DE2405652C3 - 3,6,9-trioxaundecane-1,11 -dioyl-bis- (3-carboxy-2,4,6-triiodo-anilide), its salts with physiologically acceptable bases, processes for the preparation of these compounds and X-ray contrast media containing these compounds - Google Patents
3,6,9-trioxaundecane-1,11 -dioyl-bis- (3-carboxy-2,4,6-triiodo-anilide), its salts with physiologically acceptable bases, processes for the preparation of these compounds and X-ray contrast media containing these compoundsInfo
- Publication number
- DE2405652C3 DE2405652C3 DE19742405652 DE2405652A DE2405652C3 DE 2405652 C3 DE2405652 C3 DE 2405652C3 DE 19742405652 DE19742405652 DE 19742405652 DE 2405652 A DE2405652 A DE 2405652A DE 2405652 C3 DE2405652 C3 DE 2405652C3
- Authority
- DE
- Germany
- Prior art keywords
- triiodo
- anilide
- carboxy
- bis
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 239000011780 sodium chloride Substances 0.000 title claims description 13
- 150000001875 compounds Chemical class 0.000 title claims description 11
- 150000003839 salts Chemical class 0.000 title claims description 10
- 239000002872 contrast media Substances 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 5
- 238000000034 method Methods 0.000 title claims description 4
- 229940039231 CONTRAST MEDIA Drugs 0.000 title description 3
- MBBZMMPHUWSWHV-BDVNFPICSA-N Meglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- QMQFFHSJUJDRPG-UHFFFAOYSA-N 3-amino-2,4,6-triiodobenzoic acid Chemical compound NC1=C(I)C=C(I)C(C(O)=O)=C1I QMQFFHSJUJDRPG-UHFFFAOYSA-N 0.000 claims description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 210000000941 Bile Anatomy 0.000 description 6
- -1 amine salts Chemical class 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 239000012266 salt solution Substances 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- RKXVBWUJVGVUDT-UHFFFAOYSA-N 2-[2-[2-(2-chloro-2-oxoethoxy)ethoxy]ethoxy]acetyl chloride Chemical compound ClC(=O)COCCOCCOCC(Cl)=O RKXVBWUJVGVUDT-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- FFINMCNLQNTKLU-UHFFFAOYSA-N Adipiodone Chemical compound OC(=O)C1=C(I)C=C(I)C(NC(=O)CCCCC(=O)NC=2C(=C(C(O)=O)C(I)=CC=2I)I)=C1I FFINMCNLQNTKLU-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N Chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 101700076507 DBP9 Proteins 0.000 description 2
- 230000036826 Excretion Effects 0.000 description 2
- 229940029355 Iodipamide Drugs 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 229960002072 adipiodone Drugs 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000012154 double-distilled water Substances 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N Diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 230000036081 Excretion rate Effects 0.000 description 1
- 206010019670 Hepatic function abnormal Diseases 0.000 description 1
- HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium Ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 description 1
- 210000004185 Liver Anatomy 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 210000002700 Urine Anatomy 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000007374 clinical diagnostic method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 229940009662 edetate Drugs 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001575 pathological Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000630 rising Effects 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 1
- 231100000730 tolerability Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Description
Die Erfindung betrilft 3,6,9-Trioxaundecan-l,l 1-dioyl-bis-(3-carboxy-2,4,6-trijod-anilid), dessen Salze mit physiologiscli verträglichen Basen, ein Verfahren zur Herstellung dieser Verbindungen und diese enthaltende Röntgenkontrastmittel gemäß den vorstehenden Ansprüchen.The invention relates to 3,6,9-trioxaundecane-l, l 1-dioyl-bis- (3-carboxy-2,4,6-triiodo-anilide), its salts with physiologically compatible bases, a process for the preparation of these compounds and X-ray contrast media containing them according to the above Claims.
Als Salze mit physiologisch verträglichen Basen kommen sowohl Metallsalze, wie vorzugsweise Natriumsalze sowie Lithium- und Magnesiumsalze, als auch Aminsalze, vorzugsweise Glucamin-, N-Methylglucamin-, Ν,Ν-Dimethylglucamin-, Alhanolamin-, Diälhanolamin- oder Morpholinsalze, in Betracht. Es können auch Mischungen der Salze eingesetzt werden.The salts with physiologically compatible bases are both metal salts and, preferably, sodium salts as well as lithium and magnesium salts, as well as amine salts, preferably glucamine, N-methylglucamine, Ν, Ν-dimethylglucamine, alhanolamine, Diethanolamine or morpholine salts into consideration. Mixtures of the salts can also be used will.
Die Salze sollen vorzugsweise als parenterale Gallenkontrastmittel verwendet werden.The salts are preferably intended as parenteral bile contrast agents be used.
Unter den zahlreichen, bisher für die intravenöse Cholegraphie bekannten' Verbindungen haben ausschließlich Vertreter folgender Formel eine praktische Bedeutung erlangt:Among the numerous 'previously known for intravenous cholegraphy' compounds, exclusively Representatives of the following formula gained practical importance:
COOHCOOH
COOHCOOH
NH- CO- X — CO— NHNH-CO-X-CO-NH
So sind die Verbindungen mit X — (CHj)1 (Jodipamid — DT-PS 9 36 928) und mitSo are the compounds with X - (CHj) 1 (iodipamide - DT-PS 9 36 928) and with
X = CH.-O —CHoX = CH.-O-CHo
4545
(Joglycamid — DT-PS 9 62 698) bereits seit längerer Zeit im Handel.(Joglycamid - DT-PS 9 62 698) has been in the trade for a long time.
Weitere Vertreter der allgemeinen Formel wurden beschrieben mitFurther representatives of the general formula were described with
X = CH2 — CH2 — (O — CH2 — CH2)3 X = CH 2 - CH 2 - (O - CH 2 - CH 2 ) 3
in der deutschen Offenlegungsschrift 19 22 578 und mitin German Offenlegungsschrift 19 22 578 and with
X = CH2 — CH2 — (O — CH2 — CH2J4 X = CH 2 - CH 2 - (O - CH 2 - CH 2 J 4
6060
in der deutschen Offenlegungsschrift 19 37 211.in German Offenlegungsschrift 19 37 211.
Das Bedürfnis nach immer gründlicherer radiologischer Diagnostik gerade beim schwergeschädigten Patienten mit eingeschränkter Leberleistung stellt hohe Anforderungen sowohl an die Verträglichkeit des Kontrastmittels, um schwere und schwerste Zwischenfälle zu vermeiden, als auch an seine Eigenschaft rasch und in hoher Konzentration durch die Leber in die Galle transportiert zu werden, um auch in pathologischen Fällen gute Aufnahmen zu ermöglichen.The need for more and more thorough radiological diagnostics, especially for the severely damaged Patients with impaired liver function make high demands both on tolerability of the contrast agent in order to avoid serious and serious incidents, as well as its property to be transported rapidly and in high concentration through the liver into the bile, in order also to be pathological Cases to allow good shots.
Es wurde nun gefunden, daß das 3,6,9-Trioxaundecan-l,ll-dioyl-bis-(3-carboxy-2,4,6-trijod-anilid) die geforderten Eigenschaften in hohem Maße in sich vereinigt. It has now been found that 3,6,9-trioxaundecane-l, ll-dioyl-bis- (3-carboxy-2,4,6-triiodo-anilide) combines the required properties to a high degree.
In den folgenden Tabellen wird die erfindungsgemäße Verbindung A mit den bekannten Verbindungen B, C, D und E verglichen.In the tables below, compound A according to the invention is compared with the known compounds B, C, D and E compared.
A: 3,6,9-Trioxaundecan-1,1 l-dioyl-bis-(3-carboxy-2.4,6-lrijod-anilid) A: 3,6,9-trioxaundecane-1,1 l-dioyl-bis- (3-carboxy-2,4,6-iriiodo-anilide)
B: 4,7,10-Trioxatridecan -1,13 - dioyl - bis - (3-(arboxy-2,4,6-trijod-anilid)
deutsche Offenlegungsschrift 19 22 578B: 4,7,10-trioxatridecane -1,13 - dioyl - bis - (3- (arboxy-2,4,6-triiodo-anilide)
German Offenlegungsschrift 19 22 578
C: 4,7,10,13 - Tetraoxahexadecan - 1,16 - dioyl - bis-(3-carboxy-2,4,6-trijod-anilid)
deutsche Offenlegungsschrift 19 37 211C: 4,7,10,13 - tetraoxahexadecane - 1,16 - dioyl - bis (3-carboxy-2,4,6-triiodo-anilide)
German Offenlegungsschrift 19 37 211
D: Adipinoyl-bis-(3-carboxy-2,4,6-trijod-anilid) (Jodipamid)
DBP 9 36 928D: adipinoyl-bis- (3-carboxy-2,4,6-triiodo-anilide) (iodipamide)
DBP 9 36 928
E: Diglycoloyl-bis-(3-carboxy-2,4,6-trijod-anilid) (Joglycamid)
DBP 9 62 698E: diglycoloyl-bis- (3-carboxy-2,4,6-triiodo-anilide) (joglycamide)
DBP 9 62 698
Toxizitiit (DL50) an der Ratte nach intravenöser Applikation der Methylglucaminsalzlösungen. Injcktionsgesclnsindigkeit 0,8 ml/min.Toxicity (DL 50 ) in rats after intravenous administration of the methylglucamine salt solutions. Injection rate 0.8 ml / min.
Verbindungconnection
-kg]-kg]
Λ
B
C
D
EΛ
B.
C.
D.
E.
10,5
8,0
8,010.5
8.0
8.0
3,5
7,53.5
7.5
Elimination der Verbindungen beim Hund nach intravenöser Injektion von Melhylglucaminsalzlösungen mit 300 mg Säure/kg.Elimination of the compounds in the dog after intravenous injection of melhylglucamine salt solutions with 300 mg acid / kg.
Verbindungconnection
Galle (°„ der Dosis)
1h 48hBile (° "of the dose)
1h 48h
Harn (% der Dosis) 48 hUrine (% of dose) 48 h
Die Daten der Tabelle 1 weisen die erfindungsgemäße Verbindung A als die am wenigstens toxische Substanz aus.The data in Table 1 indicate compound A according to the invention as the least toxic substance out.
Die Tabelle 2 zeigt, daß die erfindungsgemäße Verbindung A bezüglich der Ausscheidung über die Galle den Vergleichssubstanzen überlegen ist. Der Anteil der Ausscheidung mit der Galle und die Ausscheidungsgeschwindigkeit sind gegenüber den Vergleichssubstanzen heraufgesetzt.Table 2 shows that the compound A according to the invention with regard to excretion via the bile is superior to the comparison substances. The proportion of excretion with the bile and the excretion rate are compared to the comparison substances raised.
Die neue schattengebende Substanz A ist daher insbesondere in Form ihrer konzentrierten wäßrigen Salzlösungen als Injektionspräparat zur Darstellung der Galle geeignet.The new shading substance A is therefore particularly in the form of its concentrated aqueous Saline solutions suitable as an injection preparation for displaying the bile.
Es können Lösungen mit etwa 5 bis 45 %, vorzugsweise etwa 10 bis 30%, gebundenem Jod eingesetzt werden. Derartige Salzlösungen enthalten dementsprechend pro 100 ml etwa 10 bis 90 g, vorzugsweise 20 bis 60 g S.o^-Trioxaundecan-l.ll-dioyl-bis-ß-carboxy-2,4,6-trijod-anilid). Solutions with about 5 to 45%, preferably about 10 to 30%, bound iodine can be used will. Such salt solutions accordingly contain about 10 to 90 g, preferably per 100 ml 20 to 60 g of S.o ^ -trioxaundecane-l.ll-dioyl-bis-ß-carboxy-2,4,6-triiodo-anilide).
Die Herstellung der neuen Röntgenkontrastmittel auf Basis des 3,6!9-Tnoxaundecanl,ll-dioyl-bis-(3-carboxy-2,4,6-trijod-anilids) besteht darin, daß man das erfindungsgemäß erhaltene 3,6,9-Trioxaundecanl,ll-dioyl-bis-(3-carboxy-2,4,6-trijod-anilid) gegebenenfalls unter Salzbildung mit einer physiologisch verträglichen Base mit den in der Galenik üblichen Zusätzen in eine für die intravenöse Applikation geeignete Form bringt.The production of the new X-ray contrast media based on the 3.6 ! 9-Tnoxaundecanl, ll-dioyl-bis (3-carboxy-2,4,6-triiodo-anilide) consists in that the 3,6,9-trioxaundecanl, ll-dioyl-bis (3- carboxy-2,4,6-triiodo-anilide), optionally with salt formation with a physiologically compatible base with the additives customary in galenicals, into a form suitable for intravenous administration.
Für das erfindungsgemäße Verfahren kommen als reaküve Derivate der 3,6,9-Trioxaundecan-1,11-disäure insbesondere Säurehalogenide oder gemischte Anhydride in Betracht.The reactive derivatives of 3,6,9-trioxaundecane-1,11-diacid are used as reactive derivatives for the process according to the invention in particular acid halides or mixed anhydrides are suitable.
Die Umsetzung wird in einem polaren Lösungsmittel, wie Chlorbenzol, Dioxan, Dimethylacetamid,The reaction is carried out in a polar solvent such as chlorobenzene, dioxane, dimethylacetamide,
Dimethylformamid oder Acetonitril bei Temperaturen zwischen etwa 0 und 150'C, vorzugsweise zwischen und 120 C, durchgeführt.Dimethylformamide or acetonitrile at temperatures between about 0 and 150'C, preferably between and 120 C.
3,6,9 - Trioxaundecan -1,11 - dioyl - bis - (3 - carboxy-2,4,6-trijod-anilid) 3,6,9 - trioxaundecane -1,11 - dioyl - bis - (3 - carboxy-2,4,6-triiodo-anilide)
a) Kondensation in Dimethylacetamida) Condensation in dimethylacetamide
Zu einer Suspension von 51,5 g wasserfreier 3-Amino-2,4,6-trijod-benzoesäure (0,1 Mol) in 100 ml Dimethylacetamid werden unter Rühren langsam 15,5 g 3,6,9-Trioxaundecandisäuredichlorid. (0,06 Mol) eingetropft, wobei die Temperatur allmählich auf etwa 50JC ansteigt und alles in Lösung geht. Nach Rühren über Nacht wird die Lösung in 1 1 0,28 η-Natronlauge eingetropft und anschließend vorsichtig mit 200 ml 2 n-Salzsäure versetzt. Der Niederschlag wird abgesaugt, mit Wasser gewaschen und getrocknet. Die Ausbeute ist praktisch quantitativ.To a suspension of 51.5 g of anhydrous 3-amino-2,4,6-triiodo-benzoic acid (0.1 mol) in 100 ml of dimethylacetamide, 15.5 g of 3,6,9-trioxaundecanedioic acid dichloride are slowly added with stirring. (0.06 mol) was added dropwise, the temperature gradually rising to about 50 J C and everything goes into solution. After stirring overnight, the solution is added dropwise to 1 liter of 0.28 η sodium hydroxide solution, and 200 ml of 2N hydrochloric acid are then carefully added. The precipitate is filtered off with suction, washed with water and dried. The yield is practically quantitative.
b) Kondensation in Dioxanb) condensation in dioxane
In eine Lösung von 51,5 g wasserfreier 3-Amino-2,4,6-trijod-benzoesäure in 52 ml wasserfreiem Dioxan werden bei etwa 95°C 15,5 g 3,6,9-Trioxaundecandisäuredichlorid zugetropft. Nach weiterem 3stündigen Rühren und Erhitzen wird die Lösung abgekühlt, tropfenweise in 500 ml 0,4 n-Natronlauge eingerührt und wie unter a) beschrieben weiterverarbeitet. Die Ausbeute ist praktisch quantitativ.In a solution of 51.5 g of anhydrous 3-amino-2,4,6-triiodo-benzoic acid in 52 ml of anhydrous dioxane at about 95 ° C. 15.5 g of 3,6,9-trioxaundecanedioic acid dichloride are added added dropwise. After stirring and heating for a further 3 hours, the solution is cooled, dropwise in 500 ml of 0.4 N sodium hydroxide solution stirred in and processed as described under a). The yield is practically quantitative.
c) Reinigungc) cleaning
Das unter a) oder b) erhaltene Rohprodukt wird in 300 ml Methanol langsam mit soviel 12 n-Natronlauge (ca. 15 ml) versetzt bis eine mit Wasser verdünnte Probe pH 8—9 anzeigt. Nach Rühren über Nacht wird das auskristallisierte Natriumsalz vom 3,6,9-Trioxaundecan-1,11-dioyl-bis-(3-carboxy-2,4,6-trijod-anilid) abgesaugt, mit Methanol gewaschen und getrocknet. Ausbeute: 92 g (90% der Theorie).The crude product obtained under a) or b) is slowly dissolved in 300 ml of methanol with as much as 12 N sodium hydroxide solution (approx. 15 ml) added until a sample diluted with water shows pH 8-9. After stirring overnight the crystallized sodium salt of 3,6,9-trioxaundecane-1,11-dioyl-bis- (3-carboxy-2,4,6-triiodo-anilide) suctioned off, washed with methanol and dried. Yield: 92 g (90% of theory).
Die Lösung des Salzes in 900 ml Wasser wird mit Aktivkohle behandelt und mit konzentrierter Salzsäure bis pH 1 versetzt. Der Niederschlag wird abgesaugt, mit Wasser gewaschen und bei 50° C getrocknet. The solution of the salt in 900 ml of water is treated with activated charcoal and with concentrated hydrochloric acid added up to pH 1. The precipitate is filtered off with suction, washed with water and dried at 50.degree.
Ausbeute an reinem S.o^-Trioxaundecan-l.ll-dioyl-bis-(3-carboxy-2,4,6-trijod-anilid 80 g (80% der Theorie).Yield of pure S.o ^ -trioxaundecane-l.ll-dioyl-bis- (3-carboxy-2,4,6-triiodo-anilide 80 g (80% of theory).
Die Substanz schmilzt ab 175° C unter Sintern.The substance melts from 175 ° C with sintering.
Die als Zwischenprodukt benötigte 3,6,9-Trioxaundecan-l,ll-disäure kann durch Salpetersäureoxydation von Tetraäthylenglycol analog dem britischen Patent 6 39 491 hergestellt werden. Eine Reinigung der öligen Säure ist über die Isolierung des Dicyclohexylaminsalzes oder über die Destillation des Dimethylesters (Kp6 Torr = 175—180°C) möglich. Die Synthese von 3,6,9-Trioxaundecandisäure-dichlorid kann entweder nach der DOS 20 28 556 in Benzol mit Oxalylchlorid oder einfacher mit Thionylchlorid in Toluol durchgeführt werden. Nach dem Abdestillieren des Lösungsmittels hinterbleibt das gewünschte Dicarbonsäure-dichlorid. The 3,6,9-trioxaundecane-l, ll-diacid required as an intermediate product can be produced by nitric acid oxidation of tetraethylene glycol in a manner analogous to British patent 6,39,491. The oily acid can be purified by isolating the dicyclohexylamine salt or by distilling the dimethyl ester ( boiling point 6 Torr = 175-180 ° C). The synthesis of 3,6,9-trioxaundecanedioic acid dichloride can either be carried out according to DOS 20 28 556 in benzene with oxalyl chloride or more simply with thionyl chloride in toluene. After the solvent has been distilled off, the desired dicarboxylic acid dichloride remains.
Herstellung einer gebrauchsfertigen Methylglucaminsali-lösurgProduction of a ready-to-use methylglucamine salt solution
(3-carboxy-2,4,6-trijod-anilid) 287 g(3-carboxy-2,4,6-triiodo-anilide) 287 g
N-Melhylglucamin 92 gN-methylglucamine 92 g
Dinatriumedctat 0,1 gDisodium edctate 0.1 g
Bidestilliertes Wasser ad 1000 mlDouble distilled water to 1000 ml
Die Lösung wird in Ampullen oder Multivials abgefüllt und bei 1200C sterilisiert. Sie enthält 180 mg Jod/ml.The solution is filled into ampoules or Multivials and sterilized at 120 0 C. It contains 180 mg iodine / ml.
Herstellung einer gebrauchsfertigen Mischsalzlösung Preparation of a ready-to-use mixed saline solution
3,6,9-Trioxuundecan-l,ll-dioyl-bis-3,6,9-trioxuundecane-l, ll-dioyl-bis-
(3-carboxy-2,4,6-trijod-anilid) 446,8 g(3-carboxy-2,4,6-triiodo-anilide) 446.8 g
N-Mcthylglucamin 75,5 gN-methylglucamine 75.5 g
Ätznatron 13,9 gCaustic soda 13.9 g
Dinalriumedetat 0,1 gDinalrium edetate 0.1 g
Bidestilliertes Wasser ad 1000 mlDouble distilled water to 1000 ml
Die Lösung wird in Ampullen oder Multivials abgefüllt und bei 120 C sterilisiert. Sie enthält 280 mg Jod/ml.The solution is filled into ampoules or multivials and sterilized at 120 C. It contains 280 mg Iodine / ml.
Claims (4)
Priority Applications (25)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19742405652 DE2405652C3 (en) | 1974-02-04 | 3,6,9-trioxaundecane-1,11 -dioyl-bis- (3-carboxy-2,4,6-triiodo-anilide), its salts with physiologically acceptable bases, processes for the preparation of these compounds and X-ray contrast media containing these compounds | |
| DK675974A DK675974A (en) | 1974-02-04 | 1974-12-20 | |
| YU0160/75A YU36609B (en) | 1974-02-04 | 1975-01-23 | Process for obtaining 3,6,9-trioxa-undecane-1,1-dioyl-bis-(3-carboxy-2,4,6-triiodo-analides) and salts thereof with physiologically tolerated bases |
| SU2101429A SU555848A3 (en) | 1974-02-04 | 1975-01-28 | The method of obtaining bis-2,4,6triiod-3-carboxyanilide 3,6,9-trioxaundecane-1,11dioic acid or its salts |
| CS75554A CS188213B2 (en) | 1974-02-04 | 1975-01-28 | Method of preparation of 3,6,9-trioxaundecan-1,11-diocyl-bis-/3-carboxy-2,4,6 triiodanilid/ |
| FI750214A FI58589C (en) | 1974-02-04 | 1975-01-28 | ROENTGENCONTRASTMELEL INNEHAOLLANDE 3,6,9-TRIOXIUNDEKAN-1,11-DIOYL-BIS- (3-CARBOXY-2,4,6-TRIJOD-ANILID) ELLER SALT DAERAV OCH FOERFARANDE FOER FRAMSTAELLNING AV DETTA |
| AU77802/75A AU485677B2 (en) | 1974-02-04 | 1975-01-31 | New xray contrast agents |
| IL46535A IL46535A (en) | 1974-02-04 | 1975-01-31 | 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodoanilide) and x-ray contrastg preparations containing it |
| CH113575A CH609565A5 (en) | 1974-02-04 | 1975-01-31 | X-Ray contrast medium |
| IT19829/75A IT1060376B (en) | 1974-02-04 | 1975-01-31 | NEW MEANS OF CONTRAST TO RONTGEN RAYS CONSTITUTED BY 3.6.9 TRIOXAUNDECAN 1.11 DIOIL BIS 3 CARBASSES 2.4.6 ANILIDE TRIIOD |
| DD183944A DD116141A5 (en) | 1974-02-04 | 1975-01-31 | |
| EG42A EG11543A (en) | 1974-02-04 | 1975-02-02 | New x-ray contrast agents |
| SE7501158A SE409992B (en) | 1974-02-04 | 1975-02-03 | 3,6,9-TRIOXAUNDEKAN-1,11-DIOYL-BIS (3-CARBOXY-2,4,6-TRIJODANILID) FOR USE AS X-RAY CONTRAST |
| GB4481/75A GB1501507A (en) | 1974-02-04 | 1975-02-03 | X-ray contrast agents |
| AT76975A AT338413B (en) | 1974-02-04 | 1975-02-03 | X-RAY CONTRAST AGENT |
| NO750326A NO144595C (en) | 1974-02-04 | 1975-02-03 | ROENTGENKONTRASTMIDDEL. |
| CA75219351A CA1048536A (en) | 1974-02-04 | 1975-02-04 | X-ray contrast agents |
| HUSC508A HU168569B (en) | 1974-02-04 | 1975-02-04 | |
| IE218/75A IE40578B1 (en) | 1974-02-04 | 1975-02-04 | New x-ray contrast agents |
| FR7503374A FR2259591B1 (en) | 1974-02-04 | 1975-02-04 | |
| NL7501289A NL7501289A (en) | 1974-02-04 | 1975-02-04 | PREPARATION OF A ROENTGEN CONTRAST AGENT. |
| JP50014767A JPS5939420B2 (en) | 1974-02-04 | 1975-02-04 | Process for producing 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodoanilide) |
| BE153038A BE825160A (en) | 1974-02-04 | 1975-02-04 | X-RAY CONTRAST PRODUCTS THEIR PREPARATION PROCESS |
| ES434447A ES434447A1 (en) | 1974-02-04 | 1975-02-04 | X-ray contrast agents |
| ZA00750722A ZA75722B (en) | 1974-02-04 | 1975-02-04 | New x-ray contrast agents |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19742405652 DE2405652C3 (en) | 1974-02-04 | 3,6,9-trioxaundecane-1,11 -dioyl-bis- (3-carboxy-2,4,6-triiodo-anilide), its salts with physiologically acceptable bases, processes for the preparation of these compounds and X-ray contrast media containing these compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE2405652A1 DE2405652A1 (en) | 1975-08-21 |
| DE2405652B2 DE2405652B2 (en) | 1977-03-31 |
| DE2405652C3 true DE2405652C3 (en) | 1977-11-10 |
Family
ID=
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7780875B2 (en) | 2005-01-13 | 2010-08-24 | Cinvention Ag | Composite materials containing carbon nanoparticles |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7780875B2 (en) | 2005-01-13 | 2010-08-24 | Cinvention Ag | Composite materials containing carbon nanoparticles |
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