NO144595B - ROENTGENKONTRASTMIDDEL. - Google Patents
ROENTGENKONTRASTMIDDEL. Download PDFInfo
- Publication number
- NO144595B NO144595B NO750326A NO750326A NO144595B NO 144595 B NO144595 B NO 144595B NO 750326 A NO750326 A NO 750326A NO 750326 A NO750326 A NO 750326A NO 144595 B NO144595 B NO 144595B
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- carboxy
- bis
- triiodo
- dioyl
- anilide
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- 239000002872 contrast media Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 9
- 159000000000 sodium salts Chemical class 0.000 claims description 6
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 4
- 150000001875 compounds Chemical class 0.000 description 34
- 210000000941 bile Anatomy 0.000 description 16
- 229940126062 Compound A Drugs 0.000 description 12
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 12
- 230000029142 excretion Effects 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 210000002700 urine Anatomy 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 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
- 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 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 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
- 230000015572 biosynthetic process Effects 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229940029355 iodipamide Drugs 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- RYPJDHLXNFQCAS-UHFFFAOYSA-N 2-(2-hydroxyethylamino)ethanol;morpholine Chemical class C1COCCN1.OCCNCCO RYPJDHLXNFQCAS-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- -1 amine salts Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000013189 cholangiography Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 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
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- 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
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
- Physical Deposition Of Substances That Are Components Of Semiconductor Devices (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
Foreliggende oppfinnelse angår røntgenkontrastmidler The present invention relates to X-ray contrast agents
som er karakteristiske ved at de som skyggegivende materiale inneholder en ny forbindelse 3,6,9-trioxaundecan-l,11-dioyl-bis-(3-carboxy-2,4,6-trijod-anilid) med formelen: which are characteristic in that they contain as shading material a new compound 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide) with the formula:
eller salter av denne forbindelse med fysiologisk godtagbare baser. or salts of this compound with physiologically acceptable bases.
Som salter med fysiologisk godtagbare baser er metallsalter aktuelle, som f.eks. natrium-, lithium- og magnesiumsaltene, fortrinnsvis natriumsaltet, men også aminsalter, fortrinnsvis glucamin-N-methylglucamin-, N.N-dimethylglucamin-, ethanolamin-, diethanol-amin- og morfolin salter. Også blandinger av salter kan anvendes. As salts with physiologically acceptable bases, metal salts are relevant, such as e.g. the sodium, lithium and magnesium salts, preferably the sodium salt, but also amine salts, preferably glucamine-N-methylglucamine-, N.N-dimethylglucamine-, ethanolamine-, diethanolamine- and morpholine salts. Mixtures of salts can also be used.
Saltene skal fortrinnsvis anvendes som parenterale galle-kontrastmidler. The salts should preferably be used as parenteral bile contrast agents.
Blant de tallrike tidligere foreslåtte forbindelser for intravenøs cholegrafi har bare representanter for følgende formel fått en praktisk betydning: Among the numerous previously proposed compounds for intravenous cholegraphy, only representatives of the following formula have gained practical significance:
Således har forbindelsene hvor X er (CH2)4 ("Jodipamid", tysk patent 936.928) og hvor X er CH2"0-CH2 ("Joglycamid", tysk patent 962.698) allerede lenge vært i handelen. Andre representanter for den generelle formel (II) er beskrevet med Thus, the compounds where X is (CH2)4 ("Iodipamide", German patent 936,928) and where X is CH2"0-CH2 ("Joglycamide", German patent 962,698) have already been in commerce for a long time. Other representatives of the general formula ( II) is described with
X = CH2-CH2-(0-CH2-CH2)3 i tysk offentliggjørelsesskrift 1.922.578 og med X = CH2-CH2~(0-CH2"CH2)4 i tysk offentlig-gjørelsesskrift 1.937.211. X = CH2-CH2-(0-CH2-CH2)3 in German Publication No. 1,922,578 and with X = CH2-CH2~(0-CH2"CH2)4 in German Publication No. 1,937,211.
Behovet for stadig grundigere radiologisk diagnostikk The need for increasingly thorough radiological diagnostics
ved sterkt skadede pasienter med innskrenket leverfunksjon stiller høye krav såvel til forlikeligheten av kontrastmidlet, for å unn-gå alvorlige episoder, som til dets evne til å føres hurtig og i høy konsentrasjon gjennom leveren til gallen, for å mulig-gjøre god opptagelse også i patologiske tilfeller. in severely damaged patients with reduced liver function, high demands are placed both on the compatibility of the contrast agent, in order to avoid serious episodes, and on its ability to be carried quickly and in high concentration through the liver to the bile, to enable good absorption also in pathological cases.
Det har nu vist seg at den nye forbindelse 3,6,9-trioxaun-decan-1,11-dioyl-bis-(3-carboxy-2,4,6-trijod-anilid) forener de nødvendige egenskaper i høy grad. It has now been shown that the new compound 3,6,9-trioxaun-decane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide) combines the required properties to a high degree.
I de følgende to tabeller sammenlignes den nye forbindelse A med de nedenfor angitte kjente forbindelser B, C, D, E og F, som alle er frie for 5,5'-substituenter. In the following two tables, the new compound A is compared with the known compounds B, C, D, E and F listed below, all of which are free of 5,5'-substituents.
A : 3,6,9-trioxaundecan-l,11-dioyl-bis-(3-carboxy-2,4,6-trijod-anilid) A : 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide)
B : 4,7,10-trioxatridecan-l,13-dioyl-bis-(3-carboxy-2,4,6-trijod-anilid) B : 4,7,10-trioxatridecane-1,13-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide)
Tysk offentliggjørelsesskrift 1.922.578 German publication document 1,922,578
C : 4,7,10,13-tetraoxahexadecan-l,16-dioyl-bis-(3-carboxy-2,4,6-trijod-anilid) C : 4,7,10,13-tetraoxahexadecane-1,16-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide)
Norsk utlegningsskrift 120.272 Norwegian interpretation document 120.272
D : adipinoyl-bis-(3-carboxy-2,4,6-trijod-anilid) D : adipinoyl-bis-(3-carboxy-2,4,6-triiodo-anilide)
("Jodipamid") ("Iodipamide")
Tysk patent 936.928 German patent 936,928
E : diglycoloyl-bis-(3-carboxy-2,4,6-trijod-anilid) E : diglycoloyl-bis-(3-carboxy-2,4,6-triiodo-anilide)
("Joglycamid") ("Joglycamide")
Tysk patent 962.698 German patent 962,698
F : 3,6,9-trioxaundecan-l,11-dioyl-bis-(3-carboxy-2,4,6-trijod-N-methyl-anilid) F : 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-N-methyl-anilide)
Dansk utlegningsskrift 132.375 Danish interpretation document 132.375
Dataene i tabell 1 viser at den nye forbindelse A er den minst toksiske og er- vesentlig mindre toksisk enn den nært be-slektede forbindelse F som skiller seg fra forbindelse A kun ved at de to N-atomer er methylert.. The data in table 1 show that the new compound A is the least toxic and is significantly less toxic than the closely related compound F, which differs from compound A only in that the two N atoms are methylated.
Tabell 2 viser åt den nye forbindelse A er sammenligningsforbindelsene overlegen med hensyn til utskillelse over gallen. Andelen av utskillelsen over gallen og utskillelseshastigheten er høyere enn for sammenligningsforbindelsene. Table 2 shows that the new compound A is superior to the comparison compounds with regard to excretion via the bile. The proportion of excretion via the bile and the rate of excretion are higher than for the comparison compounds.
Et røntgenkontrastmiddel som skal anvendes for intravenøs choiegrafi må være slik at det overveiende utskilles gjennom leveren og gallen og bare i liten grad gjennom urinen, dvs. at kontrastmidlet må oppvise et gunstig galle/urin-forhold ved utskillelsen for å gi brukbare radiologiske opptak. Erfaringen har vist at dimere kontrastmidler av formel (III): som ikke i 5,5'-stillingene er substituert (Y=H) oppviser god utskillelse gjennom gallen i motsetning til forbindelsene med substituenter i 5,5'-stillingene, som oppviser en dårligere utskillelse gjennom gallen. Hva toksisiteten angår, forholder det seg motsatt.I norsk utlegningsskrift nr 120.94 0 beskrives 5,5'-substituerte kontrastmidler av formel (III) , hvor Y er grupper som An X-ray contrast agent to be used for intravenous choiography must be such that it is mainly excreted through the liver and bile and only to a small extent through the urine, i.e. the contrast agent must exhibit a favorable bile/urine ratio during excretion in order to provide usable radiological recordings. Experience has shown that dimeric contrast agents of formula (III): which are not substituted in the 5,5'-positions (Y=H) exhibit good excretion through the bile in contrast to the compounds with substituents in the 5,5'-positions, which exhibit a poorer excretion through the bile. As far as toxicity is concerned, the opposite is the case. In Norwegian explanatory document no. 120.94 0, 5,5'-substituted contrast agents of formula (III) are described, where Y are groups which
Disse forbindelser tåles bedre enn de forbindelser som ikke er substituert i disse stillinger, men de oppviser vesentlig dårligere utskillelse gjennom gallen (jfr. R. Barke: Røntgen-kontrastmittel, VEB Georg Thieme Leipzig 1970, s. 103 ff). These compounds are better tolerated than the compounds which are not substituted in these positions, but they exhibit significantly poorer excretion through the bile (cf. R. Barke: Røntgen-kontrastmittel, VEB Georg Thieme Leipzig 1970, p. 103 ff).
I norsk utlegningsskrift 120.940 beskrives kun i 5,5'-stillingene substituerte dimere kontrastmidler.Sammenstillingen av de farmakologiske data på sider 12 og 13 i utlegnings-skriftet bekrefter de ovenstående bemerkninger. Ved siden av gunstige toksisitetsverdier oppviser disse forbindelser lave verdier for galle/urin-utskillelseskvotienten, idet disse er fra 1,1 til 1,56, (testet på aper) hvilket utelukker anvendelse av disse forbindelser for intravenøs cholecystangiografi. I det In Norwegian explanatory document 120,940, only dimeric contrast agents substituted in the 5,5' positions are described. The compilation of the pharmacological data on pages 12 and 13 of the explanatory document confirms the above remarks. In addition to favorable toxicity values, these compounds exhibit low bile/urine excretion quotient values, ranging from 1.1 to 1.56 (tested on monkeys), which excludes the use of these compounds for intravenous cholecystangiography. In that
norske utlegningsskrift tas det ikke opp noen diskusjon om hvorvidt de der beskrevne forbindelser egner seg som galle-kontrastmidler. Således er på side 3 i patentskriftet ikke galle/urin-forholdet angitt for sammenligningsforbindelsen F (som svarer til sammenligningsforbindelse E ifølge den foreliggende beskrivelse), som er det eneste oppførte handelspreparat ("Joglycaminsyre" eller "Joglycamid"). Dette galle/urin-forhold norske elegnningsskrift, there is no discussion about whether the compounds described there are suitable as bile contrast agents. Thus, on page 3 of the patent, the bile/urine ratio is not indicated for the comparison compound F (which corresponds to the comparison compound E according to the present description), which is the only listed commercial preparation ("Joglycamic acid" or "Joglycamide"). This bile/urine ratio
er av nærværende patentinnehaver funnet å være 3,16 , (testet på aper), mot altså fra 1,1 til 1,56 for forbindelsene ifølge utlegningsskrift 120.940. I den nedenstående tabell 3 er forbindelsene A, B, C, D, E og F som er definert ovenfor (den nye forbindelse og sammenligningsforbindelsene og noen av forbindelsene fra norsk patentskrift 120.940, sammenstilt. Tabellen viser galle/urin-utskillelsesforholdene og toksisitetsverdiene og angir substitueringen i 5,5'-stillingene. De angitte farmakologiske verdier ble funnet ved forsøk på rotter. is found by the present patent holder to be 3.16, (tested on monkeys), compared to 1.1 to 1.56 for the compounds according to explanatory note 120,940. In the table 3 below, the compounds A, B, C, D, E and F that are defined above (the new compound and the comparison compounds and some of the compounds from Norwegian patent document 120,940, are compiled. The table shows the bile/urine excretion ratios and the toxicity values and indicates the substitution in the 5,5'-positions The stated pharmacological values were found in experiments on rats.
Tabell 3 nedenfor viser at samtlige forbindelser som anvendes i den kliniske praksis for intravenøs cholecystangiografi, er usubstituerte i 5,5<1->stillingene, og at disse forbindelser har et galle/urin-utskillelsesforhold som er minst 2,5 ganger høyere enn for de forbindelser som beskrives i norsk utlegningsskrift 120.940. Derav følger at den nye forbindelse A, som fortrinnsvis skal anvendes som skyggegivende substans ved intravenøs chole-cystangiograf i , med henblikk på toksisiteten kun kan sammenlignes med forbindelser som ikke er substituert i 5,5'-stillingene. Ved en slik sammenligning viser den nye forbindelse A en overraskende lav toksisitet. Table 3 below shows that all compounds used in clinical practice for intravenous cholecystangiography are unsubstituted in the 5.5<1->positions, and that these compounds have a bile/urine excretion ratio that is at least 2.5 times higher than for the connections described in Norwegian interpretation document 120.940. It follows that the new compound A, which is preferably to be used as a shadowing substance for intravenous cholecystangiography in , with regard to toxicity can only be compared with compounds that are not substituted in the 5,5' positions. In such a comparison, the new compound A shows a surprisingly low toxicity.
Ved hjelp av Valzelli-prøven (Med. exp. 11' s- 23-26, 1964) samt ved cisternal applikasjon og injeksjon i A. carotis comm. ble den neurale forlikelighet for cholecyst-cholangiografi undersøkt på rotter: By means of the Valzelli test (Med. exp. 11' p- 23-26, 1964) as well as by cisternal application and injection into A. carotis comm. the neural compatibility of cholecyst cholangiography was investigated in rats:
Av tabell 4 fremgår at den nye forbindelse A er de kjente forbindelser tydelig overlegen, særlig med hensyn til cisternal og cerebral forlikelighet. Table 4 shows that the new compound A is clearly superior to the known compounds, particularly with regard to cisternal and cerebral compatibility.
Tabell 5 nedenfor gir et uttrykk for den neurale forlikelighet av den nye forbindelse A sammenlignet med den kjente forbindelse B. Undersøkelsen er foretatt på rotter. Table 5 below gives an expression for the neural compatibility of the new compound A compared to the known compound B. The study was carried out on rats.
Forbindelsen A sees her å være klart fordelaktig fremfor forbindelse B. Compound A is seen here to be clearly advantageous over compound B.
Den nye skyggegivende forbindelse A er således, særlig i form av konsentrerte vandige oppløsninger av dens salter, egnet som injeksjonspreparat for avbildning av gallen. Der kan anvendes oppløsninger med ca. 5 - 45%, fortrinnsvis ca. 10 - 30%, bundet jod. Slike saltoppløsninger inneholder tilsvarende pr. 100 ml ca. 10 -90 g, fortrinnsvis 20 - 60 g, 3,6,9-trioxaundecan-l,11-dioyl-bis- (3-carboxy-2,4,6-trijod-anilid). The new shade-giving compound A is thus, especially in the form of concentrated aqueous solutions of its salts, suitable as an injection preparation for imaging the bile. Solutions with approx. 5 - 45%, preferably approx. 10 - 30%, bound iodine. Such salt solutions contain the equivalent per 100 ml approx. 10 - 90 g, preferably 20 - 60 g, of 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide).
Som tidligere nevnt er en med den nye forbindelse 3,6,9-trioxaundecan-1,11-dioyl-bis-(3-carboxy-2,4,6-trijod-anilid) As previously mentioned, one with the new compound is 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide)
(forbindelse A) nær beslektet forbindelse kjent, nemlig 3,6,9-trioxaundecan-1,11-dioyl-bis-(3-carboxy-2,4,6-trijod-N-methy1-anilid) (sammenligningsforbindelse F ovenfor). Denne er beskrevet bl. a. i dansk utlegningsskrift nr. 132.375, som på side 4, linjer 5-8 inneholder et avsnitt som kan tolkes i retning av at forbindelse A var kjent på inngivelsesdagen for den patent-søknad som førte til det danske utlegningsskrift. I nevnte avsnitt kommer det nemlig til uttrykk at forbindelsene ifølge det danske utlegningsskrift (såsom forbindelse F) har lavere toksisitet enn de tilsvarende forbindelser som ikke er substituert med en methylgruppe ved nitrogenatomene. Utsagnet skal imid-lertid kun leses på de ikke-methylerte forbindelser ifølge dansk patent nr. 83.912 og dansk utlegningsskrift nr. 125.243. Utsagnet ble forøvrig inntatt i teksten til det danske utlegningsskrift på et tidspunkt etter prioritetsdatoen for nærværende oppfinnelse. (compound A) closely related compound known, namely 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-N-methyl1-anilide) (comparison compound F above) . This is described in a. in the Danish interpretation document no. 132,375, which on page 4, lines 5-8 contains a section that can be interpreted in the direction that compound A was known on the filing date of the patent application that led to the Danish interpretation document. In the aforementioned section, it is expressed that the compounds according to the Danish explanatory document (such as compound F) have lower toxicity than the corresponding compounds which are not substituted with a methyl group at the nitrogen atoms. However, the statement should only be read on the non-methylated compounds according to Danish patent no. 83,912 and Danish interpretation document no. 125,243. Incidentally, the statement was included in the text of the Danish interpretation document at a time after the priority date for the present invention.
Fremstillingen av de nye røntgenkontrastmidler på basis av 3,6,9-trioxaundecan-l,11-dioyl-bis-(3-carboxy-2,4,6-trijod-anilid) kan foretas ved at 3-amino-2,4,6-trijodbenzoesyre omsettes med et. reaktivt derivat av 3,6,9-trioxaundecan-l,11-disyre og det erholdte 3,6,9-trioxaundecan-l,11-dioyl-bis-(3-carboxy-2,4,6-tri-jod-anilid) bringes i en for intravenøs applikasjon egnet form, eventuelt under saltdannelse med en fysiologisk godtagbar base med de i farmasien vanlige tilsetninger. The production of the new X-ray contrast agents based on 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodo-anilide) can be carried out by 3-amino-2,4 ,6-triiodobenzoic acid is reacted with et. reactive derivative of 3,6,9-trioxaundecane-1,11-diacid and the obtained 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-tri-iodo- anilide) is brought into a form suitable for intravenous application, possibly during salt formation with a physiologically acceptable base with the usual additions in pharmacy.
Som reaktive derivater av 3,6,9-trioxaundecan-l,11-disyre kommer særlig syrehalogenider eller blandede anhydrider i be-traktning. As reactive derivatives of 3,6,9-trioxaundecane-1,11-diacid, especially acid halides or mixed anhydrides come into consideration.
Omsetningen utføres i et polart oppløsningsmiddel, som klorbenzen, dioxan, dimethylacetamid, dimethylformamid eller acetonitril, ved temperaturer mellom ca. 0° og 150°C, fortrinnsvis mellom 20° og 120°C. The reaction is carried out in a polar solvent, such as chlorobenzene, dioxane, dimethylacetamide, dimethylformamide or acetonitrile, at temperatures between approx. 0° and 150°C, preferably between 20° and 120°C.
Eksempel 1 Example 1
Fremstilling av 3,6,9-trioxaundecan-l,11-dioyl-bis-(3-carboxy-2, 4, 6- trijod- anilid) Preparation of 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodoanilide)
a) Kondensasjon i dimethylacetamid a) Condensation in dimethylacetamide
Til en suspensjon av 51,5 g (0,1 mol) vannfri 3-amino-2,4,6-trijod-benzoesyre i 100 ml dimethylacetamid inndryppes under omrøring langsomt 15,5 g (0,06 mol) 3,6,9-trioxaundecandisyre-diklorid, hvorved temperaturen gradvis stiger til ca. 50°C To a suspension of 51.5 g (0.1 mol) of anhydrous 3-amino-2,4,6-triiodo-benzoic acid in 100 ml of dimethylacetamide, while stirring, slowly add 15.5 g (0.06 mol) of 3.6, 9-trioxaundecanedioic acid dichloride, whereby the temperature gradually rises to approx. 50°C
og alt går i oppløsning. Etter omrøring over natten dryppes opp-løsningen i 1 liter 0,28 N natronlut og tilsettes derpå forsiktig 200 ml 2 N saltsyre. Bunnfallet frasuges, vaskes med vann og tørres. Utbyttet er praktisk talt kvantitativt. and everything dissolves. After stirring overnight, the solution is dripped into 1 liter of 0.28 N caustic soda and then 200 ml of 2 N hydrochloric acid is carefully added. The precipitate is suctioned off, washed with water and dried. The yield is practically quantitative.
b) Kondensasjon i dioxan b) Condensation in dioxane
I en oppløsning av 51,5 g vannfri 3-amino-2,4,6-trijod-benzoesyre i 52 ml vannfri dioxan tildryppes ved ca. 9 5°C 15,5 g 3,6,9-trioxaundecandisyre-diklorid. Etter ytterligere 3 timers omrøring og oppvarmning avkjøles oppløsningen, dryppes under om-røring i 500 ml 0,4 N natronlut og opparbeides som beskrevet under a). Utbyttet er praktisk talt kvantitativt. Into a solution of 51.5 g anhydrous 3-amino-2,4,6-triiodo-benzoic acid in 52 ml anhydrous dioxane is added dropwise at approx. 9 5°C 15.5 g 3,6,9-trioxaundecanedioic acid dichloride. After a further 3 hours of stirring and heating, the solution is cooled, dripped while stirring into 500 ml of 0.4 N caustic soda and worked up as described under a). The yield is practically quantitative.
c) Rensning c) Cleaning
Det under a) eller b) erholdte råprodukt blir i 300 ml The crude product obtained under a) or b) is in 300 ml
methanol langsomt tilsatt ca. 15 ml 12 N natronlut inntil en med vann fortynnet prøve viser pH 8 - 9. Etter omrøring over natten frasuges det utkrystalliserte natriumsalt av 3,6,9-trioxaundecan-1,11-dioyl-bis-(3-carboxy-2,4,6-trijod-anilid), vaskes med methanol og tørres. Utbytte: 92 g (90% av det teoretiske). methanol slowly added approx. 15 ml of 12 N caustic soda 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), washed with methanol and dried. Yield: 92 g (90% of the theoretical).
Oppløsningen av saltet i 900 ml vann behandles med aktiv-kull og tilsettes konsentrert saltsyre inntil pH 1. Bunnfallet frasuges, vaskes med vann og tørres ved 50°C. The solution of the salt in 900 ml of water is treated with activated charcoal and concentrated hydrochloric acid is added until pH 1. The precipitate is suctioned off, washed with water and dried at 50°C.
Utbytte av rent 3,6,9-trioxaundecan-l,11-dioyl-bis-(3-carboxy-2,4,6-trijod-anilid)er 80 g (80% av det teoretiske). For- ■ Yield of pure 3,6,9-trioxaundecane-1,11-dioyl-bis-(3-carboxy-2,4,6-triiodoanilide) is 80 g (80% of theoretical). For- ■
bindelsen smelter ved 175°C under sintring. the bond melts at 175°C during sintering.
Det som mellomprodukt nødvendige 3,6,9-trioxaundecan-1,11-disyre kan fremstilles ved salpetersyreoxydasjon av tetra-ethylenglycol analogt med britisk patent 639.491. En rensning av den oljeaktige syre er mulig ved isolering av dicyclohexylamin-saltet eller ved destillasjon av dimethylesteren (kokepunkt ved 6 torr = 175 - 180°C. Syntesen av 3,6,9-trioxaundecandisyre-diklorid kan enten utføres ifølge tysk offentliggjørelsesskrift 2.208.556 i benzen med oxalylklorid eller enklere med thionyl-klorid i toluen. Etter avdestillering av oppløsningsmidlet blir det ønskede dicarboxylsyre-diklorid tilbake. The 3,6,9-trioxaundecane-1,11-diacid required as an intermediate can be produced by nitric acid oxidation of tetraethylene glycol analogously to British patent 639,491. A purification of the oily acid is possible by isolation of the dicyclohexylamine salt or by distillation of the dimethyl ester (boiling point at 6 torr = 175 - 180°C. The synthesis of 3,6,9-trioxaundecanedic acid dichloride can either be carried out according to German publication document 2.208. 556 in benzene with oxalyl chloride or more simply with thionyl chloride in toluene After distilling off the solvent, the desired dicarboxylic acid dichloride remains.
Eksempel 2 Example 2
Fremstilling av en bruksferdig methylglucaminsaltopp-løsning: Preparation of a ready-to-use methylglucamine saline solution:
Oppløsningen fylles i ampuller eller multiampuller og steriliseres ved 120°C. De inneholder 180 mg jod/ml. The solution is filled into ampoules or multi-ampoules and sterilized at 120°C. They contain 180 mg iodine/ml.
Eksempel 3 Example 3
Fremstilling av en bruksferdig blandingssaltoppløsning: Preparation of a ready-to-use mixed salt solution:
Oppløsningen fylles i ampuller og steriliseres ved 120°C. De inneholder 280 mg jod/ml. The solution is filled into ampoules and sterilized at 120°C. They contain 280 mg iodine/ml.
Eksempel 4 Example 4
Fremstilling av en bruksferdig natriumsaltoppløsning: Preparation of a ready-to-use sodium salt solution:
Oppløsningen fylles i ampuller og sterileres ved 120 C. De inneholder 50 mg J/ml. The solution is filled into ampoules and sterilized at 120 C. They contain 50 mg J/ml.
Claims (5)
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 |
|---|---|
| NO750326L NO750326L (en) | 1975-09-01 |
| NO144595B true NO144595B (en) | 1981-06-22 |
| NO144595C NO144595C (en) | 1981-09-30 |
Family
ID=5906762
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO750326A NO144595C (en) | 1974-02-04 | 1975-02-03 | ROENTGENKONTRASTMIDDEL. |
Country Status (23)
| Country | Link |
|---|---|
| JP (1) | JPS5939420B2 (en) |
| AT (1) | AT338413B (en) |
| BE (1) | BE825160A (en) |
| CA (1) | CA1048536A (en) |
| CH (1) | CH609565A5 (en) |
| CS (1) | CS188213B2 (en) |
| DD (1) | DD116141A5 (en) |
| DK (1) | DK675974A (en) |
| EG (1) | EG11543A (en) |
| ES (1) | ES434447A1 (en) |
| FI (1) | FI58589C (en) |
| FR (1) | FR2259591B1 (en) |
| GB (1) | GB1501507A (en) |
| HU (1) | HU168569B (en) |
| IE (1) | IE40578B1 (en) |
| IL (1) | IL46535A (en) |
| IT (1) | IT1060376B (en) |
| NL (1) | NL7501289A (en) |
| NO (1) | NO144595C (en) |
| SE (1) | SE409992B (en) |
| SU (1) | SU555848A3 (en) |
| YU (1) | YU36609B (en) |
| ZA (1) | ZA75722B (en) |
-
1974
- 1974-12-20 DK DK675974A patent/DK675974A/da unknown
-
1975
- 1975-01-23 YU YU0160/75A patent/YU36609B/en unknown
- 1975-01-28 CS CS75554A patent/CS188213B2/en unknown
- 1975-01-28 SU SU2101429A patent/SU555848A3/en active
- 1975-01-28 FI FI750214A patent/FI58589C/en not_active IP Right Cessation
- 1975-01-31 IL IL46535A patent/IL46535A/en unknown
- 1975-01-31 IT IT19829/75A patent/IT1060376B/en active
- 1975-01-31 DD DD183944A patent/DD116141A5/xx unknown
- 1975-01-31 CH CH113575A patent/CH609565A5/en not_active IP Right Cessation
- 1975-02-02 EG EG42A patent/EG11543A/en active
- 1975-02-03 GB GB4481/75A patent/GB1501507A/en not_active Expired
- 1975-02-03 AT AT76975A patent/AT338413B/en not_active IP Right Cessation
- 1975-02-03 NO NO750326A patent/NO144595C/en unknown
- 1975-02-03 SE SE7501158A patent/SE409992B/en not_active IP Right Cessation
- 1975-02-04 BE BE153038A patent/BE825160A/en not_active IP Right Cessation
- 1975-02-04 HU HUSC508A patent/HU168569B/hu unknown
- 1975-02-04 ZA ZA00750722A patent/ZA75722B/en unknown
- 1975-02-04 JP JP50014767A patent/JPS5939420B2/en not_active Expired
- 1975-02-04 ES ES434447A patent/ES434447A1/en not_active Expired
- 1975-02-04 NL NL7501289A patent/NL7501289A/en not_active Application Discontinuation
- 1975-02-04 IE IE218/75A patent/IE40578B1/en unknown
- 1975-02-04 CA CA75219351A patent/CA1048536A/en not_active Expired
- 1975-02-04 FR FR7503374A patent/FR2259591B1/fr not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS50108237A (en) | 1975-08-26 |
| IL46535A0 (en) | 1975-04-25 |
| NO144595C (en) | 1981-09-30 |
| FR2259591B1 (en) | 1978-06-30 |
| YU16075A (en) | 1982-02-25 |
| CH609565A5 (en) | 1979-03-15 |
| FI58589B (en) | 1980-11-28 |
| YU36609B (en) | 1984-08-31 |
| ATA76975A (en) | 1976-12-15 |
| FR2259591A1 (en) | 1975-08-29 |
| IE40578L (en) | 1975-08-04 |
| AU7780275A (en) | 1976-08-05 |
| BE825160A (en) | 1975-08-04 |
| DK675974A (en) | 1975-09-29 |
| SE7501158L (en) | 1975-08-05 |
| IT1060376B (en) | 1982-07-10 |
| AT338413B (en) | 1977-08-25 |
| FI58589C (en) | 1981-03-10 |
| ZA75722B (en) | 1976-01-28 |
| DD116141A5 (en) | 1975-11-12 |
| CS188213B2 (en) | 1979-02-28 |
| DE2405652A1 (en) | 1975-08-21 |
| JPS5939420B2 (en) | 1984-09-22 |
| IL46535A (en) | 1978-06-15 |
| EG11543A (en) | 1977-11-30 |
| GB1501507A (en) | 1978-02-15 |
| HU168569B (en) | 1976-05-28 |
| NL7501289A (en) | 1975-08-06 |
| CA1048536A (en) | 1979-02-13 |
| DE2405652B2 (en) | 1977-03-31 |
| SE409992B (en) | 1979-09-17 |
| FI750214A (en) | 1975-08-05 |
| ES434447A1 (en) | 1976-12-16 |
| IE40578B1 (en) | 1979-07-04 |
| SU555848A3 (en) | 1977-04-25 |
| NO750326L (en) | 1975-09-01 |
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