CN1103588C - Calcium complex of 4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedioic acid and is salts, pharmaceutical agents containing these complexes - Google Patents
Calcium complex of 4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedioic acid and is salts, pharmaceutical agents containing these complexes Download PDFInfo
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- CN1103588C CN1103588C CN 95106015 CN95106015A CN1103588C CN 1103588 C CN1103588 C CN 1103588C CN 95106015 CN95106015 CN 95106015 CN 95106015 A CN95106015 A CN 95106015A CN 1103588 C CN1103588 C CN 1103588C
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Abstract
The present invention relates to a complex of 4-(4-ethoxy-benzyl)-3,6,9-three (carboxyl methyl)-3,6,9- n-aza-2 11 3 calcium and salt, the medicament containing the Complex, the medicament of the preparation which is used to decrease the role caused by heavy metal ,and the method of the preparation.
Description
The present invention relates to contain 4-(4-ethoxy benzyl)-3,6,9-three (hydroxylation methyl)-3,6, the calcium composition of 9-three azepine heneicosanedioic acids or the medicine of its salt.
In medicine, various coordination compounies are diagnosed the medicine of usefulness especially for treating heavy metal poisoning, iron deficiency disease and being used to prepare develop.
In EP71564, described and used the contrast agent of Mai Geluming (meglumine) salt of diethylene-triamine pentaacetic acid (DTPA) gadolinium (III) coordination compound as the NMR tomographic.The preparation that contains this complex that commodity are called Magnevist (R) has obtained the approval in the global range as a NMR contrast agent.This contrast agent disperses in the extracellular after intravenous injection, and is discharged by kidney through the glomerule secretion.In fact do not observe by complete cell membrane.Magnevist
, be best suited for the visualization of pathogenic site (for example inflammation, tumor).
The chemical compound that contains DTPA or Ca-DTPA also is used for metal poisoning clinically.Iron complex is generally used for iron deficiency anemia, and the radiosiotope coordination compound (for example
99mTc-DT-PA) be used for scintigraphy.
When as NMR and X radiodiagnosis x contrast agent, the EP405704 suggestion, these chemical compounds are discharged outside kidney, thereby are suitable for liver, gallbladder and gastrointestinal imaging art.
These known coordination compounds and salt thereof can cause the problem of the compatibility and/or matching object internal stability in its clinical practice.Up to now can't be advantageously with the composition of heavy metal element itself, because the compatibility of these chemical compounds is not satisfied as Baryan.For the paramagnetic meterial of up to the present being advised and be used to examine the rotation tomographic, the gap of its effective dose in animal experiment and toxicity dose is smaller.
Therefore, needs can reduce the medicine by the influence that heavy metal caused.
The objective of the invention is to prepare this chemical compound and medicine effectively, and its preparation method is provided.Theme by characterization in claims can reach this purpose.
Have been found that 4-(4-ethoxy benzyl)-3,6,9-three (carboxylation methyl)-3,6, the calcium composition (Ca-EOB-DTPA) and the salt thereof of 9-three azepine heneicosanedioic acids are particularly useful for making the medicine that can reduce the influence that is caused by heavy metal.Especially, Ca-EOB-DTPA is suitable for removing sedimentary heavy metal in the liver.
Term EOB-DTPA can use following synonym, and promptly various enantiomer (4S or 4R) form or its any mixture.
Ca-EOB-DTPA can unexpectedly eliminate metal deposition, for example behind heavy metal poisoning in body, particularly from liver, get rid of.As be shown in the examples, by taking the content that Ca-EOB-DTPA can reduce zinc in liver and the kidney.
Find in addition, Ca-EOB-DTPA is added to the content (referring to embodiment) that the Gd-EOB-DTPA that is used for the NMR diagnosis can reduce gadolinium in liver and the bone.Show Ca-EOB-DTPA by pharmacokinetics inspection to animal model ... with Gd-EOB-DTPA similar-unexpectedly mainly eliminated (referring to embodiment) by liver.Because the Ca-DTPA of the passive same 3 times of amounts that add does not enter liver, thereby is beat all especially.Therefore adding Ca-EOB-DTPA has also quantitatively eliminated non-complex bound gadolinium from liver.
Therefore, the present invention relates to 4-(4-ethoxy benzyl)-3,6,9-three (carboxylation methyl)-3,6, inorganic and/or the organic cations salt that the calcium composition of 9-three azepine heneicosanedioic acids and these coordination compounds are compatible with physiology, these cationes are for example sodium, potassium, Mai Geluming, ethanolamine, diethanolamine, morpholine, glycosamine, dimethyl glycosamine, lysine, arginine and/or ornithine.
The invention still further relates to Ca-EOB-DTPA and salt thereof and prepare pharmaceutical preparation, the particularly purposes of the antidote of preventing from heavy metal poisoning.The preparation The compounds of this invention
From 4-(4-ethoxy benzyl)-3,6,9-three (carboxylation methyl)-3,6,9-three azepine heneicosanedioic acid-five tertiary butyl ester [as described in EP405704A1 (embodiment 8)] begin to prepare The compounds of this invention.
At first with this five-ester and the free complexant of trifluoroacetic acid prepared in reaction.Prepare coordination compound of the present invention according to disclosed method in EP71564, EP130934 and the DE-OS3401052 patent specification from this complexant.
By this complexant being converted into calcium composition (CaEOB-DTPA) with the aqua calcis reaction.Then, if desired, the hydrogen atom on the existing acidic group is replaced with inorganic and/or organic base or aminoacid.
In this case, with inorganic base (for example hydroxide, carbonate or bicarbonate) as sodium, potassium or lithium salts and/or organic base as primary, the second month in a season and tertiary amine (for example ethanolamine, glycosamine, N-methyl-and N, N-dimethyl glycosamine) and basic amino acid such as lysine, arginine and ornithine neutralize.
Because this coordination compound contains 3 free acidic groups, it can form and not only contain inorganic cation, but also contains the neutral salt-mixture of organic cation as counter ion counterionsl gegenions.
Can realize this purpose by for example following method, being about to this complexant reacts with calcium oxide or calcium salt in water slurry or solution, obtain the oxide or the salt of required element, required organic base neutralization with 1/3 or 2/3 amount, separate formed coordination salt, at random carry out purification, mix with the inorganic base of aequum then, with neutralization fully.The order that adds alkali also can be conversely.
Calcium composition by Gd-EOB-DTPA and DTPA reacts at elevated temperatures, can prepare the mixture of being made up of Ca-EOB-DTPA and Gd-EOB-DTPA.By cooperating again, can obtain the mixture of required Ca-EOB-DTPA coordination compound and Gd-EOB-DTPA.Also can carry out above-mentioned neutralization in the method.
Can prepare medicine of the present invention according to methods known in the art, be about to coordination compound of the present invention-at random add galenical additive commonly used-suspend or be dissolved in the water-bearing media, then at random with this suspension or solution sterilization.The additive that is fit to is harmless buffer (for example trimethylamine), electrolyte (for example sodium chloride) and an antioxidant (for example ascorbic acid) on the physiology for example.
If the suspension of medicine of the present invention or solution need be that intestinal is taken or be used for the aqueous solution or the physiological solt solution of other purposes, adjuvant then that itself and one or more galenicals are commonly used mixes, and these adjuvant are methylcellulose, lactose or mannitol and/or surfactant (for example lecithin, tweens for example
(R)Or Myri
(R)) and/or improve the flavoring substance (for example essential oil) of the sense of taste.
In principle even can not separate this coordination salt, promptly prepare medicine of the present invention.But must take concrete protection to guarantee chelating, in salt of the present invention and saline solution, in fact just not have the not complexed metal ion of toxic action like this.
Medicine of the present invention contains 1 μ mol/l-1mol/l coordination salt, preferred 0.5mmol/l-250mmol/l, and general dosage is the 0.005-2mmol/kg body weight, preferred 50 μ mol/kg-500 μ mol/kg.This medicine is used through intestinal and non-intestinal.
Therefore, the invention still further relates to the above-mentioned preparation method of these chemical compounds and medicine.
The following example is used for explaining in more detail purpose of the present invention.
Embodiment prepares 4-(4-ethoxy benzyl)-3,6,9-three (carboxylation methyl)-3,6,9-three azepine heneicosanedioic acid calcium composition trisodium salt method 1a) 4-(4-ethoxy benzyl)-3,6,9-three (carboxylation methyl)-3,6,9-three azepine heneicosanedioic acids
With 3.64g 4-(4-ethoxy benzyl)-3,6,9-three (carboxylation methyl)-3,6,9-three azepine heneicosanedioic acid-five tertiary butyl ester (its preparation method referring to EP0405704A2, Schering AG, Berlin, embodiment 8a) are dissolved in the 25ml trifluoroacetic acid.It stirring at room 1 hour, is mixed with the 150ml ether, and suction strainer goes out precipitation.Should precipitate in 40 ℃ of vacuum dryings, and then it was dissolved in the 200ml water, and stir 15 minutes with 2g anionite Amberlite IRA 67.With its filtration, and this solution stirred 30 minutes with the 0.5g active carbon.Leach active carbon, its lyophilizing 3 times to remove remaining trifluoroacetic acid, is obtained the 1.2g required compound, be white powder.
Analyze (with respect to anhydrous substances):
Value of calculation: C52.36% H6.31% N7.97%
Measured value: 4-(4-ethoxy benzyl)-3,6 C52.21% H6.39% N7.84%b), 9-three (carboxylation methyl)-3,6,9-three azepine heneicosanedioic acid calcium composition trisodium salts
With 4.22g 4-(4-ethoxy benzyl)-3,6,9-three (carboxylation methyl)-3,6,9-three azepine heneicosanedioic acids (8mmol) mix with 0.59g (8mmol) calcium hydroxide in 100ml water.Stirred 15 minutes, and simultaneously it was mixed with 24ml 1N sodium hydroxide solution.Gained solution is filtered to remove a small amount of suspended material, lyophilizing then through film filter.Obtain the required compound of 4.9g white powder, wherein water content is 9.4%.
Analyze (with respect to anhydrous substances): value of calculation: C 43.74% H 4.47% Ca 6.35% N 6.65% Na 10.92% measured value: C 43.91% H 4.60% Ca 6.27% N 6.61% Na 10.62%
Fusing point: still do not melt to 300 ℃ of these coordination compounds.
Specific rotatory power: [α]
D=+7.2 ° of (c=1.0 is in methanol) c) 4-(4-ethoxy benzyl)-3,6,9-three (carboxylation methyl)-3,6,9-three azepine heneicosanedioic acid calcium composition Mai Geluming salt
If the sodium hydroxide solution with among the 24ml 1N methylglucosamine solution replacement embodiment b then can obtain corresponding wheat, barley and highland barley Ge Luming salt.Method 2
Another kind method is from 4-(4-ethoxy benzyl)-3,6,9-three (carboxylation methyl)-3,6,9-three azepine heneicosanedioic acid-five tertiary butyl ester begin, in the method, do not separate part 4-(4-ethoxy benzyl)-3,6,9-three (carboxylation methyl)-3,6,9-three azepine heneicosanedioic acids, but in solution, similarly it further is converted into 4-(4-ethoxy benzyl)-3,6,9-three (carboxylation methyl)-3,6,9-three azepine heneicosanedioic acid calcium composition trisodium salts:
With 21.4g (26.5mmol) 4-(4-ethoxy benzyl)-3,6,9-three (carboxylation methyl)-3,6, the solution of 9-three azepine heneicosanedioic acid-five tertiary butyl ester in 150ml methanol refluxed 5 hours with 16ml 15N sodium hydroxide solution.
Vacuum is removed methanol on rotary evaporator, mixes with 190ml water, under agitation adds the cationite IR-120 of q.s in batches, reaches 3.0 up to pH.Leach ion-exchanger, wash this residue and purification filtrate with water.
With the 4-(4-ethoxy benzyl)-3,6 that so obtains, 9-three (carboxylation methyl)-3,6,9-three azepine heneicosanedioic acid-sodium salt solutions mix with the 1.96g calcium hydroxide, by adding 40% sodium hydroxide solution PH are transferred to 10.2.In room temperature this solution was stirred 1 hour with active carbon, use nitrocellulose filter (0.2 μ m) to filter then.
After the lyophilizing, obtain 17.84g 4-(4-ethoxy benzyl)-3,6,9-three (carboxylation methyl)-3,6, the trisodium salt of 9-three azepine heneicosanedioic acid calcium compositions is white powder, wherein water content is 7.5%.
Other analytical data are consistent with the value of first method.
The method for preparing Gd-EOB-DTPA and Ca-EOB-DTPA mixture
With 20ml 250 μ mol/ml (5000 μ mol) Gd-EOB-DTPA aqueous solution and 20ml1 μ mol/ml (20 μ mol) CaNa
3-DTPA aqueous solution.121 ℃ of heat treated after 20 minutes, observe in 20 μ mol Ca-EOB-DTPA, 4980 μ mol Gd-EOB-DTPA and 20 μ mol Gd-DTPA standard and finished again and cooperate.
The following example is the specific embodiment of this noval chemical compound model of action.
Pharmacokinetics: give male rat intravenous injection 25 μ mol/kg dosage
14The Ca-EOB-DTPA/Na of C-labelling
3Measure concentration in each organ blood back 24 hours of injection at different time.In another treated animal, measure the amount of discharging in maximum 7 days urine of peritoneal injection and the excrement respectively.
Concentration in the blood descends rapidly, and its half-life is 8 minutes.0.45L/kg volume of distribution show and accumulate in the cell, may be in hepatocyte.
After the medication 24 hours, have only 4.2% dosage to keep in vivo, and the value in the kidney regulating liver-QI is the highest.
From excrement, get rid of 2/3 dosage, in urine, collected 1/3.
The value that is observed closely similar or in fact consistent (G.schuhmann-Giampieri, H.schmitt-Willich, W.-R.press, C.Negishi, H.-J.Qeinmann, and U.Speck, Radiolgy, 1992,183,59) with the Gd coordination compound.
Reduce concentration of metal in the organism by intravenous injection Ca-EOB-DTPA:
The example of zinc
Dosage with 200 μ mol/kg is given male rat intravenous injection Ca-EOB-DT-PA/Na
3Aqueous solution was measured zinc concentration in liver and the kidney by ICP-AES after 2 days.Organ concentration Zn
[μ mol/g] liver injection preceding 5.3
4.4 kidneys injection preceding 0.9 behind the injection Ca-EOB-DTPA
0.5 injection Ca-EOB-DTPA/Na behind the injection Ca-EOB-DTPA
3Reduced the metal concentration of zinc in liver and the kidney.
In this regard, known antidote Ca-DTPA/Na
3Be invalid, because this material does not pass through hepatocyte.
By in the NMR contrast agent, adding the example that Ca-EOB-DTPA reduces concentration of metal: Gd-EOB-DTPA in the organism
Dosage with 250 μ mol/kg is given male rat intravenous injection Gd-EOB-DT-PA/Na
2Aqueous solution (solution A, B, C, D) is measured the concentration of Gd in the bone regulating liver-QI by ICP-AES after 7 days.Solution A does not contain any additives, and has added the Ca-EOB-DTPA/Na of variable concentrations among B, C, the D
3
Solution A: 0mg/ml
Solution B: 0.1mg/ml
Solution C: 0.5mg/ml
Solution D: 1.0mg/mlGd content A B C D[nmol/g] liver 1.12 ± 0.014 1.14 ± 0.028 0.90 ± 0.13 0.79 ± 0.15 bone 1.51 ± 0.08 1.39 ± 0.13 1.04 ± 0.12 0.67 ± 0.09
By adding the Ca coordination compound, obviously reduced the concentration of Gd in liver and the bone.
This discovery is very favorable because in organism last more a spot of Gd also can cause the incompatibility reaction.Because new Ca coordination compound has in fact also unexpectedly entered hepatocyte simultaneously, thereby can guarantee that the influence that will may disengage Gd from coordination compound reduces to minimum.
Ca-EOB-DTPA has improved the elimination speed of Gd-EOB-DTPA, and can reduce the organism toxicosis concentration of metal.
Claims (2)
1. contain 4-(4-ethoxy benzyl)-3,6,9-three (carboxylation methyl)-3,6,9-three azepine heneicosanedioic acid calcium compositions and the medicine that contains the galenical typical additives arbitrarily.
2. contain 4-(4-ethoxy benzyl)-3,6,9-three (carboxylation methyl)-3,6,9-three azepine heneicosanedioic acid calcium compositions and at least a following cationic salt and contain the medicine of galenical typical additives arbitrarily, these cationes are sodium, potassium, Mai Geluming, ethanolamine, diethanolamine, morpholine, glycosamine, dimethyl glycosamine, lysine, arginine or ornithine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4446712 | 1994-12-16 | ||
| DEP4446712.5 | 1994-12-16 |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 00118470 Division CN1293067A (en) | 1994-12-16 | 2000-06-30 | Use of 4-(4-ethoxybenzyl)-3,6,9-tri(carboxymethyl)-3,6,9-triazohendecanedioic acid calcium composition |
| CN 00118469 Division CN1293036A (en) | 1994-12-16 | 2000-06-30 | Use of 4-(4-ethoxygenzyl)-3,6,9-tri(carboxymethyl)-3,6,9-triazohendecanedioic acid calcium composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1124731A CN1124731A (en) | 1996-06-19 |
| CN1103588C true CN1103588C (en) | 2003-03-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 95106015 Expired - Fee Related CN1103588C (en) | 1994-12-16 | 1995-05-08 | Calcium complex of 4-(4-ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedioic acid and is salts, pharmaceutical agents containing these complexes |
| CN 00118469 Pending CN1293036A (en) | 1994-12-16 | 2000-06-30 | Use of 4-(4-ethoxygenzyl)-3,6,9-tri(carboxymethyl)-3,6,9-triazohendecanedioic acid calcium composition |
| CN 00118470 Pending CN1293067A (en) | 1994-12-16 | 2000-06-30 | Use of 4-(4-ethoxybenzyl)-3,6,9-tri(carboxymethyl)-3,6,9-triazohendecanedioic acid calcium composition |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 00118469 Pending CN1293036A (en) | 1994-12-16 | 2000-06-30 | Use of 4-(4-ethoxygenzyl)-3,6,9-tri(carboxymethyl)-3,6,9-triazohendecanedioic acid calcium composition |
| CN 00118470 Pending CN1293067A (en) | 1994-12-16 | 2000-06-30 | Use of 4-(4-ethoxybenzyl)-3,6,9-tri(carboxymethyl)-3,6,9-triazohendecanedioic acid calcium composition |
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| SA (1) | SA97180170A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1058722C (en) * | 1998-12-29 | 2000-11-22 | 四川省天然药物研究所 | Method for preparing one new compound and its use as oral heavy metal excretion promoter |
| CN115043747B (en) * | 2022-08-15 | 2022-11-25 | 康瑞鑫(天津)药物研究院有限公司 | Crystallization method of trisodium caronate and prepared trisodium caronate crystals |
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1995
- 1995-05-08 CN CN 95106015 patent/CN1103588C/en not_active Expired - Fee Related
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- 1997-06-25 SA SA97180170A patent/SA97180170A/en unknown
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| CN1293036A (en) | 2001-05-02 |
| CN1293067A (en) | 2001-05-02 |
| CN1124731A (en) | 1996-06-19 |
| SA97180170A (en) | 2005-12-03 |
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