy base group), as it and carbon atom R 1During connection, also can be oh group.
The X group is preferably asymmetric.This can be for example asymmetric replacement by for example symmetrical chain realize that (for example N-C-N is replaced to NHCONR 1) or by selecting symmetrical chain to realize.Particularly, linking group X should be polar and should be hydrophilic.
Therefore, the example of preferred construction of the present invention comprises: M and R in the formula 1Define the same.
Particularly preferred compound is a following formula: compound:
Figure A9519632700132
Compound of the present invention generally can prepare by two steps or three steps: (a) generate dimer, (b) iodate of phenyl group and (c) by making phenyl and/or optional connection portion solvation and with its replacement.
Although step (a) (b) He (c) can be carried out with any order, owing to reason economically in theory, generally preferably carry out dimer earlier and generate step, carry out the iodate step again, preferably with the iodate step the carrying out at last of process, so that reduce the waste of iodine.It can be multistep that dimer generates step itself, at first suitable active linking group is connected on the monomer, then with the gained linking group-monomer binding substance and second monomer reaction.Perhaps, dimer generates step and can generate dimer by the monomer and the monomeric association reaction of similar or common replacement.
When needing, linking group X can by to the precursor linking group for example the precursor linking group modification (for example replacement, oxidation or reduction) in precursor monomer produce.
Can use disclosed synthetic route in the document (for example being similar to the method for the production of the described compound of WO-94/14478) in all cases.
Dimer compound of the present invention can be used as X-ray contrast medicine, and they can produce diagnostic contrast agents with the carrier and the excipient preparation of routine for this reason.
Therefore, from another aspect, the invention provides and comprise the carrier that can tolerate on formula I compound (definition as above) and at least a physiology or the diagnosis composition of vehicle, for example is the aqueous solution in water for injection, also is added with plasma ion or dissolved oxygen alternatively.
Contrast agent composition of the present invention can be an available enriched material or can be formed in the form of the enriched material of dilution before the administration immediately.The iodine concentration of the composition of available form generally is at least 100mgI/ml immediately, preferably is at least 150mgI/ml, and general preferred concentration is 300mgI/ml, for example 320-400mgI/ml at least.Iodine concentration is high more, and diagnostic value is high more, but the viscosity and the osmolality of solution are also high simultaneously.In general, the maximum iodine for given compound concentrates the high limit of tolerance that will depend on its solubleness and viscosity and osmolality.
For the contrast medium of drug administration by injection, under envrionment temperature (20 ℃), the high limit of tolerance of the viscosity of solution is 30mPas preferably; Yet, also be admissible up to the viscosity of 50mPas even 60mPas, though in the paediatrics radiography, can depart to some extent.For the contrast medium (for example in vasography) that will inject by agglomerate, must consider the infiltration toxic action, osmolality is preferably lower than 1 Osm/kg H 2O particularly is lower than 850 Osm/kg H 2O, particularly isotonicity is no more than 50, preferably is no more than 10 mOsm (about 300mOsm/kgH 2O).
Dimer of the present invention has satisfied such viscosity, osmolality and iodine concentration requirement at an easy rate.Really, can reach effective iodine concentration with hypertonicity solution.Therefore, preferably set up the perviousness of solution, so that reduce the toxicity contribution that produces by the ionic influence of unbalance after the agglomerate injection by adding the plasma body positively charged ion.Such positively charged ion preferably is included in the scope of WO-90/01194 and WO-91/13636 proposition.
For contrast medium of the present invention, contrast medium especially for vasography, preferred plasma body cations is as follows: sodium 2-100, especially 15-75,20-7 particularly, more especially 25-35mM calcium is no more than 3.0, preferred 0.05-16, especially 0.1-0.2, particularly 0.15-0.7mM potassium is no more than 2, preferred 0.2-1.5, especially 0.3-1.2, particularly 0.4-0.9mM magnesium is no more than 0.8, preferred 0.05-0.6, especially 0.1-0.5, particularly 0.1-0.25mM
The plasma body positively charged ion can be generally or is partly existed with the form of the gegenion of ionic contrast medium.Perhaps, they generally be with physiology on the form of salt (for example muriate, vitriol, phosphoric acid salt, supercarbonate etc.) of the gegenion that can tolerate, especially preferably use the plasma body negatively charged ion.
Except containing the plasma body positively charged ion, contrast medium can also contain other gegenion, and wherein dimer is ionic, and can tolerate on the certain preferably physiology of such gegenion.Such ionic example comprises: basic metal and alkaline-earth metal ions, ammonium, meglumine, thanomin, diethanolamine, muriate, phosphoric acid salt and supercarbonate.Also can use in the pharmacy field other conventional gegenion.In addition, composition also contains other conventional ingredient in the x-ray contrast agent, for example buffer reagent etc.
With reference to following non-limiting example the present invention is described.Embodiment 1.N, N '-two [2,4,6-three iodo-3,5-two (2,3-dihydroxy phenyl aminocarboxyl) phenyl] urea be amino-2,4 a.5-, 6-three iodo-N, N '-two (2,3-diacetoxy propyl group) isophthaloyl amine
Will be according to the 5-amino-2,4 of GB-A-1548594 preparation, 6-three iodo-N, N '-two (2, the 3-dihydroxypropyl) isophthaloyl amine (14.08 grams, 0.02 mole) is suspended in the pyridine (200 milliliters), under stirring and cooling, drip diacetyl oxide (57.1 grams, 0.56 mole).After stirring is spent the night, mixture is poured in ethyl acetate (300 milliliters) and 20% aqueous hydrochloric acid (200 milliliters).After the extraction, organic phase is also evaporated with 2M aqueous hydrochloric acid (20 milliliters), salt solution (70 milliliters) washing, dry (sodium sulfate), obtains 17.4 gram (100%) crude products.Thick material directly uses unlike being further purified, HPLC with 1The analysis revealed of H NMR, degree of purity of production is greater than 97%. 1H NMR (acetone-d 6): 8.76-8.83 (m, 2H, NH), 5.50 (br s, 2H, NH 2), 5.20-5.32 (m, 2H), 4.43 (dd, J 1=11.8 Hz, J 2=3.4 Hz, 2H), 4.29 (dd, J 1=11.8 Hz, J 2=6.0Hz), and 3.69-3.86 (m, 2H), 3.49-3.63 (m, 2H), 1.95-2.07 (m, 12H) .MS (ESP): 706 (M+1) .b.N, N '-two [2,4,6-three iodo-3,5-two (2,3-diacetoxy propyl group aminocarboxyl) phenyl] urea
With 5-amino-2,4,6-three iodo-N, N '-two (2,3-diacetoxy propyl group) isophthaloyl amine (10.4 grams, 0.012 mole) is dissolved in the anhydrous dioxane (20 milliliters), adds 20% solution (3.1 milliliter) of carbonyl chloride in toluene.Mixture was stirred for 1 week at ambient temperature in the sealing thick-walled vessel.After the evaporation, resistates is with preparing the HPLC purifying.Output 10.0 grams (94%). 1H NMR:8.24-8.98 (m, 6H, NH), 5.07 (br s, 4H), 4.12-4.35 (m, 8H), 3.31-3.60 (m, 8H), 2.00 (s, 24H, CH 3CO) .MS (ESP): 1771 (M +) c.N, N '-two [2,4,6-three iodo-3,5-two (2,3-dihydroxypropyl aminocarboxyl) phenyl] urea
With N, N '-two [2,4,6-three iodo-3,5-two (2,3-diacetoxy propyl group aminocarboxyl) phenyl] urea (4.0 gram, 2.26 mmoles) is dissolved in 1: 1 mixture (25 milliliters) of the water that contains sodium hydroxide (1.44 grams, 36 mmoles) and methyl alcohol.40 ℃ down stir 6 hours after, handle with strong-acid ion exchange resin (Amberlyst 15), evaporating solns, evaporate pure products.Output: 3.24 grams (100%). 1H NMR (DMSO-d 6): 7.98-8.60 (m, 6H, NH), 4.65-4.80 (m, 4H), 4.44-4.57 (m, 4H), 3.62-3.75 (m, 4H), 3.02-3.55 (m, 16H). 13C NMR (DMSO-d 6): 170.7,170.4,170.3,151.8,151.7,150.1,143.5,100.9,100.8,100.7,100.5,100.3,89.8,89.6,70.1,70.0,64.1,42.7,42.6.MS (ESP): 1458 (M ++ Na +). embodiment 2:N, N '-two [2,4,6-three iodo-3,5-two (2,3-dihydroxypropyl aminocarboxyl) phenyl]-N-methyl-urea
With N, N '-two [2,4,6-three iodo-3,5-two (2,3-dihydroxypropyl aminocarboxyl) phenyl] urea (7.32 grams, 5.1 mmoles) is dissolved in the 2M aqueous sodium hydroxide solution (10 milliliters), adds methyl-iodide (0.95 milliliter).Mixture was stirred 60 hours at ambient temperature, handle with strong-acid ion exchange resin (Amberlyst 15), evaporating solns is with preparation HPLC purifying.Output: 4.7 grams (63%), product is a white solid. 1H NMR (DMSO-d 6): 8.80 (br d, 1H, NH), 8.42 (br d, 3H, NH), 8.05 (br d, 1H, NH), 4.42-4.85 (m, 8H), 3.01-3.78 (m, 23H). 13C NMR (DMSO-d 6): 170.2,170.1,170.0,152.6,152.5,150.7,150.3,150.2,149.5,144.2,101.3,101.2,100.0,99.5,90.5,90.1,70.5,70.3,64.4,64.3,43.1,42.9,36.0. MS (ESP): 1470 (M ++ Na +). embodiment 3:N, N '-two [2,4,6-three iodo-3,5-two (2,3-dihydroxypropyl aminocarboxyl) phenyl]-N-hydroxyethyl-urea
With N, N '-two [2,4,6-three iodo-3,5-two (2,3-dihydroxypropyl aminocarboxyl) phenyl]-urea (2.0 grams, 1.4 mmoles) is dissolved in the water (13 milliliters) that contains 2M sodium hydroxide (7 milliliters).Add ethylene bromohyrin (1 gram, 8.4 mmoles), mixture was stirred 60 hours at ambient temperature, handle with strong-acid ion exchange resin (Amberlyst 15), evaporation and with preparation HPLC purifying obtains 1.45 and restrains (70%) white solid product. 1H NMR (DMSO-d 6): 9.10-9.38 (m, 1H, NH), 7.90-8.65 (m, 4H, NH), 3.02-3.91 (m, 24H). 13C NMR (DMSO-d 6): 170.2,153.2,150.9,150.3,149.1,144.1,101.3,100.9,100.7,100.3,90.6,89.8,70.5,70.4,70.1,64.4,63.2,60.6,53.2,43.1, MS (ESP): 1502 (M ++ Na +). embodiment 4:N, N '-two [2,4,6-three iodo-3-(2,3-dihydroxypropyl aminocarboxyl)-5-(1,3-dihydroxyl third-2-base aminocarboxyl) phenyl] urea is amino-2,4 a.1-, 6-three iodo-3,5-m-phthaloyl chloride
With 1-amino-2,4,6-three iodo-3,5-m-phthalic acid (200 grams, 0.358 mole) is added in the thionyl chloride (150 milliliters).Mixture was stirred 6 hours under reflux temperature, allow it be cooled to envrionment temperature then.After the evaporation, solid residue is dissolved in the ethyl acetate (300 milliliters), is evaporated to dried once more.Resistates is dissolved in the ethyl acetate (2000 milliliters).Gained solution is used sodium-chlor (250 gram) and the solution washing of sodium bicarbonate (120 gram) in water (2000 milliliters) that has been cooled to 0 ℃.Tell organic phase, with salt water washing and dry (sodium sulfate).Evaporate 202 the gram (94%) white solid product. 1H NMR (DMSO-d 6): 10.79 (br s, 2H). 13C NMR (DMSO-d 6): 170.1,149.7,149.4,78.94,78.90.MS (ESP, m/e): 595,593 (M +). b.1-amino-2,4,6-three iodo-3-(2-acetoxyl group ethylamino aminocarboxyl)-5-(1,3-diacetoxy third-2-base aminocarboxyl) benzene
With 1-amino-2,4,6-three iodo-3,5-m-phthaloyl chloride (10.0 grams, 16.8 mmoles) is dissolved in anhydrous N, N-N,N-DIMETHYLACETAMIDE (DMAC, 80 milliliters) in, add triethylamine (14 milliliters) and add 2-amino-1, ammediol (2.14 grams, 23.55 mmole), mixture was stirred 60 hours.Add thanomin (5.0 milliliters), with mixture restir 24 hours.Behind the evaporating solvent, solid residue is dissolved in the pyridine (250 milliliters), adds diacetyl oxide (200 milliliters).Stir after 20 hours, evaporating solvent is dissolved in resistates in the ethyl acetate.With solution with water, diluted hydrochloric acid aqueous solution, sodium bicarbonate aqueous solution washing, dry (sal epsom) and evaporation.Silica gel chromatography, with ethyl acetate/heptane (6: 1) wash-out, then (RP-18, acetonitrile: purifying water 35: 65) gets 4.74 gram (35%) products with preparation HPLC. 1H NMR (CDCl 3): 6.01-6.17 (2br s, 2H, NH), 5.11 (br s, 2H, NH 2), 4.59-4.67 (m, 1H, CH), 4.22-4.40 (m, 6H, CH 2O), 3.69-3.78 (m, 2H, NCH 2), 2.12 (s, 3H), 2.08 (s, 6H) .MS (ESP, m/e): 823 ([M+Na] +), 801 ([M+1] +) .c.N, N '-two [2,4,6-three iodo-3-(2,3-dihydroxypropyl aminocarboxyl)-5-(1,3-dihydroxyl third-2-base aminocarboxyl) phenyl] urea
With 1-amino-2,4,6-three iodo-3-(2-acetoxyl group ethylamino aminocarboxyl)-5-(1,3-diacetoxy third-2-base aminocarboxyl) benzene (0.976 gram, 1.20 mmole) in heavy wall, the flask of jumping a queue, mix, then 60 ℃ of insulations 18 hours with carbonyl chloride (8.86 milliliter 20% toluene solution) and dioxane (3 milliliters).Mixture is cooled to envrionment temperature, evaporating solvent.Add dioxane (15 milliliters), under barometric point, steam and remove.This process is repeated twice.Add dioxane (10 milliliters), 1-amino-2,4,6-three iodo-3-(2-acetoxyl group ethylamino carbonyl)-5-(1,3-diacetoxy third-2-base aminocarboxyl) benzene (0.926 gram, 1.16 mmole) and (26 milligrams of trifluoroacetic acid mercury, 0.23 mmole), with time of 1 hour evaporating solvent under barometric point once more.Add dioxane (10 milliliters), mixture was stirred 16 hours at ambient temperature.Solvent is evaporated once more, after the evaporation, resistates is dissolved in the mixture of methyl alcohol (35 milliliters) and 0.4M aqueous sodium hydroxide solution (50 milliliters).Stir after 2 hours, solution is neutralized with storng-acid cation exchange resin, filter and lyophilize.With resistates preparation HPLC purifying.Output: 0.43 gram (27%). 1H NMR (DMSO-d 6): 8.03-8.59 (m, 6H), 4.42-4.77 (m, 6H), 3-10-3.83 (m, 18H). embodiment 5:N, N '-two [2,4,6-three iodo-3-(2,3-dihydroxypropyl aminocarboxyl)-5-(1,3-dihydroxyl third-2-base aminocarboxyl) phenyl]-N-hydroxyethyl urea
Will be from the N of embodiment 4, N '-two [2,4,6-three iodo-3-(2,3-dihydroxypropyl aminocarboxyl)-5-(1,3-dihydroxyl third-2-base aminocarboxyl) phenyl] urea (027 gram, 0.2 mmole) is dissolved in the water (7 milliliters) that contains 2M aqueous sodium hydroxide solution (1.0 milliliters) and ethylene bromohyrin (0.084 milliliter, 1.2 mmoles).After succeeding 20 hours, solution is neutralized with storng-acid cation exchange resin, be evaporated to dried.With resistates preparation HPLC purifying.Output: 138 milligrams (50%). 1H NMR (DMSO-d 6): 9.06-9.22 (m, 1H), 8.03-8.46 (m, 4H), 4.22-4.69 (m, 7H), 3.43-3.87 (m, 22H). embodiment 6.N, N '-two [2,4,6-three iodo-3-(2-hydroxyethyl aminocarboxyl)-5-(1,3-dihydroxyl third-2-base aminocarboxyl) phenyl]-N-(2, the 3-dihydroxypropyl) urea
With N, N '-two [2,4,6-three iodo-3-(2,3-dihydroxypropyl aminocarboxyl)-5-(1,3-dihydroxyl third-2-base aminocarboxyl) phenyl] urea (0.25 gram, 0.18 mmole) be dissolved in the water (5 milliliters), then add 2M aqueous sodium hydroxide solution (2.1 milliliters), after 5 minutes, add N-PROPYLE BROMIDE-2,3-glycol (0.196 milliliter).With solution stirring 4 days,, be evaporated to dried with the storng-acid cation exchange resin neutralization.Resistates with preparation HPLC purifying, is obtained 38 milligrams of (14%) white solid product.MS (ESP, m/e): 1450 (M +) embodiment 7.N, N '-two [2,4,6-three iodo-3-(2-hydroxyethyl aminocarboxyl)-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea a.1-amino-2,4,6-three iodo-3-(2-acetoxyl group ethylamino carbonyl)-5-(2,3-dihydroxypropyl aminocarboxyl) benzene
Will be according to the 1-amino-2,4 of embodiment 4a preparation, 6-three iodo-3,5-m-phthaloyl chloride (3.03 grams, 5.1 mmoles) is added in the solution of triethylamine (4.26 milliliters) in DMAC (20 milliliters).Add 1-amino-2, the solution of ammediol (0.52 gram, 5.6 mmoles) in DMAC (3 milliliters), stir 16 hours at ambient temperature after, add thanomin (1.55 grams, 25.5 mmoles).Behind the restir 16 hours, evaporating solvent was dissolved in resistates in the pyridine (75 milliliters), adds diacetyl oxide (60 milliliters), with solution stirring 17 hours.Evaporating solvent is dissolved in resistates in the ethyl acetate, and water, 0.2M aqueous hydrochloric acid, sodium bicarbonate aqueous solution wash this solution, dry (sal epsom) and evaporation.With preparation HPLC purifying, obtain 1.28 gram (31%) white solid product. 1H NMR (DMSO-d 6): 8.60-8.71 (m, 2H), 5.42-5.51 (m, 1H), 5.02-5.13 (m, 1H), 4.24-4.33 (m, 1H), 4.08-4.21 (m, 3H), 3.32-3.49 (m, 5H), 2.00 (2s, 9H) .MS (ESP, m/e): 823 ([M+Na] +), 801 (M+1) b.N, N '-two [2,4,6-three iodo-3-(2-hydroxyethyl aminocarboxyl)-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea
In the heavy wall flask, with 1-amino-2,4,6-three iodo-3-(2-acetoxyl group ethylamino carbonyl)-5-(2,3-diacetoxy propyl group aminocarboxyl) benzene (1.99 grams, 2.48 mmoles) is dissolved in the toluene solution (20%, 18 milliliter) of dioxane (7 milliliters) and carbonyl chloride.With mixture heating up to 60 ℃, be incubated 16 hours, be cooled to envrionment temperature after, evaporating solvent.Add dioxane (10 milliliters), under barometric point, distill.This process repeats 3 times.Resistates is dissolved in contains trifluoroacetic acid mercury (35 milligrams) and 1-amino-2,4, in the dioxane (10 milliliters) of 6-three iodo-3-(2-acetoxyl group ethylamino carbonyl)-5-(2,3-diacetoxy propyl group aminocarboxyl) benzene (2.0 grams, 2.50 mmoles).With the flask heating, slowly steaming desolventizes.Add another part dioxane (10 milliliters), and then distillation.Resistates is dissolved in the mixture of methyl alcohol (60 milliliters) and 0.22M aqueous sodium hydroxide solution (90 milliliters).Stir after 6 hours, solution is neutralized with storng-acid cation exchange resin, behind the evaporating solvent, resistates with preparation HPLC purifying, is obtained 1.26 gram (37%) white solid product. 1H NMR (DMSO-d 6): 8.02-8.67 (m, 6H), 4.60-4.84 (m, 4H), 4.43-4.57 (m, 2H), 3.02-3.75 (m, 18H). 13C NMR (DMSO-d 6): 169.7,169.5,151.4,150.0,142.9,99.9,89.6,70.1,70.0,69.9,64.0,59.2,42.6,41.7. embodiment 8.N, N '-two [2,4,6-three iodo-3-(2-hydroxyethyl aminocarboxyl)-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl]-N-hydroxyethyl urea
With N, N '-two [2,4,6-three iodo-3-(2-hydroxyethyl aminocarboxyl)-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea (0.216 gram, 0.157 mmole) is dissolved in water (6 milliliters) and 2M aqueous sodium hydroxide solution (0.9 milliliter) and the ethylene bromohyrin (0.067 milliliter).Mixture was stirred 4 days,, be evaporated to dried with the storng-acid cation exchange resin neutralization.Resistates with preparation HPLC purifying, is obtained 105 milligrams of (147%) white solid product. 1H NMR (DMSO-d 6): 9.11-9.22 (m, 1H), 7.84-8.61 (m, 4H), 4.41-4.80 (m, 7H), 3.02-3.87 (m, 22H). 13C NMR (DMSO-d 6): 170.2,169.9,153.2,151.0,150.9,150.4,144.2,144.1,100.2,70.5,64.4,60.6,59.6,43.1,42.1.MS (ESP, m/e): 1450 (M +) embodiment 9.N, N '-two [2,4,6-three iodo-3-(2-hydroxyethyl aminocarboxyl)-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl]-N-(2, the 3-dihydroxypropyl) urea
With N, N '-two [2,4,6-three iodo-3-(2-hydroxyethyl aminocarboxyl)-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea (0.353 gram, 0.257 mmole) be dissolved in water (8 milliliters) and 2M aqueous sodium hydroxide solution (0.9 milliliter) and 1-bromo-2, in the 3-dihydroxypropane (0.136 milliliter, 1.55 mmoles).After at room temperature stirring 150 hours, neutralize with storng-acid cation exchange resin.Be evaporated to driedly, resistates with preparation HPLC purifying, is obtained 100 milligrams of (27%) white solid product. 1H NMR (DMSO-d 6): 9.45-9.63 (m, 1H), 7.94-8.68 (m, 4H), 5.82-6.07 (m, 1H), 5.12 (br s, 1H), 4.43-4.80 (m, 6H), 4.13 (m, 1H), 3.04-3.97 (m, 14H). 13C NMR (DMSO-d 6): 169.8,169.5,153.5,150.8,150.5,150.0,149.9,143.7,99.8,90.3,70.0,64.O, 59.2,42.7,41.7. embodiment 10.N, N '-two [2,4,6-three iodo-3-acetylaminohydroxyphenylarsonic acid 5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea a.N, N '-two (3-nitro-5-carboxyl phenyl) urea
1-nitro-3-benzaminic acid (9.11 grams, 50 mmoles) and carbonyl chloride (13 milliliter 20% toluene solution) and yellow soda ash (7.4 grams, 70 mmoles) are mixed in toluene (20 milliliters).Mixture was stirred 2 hours down at 60 ℃, stirred at ambient temperature then 16 hours.Add toluene (4 milliliters) again, continue down to stir 9 hours at 100 ℃.Add toluene (4 milliliters), continue to stir 20 hours down at 40 ℃.After being cooled to room temperature, solution is poured in the 1M aqueous hydrochloric acid (200 milliliters).Filtering pale precipitation thing with ethanol and 2M aqueous hydrochloric acid (4 milliliters) washing, filters and drying.Output: 8.2 grams (84%). 1H NMR (DMSO-d 6): 9.63 (s, NH, 2H), 8.65 (dd, J 1=J 2=22Hz, 2H), 8.34 (dd, J 1=1.6Hz, J 2=1.5Hz, 2H), 8.18 (dd, J 1=1.5Hz, J 2=1.3Hz, 2H), 3.3-3.8 (br s, 2H, OH). 13C NMR (DMSO-d 6): 165.8,152.7,148.5,141.4,133.1,125.3,117.3,116.6.MS (ESP, m/e): 389 (M +, 100%), 411 ([M+Na] +, 55%) and b.N, N '-two (3-nitro-5-methoxycarbonyl phenyl) urea
With N, N '-two (3-nitro-5-carboxyl phenyl) urea (0.5 gram, 1.3 mmoles) is dissolved in the methyl alcohol (15 milliliters) that contains the vitriol oil (15 milliliters), and solution was stirred 20 hours down at 60 ℃.After being cooled to envrionment temperature, pour solution in the water (40 milliliters).The filtering yellow mercury oxide is with sodium hydroxide saturated aqueous solution and water washing and dry.Output 0.53 gram (98%). 1H NMR (DMSO-d 6): 9.78 (br s, NH, 1H), 8.68 (dd, J 1=2.1Hz, J 2=2.0Hz, 2H), 8.46 (dd, J 1=2.2Hz, J 2=2.0Hz, 2H), 8.23 (dd, J 1=2.2Hz, J 2=2.0Hz, 2H), 3.92 (s, OCH 3, 6H). 13C NMR (DMSO-d 6): 164.9,153.1,148.5,142.0,131.6,124.9,117.0,116.9.c.N, N '-two [3-nitro-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea
With N, N '-two (3-nitro-5-methoxycarbonyl phenyl) urea (0.209 gram, 0.5 mmole) and 1-amino-2, ammediol (0.114 gram, 0.5 mmole) is heated to 95 ℃.After 30 minutes, pressure is reduced to 200mmHg, continued to be heated to 3 hours.The reaction mixture crude product with preparation HPLC purifying, is got 164 milligrams of (61%) white solid product. 1H NMR (DMSO-d 6): 9.61 (s, 2H), 8.79 (t, J=6.4Hz, 2H), 8.67 (dd, J 1=2.1, J 2=2.0Hz, 2H), 8.36 (dd, J 1=2.1Hz, J 2=2.0Hz, 2H), 8.25 (dd, J 1=J 2=2.0Hz, 2H), 4.84 (d, J=4.5Hz, OH, 2H), 4.58 (t, J=5.6Hz, OH, 2H), 3.65 (m, 2H), 3.30-3.50 (m, 6H), 3.21 (m, 2H). 13C NMR (DMSO-d 6): 164.8,152.6,148.5,141.1,136.8,124.2,115.9,115.4.MS (ESP, m/e): 537 (M +, 100%), 519 ([M-H 2O] +, 56%) and .d.N, N '-two [3-amino-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea
With N, N '-two [3-nitro-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea (0.103 gram, 0.19 mmole) is dissolved in the mixture of the methyl alcohol (14 milliliters) that contains 2M aqueous hydrochloric acid (0.2 milliliter) and Pd/C catalyzer and water (6 milliliters).Under 60 pounds/square inch, carry out hydrogenation.Filtration catalizer, evaporating solvent.Resistates is dissolved in the water again lyophilize.Obtain 0.102 gram (97%) product. 1H NMR (D 2O): 7.60 (s, 4H), 7.29 (s, 2H), 3.74-3.82 (m, 2H), 3.38-3.54 (m, 4H), 3.22-3.37 (m, 4H). 13C NMR (D 2O): 168.6,154.0,139.9,136.1,131.1,118.6,118.5,117.0,116.9,116.2,70.1,63.2,42.4.Ms (ESP, m/e): 477 (M +, 100%). e.N, N '-two [3-amino-2,4,6-three iodo-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea
With N, N '-two [3-amino-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea (0.50 gram, 0.91 mmole) is dissolved in the mixture of methyl alcohol (4 milliliters) and water (46 milliliters), adds KICl 2The aqueous solution (6 mmole).With aqueous hydrochloric acid the pH value is adjusted to 2.Solution was stirred 20 hours down at 40 ℃.After adding the sodium pyrosulfate aqueous solution, evaporating solvent with resistates development three times, obtains 1.02 gram (89%) products with methanol-water (3: 7). 1H?NMR(DMSO-d 6)：8.41(br?s，1H)，8.20-8.33(m，2H)，8.11-8.17(d，J＝7.0?Hz，1H)，5.40(br?s，NH 2，4H)，3.62-3.74(m，2H)，3.44-3.52(m，2H)，3.34-3.43(m，2H)，3.21-3.32(m，2H)，3.07-3.21(m，2H). 13C?NMR(DMSO-d 6)：170.7，170.6，151.9，149.3，148.9，143.1，143.0，142.8，70.6，70.4，64.4，43.1，43.0.
MS (ESP, m/e): 1232 (M +, 20%), 1254 ([M+Na] +, 100%), 1270 ([M+K] +, 50%) and .f.N, N '-two [2,4,6-three iodo-3-(2-hydroxyethyl aminocarboxyl)-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl]-N-(2, the 3-dihydroxypropyl) urea
With N, N '-two [3-amino-2,4,6-three iodo-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea (0.115 gram, 0.126 mmole) mixes (2 milliliters) and the vitriol oil (3) with diacetyl oxide.Mixture was stirred 5 hours down at 70 ℃, stirred at ambient temperature then 17 hours.Behind the evaporating solvent, resistates is dissolved in the mixture of methyl alcohol (2.5 milliliters) and water (0.4 milliliter).With the 10M aqueous sodium hydroxide solution pH value is adjusted to 10.Stirred 5 hours down at 50 ℃.Behind the evaporating solvent, the resistates water is developed.With solid filtering and dry.Output 0.15 gram (90%). 1H NMR (DMSO-d 6): 9.80-10.10 (2br s, 2H), 8.20-8.75 (m, 4H), 4.70 (s, OH, 2H), 4.48 (s, OH, 2H), 3.64-3.98 (m, 2H), 3.41-3.56 (m, 4H), 3.03-3.26 (m, 4H), 2.04 (s, 6H). 13C NMR (DMSO-d 6): 170.3,170.2,168.3,168.2,168.1,151.9,151.7,150.3,144.4,144.3,108.2,108.1,99.5,99.4,99.3,99.2,98.1,98.0,97.9,70.6,70.4,64.4,43.1, and 23.5.MS (ESP, m/e): 1339 ([M+Na] +, 100%). embodiment 11.N, N '-two [2,4,6-three iodo-3-(2-glycoloyl amino)-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea a.N, N '-two [3-amino-2,4,6-three iodo-5-(2,3-diacetoxy propyl group aminocarboxyl) phenyl] urea
With N, N '-two [3-amino-2,4,6-three iodo-3-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea (1.23 grams, 1.0 mmoles) is dissolved in the mixture of diacetyl oxide (5 milliliters), pyridine (5.5 milliliters) and DMF (5 milliliters).Solution was at room temperature stirred 65 hours evaporating solvent.Resistates is dissolved in the methylene dichloride (250 milliliters).Water (2x50 milliliter), 0.1M aqueous hydrochloric acid (50 milliliters) and saturated sodium bicarbonate aqueous solution washing.After dry (sodium sulfate) and the evaporation, with NMR and HPLC to resistates analysis learn, be pure products basically.Output: 1.0 grams (71%). 1H NMR (DMSO-d 6): 8.73 (br s, 1H), 8.44-8.63 (m, 2H), 8.32-8.45 (m, 1H), 5.30-5.45 (s, NH 2, 4H), 5.02-5.16 (m, 2H), 4.10-4.37 (m, 4H), 1.80-2.05 (m, 12H). 13C NMR (DMSO-d 6): 170.8,170.6,170.3,149.1,148.9,148.3,147.8,143.3,143.2,136.6,124.4,92.6,92.0,70.1,70.0,63.5,21.5,21.0.MS (ESP, m/e): 1400 (M +, 100%) and .b.N, N '-two [2,4,6-three iodo-3-(2-acetoxyl group kharophen)-5-(2,3-diacetoxy propyl group aminocarboxyl) phenyl] urea
With N, N '-two [3-amino-2,4,6-three iodo-5-(2,3-diacetoxy propyl group aminocarboxyl) phenyl] urea (1.0 grams, 0.71 mmole) is dissolved in the alpha-Acetoxyacetyl chloride (5 milliliters), and solution was stirred 24 hours at ambient temperature.Be heated to 60 ℃, be incubated 2.5 hours, to doing, resistates water (40 milliliters) is developed with solution evaporation.Filtering brown throw out, water (20 milliliters) washing and dry once more.Output: 0.92 gram (81%). 1H NMR (DMSO-d 6): 10.05-10.30 (m, 2H), 8.62-9.06 (m, 2H), 8.22-8.58 (m, 2H), 5.02-5.15 (m, 2H), 4.66 (br s, 4H), 4.23-4.39 (m, 2H), 4.12-4.23 (m, 2H), 3.25-3.62 (m, 4H), 2.11 (s, 6H), 2.00 (s, 12H). 13C NMR (DMSO-d 6): 170.7,170.4,170.1,165.7,150.1,150.0,144.5,144.4,143.3,143.2,108.5,108.3,108.1,97.6,97.3,70.0,63.5,62.6,61.0,21.5,21.0.MS (ESP, m/e): 1599 (M +, 100%), 1621 ([M+Na] +, 23%) and .c.N, N '-two [2,4,6-three iodo-3-(2-glycoloyl amino)-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea
With N, N '-two [2,4,6-three iodo-3-(2-acetoxyl group kharophen)-5-(2,3-diacetoxy propyl group aminocarboxyl) phenyl] urea (0.88 gram, 0.55 mmole) is dissolved in the mixture of methyl alcohol (10 milliliters) and 2M sodium hydroxide (2.5 milliliters).After stirring 15 minutes at ambient temperature, the pH value is adjusted to 4, after the filtration, is evaporated to dried with strong-acid ion exchange resin.With resistates preparation HPLC purifying.Output: 0.58 gram (78%). 1H NMR (DMSO-d 6): 9.68-9.93 (m, 2H), 8.42-8.64 (m, 2H), 8.24-8.48 (m, 2H), 4.00 (s, OH, 6H), 3.60-3.73 (m, 6H), 3.36-3.54 (m, 6H), 3.04-3.38 (m, 4H). 13C NMR (DMSO-d 6): 171.0,170.8,170.6,170.3,170.2,151.8,151.7,150.3,150.2,144.3,144.1,143.9,143.8,108.1,108.0,107.9,99.5,99.3,97.9,97.8,97.7,70.4,64.4,62.3, and 43.1.MS (ESP, m/e): 1349 (M +, 36%), 1379 ([M+Na] +100%). embodiment 12.N, N '-two [2,4,6-three iodo-3-(2-hydroxyl propionamido)-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea a.N, N '-two [3-amino-2,4,6-three iodo-5-(2,3-diacetoxy propionamido)-and 5-(2,3-diacetoxy propyl group aminocarboxyl) phenyl] urea
With the N that as above prepares, N '-two [3-amino-2,4,6-three iodo-5-(2,3-acetoxyl group propyl group aminocarboxyl) phenyl] urea (1.0 grams, 0.71 mmole) and 2-acetoxyl group propionyl chloride (4.0 milliliters) mixing, stirred 2 hours down at 60 ℃, stirred 14 hours down at 85 ℃.Evaporating solvent, water (50 milliliters) development.Leaching green solid needn't refine, and is directly used in down the step.Output 0.92 gram (79%). 1H NMR (DMSO-d 6): 10.08-10.25 (m, 2H), 8.70-9.30 (m, 2H), 8.08-8.75 (m, 2H), 5.15-5.27 (m, 2H), 5.03-5.16 (m, 2H), 4.23-4.36 (m, 2H), 4.11-4.25 (m, 2H), 3.23-3.54 (m, 4H), 2.10 (s, 3H), 2.06 (2s, 15H), 1.47-1.55 (m, 6H). 13C NMR (DMSO-d 6): 170.7,170.4,170.0,151.8,150.1,149.0,144.5,143.3,143.2,108.3,107.9,106.4,97.7,97.6,70.5,70.0,69.9,63.6,63.5,63.4,21.5,21.3,21.0,18.0.b.N, N '-two [2,4,6-three iodo-3-(2-hydroxyl propionamido)-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea
With N, N '-two [3-amino-2,4,6-three iodo-3-(2-acetoxyl group propionamido)-5-(2,3-diacetoxy propyl group aminocarboxyl) phenyl] urea (0.85 gram, 0.52 mmole) is dissolved in the mixture of methyl alcohol (10 milliliters) and 2M sodium hydroxide (2.5 milliliters).Solution was at room temperature stirred 2 hours.With strong-acid ion exchange resin the pH value is adjusted to 4, after the filtration, is evaporated to dried.With resistates preparation HPLC purifying.Output: 370 grams (51%). 1H NMR (DMSO-d 6): 9.58-9.84 (m, 2H), 8.22-8.64 (m, 4H), 5.50-5.70 (m, 2H), 4.67 (br s, OH, 2H), 4.48 (br s, OH, 2H), 4.13-4.17 (m, 2H), 3.64-3.75 (m, 2H), 3.40-3.61 (m, 2H), 3.26-3.35 (m, 2H), 3.07-3.25 (m, 4H), 1.35-1.42 (m, 6H). 13C NMR (DMSO-d 6): 173.0,172.8,170.3,170.2,151.8,150.2,144.2,143.9,108.0,99.5,99.2,97.8,97.6,97.5,70.4,70.3,68.0,64.4,43.1,21.5,21.0.MS (ESP, m/e): 1374 (M +, 20%), 1397 ([M+Na] +, 100%). embodiment 13.N, N-two [2,4,6-three iodo-3-(2,3-dihydroxyl propionamido)-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea a.N, N '-two [3-amino-2,4, and 6-three iodo-3-(2,2-dimethyl-1,3-dioxolane-4-formamido-)-and 5-(2,3-diacetoxy propyl group aminocarboxyl) phenyl] urea
With 2,2-dimethyl-1,3-dioxolane-4-formic acid sylvite (1.50 grams, 8.1 mmoles) is cooled to 0 ℃.Add oxalyl chloride (1.03 grams, 8.1 mmoles), solution was stirred 2 hours down at 0 ℃, stirred at ambient temperature then 24 hours.Filtering mixt, evaporated filtrate.Add the as above N of preparation then, N '-two [3-amino-2,4,6-three iodo-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] solution of urea (1.9 grams, 1.36 mmoles) in N,N-DIMETHYLACETAMIDE (10 milliliters), stirred gained solution 60 hours at ambient temperature.Add ether (60 milliliters), generate precipitation, use ether (50 milliliters) development again, obtain 1.88 gram (84%) products. 1H NMR (DMSO-d 6): 9.57-10.10 (m, 2H), 8.26-8.55 (m, 4H), 3.08-4.37 (m, 16H), 1.87-2.04 (m, 12H). 13C NMR (DMSO-d 6): 172.4,170.9,170.1,150.1,147.0,144.4,143.8,141.9,127.9,100.1,99.8,99.6,99.1,97.7,97.6,97.4,74.2,70.4,66.9,66.8,64.8,64.4,64.1,43.1,43.0,37.9,35.0,21.8, and 21.5.MS (ESP, m/e): 1656 (M +, 100%), 1679 ([M+Na] +, 80%) and .b.N, N '-two [2,4,6-three iodo-3-(2,3-dihydroxyl propionamido)-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] urea
With N, N '-two [3-amino-2,4,6-three iodo-3-(2,2-dimethyl-1,3-dioxolane-4-formamido-)-5-(2,3-diacetoxy propyl group aminocarboxyl) phenyl] urea (0.60 gram, 0.36 mmole) mixes with the methyl alcohol (40 milliliters) of salt of wormwood (0.40 gram, 2.8 mmoles).With solution stirring 88 hours, solution is filtered, filtrate is evaporated to dried.Resistates is dissolved in water (20 milliliters) is adjusted to 2 with the 2M aqueous hydrochloric acid.Stir after 3 hours, solution evaporation is extremely done, with resistates preparation HPLC purifying.Separate two kinds of isomer cuts and collect it.Output: 240 milligrams (cut 1)+45 milligrams (cut 2); 56%.Physical data, cut 1: 1H NMR (DMSO-d 6): 9.67-9.90 (m, 2H), 8.23-8.60 (m, 4H), 3.06-3.84 (m, 16H), 4.02-4.20 (m, 8H). 13C NMR (DMSO-d 6): 171.0,170.8,170.3,170.2,151.8,151.7,150.2,144.3,144.1,143.9,143.8,108.1,108.0,107.8,99.5,99.3,99.2,97.8,97.6,74.2,70.4,64.7,64.4,43.2, and 43.1. MS (ESP, m/e): 1408 (M +, 100%), 1431 ([M+Na] +, 10%) and .Fraction 2:9.62-10.05 (m, 2H), 8.25-8.60 (m, 4H), and 5.65-5.90 (m, 2H), 4.62-4.90 (m, 4H), and 4.42-4.53 (m, 2H), 4.02-4.10 (m, 2H), and 3.40-3.82 (m, 10H), 3.05-3.32 (m, 4H). embodiment 14.N, N '-two [2,4,6-three iodo-3-amino-5-(1,3-diacetoxy third-2-base aminocarboxyl) phenyl] urea a.N, N '-two [3-nitro-5-(1,3-dihydroxypropyl-2-aminocarboxyl) phenyl] urea
According to being similar to the described synthetic method of embodiment 10c, from N, N '-two (3-nitro-5-methoxycarbonyl phenyl) urea (12.0 grams, 28.7 mmoles) and serinol (6.83 grams, 75 mmoles) set out and react.The reaction product crude product is developed with acetonitrile (2x50 milliliter), water (200 milliliters) with acetonitrile (3x50 milliliter), obtained 95% pure products.Output: 12.0 grams (78%). 1H NMR (DMSO-d 6): 10.06,9.72 (2s, ArNH, 2H), 8.68-8.73 (m, 2H), 8.44-8.51 (m, 2H), 8.38-8.43 (m, 2H), 8.23-8.27 (m, 2H), 4.66-4.73 (m, 4H), 3.92-4.13 (m, 2H), 3.44-3.60 (m, 8H). 13C NMR (DMSO-d 6): 164.9,164.6,152.9,148.6,148.4,141.9,141.1,137.0,131.8,124.9,124.4,117.1,115.7,115.3,60.7,54.8,53.3.b.N, N '-two [2,4,6-three iodo-3-amino-5-(1,3-hydroxypropyl-2-base aminocarboxyl) phenyl] urea
With N, N '-two [3-nitro-5-(1,3-dihydroxypropyl-2-aminocarboxyl) phenyl] urea (5.6 gram, 10.4 mmoles) is dissolved in the mixture of the methyl alcohol (100 milliliters) that contains 2M aqueous hydrochloric acid (10.4 milliliters) and Pd/C catalyzer (10%, 0.5 gram) and water (14 milliliters).Under 60 pounds/square inch, carry out hydrogenation.Filtration catalizer, evaporation methyl alcohol.With aqueous solution lyophilize.Resistates is dissolved in the mixture of methyl alcohol (36 milliliters) and water (775 milliliters), adds KICl then 2(32.9 grams, 97 mmoles).Stir after 72 hours, add the 2M sodium pyrosulfate aqueous solution, the filtering solid.Behind methyl alcohol (3x50 milliliter) washing precipitate, dried residue.Output: 13.9 grams (76%). 1H NMR (DMSO-d 6): 7.90-8.36 (m, 4H), 5.32-5.40 (m, 4H), 3.30-4.25 (m, 14H). 13C NMR (DMSO-d 6): 170.1,151.9,149.1,148.9,148.8,146.6,143.1,143.0,88.8,88.6,83.0,82.8,81.5,78.7,78.6,78.5,76.9,59.8,53.6,53.5.MS (ESP, m/e): 1254 ([M+Na] +, 100%) and .c.N, N '-two [2,4,6-three iodo-3-amino-5-(1,3-diacetoxy third-2-base aminocarboxyl) phenyl] urea
With N, N '-two [2,4,6-three iodo-3-amino-5-(1,3-hydroxypropyl-2-base aminocarboxyl) phenyl] urea (4.0 grams, 3.26 mmoles) is dissolved in the mixture of diacetyl oxide (10 milliliters) and pyridine (10.5 milliliters).Mixture was stirred 16 hours at ambient temperature.Evaporating solvent.Resistates is suspended in the water (150 milliliters).The filtering solid, with 0.1M HCl (2x50) aqueous solution, water (2x50 milliliter) washing, drying.Output: 3.8 grams (84%). 1H NMR (DMSO-d 6): 8.55-8.95 (m, 2H), 8.10-8.35 (m, 2H), 5.36-5.68 (m, 4H), 4.10-4.20 (m, 8H), 3.83-3.95 (m, 2H), 1.99-2.07 (m, 12H). 13C NMR (DMSO-d 6): 170.7,170.2,149.0,148.9,148.7,143.3,143.2,143.1,89.2,82.8,78.5,78.3,78.2,62.6,47.4,21.3.MS (ESP, m/e): 1422 ([M+Na] +, 70%), 1478 ([M+C 5H 5N] +, 100%). embodiment 15:N-[3-hydroxymethyl-5-(2,3-dihydroxypropyl aminocarboxyl)-2,4, the 6-triiodophenyl]-N '-[3,5-two (2,3-dihydroxypropyl aminocarboxyl)-2,4,6-triiodophenyl] urea methylol-3-nitro-5-methyl benzoate a.1-
1-nitroisophthalic acid one methyl esters (22.5 grams, 100 mmoles) is dissolved in the anhydrous tetrahydro furan (675 milliliters), adds BF 3ET 2O (25.2 milliliters, 200 mmoles).Slowly add sodium borohydride (5.1 grams, 135 mmoles) with time of l hour then in batches.Behind the restir 2 hours, slowly add ethanol (20 milliliters), then add entry (200 milliliters) and ether (400 milliliters).Make to be separated, water with ether (100 milliliters) washing once.Merge organic phase, with the saturated sodium bicarbonate aqueous solution washing, with dried over sodium sulfate and evaporation.Output: 20 grams (96%), the HPLC analysis revealed, product purity is greater than 95%. 1H NMR (CDCl 3): 8.72 (s, 1H), 8.42 (s, 1H), 8.32 (s, 1H), 4.86 (s, 2H), 3.97 (s, 3H), 2.37 (br s, 1H) .b.1-methylol-3-nitro-5-(2,3-dihydroxypropyl aminocarboxyl) benzene
With 2,3-dihydroxy-propylamine (9.6 grams, 106 mmoles) mixes with the methyl esters of embodiment 3a (20.5 grams, 97 mmoles), with mixture heating up to 90 ℃.After 45 minutes, pressure is reduced to 200mmHg, continues heating 2 hours.The HPLC analysis revealed, product purity is greater than 95%.Needn't be further purified, it is directly used in next step.Output: 22.8 grams (87%). 1H NMR (CD 3OD): 8.57 (s, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 4.77 (s, 2H), 3.81-3.88 (m, 1H), 3.39-3.63 (m, 4H) .c.3-methylol-5-(2,3-dihydroxypropyl aminocarboxyl) aniline
Is catalyzer with Pd/C (10%, 100 milligram) with 1-methylol-3-nitro-5-(2,3-dihydroxypropyl aminocarboxyl) benzene (12.0 gram, 44.4 mmoles) under 60 pounds/square inch, carries out hydrogenation.Remove by filter catalyzer, evaporation residue.Add methyl alcohol (10 milliliters) with the precipitation white solid product, filter out and drying.Output: 6.6 grams (62%). 1H NMR (CD 3OD): 7.05-7.09 (m, 1H), 6.98-7.03 (m, 1H), 6.83-6.87 (m, 1H), 4.53 (s, 2H), 3.77-3.85 (m, 1H), 3.8-3.59 (m, 4H), 3.32-3.42 (m, 1H) MS (ESP, m/e): 241 ([M+1] +, 100%) and .d.3-methylol-5-(2,3-dihydroxypropyl aminocarboxyl)-2
3-methylol-5-(2,3-dihydroxypropyl aminocarboxyl) aniline (500 milligrams, 2.1 mmoles) are dissolved in the water (175 milliliters), with added KICl in 8 hours in batches 2The aqueous solution (70%, w/w), each 0.1 milliliter.Add 1.0 milliliters of KICl altogether 2Solution.Through after reaction times of 6 hours altogether, solution is extracted with ethyl acetate (1000 milliliters), with its separation, with sodium sulfate (0.2M, 100 milliliters) solution washing.Evaporation then obtains 432 milligrams of (33%) pure products with preparation HPLC purifying. 1H NMR (CD 3OD): 5.10 (s, 2H), 3.90-3.98 (m, 1H), 3.72 (ddd, J 1=0.7Hz, J 2=4.2Hz, J 3=11.4Hz), and 1H), 3.60 (dd, J 1=6.0Hz, J 2=11.4Hz, 1H), 3.49 (ddd, J 1=1.2Hz, J 2=6.0Hz, J 3=13.5Hz, 1H), 3.37 (ddd, J 1=1.2Hz, J 2=6.1Hz, J 3=13.2Hz, 1H), 2.62 (s, 1H), 2.28 and 2.34 (2s, 2H) .MS (ESP, m/e): 618 (M +, 100%), 640 ([M+Na] +, 55%) and .e.3-acetoxy-methyl-5-(2,3-diacetoxy propyl group aminocarboxyl)-2
3-methylol-5-(2,3-dihydroxypropyl aminocarboxyl)-2 (1.32 grams, 2.1 mmoles) is dissolved in the pyridine (10 milliliters) that contains diacetyl oxide (10 milliliters).Mixture was at room temperature stirred 2 hours, add methylene dichloride (100 milliliters).Water (3x25 milliliter) washs this solution.Organic phase water (3x50 milliliter) and saturated sodium bicarbonate aqueous solution (2x50 milliliter) washing.After dry (sal epsom) and the evaporation, with dodging residue purified by chromatography, be eluent with the mixture of methylene dichloride and methyl alcohol (95: 5).Output: 1.30 grams (82%). 1H NMR (CDCl 3): 5.99 (br s, 1H), 5.52 (s, 2H), 5.25 (brs, 1H), 5.11 (s, 2H), 4.23-4.45 (m, 2H), 3.56-3.87 (m, 3H), 2.08 (s, 9H) .f.N-[3-acetoxy-methyl-5-(2,3-diacetoxy propyl group aminocarboxyl)-2,4, the 6-triiodophenyl)-N '-[3,5-two (2,3-dihydroxypropyl aminocarboxyl)-2,4, the 6-triiodophenyl] urea
With 3,5-two (2,3-diacetoxy propyl group aminocarboxyl)-2 (260 milligrams, 0.30 mmole) is dissolved in the dioxane (1.0 milliliters), adds the toluene solution (1.93M, 1.8 milliliters) of carbonyl chloride.The sesame seed cake envelope is tight, be heated to 60 ℃ then, be incubated 17 hours.After being cooled to envrionment temperature, remove solvent under reduced pressure.Add dioxane (3 milliliters), once more distillation.This process is repeated 2 times.Add dioxane (1 milliliter), then add 3-acetoxyl group-5-(2,3-diacetoxy propyl group aminocarboxyl)-2 (0.245 gram, 0.31 mmole) and Hg (OCOCF3) 2 (20 milligrams).Mixture was stirred 16 hours at ambient temperature, and evaporating solvent is with resistates preparation HPLC purifying.Output: 0.192 gram (39%).MS (ESP, m/e): 1643 (M +, 100%), 1665 ([M+Na] +, 34%) and .f.N-[3-hydroxymethyl-5-(2,3-dihydroxypropyl aminocarboxyl)-2,4, the 6-triiodophenyl]-N '-[3,5-two (2,3-dihydroxypropyl aminocarboxyl)-2,4,6-triiodophenyl] urea
The product of embodiment 15f is dissolved in the mixture of methyl alcohol (5 milliliters) and water (5 milliliters), the pH value is adjusted to 12 with the 2M aqueous sodium hydroxide solution.Stir after 2 hours, the pH value is adjusted to 6.5 with the HCl aqueous solution.Evaporating solvent.With preparation HPLC purified product.Output: 68 milligrams (44%).MS (ESP, m/e): 1349 (M +, 15%), 1372 ([M+Na] +100%). embodiment 16:2; 4; 6-three iodo-3-acetylaminohydroxyphenylarsonic acid 5-(1; 3-dihydroxyl third-2-base aminocarboxyl) phenyl amino carbonyl-2 '; 4 ', 6 '-three iodo-3 '-acetylamino-5 '-(1,3-dihydroxyl third-2-base aminocarboxyl)] benzene nitro-3-amino-5-methyl benzoate hydrochloride a.1-
1-nitro-3-benzaminic acid (15.0 grams, 82.4 mmoles) is dissolved in the methyl alcohol (100 milliliters), in solution, fed the HCl gas bell 30 minutes.After stirring 17 hours at ambient temperature, evaporating solvent, resistates obtains white solid product with ether (3x50 milliliter) washing.Output: 15.8 grams (82%). 1H NMR (DMSO-d 6): 7.78-7.81 (m, 1H), 7.68-7.71 (m, 1H), 7.65-7.67 (m, 1H), 5.00 (s, NH 3, 3H) 3.83 (s, OCH 3, 3H) .b.3-nitro-methoxycarbonyl phenyl amino carbonyl-(3 '-nitro-5 '-methoxycarbonyl benzene)
1-nitro-3-amino-methyl benzoate hydrochloride (0.92 gram, 4.72 mmoles) and 5-nitroisophthalic acid one methyl esters (1.06 grams, 4.27 mmoles) are suspended in POCl 3In the mixture of (4 milliliters) and toluene (15 milliliters).With mixture heating up, be homogeneous phase until solution.Then solution was stirred 16 hours at ambient temperature.Evaporating solvent is dissolved in the oily resistates in the methylene dichloride.Solution with the 0.1M HCl aqueous solution (3x50 milliliter) and saturated sodium bicarbonate aqueous solution (50 milliliters) washing, is handled dry (sal epsom), evaporation with charcoal.HPLC analysis revealed, product are pure basically.Output: 1.25 grams (66%). 1H NMR (DMSO-d 6): 11.28 (s, 1H), 9.09 (t, J=1.8Hz, 1H), 9.03 (t, J=1.8Hz, 1H), 8.95 (t, J=1.7Hz, 1H), 8.81 (t, J=1.6Hz, 1H), 8.78 (t, J=1.7Hz, 1H), 8.38 (2t, J 1=1.6Hz, J 2=1.5Hz, 1H), 3.96 (s, OCH 3, 3H), 3.93 (s, OCH 3, 3H) .MS (ESP, m/e): 426 ([M+Na] +, 100%), 442 ([M+K] +, 14%) and .c.3-nitro-5-(1,3-dihydroxyl third-2-base aminocarboxyl) phenyl amino carbonyl-[3 '-nitro-5 '-(1,3-dihydroxyl third-2-base aminocarboxyl) benzene]
With 3-nitro-5-methoxycarbonyl phenyl amino carbonyl-(3 '-nitro-5 '-methoxycarbonyl benzene) (0.40 gram, 1.0 mmoles) mix with serinol (0.23 gram, 2.5 mmoles), is heated to 95 ℃.After 30 minutes, pressure is reduced to 200mmHg, continues heating 3 hours.With reaction mixture preparation HPLC purifying.Output: 0.27 gram (52%). 1H NMR (DMSO-d 6): 11.2 (br s, 1H), 8.94-8.98 (m, 2H), 8.89-8.92 (m, 2H), 8.61-8.65 (m, 1H), 8.61 (d, J=7.2Hz, 1H), 8.52-8.55 (m, 1H), 8.46 (d, J=7.8Hz, 1H), 4.60-4.81 (m, 4H), 3.96-4.08 (m, 2H), 3.51-3.59 (m, 8H) .MS (ESP, m/e): 522 (M +, 100%), 504 ([M-H 2O] +, 65%) and .d.3-amino-5-(1,3-dihydroxyl third-2-base aminocarboxyl) phenyl amino carbonyl-[3 '-nitro-5 '-(1,3-dihydroxyl third-2-base aminocarboxyl) benzene] dihydrochloride
With 3-nitro-5-(1,3-dihydroxyl third-2-base aminocarboxyl) the phenyl amino carbonyl-[3 '-nitro-5 '-(1,3-dihydroxyl third-2-base aminocarboxyl) benzene] (1.03 grams, 1.98 mmole) under 60 pounds/square inch pressure, hydrogenation in the solution that contains methyl alcohol (40 milliliters), concentrated hydrochloric acid (2 milliliters), water (2 milliliters) and Pd/C catalyzer (10%, 0.2 gram).Filtration catalizer, evaporating solvent.Add entry (150 milliliters) then, then with the solution lyophilize.Output: 0.98 gram (93%). 1H NMR (DMSO-d 6Containing 1%TFA): 10.83 (s, 1H), 8.25 (d, J=8.0Hz, 1H), 8.23 (t, J=2.0Hz, 1H), 8.12 (d, J=8.0Hz, 1H), 8.07 (t, J=2.0Hz, 1H), 8.03 (t, J=2.0Hz, 1H), 7.73 (t, J=2.0Hz, 1H), 7.70 (t, J=2Hz, 1H), 7.46 (t, J=2.0Hz, 1H), 4.30 (br s, 6H), 3.95-4.01 (m, 2H), 3.54 (t, J=5.5Hz, 8H) .MS (ESP, m/e): 461 (M +, 100%) and .e.3-amino-5-(1,3-dihydroxyl third-2-base aminocarboxyl) phenyl amino carbonyl-[3 '-amino-2 ', 4 ', 6 '-three iodo-5 '-(1,3-dihydroxyl third-2-base aminocarboxyl) benzene]
With 3-amino-5-(1,3-dihydroxyl third-2-base aminocarboxyl) the phenyl amino carbonyl-[3 '-nitro-5 '-(1,3-dihydroxyl third-2-base aminocarboxyl) benzene] dihydrochloride (0.50 gram, 0.94 mmole) be dissolved in the mixture of methyl alcohol (225 milliliters) and water (675 milliliters), the pH value be adjusted to 2.0 with the HCl aqueous solution.Add KICl 2(1.91 grams, 5.64 mmoles) stir solution 48 hours down at 40 ℃, add NaHSO 3The aqueous solution makes reaction terminating.Behind the evaporating solvent, with resistates preparation HPLC purifying.Output: 0.05 gram (8.3%). 1H NMR (DMSO-d 6): 9.85-10.05 (m, 1H), 8.87-9.00 (m, 1H), 7.80-8.15 (m, 1H), 5.52 (s, NH 2, 2H), 5.47 (s, NH 2, 2H), 4.40 (t, J=7.0Hz, 2H), 4.15-4.24 (m, 2H), 4.06 (d, J=7.0Hz, 1H), 4.04 (d, J=7.0Hz, 1H), 3.78-3.85 (m, 3H), 3.57-3.64 (m, 3H), 3.40-3.56 (m, 2H). 13C NMR (DMSO-d 6): 170.3,170.2,165.7,150.0,149.9,149.6,148.9,148.1,148.0,147.5,141.7,64.2,59.7,53.4.MS (ESP, m/e): 1215 (M +, 100%) and .f.3-acetylaminohydroxyphenylarsonic acid 2,4,6-three iodo-5-(1,3-dihydroxyl third-2-base aminocarboxyl) phenyl amino carbonyl-[3 '-acetylamino-2 ', 4 ', 6 '-three iodo-5 '-(1,3-dihydroxyl third-2-base aminocarboxyl) benzene]
With 3-amino-2,4,6-three iodo-5-(1,3-dihydroxyl third-2-base aminocarboxyl) the phenyl amino carbonyl-[3 '-amino-2 ', 4 ', 6 '-three iodo-3 '-5 '-(1,3-dihydroxyl third-2-base aminocarboxyl) benzene] (75 milligrams, 0.062 mmole) be dissolved in the diacetyl oxide (0.6 milliliter) that contains the vitriol oil (0.04 milliliter).Mixture heating up is rolled 60 ℃, be incubated 75 minutes, after the cooling, evaporating solvent.Dark-coloured resistates is dissolved in the mixture of methyl alcohol (0.35 milliliter) and water (0.15 milliliter), the pH value is adjusted to 10-11, solution was stirred 5 hours down at 50 ℃ with the 2M aqueous sodium hydroxide solution.After being cooled to envrionment temperature, the pH value is adjusted to 7, evaporating solvent with the 2M HCl aqueous solution.Resistates is with preparing the HPLC purifying.Output: 0.076 gram (94%). 1H.NMR (DMSO-d 6): 10.27-10.48 (m, 1H), 9.97 (br s, 1H), 9.94 (br s, 1H), 8.21 (d, J=7.0Hz, 1H), 8.11 (d, J=7.0Hz, 1H), 4.43-4.56 (m, 4H), 3.72-3.88 (m, 2H), 3.60-3.70 (m, 4H), 3.40-3.60 (m, 4H), 2.07-2.08 (m, 6H). 13C NMR (DMSO-d 6): 169.9,169.7,168.2,165.2,151.0,148.4,144.7,144.6,144.3,144.2,142.8,142.7,59.6,59.5,53.6,31.1. MS (ESP, m/e): 1300 (M +, 100%). embodiment 17.2,4; 6-three iodo-hydroxyacetyl amino-5-(1,3-dihydroxyl third-2-base aminocarboxyl) phenyl amino carbonyl-2 ', 4 '; 6 '-three iodo-3 '-hydroxyacetyl amino-5 '-(1; 3-dihydroxyl third-2-base aminocarboxyl) benzene] a.2,4,6-three iodo-3-amino-5-(1; 3-diacetoxy third-2-base aminocarboxyl) phenyl amino carbonyl-2 '; 4 ', 6 '-three iodo-3 '-amino-5 '-(1,3-diacetoxy third-2-base aminocarboxyl) benzene]
Will be according to the 3-amino-2 of the foregoing description 15 described preparations, 4,6-three iodo-5-(1,3-dihydroxyl third-2-base aminocarboxyl) the phenyl amino carbonyl-[3 '-amino-2 ', 4 ', 6 '-three iodo-5 '-(1,3-diacetoxy third-2-base aminocarboxyl) benzene] (0.10 gram, 0.082 mmole) be dissolved in the mixture of diacetyl oxide (5 milliliters) and pyridine (5.5 milliliters).Mixture was stirred 16 hours down at 40-45 ℃, and evaporating solvent is dissolved in resistates in the ethyl acetate (25 milliliters).Water (25 milliliters), the 0.5M HCl aqueous solution, water and saturated sodium bicarbonate aqueous solution washing are with solution drying (sal epsom), evaporating solvent.Output: 0.11 gram (100%). 1H_NMR (DMSO-d 6): 9.94-10.04 (m, 1H), 8.67 (d, J=7.0Hz, 1H), 8.65 (d, J=7.0Hz, 1H), 5.54 (s, NH 2, 2H), 5.50 (s, NH 2, 2H), 4.27-4.40 (m, 2H), 4.11-4.16 (m, 8H), 2.01-2.03 (m, 12H). 13C NMR (DMSO-d 6): 170.7,170.4,170.3,165.7,149.6,149.5,149.0,148.2,147.6,141.8,139.8,62.6,47.4,21.3.MS (ESP, m/e): 1385 (M +, 100%) and .b.2,4,6-three iodo-hydroxyacetyl amino-5-(1,3-dihydroxyl third-2-base aminocarboxyl) phenyl amino carbonyl-2 ', 4 ', 6 '-three iodo-3 '-hydroxyacetyl amino-5 '-(1,3-dihydroxyl third-2-base aminocarboxyl) benzene]
With 2,4,6-three iodo-3-amino-5-(1,3-diacetoxy third-2-base aminocarboxyl) phenyl amino carbonyl-2 ' 4 ' 6 '-three iodo-3 '-amino-5 '-(1,3-diacetoxy third-2-base aminocarboxyl) benzene] (94 milligrams, 0.068 mmole) be suspended in the alpha-Acetoxyacetyl chloride (3 milliliters).Mixture was stirred 4 hours down at 65 ℃, allow its cooling, evaporation then.Resistates is dissolved in methyl alcohol (3 milliliters), water (3 milliliters) and the 1M aqueous sodium hydroxide solution (0.50 milliliter), then with solution stirring 3 hours.With storng-acid cation exchange resin solution is neutralized.Evaporating solvent.Resistates is with preparing the HPLC purifying.90 milligrams of yields (100%).MS (ESP, m/e): 1582 (M +100%. embodiment 18:2; 4; 6-three iodo-3-acetylamino-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl amino carbonyl-2 ', 4 '; 6 '-three iodo-3 '-acetylamino-5 '-(2; 3-dihydroxypropyl aminocarboxyl)] benzene a.3-nitro-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl amino carbonyl-[3 '-nitro-5 '-(2,3-dihydroxypropyl aminocarboxyl) benzene]
With 3-nitro-5-methoxycarbonyl phenyl amino carbonyl-(3 '-nitro-5 '-methoxycarbonyl benzene) (1.21 gram, 3.0 mmoles) be suspended in amino the third-2, in the 3-glycol (0.55 gram, 6.0 mmoles), with mixture heating up to 90 ℃.After 30 minutes, pressure is reduced to 200mmHg, continues heating 90 minutes.Product is with preparing the HPLC purifying.Output: 0.73 gram (47%). 1H NMR (DMSO-d 6): 11.32 (s, 1H), 9.02 (t, J=6.0Hz, 1H), 8.93-8.97 (m, 3H), 8.88 (t, J=1.7Hz, 1H), 8.86 (t, J=6.0Hz, 1H), 8.68 (t, J=1.5Hz, 1H), 8.51 (t, J=1.8Hz, 1H), 3.62-3.72 (m, 2H), and 3.3 6-3.48 (m, 2H), 3.33-3.36 (m, 4H), 3.18-3.29 (m, 2H), 3.09 (s, 4H) .MS (ESP, m/e): 545 ([M+Na] +, 65%), 522 (M +, 100%), 504 ([M-18] +, 19%) and .b.3-amino-2,4,6-three iodo-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl amino carbonyl-[3 '-amino-2 ', 4 ', 6 '-three iodo-5 '-(2,3-dihydroxypropyl aminocarboxyl) benzene]
With 3-nitro-5-(2,3-dihydroxypropyl aminocarboxyl) the phenyl amino carbonyl-[3 '-nitro-5 '-(2,3-dihydroxypropyl aminocarboxyl) benzene] (2.0 grams, 2.0 mmole) in the solution that contains methyl alcohol (70 milliliters), concentrated hydrochloric acid (4 milliliters), water (4 milliliters) and Pd/C catalyzer (10%, 0.6 gram), hydrogenation under 60 pounds/square inch.Filtration catalizer, evaporating solvent.Add entry (150 milliliters) then, with the solution lyophilize.Output 2.0 grams (98%).Crude product is used for next step immediately, needn't purifying: product is dissolved in the methyl alcohol (1: 3,1200 milliliters), adds KICl 2The aqueous solution (5.34 grams, 22.6 mmoles).Reaction mixture was stirred 30 hours down at 40 ℃, add 0.5M NaHSO then 3(1 milliliter) aqueous solution.Behind the evaporating solvent, resistates is with preparing the HPLC purifying.Output: 0.63 gram (13%). 1H NMR (DMSO-d 6): 9.86-10.00 (m, 1H), 8.18-8.45 (m, 2H), 5.44-5.47 (m, 4H), 4.66-4.78 (m, 2H), 4.45-4.55 (m, 2H), 3.59-3.78 (m.2H), 3.41-3.56 (m, 2H), 3.30-3.43 (m, 2H), 3.10-3.36 (m, 2H). 13C NMR (DMSO-d 6): 170.7,165.6,149.9,148.5,147.8,147.1,140.8,108.0,85.2,84.4,80.9,79.2,78.3,70.0,64.0,42.6.MS (ESP, m/e): 1216 (M +, 100%), 1238 ([M+Na] +, 20%.c.2,4,6-three iodo-3-acetylamino-5-(2,3-hydroxypropyl aminocarboxyl) phenyl amino carbonyl-2 ', 4 ', 6 '-three iodo-3 '-acetylamino-5 '-(2,3-dihydroxypropyl aminocarboxyl)] benzene
With 3-amino-2,4,6-three iodo-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl amino carbonyl-[3 '-amino-2,4,6-three iodo-5 '-(2,3-dihydroxypropyl aminocarboxyl) benzene] (100 milligrams, 0.082 mmole) be dissolved in the diacetyl oxide (7 milliliters).Drip a vitriol oil and mixture is descended stirring 1.5 hours at 60 ℃.With solvent evaporation, resistates is dissolved in the mixture (3: 1,10 milliliters) of methyl alcohol and water.With the 2M aqueous sodium hydroxide solution pH value is adjusted to 13.Mixture was stirred 16 hours down at 50 ℃, and water (20 milliliters) dilution is adjusted to neutrality with strong-acid ion exchange resin with the pH value.Evaporating solvent, resistates is with preparing the HPLC purifying.Output: 75 milligrams (71%).MS (ESP, m/e): 1301 (M +, 81%), 1324 ([M+Na] +, 100%. embodiment 19:2,4; 6-three iodo-3-hydroxyacetyl amino-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl amino carbonyl-2 ', 4 '; 6 '-three iodo-3 '-hydroxyacetyl amino-5 '-(2; 3-dihydroxypropyl aminocarboxyl)] benzene a.2,4,6-three iodo-3-amino-5-(2; 3-diacetoxy propyl group aminocarboxyl) phenyl amino carbonyl-2 '; 4 ', 6 '-three iodo-3 '-amino-5 '-(2,3-diacetoxy propyl group aminocarboxyl)] benzene
Will be according to the 3-amino-2 of embodiment 17 preparations, 4,6-three iodo-5-(2,3-dihydroxypropyl aminocarboxyl) the phenyl amino carbonyl-[3 '-amino-2 ', 4 ', 6 '-three iodo-5 '-(2,3-dihydroxypropyl aminocarboxyl) benzene] (100 milligrams, 0.082 mmole) be dissolved in the mixture of diacetyl oxide (2 milliliters) and pyridine (2 milliliters).Mixture was stirred 17 hours at ambient temperature.With solvent evaporation, resistates is dissolved in the ethyl acetate (50 milliliters).After aqueous hydrochloric acid (0.1M, 25 milliliters), saturated sodium bicarbonate aqueous solution washing, dry (sodium sulfate) and evaporation.Resistates is with preparing the HPLC purifying.Output: 100 milligrams (88%). 1H NMR (DMSO-d 6): 9.89-10.27 (m, 1H), 8.56-8.70 (m, 2H), 5.54 (s, 2H), 5.51 (s, 2H), and 5.06-5.13 (m, 2H), 4.25-4.36 (m, 2H), 4.16-4.22 (m, 2H), 3.30-3.58 (m, 4H), 2.02 (s, 12H). MS (ESP, m/e): 1385 (M +, 100%), 1464 ([M+pyridine] +, 19%). b.2,4,6-three iodo-3-hydroxyacetyl amino-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl amino carbonyl-2 ', 4 ', 6 '-three iodo-3 '-hydroxyacetyl amino-5 '-(2,3-dihydroxypropyl aminocarboxyl)] benzene
With 2,4,6-three iodo-3-amino-5-(2,3-diacetoxy propyl group aminocarboxyl) phenyl amino carbonyl-2 ', 4 ', 6 '-three iodo-3 '-amino-5 '-(2,3-diacetoxy propyl group aminocarboxyl)] benzene is (35 milligrams, 0.025 mmole) be dissolved in the alpha-Acetoxyacetyl chloride (1 milliliter),, be incubated 1.5 hours with mixture heating up to 70 ℃.After being cooled to envrionment temperature, evaporating solvent, resistates be dissolved in the mixture (3: 1,1 milliliter) of methyl alcohol and water.Add 1M aqueous sodium hydroxide solution (0.23 milliliter), stir after 15 minutes, add entry (20 milliliters), solution is neutralized with strong-acid ion exchange resin.Evaporating solvent, resistates is with preparing the HPLC purifying.Output: 14 milligrams (61%).HPLC.Yield:14mg (61%) .MS (ESP, m/e): 1332 (M +, 100%). embodiment 20:2,4; 6-three iodo-3-(2-hydroxyl propionyl amino)-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl amino carbonyl-2 ', 4 '; 6 '-three iodo-3 '-(2-hydroxyl acyl amino)-5 '-(2,3-dihydroxypropyl aminocarboxyl)] benzene
With 2,4,6-three iodo-3-amino-5-(2,3-diacetoxy propyl group aminocarboxyl) phenyl amino carbonyl-2 ', 4 ', 6 '-three iodo-3 '-amino-5 '-(2,3-diacetoxy propyl group aminocarboxyl)] benzene (100 milligrams, 0.072 mmole) is dissolved in α-acetoxyl group propionyl chloride (1 milliliter).Mixture was stirred 17 hours down at 40 ℃.With solvent evaporation, resistates is suspended in the mixture (1: 1,4 milliliters) of methyl alcohol and water.Add aqueous sodium hydroxide solution (1M, 0.5 milliliter), with solution stirring 5 hours.Add entry (20 milliliters) and the pH value is adjusted to neutrality with strong-acid ion exchange resin.Evaporating solvent, resistates is with preparing the HPLC purifying.Output: 33 milligrams (43%). 1H NMR (DMSO-d 6): 10.16-10.55 (m, 1H), 9.54-9.86 (m, 2H), 8.40-8.65 (m, 2H), 5.60 (br s, 2H), 4.70 (br s, 2H), 4.46 (br s, 2H), 4.08-4.22 (m, 2H) .3.60-3.71 (m, 2H), 3.32-3.58 (m, 2H), and 3.15-3.32 (m, 2H), 3.04-3.22 (m, 4H), 1.39 (d, J=7.0Hz, 6H). 13C NMR (DMSO-d 6): 172.4,170.0,169.8,169.7,150.7,148.0,143.8,143.2,143.1,142.3,104.6,100.8,100.2,100.0,99.8,97.2,96.9,95.0,90.7,90.5,69.8,67.6,64.0,42.7, and 21.0.MS (ESP, m/e): 1361 (M +, 100%), 1383 ([M+Na] +, 25%. embodiment 21 2 [2,4,6-three iodo-N, N '-(2, the 3-dihydroxypropyl)-3,5-diacetyl aminophenyl] ether a.3, the 5-dinitroanisol
Sodium (575 milligrams, 25 mmoles) is dissolved in the anhydrous methanol (100 milliliters).Then, add 1 (4.26 milligrams, 20 mmoles), solution stirring is spent the night.Behind the evaporating solvent, add entry and filtering throw out, wash with water, drying.Product is directly used in down the step, needn't purifying.Output 3.4 grams (86%). 1H NMR (CDCl 3): 8.65 (t, J=2.0Hz, 1H), 8.06 (d, J=2.0Hz, 2H), 4.01 (s, 1H) .b.3,5-dinitrophenol(DNP)
With 3, the 5-dinitroanisol (1.36 grams, 6.9 mmoles) and the dense HBr aqueous solution are heated to reflux temperature, are incubated 16 hours.After being cooled to envrionment temperature, the filtering solid residue.Wash with water and drying.Output: 325 milligrams (26%). 1H NMR (CDCl 3): 8.64 (t, J=2.0Hz, 1H), 8.04 (d, J=2.0Hz, 2H), 2.0 (br s, 1H) .c.3,5-diacetyl amino-phenols
With 3,5-dinitrophenol(DNP) (325 milligrams, 1.77 mmoles) is dissolved in the glacial acetic acid (20 milliliters), with Pd-C catalyzer (10%, 50 milligram) hydrogenation under 60 pounds/square inch.Filter reaction mixture adds diacetyl oxide (2 milliliters).Solution is added to 100 ℃.Allow it cool off once more then.Evaporation removes and desolvates, and resistates silica gel chromatography purifying is with mixture (10: the 90) wash-out of methyl alcohol and ethyl acetate.90 milligrams of output (24%). 1H NMR (CD 3OD): 7.24 (t, J=2.0Hz, 1H), 6.92 (d, J=2.0Hz, 2H), 2.12 (s, 6H) .d.3,5-dinitrophenyl-3 ', 5 '-diacetyl aminophenyl ether
With 3,5-diacetyl amino-phenol (90 milligrams, 0.43 mmole) and trinitrobenzene (0.111 gram, 0.52 mmole) are dissolved in the dry DMF (10 milliliters), add salt of wormwood (0.124 gram, 0.90 mmole).Stir after 17 hours, add entry (20 milliliters), with this solution of ethyl acetate extraction.After water (2x10 milliliter) washing, dry (sodium sulfate), evaporating solvent, resistates silica gel chromatography purifying.Use eluent ethyl acetate.Output: 0.121 gram (75%).MS (ESP, m/e): 375 ([M+1] +, 100%), 397 ([M+Na] +, 39%), 413 ([M+K] +, 35%). e. two (3,5-diacetyl aminophenyl) ether
With 3,5-dinitrophenyl-3 ', 5 '-diacetyl aminophenyl ether (0.12 gram, 0.32 mmole) is dissolved in the glacial acetic acid (5 milliliters), is heated to reflux temperature.Add iron powder (0.3 gram) with 5 minutes times in batches.Reflux after 2 hours, solution is allowed be advisable be cooled to envrionment temperature, add diacetyl oxide (1.5 milliliters) and continue heating 2 hours again.Evaporation removes and desolvates then, handles resistates with ethyl acetate, filters and evaporation.Resistates is dissolved in the acetone, solution is filtered by silicagel pad.Evaporating solvent obtains 84 gram (66%) products. 1H NMR (CD 3OD): 7.62 (s, 2H), 7.08 (s, 4H), 2.12 (s, 12H) .MS (ESP, m/e): 399 ([M+1] +, 62%), 421 ([M+Na] +, 41%), 437 ([M+K] +, 100%) and .f. two (3,5-diacetyl amino-2,4,6-diiodo-phenyl) ether
Carry out the iodate of two (3,5-diacetyl aminophenyl) ether, for example described KICl that uses of document with the standard method of iodate activated aromatics 2Carry out at the aqueous solution or in water and alcoholic acid mixture (referring to for example EP-A-501875 and DE-A-2629228).The purifying of product is used and is undertaken by chromatogram or recrystallization.G. two [2,4,6-three iodo-N, N '-(2, the 3-dihydroxypropyl)-3,5-diacetyl aminophenyl] ether
According to be similar to the described reaction of document carry out two (3,5-diacetyl amino-2,4; 6-diiodo-phenyl) alkylation of ether, for example with sodium methylate as alkali, at polar solvent for example propylene glycol and 3-chloropropane-1; the 2-glycol carries out in (referring to for example, US 4250113).Product is with preparing the HPLC purifying.Embodiment 22. 2 [3-hydroxyacetyl amino-5-(2,3-dihydroxypropyl aminocarboxyl)-2,4,6-triiodophenyl] methyl alcohol a. two (3-acetylphenyl) ketone
Methyl phenyl ketone (57.6 grams, 0.48 mmole) and aluminum chloride (160 grams, 1.2 moles) are mixed, in argon atmospher, be heated to 100 ℃, be incubated 30 minutes.After being cooled to envrionment temperature, add tetracol phenixin (300 milliliters), with mixture heating up to reflux temperature 4 hours.After being cooled to envrionment temperature, add the mixture (300 milliliters, 1: 1) of entry and concentrated hydrochloric acid.Water is with chloroform extraction (3x200 milliliter), with the organic phase evaporation that merges.Resistates is dissolved in 70% ethanol (400 milliliters), with the of short duration reflux temperature that is heated to of solution.Evaporating solvent is then used the aqueous acetone recrystallization, obtains pure products.Output: 49.9 grams (77%). 1H NMR (CDCl 3): 8.36 (t, J=1.5Hz, 2H), 8.20 (dt, J d=7.8Hz, J t=1.5Hz, 2H), 7.98 (dt, J d=7.7Hz, J t=1.5Hz, 2H), 7.62 (t, J=7.7Hz, 2H), 2.65 (s, 6H) .MS (ESP, m/e): 268 (M +, 100%) and .b. two (3-nitro-5-carboxyl propyl group) ketone
Two (3-acetylphenyl) ketone (60.0 grams, 0.224 mmole) is dissolved in the vitriol oil (400 milliliters).Solution is cooled to 0 ℃.Then, drip the mixture of the concentrated nitric acid (120 milliliters) and the vitriol oil (120 milliliters).Then solution was stirred 17 hours at ambient temperature.Again 40 ℃ stir down 24 hours, 60 ℃ stir 6 hours down after, reaction mixture is poured on ice, the collecting precipitation thing washes with water and dry.Output: 77.6 grams (96%). 1H NMR (DMSO-d 6): 8.83 (t, J=1.8Hz, 2H), 8.67 (t, J=1.8Hz, 2H), 8.57 (t, J=1.8Hz, 2H), 3.9 (br s, 2H) .MS (ESP -, m/e): 359 ([M-1] -, 100%) and .c. two (3-nitro-5-carboxyl phenyl) ketone dimethyl ester dimethyl ketal
Two (3-nitro-5-carboxyl phenyl) ketone (10.0 grams, 28 mmoles) is dissolved in the methyl alcohol (250 milliliters) that contains the vitriol oil (20 milliliters), solution was heated to reflux temperature 17 hours.Evaporating solvent adds (300 milliliters) mixture of entry (70 milliliters) and ethyl acetate.Tell organic phase, drying.Behind the evaporating solvent, resistates is dissolved in the tetrahydrofuran (THF) that contains salt of wormwood (3.87 grams, 28 mmoles) and methyl iodide (5.0 milliliters).This solution was stirred 70 hours at ambient temperature.Filter reaction mixture is evaporated to dried.Resistates is with preparing the HPLC purifying.Output: 2.6 grams (25%). 1H NMR (CDCl 3): 8.76-8.78 (m, 2H), 8.58 (t, J=1.7Hz, 2H), 8.41 (t, J=1.6Hz, 2H), 3.98 (s, 6H), 3.19 (s, 6H) .MS (EI, m/e): 403 ([M-OCH 3] +, 100%) and .d. two [3-nitro-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] ketone
With two (3-nitro-5-carboxyl phenyl) ketone dimethyl ester dimethyl ketal (1.0 grams, 2.3 mmole) be dissolved in contain amino the third-2, in the methyl alcohol (3.0 milliliters) of 3-glycol (0.84 gram, 9.2 mmoles), mixture is heated to 95 ℃ under 200mmHg, is incubated 2.5 hours.After being cooled to envrionment temperature, evaporation removes and desolvates.Resistates is with preparing the HPLC purifying.Output: 0.78 gram (67%). 1H NMR (DMSO-d 6): 9.03-9.15 (m, 2H), 8.90-9.03 (m, 2H), 8.58-8.73 (m, 4H), 4.38 (br s, 2H), 4.12 (br s, 2H), 3.61-3.70 (m, 2H), 3.39-3.48 (m, 2H), 3.35 (br s, 2H), 3.33 (br s, 2H), 3.15-3.26 (m, 2H). 13C NMR (DMSO-d 6): 163.9,148.3,138.1,137.9,136.9,134.4,126.9,126.4,70.5,64.3,43.8.MS (ESP -, m/e): 504 (M -, 100%) and .e. two [3-amino-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] methyl alcohol
Two [3-nitro-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] ketone (0.70 gram, 1.4 mmoles) is dissolved in the methyl alcohol (40 milliliters), with Pd/C catalyzer (10%, 0.6 gram), hydrogenation under 60 pounds/square inch.Filtration catalizer, evaporating solvent. 1H NMR analysis revealed is converted into product fully.Output: 0.62 gram (100%) 1H NMR (DMSO-d 6): 8.36-8.57 (m, 1H), 7.77-8.35 (m, 3H), 7.04-7.72 (m, 4H), 5.62-5.75 (m, 1H), 5.10 (br s, 1H), 4.23 (br s, 1H), 4.06 (br s, 2H), 3.60-3.85 (m, 4H), 2.91-3.40 (m, 10H) .MS (ESP, m/e): 449 (M +, 100%) and .f. two [3-amino-5-(2,3-dihydroxypropyl aminocarboxyl)-2,4,6-triiodophenyl] methyl alcohol
Carry out the iodate of two [3-amino-5-(2,3-dihydroxypropyl aminocarboxyl) phenyl] methyl alcohol, for example described KICl that uses of document with the standard method of iodate activated aromatics 2Carry out at the aqueous solution or in water and alcoholic acid mixture (referring to for example EP-A-501875 and DE-A-2629228).The purifying of product is undertaken by chromatogram or recrystallization.G. two [3-hydroxyacetyl amino-5-(2,3-dihydroxypropyl aminocarboxyl)-2,4,6-triiodophenyl] methyl alcohol
According to the method that is similar to embodiment 19b, carry out the acidylate of two [3-amino-5-(2,3-dihydroxypropyl aminocarboxyl)-2,4,6-triiodophenyl] methyl alcohol with alpha-Acetoxyacetyl chloride.Then with aqueous sodium hydroxide solution with the crude product hydrolysis.Product is with preparing the HPLC purifying.

Claims (14)

1. the compound of formula I and isomer thereof:
Figure A9519632700021
In the formula, each C 6C 5Part can be identical or different; Each R represents hydrogen or iodine atom or group M, at each C 6R 5The non-adjacent R group of on the part two or three is represented the iodine atom, at each C 6R 5On the part one, two or three R groups represent the M group; The X representative provides and connects two C 6R 5The group of 1,2 or 3 atomchains of group; M is the nonionic hydrophilic parts independently of one another.
2. the described compound of claim 1, wherein X is the ketonic oxygen base or contains ketonic oxygen base group, each C in connection chain 6R 5Group is that triiodophenyl or each R are not the groups of hydrogen.
3. the described compound of claim 1, wherein each M is monohydroxy alkyl or polyhydroxy alkyl group.
4. the described compound of claim 1, wherein X connects and composes two C 6R 5The asymmetric group of 2 or 3 atomchains of group.
5. the described compound of claim 1, wherein two C 6R 5Group is different the replacement.
6. the described compound of claim 1, wherein at least one C 6R 5Group has following structure: Wherein, two R groups are identical or different.
7. the described compound of claim 1, wherein at least one C 6R 5Group has following structure:
Figure A9519632700031
Wherein, the M group is identical or different.
8. the described compound of claim 1, wherein the M group is straight or branched C 1-10Alkyl group, one or more CH in this alkyl 2Or CH part is by oxygen or nitrogen-atoms substitutes or this alkyl is selected from sulphur that oxygen, hydroxyl, amino, carbonyl derivative and oxygen replaces and the group of phosphorus atom replaces by one or more.
9. the described compound of claim 1, wherein the M group is to be connected to polyhydroxy alkyl, hydroxy alkoxy alkyl or hydroxyl multi-alkoxy alkyl group on the phenyl by amido linkage alternatively.
10. the described compound of claim 1, wherein the M group is selected from:
-CONH-CH 2CH 2OH， -OCOCH 3，
-CONH-CH 2CHOHCH 2OH， -N(COCH 3)H，
-CONH-CH (CH 2OH) 2,-N (COCH 3) C 1-3-alkyl
-CON(CH 2CH 2OH) 2，
-CONH 2，
-CONHCH 3,-N (COCH 3) one, two and trihydroxy-C 1-4Alkyl ,-N (COCH 2OH) one, two and trihydroxy-C 1-4Alkyl ,-C (COCH 3) (one, two and trihydroxy-C 1-4Alkyl) 2
-N-(COCH 2OH) 2，
-CON(CH 2CHOHCH 2OH)(CH 2CH 2OH)，
-CONH-C (CH 2OH) 3With
-CONH-CH(CH 2OH)(CHOHCH 2OH)。
11. the described compound of claim 1, wherein the M group is poly-hydroxy C 1-4Alkyl group.
12. the described compound of claim 1, wherein X is Sauerstoffatom or following formula group:
NR 1, CO, SO 2, CR 2 1, COCO, CONR 1, COCR 2 1, SOCR 2 1, SO 2NR 1, CR 2 1CR 2 1, CR 2 1NR 1, CR 1 2O, NR 1CONR 1, OCONR 1, CONR 1CO, CONR 1CR 1 2, OCOO, CR 1 2OCR 1 2, OCR 1 2CO, CR 1 2CONR 1, CR 1 2CR 1 2CR 1 2, COCR 1R 1CO, CR 1 2NR 1CR 1 2, CR 1 2SO 2NR 1, CR 1 2OCO, NR 1SO 2NR 1, R wherein 1Be hydrogen or C that replaced by hydroxyl, alkoxyl group alternatively, oxa-or oxo 1-6Alkyl or alkoxy base or when being connected with carbon, R 1It also can be hydroxyl.
13. the described compound of claim 1, its structure is as follows: Wherein, M defines with claim 1, R 1Definition is with claim 12.
14. a diagnosis composition, it comprises the carrier or the vehicle that can tolerate on any formula I compound that defines in the aforesaid right requirement and at least a physiology.
CN 95196327 1994-09-23 1995-09-22 Iodinated X-ray-contrast media Pending CN1164225A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103951585A (en) * 2007-07-12 2014-07-30 通用电气医疗集团股份有限公司 Contrast agents

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103951585A (en) * 2007-07-12 2014-07-30 通用电气医疗集团股份有限公司 Contrast agents
CN103980154B (en) * 2007-07-12 2015-02-25 通用电气医疗集团股份有限公司 Contrast agents
US9738596B2 (en) 2007-07-12 2017-08-22 Ge Healthcare As Contrast agents

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