CN1167443A - Use of metal complexes as liver and gall bladder radiodiagnosis agents in computer tomography - Google Patents
Use of metal complexes as liver and gall bladder radiodiagnosis agents in computer tomography Download PDFInfo
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- CN1167443A CN1167443A CN95196523A CN95196523A CN1167443A CN 1167443 A CN1167443 A CN 1167443A CN 95196523 A CN95196523 A CN 95196523A CN 95196523 A CN95196523 A CN 95196523A CN 1167443 A CN1167443 A CN 1167443A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
Abstract
Described are metal complexes of DTPA derivatives substituted with a benzyl group in the 4 or 5 position, the complexes being suitable for use as contrast media in computed tomography of the liver and the bile ducts.
Description
The present invention relates in the hepatobiliary radiodiagnostics, the especially application of metal composite among the CT diagnostics.
Early stage discriminating especially hepatic metastases tumor of focus hepatic disease and liver tumor are one of most important diagnosis problems among the oncology.Can use four kinds of iconography methods to this: scintigraphy, ultrasound wave cardiotokography, computer tomography (CT) and magnetic resonance imaging,MRI art (MR).Do not have but each method all has its pluses and minuses a kind of method itself according to now standard be best and in fact each method all have benefited from contrast agent [Harned special, the intravenous injection that can tolerate, R.K., Chezmar, J.L., Nelson, R.C.: neoplastic iconography (Imaging of patients with potentially resectable hepativneoplasms) in the resectable invisible liver.U.S.'s radiology magazine (AJR) 159,1191-1194 (1992)].
The spatial resolution of scintigraphy is too little, and makes its application limited because of its radiopharmaceutical specificity not enough or too high (only can be used for the minority tumor type), does not therefore mention it in the summary title.The ultrasound wave cardiotokography is similarly reliable inadequately to pathological changes in the proof entity focus liver at present, because these focuses usually can not be distinguished with normal liver tissue on its acoustic characteristic fully mutually.Expose behind the liver in the operation and can confirm small lesion in the hepatic tissue when utilizing high frequency probe.Magnetic resonance imaging,MRI art (MR) can show whole liver, has high spatial resolution simultaneously, and looks its measuring method, can also have the high resolution of organizing.The intravenous injection that the well tolerable property of tool arranged is used for the clinical trial of MR with contrast agent, and these contrast agent can improve the value of this image method.But shortcoming is, continuing has pseudo-shadow of action and the expense costliness of machine own in the high-resolution measurement processes of a few minutes, and this has limited its application.
Computer tomography (CT) was ideal liver diagnosis technology originally.Instrument with the modern times can show whole liver with splendid spatial resolution in 30 seconds.A liver aspect takes about 1 second, and moving due to breathing and the enterokinesia worked hardly like this.The expense of CT is obviously cheap in MR.Low this shortcoming of tissue density's resolution must remedy by contrast agent certainly.Be applied to clinical contrast agent at present following several probability is arranged: 1. rapidly intravenous injection or perfusion contrast agent of high dose (50-100g).A few minutes can appear in some cases between focus and normal liver tissue radiography strengthens difference, and its principle is groundwater increment, organize the difference of relative blood flow amount and ECS.Have only the mentioned modern times of application and very high speed CT machine, instantaneous being used for that this contrast agent heterogeneity can be distributed diagnosed.2. the urinary radiopaque medium of using always behind the 120g 4-6 hour at least can be observed the normal hepatocytes essence that absorbs contrast agent and scarcely absorbs to have between the hepatopathy kitchen range of contrast agent the only a few patient and strengthens contrast preferably.This technology is called delaying sweep, and its reliability and cogency are still not enough, so can not conventionally use.3. in the arterialness portography, a conduit for example must be imported in the Mesenteric artery, then patient be delivered to the CT machine, in the about 150ml contrast agent of perfusion, scan.This technology tool is traumatic, time-consuming and expensive, but the existence and the most reliable localized foundation of hepatic metastases tumor can be provided at present.This foundation could be excised metastasis to decision and be had decisive meaning.Although therefore the cost of arterialness portal phlebography CT examination is high, still routine is carried out before art.
Above-described problem is: present employed radiopaque contrast medium is not to accumulate in the liver originally as the urinary radiopaque medium product.But in order to obtain certain contrast, available very a large amount of contrast agent pours into liver (dynamic scan) in short-term by blood flow, perhaps attempts still finding in very late time point top patient's liver parenchyma the contrast agent (" delaying sweep ") of 1-2%.
The diagnosis of obvious necessary raising liver lesion is because current approach efficient is too low, too expensive or load too big to patient.Therefore there is countless tests to desire to obtain the radiopaque contrast medium of the injectable liver specificity of intravenous in decades.Only mention from a large amount of inspected medicines several (seeing Table 1-2): thorotrast (the colloid suspension of thorium anhydride) can form splendid liver radiography contrast, but can not be excreted.Cause liver neoplasm in the α-many decades of radiation body thorium after injection.Schering Corp released Hepatoselectan in 1940 and comes into the market, and it is a kind of Emulsion of the most tiny drop of teriodide oil.Because of acute side effects has to withdraw from market.The substitute products of other company and seminar (EOE-13, AG-60-99 etc.) is still just abandoned because of same problem when clinical experimental stage.Table 1: the suspension class used for intravenous injection oily suspension title trier of company situation AG 60-99 Guerbet Lamarque 100 patients, stop EOE 13-Vermess hundreds of patient, stop EOE 14 Abbott-only preclinical phase perfluoro-octyl bromide Boehringer Bruneton Clinical Laboratory termination
Iodole (Intraiodol) in the Ingelheim-Lunderquist clinical examination stops intra arterial injection without approval table 2 of oily suspension fat iodole (Lipiodol)-numerous users: Amidotrizoat-Rosenberg is to human side effect rate or Iotrolan height for the liposomal lipid plastid title proofer of company situation, does not give earlier clever Krause animal experiment Iopamidol Bracco Musu animal experiment Ioxaglat Guerbet Corot animal experiment of license Iopromid
All medicaments preparation (suspension, Emulsion, liposome) also have shortcoming in addition except that many pharmacopedics problems, the high dose (5-20g) that promptly is used for radiodiagnosis can cause the distinctive side effect that is difficult to avoid.Therefore pay very big effort at the sixties and early eighties and sought in CT examination can capacity to accumulate in water solublity radiopaque contrast medium in the liver.Such material is equipped with 6 iodine atoms for every mole at the most, simultaneously very effective and well-tolerated in the check of animal experiment.Attractive is that effect in some different animals kinds has more different.So far still do not have a kind ofly to contain the iodine water soluble contrast material and can in the human liver, reach enough concentration, so that it is hopeful to be developed and is used for CT examination through what detect.Have a representative instance to be published in Muetzel in the test of many failures, W., Wegener 0.H., Souchon, R. and Weinmann, H.-J.'s " water soluble contrast material is used for the CT examination of liver: the Canis familiaris L. experimental study ".In Amiel (editor): the contrast agent in the radiology, Lyon1981, Springer publishing house, Berlin, Heidelberg, New York 1982,320-323 page or leaf, table 1.In this article, compare with many animal species, in the mankind, do not obtain enough liver radiographies yet and strengthen.
Intravenous cholangiographic agent such as Introxinat and Ioglycamat can optionally assemble in liver.Certainly this process has its limitation very much on capacity.When concentration is 5 μ g iodine/ml blood plasma, also can reach 5 times concentration in the liver, and when concentration is 50 μ g iodine/ml, concentration in the liver has only 2 times concentration, when concentration is 500 μ g iodine/ml, then the concentration in the liver is starkly lower than the concentration in the blood plasma and has lost diagnostic significance, because can not differentiate accumulative tissue and simple perfusion this moment.And CT can differentiate be the above iodine concentration of 1mg/ml (Speck, U., Muetzel, W., Herz-Huebner, U., Siefert, the pharmacology of H.M.:Iotroxin acid, a kind of new intravenous injection is with cholangiography agent I.Animal pharmaceuticals kinetics and radiology.Drug research 28,2143-2149 (1978)).
Therefore can determine: what need is on preferred water miscible and the pharmacopedics superperformance, stable, that can tolerate, that dosage specific and that ether is not high works radiopaque contrast medium to be arranged, although the effort of decades is arranged up to now, still without any a kind of product, perhaps just be in the promising clinical trial phase on the market.Such medicament is difficult to seek, because can not predict its absorption, gathering and pass through the excretory kind dependency of liver by means of the animal experiment detection; After animal test results is used in the mankind and draws many disappointed results in addition, be considered to be re-used as and judged a kind of material or the suitable or inappropriate sign of material type.
The containing metal contrast agent that is used for the magnetic resonance imaging,MRI technology also absorbs lonizing radiation.Therefore in some cases, tested and these materials are used for CT (Schild, H.H. etc.: gadolinium DTPA (Magnevist) is as the contrast agent of arterialness DSA.Radiology progress 160,218-221 (1994); Quinn, A.D. etc.: Gd-DTPA: a kind of alternative CT contrast agent.Computer is supported 18 phases of layer scanning technology magazine (J.Comput.Assist.Tomogr.), 634-636 (1994)).Be contemplated that present spendable metal composite per molecule only forms the correlated metal ion of radiography in conjunction with one, and the radiopaque contrast medium that contains iodine contains 3 or 6 iodine atoms.Although some metal ions have higher stress efficacy (Zwicker, C., Langer, M., Langer, R., Keske, U.: be used for the iodate of CT and the comparison of non-iodinated contrast media than iodine.Radiological study (Invest.Radiol.) 26,162-164 (1991)), contain diodone and also in any relevant explanation indication, do not replaced so far by metallo-chelate.
Utilizing metallo-chelate is to absorb in the molecule that the constituent content of lonizing radiation is very low (to contain the iodine radiopaque contrast medium: 3 to 6 iodine atom/molecule as a major defect of radiopaque contrast medium; Mr angiography agent: 1 metal ion/molecule).The radiography contrast that forms is faint equally, so metal composite almost only is used for the tentative inspection of lonizing radiation.Low like this concentration of metal ions is just enough in MR, because they influence the proton of Fast transforms in the water, and metal itself must manifest in lonizing radiation.
Therefore task of the present invention is: by known, be suitable for selecting some materials in Image Diagnosis, the pharmacopedics material based on metallo-chelate, with preparation be used for that radiodiagnosis, especially CT diagnose, be suitable for the hepatobiliary contrast agent.
The present invention has finished this task, and claims invading the exterior is understood its inventive features.The theme that the present invention therefore relates in claims being characterized.
Now invent: metal and the metal composite that chelating agent constituted of being 44-51 or 56-83 by an atomic number are suitable for preparing contrast agent, to be applied to the radiography Contrast-Enhanced CT and Tumoral of liver and biliary tract.
Therefore the present invention relates to the chemical compound (I) of general formula I,
X is that a hydrogen atom or atomic number are 44-51 or 56-83 independently of each other
A metal ion equivalent of element, R
1One of be formula-CH
2-C
6H
4-(0) r-R
2A residue, wherein aromatic rings can adjacent,
Or para-position is substituted, and another R
1Residue is a hydrogen atom, R
2Be an alkyl, it by 1-6 carbon atom and 0-2 oxygen atom form,
Phenyl or benzyl or hydrogen atom r are numeral 0 or 1, and wherein carboxyl also can be the amide form, adds to reaching the cation of the required in case of necessity physiological tolerance of charge balance.
The R of general formula I
1Base also can use the benzyl of replacement, for example methoxy-benzyl, ethoxy benzyl, propoxyl group benzyl, butoxy benzyl, amoxy benzyl, benzyloxy benzyl, methyl-benzyl, Ethylbenzyl, propyl group propyl group, butyl benzyl, amyl group benzyl and benzyl benzyl.Preferred R
1Be ethoxy benzyl and butyl benzyl.The substituent group of benzyl can be at 2-, on 3-or the 4-position, also is ortho position, a position or para-position.Preferred ortho position and para-orientating group, especially preferred para-position residue.
R
1Can be 3,6,9-three azepines-3,6 are on the 4-or 5-position of 9-three (carboxyl methyl)-heneicosanedioic acid, preferably on the 4-position.R on other position
1Be hydrogen atom.
The residue that preferably contains aerobic (r=1).Especially preferred ethoxy benzyl.
As R
2, can contain C in the chemical compound
1-to C
6-alkyl, for example methyl, ethyl, propyl group, butyl, amyl group or hexyl.C
3-to C
6-alkyl can be for straight or branched at this, for example isopropyl, isobutyl group, the tert-butyl group, neopentyl or isohesyl.Alkyl also can contain 2 oxygen atom (not considering natural per-compound at this) at the most, for example ethoxyethyl group, ((ethyoxyl-) ethyoxyl) ethyl or methoxy-propyl.
The preferred lanthanide series of metal ion.(see embodiment 8) in the observation under the practice condition, prove that holmium, erbium and an an ancient unit of weight equal to 20 or 24 *taels of silver are more suitable than MR commonly used element gadolinium and dysprosium, thulium is because of the valency height, from the angle of economy and not too suitable, but suitable equally in theory.Especially the chelate of lutecium, praseodymium, cerium, hafnium, lead and bismuth possesses more superior characteristic.
Carboxyl can be that also the amide form occurs, and for example is alkyl-or dialkyl amide, and alkyl has 1-4 carbon atom here, or is the morpholide base.Be the not negative load in amide functional position with carboxyl-functional contrasts.Therefore when carboxyl-functional was converted to amide functional, the electric charge of complex also changed.In general should there be carboxyl-functional as much as possible to be converted to amide functional, just can forms electroneutral complex.
Cation as physiological tolerance for example has: Na
+, Ca
2+, Mg
2+, and Zn
2+And organic cation of following organic base: meglumin, glycosamine, arginine, ornithine, lysine, 2-amino-1,3,4-butantriol and ethanolamine.Following chemical compound is particularly suited for application of the present invention: 3,6,9-three azepines-3,6, gadolinium (III) complex of 9-three (carboxyl methyl)-4-(4-ethyoxyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, an an ancient unit of weight equal to 20 or 24 *taels of silver (III) complex of 9-three (carboxyl methyl)-4-(4-ethyoxyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, praseodymium (III) complex of 9-three (carboxyl methyl)-4-(4-ethyoxyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, cerium (III) complex of 9-three (carboxyl methyl)-4-(4-ethyoxyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, lutecium (III) complex of 9-three (carboxyl methyl)-4-(4-ethyoxyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, hafnium (IV) complex of 9-three (carboxyl methyl)-4-(4-ethyoxyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, bismuth (III) complex of 9-three (carboxyl methyl)-4-(4-ethyoxyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6,9-three (carboxyl methyl)-5-{4-[2-(2-ethoxy ethoxy)-ethyoxyl]-benzyl)-an ancient unit of weight equal to 20 or 24 *taels of silver complex of heneicosanedioic acid, 3,6,9-three azepines-3,6, lead (II) complex of 9-three (carboxyl methyl)-4-(4-ethyoxyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, an an ancient unit of weight equal to 20 or 24 *taels of silver (III) complex of 9-three (carboxyl methyl)-4-(2-ethyoxyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, gadolinium (III) complex of 9-three (carboxyl methyl)-4-(4-butyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, an an ancient unit of weight equal to 20 or 24 *taels of silver (III) complex of 9-three (carboxyl methyl)-4-(4-butyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, praseodymium (III) complex of 9-three (carboxyl methyl)-4-(4-butyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, hafnium (IV) complex of 9-three (carboxyl methyl)-4-(4-butyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, bismuth (III) complex of 9-three (carboxyl methyl)-4-(4-butyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, lutecium (III) complex of 9-three (carboxyl methyl)-4-(4-butyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, lead (II) complex of 9-three (carboxyl methyl)-4-(4-butyl-benzyl)-heneicosanedioic acid, with and salt and amide.
The method just operation of a routine concerning the professional for preparing The compounds of this invention.Existing explanation among this external EP 0 405 704 of these materials of minority and preparation method thereof and the US 4,880,008.Preparation method also has been described in the embodiment of this material, and the professional can adjust according to its needs, to obtain required chemical compound.
Cited metal composite preferably uses with the form of aseptic aqueous solution.They are except that containing the metal composite that absorbs lonizing radiation, also contain pharmacopedics auxiliary substance commonly used, as buffer agent, alkali, acid, stabilizing agent, organic solvent, the material that is used to adapt to osmolarity and viscosity, the adjuvant that plays pharmacological action and excessive free chelating agent or its ion that has loose bonded physiological tolerance such as Ca
2+, Mg
2+And Zn
2+Salt/complex, to promote the drainage of heavy metal.Suitable material and concentration range thereof are that the professional is known, and can discover and seize in the literature.
The preferred 0.1Mol to 1.0Mol of the concentration of metal composite is based on the metal ion meter of radiography contrast usefulness.Different with the related complex dissolubility can make concentration higher or lower as requested.Reach the enhanced dosage of liver interimage and be about the 0.1-0.5mmol/kg body weight, preferable range is 0.2-0.6mmol/kg.
According to usual way administration medically.Perfusion or injection in preferred 1 minute to the 30 minutes time angular vein.
Amazingly be, although the absorbability of representing with the radiation absorption of per molecule when using on mankind for the first time is relatively poor, but still obtained CT when this metallo-chelate is used in human body and gone up enough lonizing radiation Absorptions in the liver, and do not used non-specific dosage so high when containing the iodine radiopaque contrast medium.Simultaneously, run-up and persistent period length satisfy the requirement that CT diagnoses in the liver.Administering mode is non-damage (a for example intravenous).Toleration is good (on seeing) in required dosage range.
Can affirm in a word: the material that is used in this explanation has successfully obtained the contrast agent accumulation at human liver first, and it can be used as the diagnostic message that has utilization to be worth in the CT technology of current use.This achievement more makes us pleasantly surprised than following aspect: ◆ for seeking to reach the medicament of this purpose, once wasted decades, although ◆ contain the iodine radiopaque contrast medium and have in all theoretical desired molecular characterizations and the molecule height and contain and form the correlated element of radiography, but still can not meet the demands, ◆ the material of using according to the present invention requires high 10 times dosage than MR, and do not lose the sign of physiological tolerance, ◆ contain the iodine radiopaque contrast medium according to the concentration in the people liver that application of the present invention reached at other classics and reached, these contrast agent are not therefore to be used for CT to improve the diagnosis of liver inner disease foci, ◆ animal test results proves, contrast agent is applicable to the radiography accumulation of liver CT and reliable fully.
Following examples are used to illustrate the present invention, but are not that desire is confined to this with the invention object.Embodiment 13,6,9-three azepines-3,6, the lutecium complex of the disodium salt of 9-three-(carboxyl methyl)-5-(4-ethyoxyl-benzyl)-heneicosanedioic acid a) 3,6,9-three azepines-3,6,9-three-(tert-butoxycarbonyl methyl)-5-(4-ethoxy benzyl)-heneicosanedioic acid-two-tert-butyl ester
With 16.7g (21.4mmol) 3,6,9-three azepines-3,6,9-three-(tert-butoxycarbonyl methyl)-5-(4-hydroxybenzyl)-heneicosanedioic acid-two-tert-butyl ester (DOS 3710730) is dissolved in the anhydrous N of 50ml, in the dinethylformamide, under argon, react in the time of 0 ℃ with 0.94g (23.5mmol) sodium hydride dispersion (60% in mineral oil).Stirred precipitate 15 minutes, and added 3.74g (24.0mmol) iodoethane then, allow reaction temperature rise to room temperature, continue then to stir 4 hours.Precipitate added repeatedly use water solublity sodium bicarbonate solution shake in the toluene then, so that react completely.Separate organic facies, use dried over mgso, filtration and evaporation.The oily residue on silica gel with ethane/diethyl ether/triethylamine chromatography, converge and evaporate the distillation that contains product.Yield: 16.4g (theoretical value 94.8%) water white oil.Analyze (based on not solvent-laden material): theoretical value: C 63.92 H 9.11 N 5.20 O 21.78 value of calculation: C 63.77 H 9.28 N 5.13b) 3,6,9-three azepines-3,6, the lutecium complex of the disodium salt of 9-three-(carboxyl methyl)-5-(4-ethyoxyl-benzyl)-heneicosanedioic acid
The chemical compound that 16.1g (20mmol) a) is prepared according to embodiment is dissolved in the oxolane of 50ml, add 60ml 2N sodium hydroxide solution then, 60 ℃ were stirred 2 hours down, regulate pH1 with concentrating hydrochloric acid, concentrate with the rotary evaporator height, use ion exchange chromatography (cationite (H then
+-shape), eluent: the purification residue water solublity ammonia solution).With eluent evaporation and under vacuum finish-drying, draw free chelating agent thus.
Valeric acid added in the 250ml water react with 3.98g (10mmol) luteium oxide.100 ℃ were stirred this suspension 36 hours down and filtration.Regulating pH with the 1N sodium hydroxide solution then is 7.3.Agitating solution 1 hour and filtration after adding the 1.6g activated carbon under 80 ℃ at last.Get the colorless solid thing after the lyophilization filtrate.
Yield: 14.1g (theoretical value 94.8%) analyzes (based on anhydrous material): theoretical value: C 37.16 H 3.80 N 5.65 O 23.67 Lu 23.53 Na 6.18 value of calculation: C 37.03 H 3.94 N5.51 Lu 23.38 Na 5.90 embodiment 23,6,9-three azepines-3,6, an ancient unit of weight equal to 20 or 24 *taels of silver complex of the disodium salt of 9-three-(carboxyl methyl)-4-(2-ethyoxyl-benzyl)-heneicosanedioic acid is N-benzyl oxygen base carbonyl-3-[2-hydroxy phenyl a)]-alanine-methyl ester
(2-hydroxy phenyl alanine Heraeus) is suspended in the 48ml methanol, cools off in ice bath, uses 7.6ml (105mmol) thionyl chloride to react in the drop mode then with 9.5g (52.4mmol) neighbour-tyrosine.After one hour under refluxing this material of heating and stirring three hours.Then at room temperature stir and spend the night.Evaporation drying is added in the methanol, evaporates and repeats this process two times with residue.Add 50ml water, regulating pH with the 1.5mol sodium carbonate liquor is 8.5, and adds 22.1ml (63mmol) benzyl chloroformate under monitoring pH.Stirred four hours under the room temperature, separate organic facies, wash and use dried over sodium sulfate with water.Evaporation back glue silicon (dichloromethane/ethyl acetate) chromatography.
Yield: 13.5g (theoretical value 78.2%) water white oil, it is crystallization gradually.Analyze (based on not solvent-laden material): theoretical value: C 65.64 H 5.82 N 4.25 O 24.29 value of calculation: N-benzyl oxygen base carbonyl-3-[2-ethoxy benzyl C 65.57 H 5.68 N 4.30b)]-alanine-methyl ester
Embodiment neighbour-phenol 10.2g (31mmol) a) is dissolved in 6ml N at 40 ℃, and dinethylformamide is with 9.2g (66.5mmol) potassium carbonate and the reaction of 0.3ml water.Then drop is added 5.7ml (43.4mmol) dithyl sulfate and was stirred 3.5 hours.Add 6.6ml ammonia and left standstill material 1 hour.Add little water then, and extract with t-butyl methyl ether.Separate organic facies, with dilute sulphuric acid and water washing.With dried over sodium sulfate, the evaporation of filtration back and silica gel column chromatography residue.
Yield: 8.2g (theoretical value 74%) water white oil.Analyze (based on not solvent-laden material): theoretical value: C 67.21 H 6.49 N 3.92 O 22.38 value of calculation: N-benzyloxycarbonyl-2-[2-ethoxy benzyl C 67.09 H 6.53 N 3.77c)]-the 2-cholamine
With 7.9g (22mmol) N-benzyloxycarbonyl-3-[2-ethoxyl phenenyl]-alanine-methyl ester (embodiment b) is dissolved in the 63ml t-butyl methyl ether and reacts with 1.1g (30.1mmol) sodium borohydride.Add 15ml methanol under 5 ℃ and under constant temperature, stirred 5 hours.Then 1.5ml acetic acid is dissolved in and adds behind the 5ml oxolane, add 9ml water, and at room temperature stirred 10 minutes.Separate organic facies, wash and use dried over sodium sulfate with water.Blotted dry agent, evaporated filtrate and with residue with silica gel column chromatography to purify.
Yield: 7.25g (theoretical value 100%) water white oil, crystallization fully rapidly.Analyze (based on not solvent-laden material): theoretical value: C 69.28 H 7.04 N 4.25 O 19.43 value of calculation: N-benzyloxycarbonyl-2-[2-ethoxy benzyl C 69.32 H 7.00 N 4.18d)]-1 dihydric salt hydrochlorate
With embodiment c) ethanol 7.2g (22mmol) be dissolved in the 18ml oxolane and at room temperature add 4.9ml (35mmol) triethylamine.Adding 2.54ml (32.6mmol) mesyl chloride is dissolved in the 2ml oxolane and stirred 6 hours at 20 ℃.Then under 30 ℃ to 45 ℃ room temperature, splash into 22.2ml (330mmol) ethylenediamine.Be heated to 50 ℃ and stirred material 4 hours.Evaporation reaction mixture then adds ethyl acetate with residue and washes with water.Organic facies is cooled off in ice bath and reacted with concentrated hydrochloric acid.Blot formed precipitate, with cold isopropanol washing and dry down at 50 ℃.
Yield: 7.5g (theoretical value 76.7%) colorless solid thing.Analyze (based on not solvent-laden material): theoretical value: C 56.76 H 7.03 Cl 15.95 N 9.45 O 10.80 value of calculation: 2-[2-ethoxy benzyl C 56.62 H 7.11 Cl 15.80 N 9.36e)]-the 1 dihydrochloride
With embodiment d) the ammonia 7.2g (16.2mmol) of Z-protection be suspended in the 72ml methanol, add palladium (10%) and 0.5ml water on the 1.08g activated carbon, and hydrogenation under normal pressure and room temperature.After the hydrogen absorption process finishes, filtering catalyst and evaporated filtrate.
Yield: 4.9g (theoretical value 97.5%) colorless solid thing.Analyze (based on not solvent-laden material): theoretical value: C 50.33 H 8.12 Cl 22.85 N 13.54 O 5.16 value of calculation: C 50.17 H 8.34 Cl 23.11 N 13.40f) 3,6,9-three azepines-3,6,9-three-(tert-butoxycarbonyl methyl)-4-(2-ethoxy benzyl)-heneicosanedioic acid-two-tert-butyl ester
11.2g (81.5mmol) potassium carbonate is dissolved in the 11ml water, and adds 4.8g (15.5mmol) triamine (embodiment e) down at 35 ℃.Point is added dropwise to 12.5ml (85.3mmol) bromoacetic acid-tert-butyl ester and stirred material 7 hours down at 65 ℃.Stir under the room temperature after 18 hours, reactant mixture and water are reacted and use the ethyl acetate jolting.Organic facies is by dried over sodium sulfate, evaporation and precipitate glue silicon (methylene chloride) chromatography.Get pentyl ester after evaporating the fraction that contains product, be faint yellow oily thing.
Yield: 11.9g (theoretical value 95%) analyzes (based on not solvent-laden material): theoretical value: C 63.92 H 9.11 N 5.20 0 21.78 value of calculation: C 64.05 H 9.23 N 5.07g) 3,6,9-three azepines-3,6,9-three-(carboxyl methyl)-4-(2-ethoxy benzyl)-heneicosanedioic acid
Will be by embodiment f) gained pentyl ester 11.75g (14.5mmol) is dissolved in the 86ml methanol, and with the solution reaction of 4.65g (116.3mmol) sodium hydroxide in 7.1ml water.65 ℃ are stirred 4 hours, then evaporative removal methanol, interpolation water and evaporation once more down.Water absorbs and regulates pH with acid ion exchangers is 1.8.Further concentrate water miscible solution after leaching exchange liquid, and by preparation HPLC (water/methanol/pH2.5) purify.Evaporation contains the liquid fractionation of product, absorbs lyophilization then in the entry once more.
Yield: 4.9g (theoretical value 64%) analyzes (based on not solvent-laden material): theoretical value: C 52.37 H 6.31 N 7.97 O 33.36 value of calculation: C 52.19 H 6.46 N 7.88h) 3,6,9-three azepines-3,6, an ancient unit of weight equal to 20 or 24 *taels of silver complex of the disodium salt of 9-three-(carboxyl methyl)-4-(2-ethyoxyl-benzyl)-heneicosanedioic acid
With embodiment g) gained pentyl ester 3.72g (7.05mmol) is dissolved in the 19ml water at 60 ℃, and press five equilibrium and the reaction of 1.85g (3.53mmol) carbonic acid an ancient unit of weight equal to 20 or 24 *taels of silver.Compoundly finish after-filtration, regulate pH and be 7.0,100 ℃ down with the 0.2g activated carbon stir 10 minutes, filter and with the filtrate lyophilizing again.
The colourless dried frozen aquatic products of yield: 4.6g (theoretical value 88%).Analyze (based on anhydrous material): theoretical value: C 37.26 H 3.81 N 5.67 O 23.74 Yb 23.34 Na 6.20 value of calculation: C 37.13 H 4.02 N 5.55 Yb 23.18 Na 5.87 embodiment 3a) 3,6,9-three azepines-3,6, an ancient unit of weight equal to 20 or 24 *taels of silver complex of the dimethyl Portugal amine salt of 9-three-(carboxyl methyl)-4-(4-ethoxy benzyl)-heneicosanedioic acid
With 2.9g (5.5mmol) 3,6,9-three azepines-3,6,9-three-(carboxyl methyl)-4-(4-ethoxy benzyl)-heneicosanedioic acid (EP 0405704, embodiment 8b) is suspended in the 20ml water, and 60 ℃ down and 1.45g (2.75mmol) carbonic acid an ancient unit of weight equal to 20 or 24 *taels of silver compound.After reaction finishes precipitate and methyl glucose ammonia are neutralized.Filter, by lyophilization filtrate, must metal composite.
The colourless dried frozen aquatic products of yield: 5.7g (theoretical value 95.3%).Analyze (based on anhydrous material): theoretical value: C 40.85 H 5.93 N 6.44 O 30.88 Yb 15.90 value of calculation: C 40.67 H 6.08 N 6.17 Yb 15.62b) 3,6,9-three azepines-3,6, two-(2-amino-1 of 9-three-(carboxyl methyl)-4-(4-ethoxy benzyl)-heneicosanedioic acid, 3,4-butantriol)-an ancient unit of weight equal to 20 or 24 *taels of silver complex of salt
If should compound acid and 2-amino-1,3, the neutralization of 4-butantriol, then with embodiment a) identical method get title compound.C) 3,6,9-three azepines-3,6, the strontium complex of the disodium salt of 9-three-(carboxyl methyl)-4-(4-ethoxy benzyl)-heneicosanedioic acid
If also with the reaction of part (EP 0405704, embodiment 8b) and strontium carbonate, with the sodium hydroxide solution neutralization, then with embodiment a) identical method get title compound.D) 3,6,9-three azepines-3,6, an ancient unit of weight equal to 20 or 24 *taels of silver complex of the disodium salt of 9-three-(carboxyl methyl)-4-(4-ethoxy benzyl)-heneicosanedioic acid
With 2.1g (4mmol) 3,6,9-three azepines-3,6,9-three-(carboxyl methyl)-4-(4-ethoxy benzyl)-heneicosanedioic acid (EP 0405704, embodiment 8b) be suspended in the 15ml water and 60 ℃ down and 1.05g (2mmol) carbonic acid an ancient unit of weight equal to 20 or 24 *taels of silver compound.After the compound end, neutralize with the 1N sodium bicarbonate solution.Filter composite solution and lyophilization filter, liquid gets title compound.
The colourless dried frozen aquatic products of yield: 3.0g (theoretical value 100%).Analyze (based on anhydrous material): theoretical value: C 37.26 H 3.81 N 5.67 O 23.74 Yb 23.34 Na 6.20 value of calculation: C 37.14 H 4.11 N 5.50 Yb 23.22 Na 5.94e) 3,6,9-three azepines-3,6, the lutecium compound of the disodium salt of 9-three-(carboxyl methyl)-4-(4-ethoxy benzyl)-heneicosanedioic acid
With 3.0g (5.7mmol) 3,6,9-three azepines-3,6,9-three-(carboxyl methyl)-4-(4-ethoxy benzyl)-heneicosanedioic acid (EP 0405704, embodiment 8b) is suspended in the 15ml water, and 95 ℃ down and 1.07g (2.7mmol) luteium oxide compound.After the compound end, neutralize with the 1N sodium bicarbonate solution.Filter this solution and lyophilization filtrate, get title compound.
The colourless dried frozen aquatic products of yield: 3.9g (theoretical value 92%).Analyze (based on anhydrous material): theoretical value: C 37.16 H 3.80 N 5.65 O 23.67 Yb 23.53 Na 6.18 value of calculation: C 37.02 H 4.01 N 5.53 Yb 23.26 Na 5.87
Can obtain corresponding bismuth complex (by waltherite), hafnium complex (by hafnium hydroxide), plumbous complex (by ceruse), lanthanum complex (by lanthanum carbonate), dysprosium complex (by dysprosia), erbium complex (by the carbonic acid erbium), terbium complex (by terbium carbonate), holmium complex (by the carbonic acid holmium), praseodymium complex (by praseodymium carbonate) with identical method.Embodiment 43,6,9-three azepines-3,6, the gadolinium compound of the disodium salt of 9-three-(carboxyl methyl)-4-(2-butoxy benzyl)-heneicosanedioic acid is N-benzyloxycarbonyl-3-[2-butoxy phenyl a)]-alanine-ethyl ester
With embodiment 2a) neighbour-phenol 5.0g (15.2mmol) under 40 ℃, be dissolved in the N of 4ml, dinethylformamide adds 4.5g (31.1mmol) potassium carbonate and 0.2ml water.Then point is added dropwise to the n-butyl bromide of 2.1g (15.5mmol) and stirred 5 hours.Add 3.2ml ammonia and left standstill material 1 hour.Add little water then and extract with t-butyl methyl ether.Separate organic facies, use dilute sulfuric acid and water washing.With dried over sodium sulfate, the evaporation of filtration back and silica gel column chromatography residue.
Yield: 4.7g (theoretical value 80.2%) water white oil.Analyze (based on not solvent-laden material): theoretical value: C 68.55 H 7.06 N 3.63 O 20.75 value of calculation: N-benzyloxycarbonyl-2-[2-butoxy benzyl C 68.42 H 7.18 N 3.59b)]-the 2-ethylaminoethanol
Will (embodiment N-benzyloxycarbonyl-3-[2-butoxy phenyl a)]-alanine-ethyl ester 3.9g (11mmol) is dissolved in the 30ml t-butyl methyl ether, and adding 0.55g (15mmol) sodium borohydride.3 ℃ of following interpolation 8ml methanol also stirred 5 hours under constant temperature.Add after then 0.8ml acetic acid being dissolved in the 3ml oxolane, add 5ml water and also at room temperature stirred 10 minutes.Separate organic facies, wash, use dried over sodium sulfate with water.Draw desiccant, evaporated filtrate and silica gel column chromatography with the purification residue.
Yield: 3.4g (theoretical value 86.5%) water white oil.Analyze (based on not solvent-laden material): theoretical value: C 70.56 H 7.61 N 3.92 O 17.90 value of calculation: N-benzyloxycarbonyl-2-[2-butoxy phenyl C 70.43 H 7.60 N 4.07c)]-1,4,7-triazaheptane dihydrochloride is with embodiment b) pure 3.1g (8.8mmol) be dissolved in the 8ml oxolane, and at room temperature add 2.0ml (14mmol) triethylamine.Add 1.02ml (13mmol) the methanesulfonic acid chlorine that is dissolved in the 1ml oxolane, and stirred 5 hours down at 20 ℃.Then under 35 ℃ to 45 ℃ temperature, drip 8.9ml (132mmol) ethylenediamine.Be heated to 50 ℃ and stirred material 3 hours.Then evaporation reaction mixture, residue is added income ethyl acetate and washing with water.Organic facies is cooled off in ice bath and reacted with concentrated hydrochloric acid.Draw precipitate, wash and drying under 50 ℃ with cold isopropanol.
Yield: 3.8g (theoretical value 91.4%) yellow solid.Analyze (based on not solvent-laden material): theoretical value: C 58.47 H 7.47 Cl 15.01 N 8.89 O 10.16 value of calculation: 2-[2-butoxy benzyl C 58.28 H 7.24 Cl 14.93 N 8.73d)]-the 1 dihydrochloride
With embodiment c) the protected amine 3.6g of Z-(8.1mmol) be suspended in the 35ml methanol, add 0.4g palladium (10%) and 0.3ml water and hydrogenation under normal pressure and room temperature on the activated carbon.Hydrogenation leaches catalyst and evaporated filtrate after finishing.
Yield: 2.4g (theoretical value 87.6%) yellow solid.Analyze (based on not solvent-laden material): theoretical value: C 53.25 H 8.64 Cl 20.96 N 12.42 O 4.73 value of calculation: C 53.08 H 8.72 Cl 21.23 N 12.29e) 3,6,9-three azepines-3,6,9-three-(tert-butoxycarbonyl methyl)-4-(2-butoxy benzyl)-heneicosanedioic acid-two-tert-butyl ester
Be dissolved in 5.3g (38.8mmol) potassium carbonate in the 5ml water and adding 2.3g (7.4mmol) three ammonia-dihydrochloride (embodiment d) under 35 ℃.Point is added dropwise to 5.9ml (40.6mmol) bromoacetic acid-tert-butyl ester, stirs material 8 hours down at 60 ℃.Stir after 15 hours under the room temperature, in reactant mixture, add water and use the ethyl acetate jolting.Organic facies dried over sodium sulfate, evaporation, silica gel (ethyl acetate/acetone) chromatography residue.After evaporation contained the fraction of product, getting pentyl ester was water white oil.
Yield: 5.3g (theoretical value 85.7%) analyzes (based on not solvent-laden material): theoretical value: C 64.64 H 9.28 N 5.03 O 21.05 value of calculation: C 64.77 H 9.34 N 4.88f) 3,6,9-three azepines-3,6,9-three-(carboxyl methyl)-4-(2-butoxy benzyl)-heneicosanedioic acid
With embodiment e) pentyl ester 5.11g (6.3mmol) be dissolved in 4 0ml methanol, add 2.02g (50.6mmol) sodium hydroxide in the 3.1ml water.Stirred 3 hours down at 55 ℃, then evaporate methanol, add entry and evaporation once more.Water absorbs and regulates pH with acid ion exchangers is 1.9.After leaching exchanger, further concentrated aqueous solution is also with preparation HPLC (water/methanol/pH 2.8) purification valeric acid.Evaporation contains the liquid fractionation of product, absorbs in the entry once more and lyophilization.
The colourless dried frozen aquatic products of yield: 2.9g (theoretical value 82.8%).Analyze (based on not solvent-laden material): theoretical value: C 54.05 H 6.71 N 7.56 O 31.68 value of calculation: C 53.91 H 6.76 N 7.39g) 3,6,9-three azepines-3,6, the gadolinium compound of the disodium salt of 9-three-(carboxyl methyl)-4-(2-butoxy benzyl)-heneicosanedioic acid
Under 85 ℃ with 2.48g (4.7mmol) embodiment f) valeric acid be suspended in the 20ml water, and press the reaction of five equilibrium and 0.85g (2.35mmol) Gadolinia..After the compound end, filter, regulate pH and be 7.2, with the 0.2g activated carbon 90 ℃ stir 10 minutes, filter again, lyophilizing filtrate.
The colourless dried frozen aquatic products of yield: 3.5g (theoretical value 98.8%).Analyze (based on anhydrous material): theoretical value: C 39.84 H 4.28 N 5.58 O 23.35 Gd 20.86 Na 6.10 value of calculation: C 39.73 H 4.39 N 5.47 Gd 20.71 Na 5.94 embodiment 53,6,9-three azepines-3,6,9-three-(carboxyl methyl)-5-{4-[2-(2-ethoxy ethoxy)-ethyoxyl]-benzyl)-an ancient unit of weight equal to 20 or 24 *taels of silver complex of the disodium salt of heneicosanedioic acid a) 3,6,9-three azepines-3,6,9-three-(tert-butoxycarbonyl methyl)-5-{4-[2-(2-ethoxy ethoxy)-ethyoxyl]-benzyl }-heneicosanedioic acid-two-tert-butyl ester
With 16.7g (21.4mmol) 3,6,9-three azepines-3,6,9-three-(tert-butoxycarbonyl methyl)-5-(4-hydroxybenzyl)-heneicosanedioic acid-two-tert-butyl ester (DOS 3710730) is dissolved in the anhydrous N of 50ml, in the dinethylformamide, following and 0.94g (23.5mmol) sodium hydride dispersion (60% in the vegetable oil) reaction of argon in the time of 0 ℃.Stir material 15 minutes, then add 4.73g (24.0mmol) 2-(2-ethoxy ethoxy)-bromoethane, make reaction temperature bring up to room temperature and continue to stir 4 hours.Material is absorbed in the toluene and repeatedly uses the sodium bicarbonate aqueous solution jolting, to separate.Separate organic facies, use dried over mgso, filtration, evaporation.The glue silicon layer that butyrous residue is made eluant in order to hexane/diethyl ether/triethylamine is analysed, converge the liquid fractionation and the evaporation that contain product.
Yield: 17.7g (theoretical value 92.4%) water white oil.Analyze (based on not solvent-laden material): theoretical value: C 62.99 H 9.11 N 4.69 O 23.21 value of calculation: C 63.07 H 9.27 N 4.75b) 3,6,9-three azepines-3,6,9-three-(carboxyl methyl)-5-{4-[2-(2-ethoxy ethoxy)-ethyoxyl]-benzyl)-an ancient unit of weight equal to 20 or 24 *taels of silver complex of the disodium salt of heneicosanedioic acid
13.4g (15.0mmol) is dissolved in the 35ml oxolane and adds 45ml 2N sodium hydroxide solution according to the chemical compound of a) preparation, under 60 ℃, stirred 2 hours, regulate pH with concentrated hydrochloric acid and be 1, concentrate, also use ion exchange chromatography (cationite (H with the rotary evaporator height
+-form), eluent: purification residue ammonia spirit).With eluent evaporation and under vacuum finish-drying, draw free complexing agent thus.
Valeric acid is absorbed in the 150ml water, adds 3.94g (7.5mmol) carbonic acid an ancient unit of weight equal to 20 or 24 *taels of silver.60 ℃ were stirred suspension 3 hours down and filtration.Regulating pH with the 1N sodium hydroxide solution then is 7.3.Agitating solution 1 hour and filtration after adding the 1.0g activated carbon under 80 ℃ at last.Get the colorless solid thing after the lyophilization filtrate.
Yield: 11.4g (theoretical value 91.6%) analyzes (based on anhydrous material): theoretical value: C 39.09 H 4.37 N 5.07 O 25.07 Yb 20.86 Na 5.54 value of calculation: C 38.84 H 4.45 N 5.02 Yb 20.69 Na 5.30 embodiment 6
Inject 3 of 0.25mol 5 routine hepatic metastases tumor people with the dosage of 0.35mmol/kg, 6,9-three azepines-3,6, the gadolinium III-complex solution (Gd-EOB-DTPA of the disodium salt of 9-three-(carboxyl methyl)-4-(4-butoxy benzyl)-ten-docosandioic acid, in the embodiment of EP 0405704 8c, illustrate) back 10 to 60 minutes, the normal hepatic parenchymal Huo Si Fil unit of getting (HU) density value increases.This dosage is equivalent to 16g complex/patient 70kg approximately.Table 3
Inject back 60 minutes of injection in back 10 minutes
HU?????????????????HU
Case 1 19 26
Case 2 12 25
Case 3 10 17
Case 4 18 32
Case 5 15 32
Compare with disclosed by nineteen eighty-twos such as Muetzel, as to be used in particular for liver diagnosis hexaiodo SH L 433 (formula XI).
When dosage is 360mg iodine/kg (about 25g iodine/patient 70kg), accumulation only is＜10HU (monkey, Canis familiaris L., Mus:＞40HU).90% (hexaiodizated at the most the mankind by the Iotroxinat of bile excretion, 2 carboxyls) but when dosage is the about 7g iodine of maximum dosis tolerata/patient 70kg, accumulation in liver has only 15HU (Huebner, K.H.: the CT density measure of liver, spleen and kidney behind the intravenous group notes liver contrast agent.Radiology progress (Fortschr.Roentgenstr.) 129,289-297 (1978)).
Therefore comparatively speaking: the gadolinium (each molecule only contains 1 gadolinium ion) with about 3.5g composite form can obtain much higher times lonizing radiation absorption than the 7g iodine of the 25g iodine of using SH L 433 (formula XI) or Iotroxinat in the people liver, although these two kinds of contrast agent are hexaiodizated chemical compound.Embodiment 7 prepares following solution:
0.1mol 3,6,9-three azepines-3,6, the holmium (II) of 9-three-(carboxyl methyl)-4-(4-butyl benzyl)-heneicosanedioic acid-complex two Mai Geluming salt;
0.005mol 3,6,9-three azepines-3,6, the holmium (II) of 9-three-(carboxyl methyl)-4-(4-butyl benzyl)-heneicosanedioic acid-complex wheat, barley and highland barley Ge Luming salt, in 1 liter of 5% mannose solution, pH7.0.
This solution is injected in 30 minutes with the dosage of 0.3mmol/kg body weight.Before the injection, when injection finishes and injection carried out CT scan with usual manner in 30 minutes after finishing.Embodiment 8
With 3,6,9-three azepines-3,6, the metal ion of 9-three-(carboxyl methyl)-4-(4-ethoxy benzyl)-heneicosanedioic acid disodium salt and various absorption lonizing radiation is compound, and the water mould is measured the density value of each reagent under various concentration then, because should measure corresponding to the Intraabdominal density value of the mankind.Measurement is to carry out under the voltage 137kV of routine and 110mA with CT machine commonly used.Table 4
CT value result (HU ± SD)
| Element | Concentration (mmol/L) | ????HU±SD |
| ????H 2O | ?????- | ????14???23 |
| ????Gd | ????50 ????500 | ????218????23 ????1680???33 |
| ????Tb | ????50 ????500 | ????228????25 ????1760???45 |
| ????Dy | ????50 ????500 | ????226????23 ????1840???42 |
| ????Ho | ????50 ????500 | ????221????29 ????1890???40 |
| ????Er | ????50 ????500 | ????254????24 ????1955???57 |
| ????Yb | ????50 ????500 | ????252????18 ????1980???42 |
| ????J | ????50 ????500 | ????110????25 ????914????27 |
Compare with iodine, rare earth metal has amazing high effect, and it perhaps can be owing to formed special measuring condition in the abdominal CT.In the scope of lanthanide series, element gadolinium that erbium, an an ancient unit of weight equal to 20 or 24 *taels of silver and holmium are better than often being studied up to now and dysprosium.Embodiment 9 processs of the test
15 examples are clearly had inject 0.2,0.35 and the Gd-EOB-DTPA (embodiment 6) back 10 minutes, 60 minutes of 0.5mmol/kg and (N=5) carried out the Hepatic CT inspection in 120 minutes in the venous patient of hepatic metastases tumor.
With Gd-EOB-DTPA (0.25mmol/L) intravenous drip Filling Pipe intravenous.0.2 and inject time of 0.35mmol/kg dosage is that 20 minutes, maximum dose level 0.5mmol/kg are 30 minutes.
Patient confirms that through the histology primary tumo(u)r (the N=9 example has colorectal carcinoma, N=2 example to have intestinal cancer, N=1 example to have gastric cancer, N=1 example to have leiomyosarcoma, N=1 example that Ovarian Cystadenocarcinoma is arranged) is arranged, and metastatic tumor (N≤5 examples) confirmed through contrast agent enhanced CT with interior in the previous moon of Gd-EOB-DTPA research.Patient's exclusion standard is: the age was less than 18 years old, the medical history that occurs serious side effects or anaphylaxis side effect behind the injection of contrast medium is arranged, used Gd-EOB-DTPA in advance, study in preceding 24 hours at this and to use contrast agent, transplant organ is arranged, women before menopause, before this research or underwent surgery or needle biopsy of liver in later 24 hours, patient's analysis data obvious deviation is in normally.
Before intravenous injection Gd-EOB-DTPA,, carry out CT examination with Siemens Company-spiral-CT machine with injection back 10 minutes, 60 minutes, (N=5) 120 minutes.20-30 measures whole liver in second when respiratory standstill.The bed spacing is that 8mm/ second, bed thickness are 8mm.By two irrelevant observers contrast the forward and backward image of radiography in quality (fabulous, good, medium, slightly, do not have to take on a new look) and quantitatively (measurement CT value) assess.
Toleration to Gd-EOB-DTPA records by checking ordinary circumstance, record vital index and assay hematuria index.The result
After vein injects Gd-EOB-DTPA, find that increasing of normal liver CT value is relevant with dosage.Fig. 1 shows the time graph that confirms patient's interior CT value of liver behind start injection 0.2 (o), 0.35 (◆) and 0.5 (A) mmol/kg Gd-EOB-DTPA of primary tumo(u)r through the histology.The CT value of hepatic metastases tumor is with symbol
Expression.
The CT value of hepatic metastases tumor does not change.Shown gallbladder and bile duct in addition.
Being presented at of hepatic metastases tumor all is improved after the Gd-EOB-DTPA that respectively organizes dosage injects, and is fabulous in two high dosage groups.Average 2 prior undiscovered metastatic tumors have been found with increasing again behind the maximum dose level.The mean size of the minimum metastatic tumor of being found also correspondingly is decreased to 16.6mm by 20.3mm.Find the focus of a prior undiscovered diameter 7mm behind the patient injection Gd-EOB-DTPA of one routine known right lobe of liver metastatic tumor again at leftlobe of liver.
The general toleration of Gd-EOB-DTPA is good.Only observe 4 lighter be medium side effect.2 routine patients tell the burn feeling of injection site or continue to disappear after several seconds or a few minutes.Nauseating, epigastrium tenderness that other side effect has.Laboratory values is analyzed Non Apparent Abnormality.3 routine patients find to have amino transaminase of aspartic acid and phenylalanine ammonia transaminase's slight rising but perhaps this be due to the hepatic metastases tumor.
In a word, Gd-EOB-DTPA is the good effective liver and gall CT contrast agent of a kind of toleration.
Claims (11)
1. the application of the chelate of general formula I
Wherein, X is that a hydrogen atom or atomic number are 44-51 or 56-83 independently of each other
A metal ion equivalent of element, R
1One of be formula-CH
2-C
6H
4-(O) r-R
2A residue, wherein aromatic rings can adjacent, or right
The position is substituted, and another R
1Residue is a hydrogen atom, R
2Be a hydrocarbon, it by 1-6 carbon atom and 0-2 oxygen atom form, a benzene
Base or benzyl or hydrogen atom r be digital 0 or 1, wherein carboxyl also can be the amide form, they are with being the cation that reaches the required in case of necessity physiological tolerance of charge balance, be applied to medical diagnosis, it is characterized by: they are used for the CT diagnostic method of liver and biliary tract.
2. according to the application of the chelate of claim 1, it is characterized by: compound metal is a group of the lanthanides atom.
3. according to the application of the chelate of claim 1 and 2, it is characterized by: compound metal is cerium, praseodymium, gadolinium, dysprosium, holmium, erbium, an an ancient unit of weight equal to 20 or 24 *taels of silver or lutecium.
4. according to the application of the chelate of claim 1, it is characterized by: compound metal is hafnium, bismuth or lead.
5. according to the application of the chelate of claim 1, it is characterized by: the cation of at least one physiological tolerance is Na
+, Ca
2+, Mg
2+Or organic base meglumin, glycosamine, arginine, ornithine, lysine, 2-amino-1,3, a cation of 4-butantriol and ethanolamine.
6. according to the application of the chelate of claim 1, it is characterized by: r is 0.
7. according to the application of the chelate of claim 1, it is characterized by: r is 1.
8. according to the application of the chelate of claim 1, it is characterized by: R
2Be methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, phenyl or benzyl.
9. according to the application of the chelate of claim 1, it is characterized by: R
1In neighbour-position or right-position.
10. according to the application of the chelate of claim 1, it is characterized by: chelate is 3,6,9-three azepines-3,6, gadolinium (III) complex of 9-three (carboxyl methyl)-4-(4-ethyoxyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, an an ancient unit of weight equal to 20 or 24 *taels of silver (III) complex of 9-three (carboxyl methyl)-4-(4-ethyoxyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, praseodymium (III) complex of 9-three (carboxyl methyl)-4-(4-ethyoxyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, lutecium (III) complex of 9-three (carboxyl methyl)-4-(4-ethyoxyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, cerium (III) complex of 9-three (carboxyl methyl)-4-(4-ethyoxyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, hafnium (IV) complex of 9-three (carboxyl methyl)-4-(4-ethyoxyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, bismuth (III) complex of 9-three (carboxyl methyl)-4-(4-ethyoxyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6,9-three (carboxyl methyl)-5-{4-[2-(2-ethoxy ethoxy)-ethyoxyl]-benzyl)-an ancient unit of weight equal to 20 or 24 *taels of silver complex of heneicosanedioic acid, 3,6,9-three azepines-3,6, lead (II) complex or 3 of 9-three (carboxyl methyl)-4-(4-ethyoxyl-benzyl)-heneicosanedioic acid, 6,9-three azepines-3,6, an an ancient unit of weight equal to 20 or 24 *taels of silver (III) complex of 9-three (carboxyl methyl)-4-(2-ethyoxyl-benzyl)-heneicosanedioic acid.
11. according to the application of the chelate of claim 1, it is characterized by: chelate is 3,6,9-three azepines-3,6, gadolinium (III) complex of 9-three (carboxyl methyl)-4-(4-butyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, an an ancient unit of weight equal to 20 or 24 *taels of silver (III) complex of 9-three (carboxyl methyl)-4-(4-butyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, praseodymium (III) complex of 9-three (carboxyl methyl)-4-(4-butyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, lutecium (III) complex of 9-three (carboxyl methyl)-4-(4-butyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, hafnium (IV) complex of 9-three (carboxyl methyl)-4-(4-butyl-benzyl)-heneicosanedioic acid, 3,6,9-three azepines-3,6, bismuth (III) complex of 9-three (carboxyl methyl)-4-(4-butyl-benzyl)-heneicosanedioic acid, or 3,6,9-three azepines-3,6, lead (II) complex of 9-three (carboxyl methyl)-4-(4-butyl-benzyl)-heneicosanedioic acid.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US35108694A | 1994-11-30 | 1994-11-30 | |
| US08/351,086 | 1994-11-30 | ||
| US38740895A | 1995-02-13 | 1995-02-13 | |
| US08/387,408 | 1995-02-13 | ||
| US48056695A | 1995-06-07 | 1995-06-07 | |
| US08/480,566 | 1995-06-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1167443A true CN1167443A (en) | 1997-12-10 |
Family
ID=27407981
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95196523A Pending CN1167443A (en) | 1994-11-30 | 1995-11-20 | Use of metal complexes as liver and gall bladder radiodiagnosis agents in computer tomography |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0794800A1 (en) |
| JP (1) | JPH10509734A (en) |
| CN (1) | CN1167443A (en) |
| AU (1) | AU4173896A (en) |
| CA (1) | CA2206558A1 (en) |
| CZ (1) | CZ166797A3 (en) |
| FI (1) | FI972285A (en) |
| HU (1) | HUT77553A (en) |
| IL (1) | IL116207A0 (en) |
| NO (1) | NO972458L (en) |
| PL (1) | PL320482A1 (en) |
| SK (1) | SK68897A3 (en) |
| WO (1) | WO1996016678A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106163571A (en) * | 2014-02-18 | 2016-11-23 | 麦迪西斯医药公司 | Reverse micelle system is for delivering the purposes of the chelating agen of radionuclide and metal |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6117412A (en) * | 1995-01-26 | 2000-09-12 | Nycomed Imaging As | Non-cluster type bismuth compounds |
| GB9501560D0 (en) * | 1995-01-26 | 1995-03-15 | Nycomed Imaging As | Contrast agents |
| EP0885616A1 (en) * | 1997-06-20 | 1998-12-23 | Schering Aktiengesellschaft | Use of intravenous contrast agents, and apparatus for projectionsmammography |
| SG186259A1 (en) * | 2010-06-11 | 2013-01-30 | Bayer Ip Gmbh | Process for preparing crystalline 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioic acid and use for production of primovist® |
| JP2012254973A (en) * | 2011-05-18 | 2012-12-27 | Sumitomo Chemical Co Ltd | Aliphatic amine-coordinated cerium complex and device containing the complex |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3922005A1 (en) * | 1989-06-30 | 1991-01-10 | Schering Ag | DERIVATIVED DTPA COMPLEXES, PHARMACEUTICAL AGENTS CONTAINING THESE COMPOUNDS, THEIR USE AND METHOD FOR THE PRODUCTION THEREOF |
| DE4011684A1 (en) * | 1990-04-06 | 1991-10-10 | Schering Ag | DTPA MONOAMIDES, PHARMACEUTICAL AGENTS CONTAINING THESE COMPOUNDS, THEIR USE AND METHOD FOR THE PRODUCTION THEREOF |
| GB9122984D0 (en) * | 1991-10-30 | 1991-12-18 | Salutar Inc | Contrast media |
-
1995
- 1995-11-20 HU HU9800178A patent/HUT77553A/en unknown
- 1995-11-20 WO PCT/EP1995/004547 patent/WO1996016678A1/en not_active Application Discontinuation
- 1995-11-20 PL PL95320482A patent/PL320482A1/en unknown
- 1995-11-20 CN CN95196523A patent/CN1167443A/en active Pending
- 1995-11-20 CA CA002206558A patent/CA2206558A1/en not_active Abandoned
- 1995-11-20 CZ CZ971667A patent/CZ166797A3/en unknown
- 1995-11-20 AU AU41738/96A patent/AU4173896A/en not_active Abandoned
- 1995-11-20 EP EP95940207A patent/EP0794800A1/en not_active Withdrawn
- 1995-11-20 JP JP8517855A patent/JPH10509734A/en active Pending
- 1995-11-20 SK SK688-97A patent/SK68897A3/en unknown
- 1995-11-30 IL IL11620795A patent/IL116207A0/en unknown
-
1997
- 1997-05-29 NO NO972458A patent/NO972458L/en not_active Application Discontinuation
- 1997-05-29 FI FI972285A patent/FI972285A/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106163571A (en) * | 2014-02-18 | 2016-11-23 | 麦迪西斯医药公司 | Reverse micelle system is for delivering the purposes of the chelating agen of radionuclide and metal |
| CN106163571B (en) * | 2014-02-18 | 2020-10-16 | 麦迪西斯医药公司 | Use of reverse micelle systems for delivery of chelators of radionuclides and metals |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0794800A1 (en) | 1997-09-17 |
| NO972458D0 (en) | 1997-05-29 |
| NO972458L (en) | 1997-05-29 |
| HUT77553A (en) | 1998-05-28 |
| WO1996016678A1 (en) | 1996-06-06 |
| CA2206558A1 (en) | 1996-06-06 |
| FI972285A0 (en) | 1997-05-29 |
| JPH10509734A (en) | 1998-09-22 |
| AU4173896A (en) | 1996-06-19 |
| SK68897A3 (en) | 1998-10-07 |
| CZ166797A3 (en) | 1997-11-12 |
| PL320482A1 (en) | 1997-09-29 |
| MX9703974A (en) | 1997-09-30 |
| FI972285A (en) | 1997-05-29 |
| IL116207A0 (en) | 1996-01-31 |
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