NO127239B - - Google Patents
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- NO127239B NO127239B NO03753/71*[A NO375371A NO127239B NO 127239 B NO127239 B NO 127239B NO 375371 A NO375371 A NO 375371A NO 127239 B NO127239 B NO 127239B
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- aliphatic carboxylic
- carboxylic acid
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- -1 (3,5-diamino-2,4,6-triiodobenzoyl)-amino Chemical class 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 11
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 claims description 8
- 239000002872 contrast media Substances 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 claims description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000010933 acylation Effects 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 238000007487 urography Methods 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 125000003412 L-alanyl group Chemical group [H]N([H])[C@@](C([H])([H])[H])(C(=O)[*])[H] 0.000 description 4
- ZAVIHPOYMGHVQY-UHFFFAOYSA-N NC(C(I)=C(C(NCC(O)=O)=O)C(I)=C1N)=C1I Chemical compound NC(C(I)=C(C(NCC(O)=O)=O)C(I)=C1N)=C1I ZAVIHPOYMGHVQY-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- NNOHXABAQAGKRZ-UHFFFAOYSA-N 3,5-dinitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC(C(Cl)=O)=CC([N+]([O-])=O)=C1 NNOHXABAQAGKRZ-UHFFFAOYSA-N 0.000 description 3
- 230000021736 acetylation Effects 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 230000026045 iodination Effects 0.000 description 2
- 238000006192 iodination reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- ZMMSWDCZEHRVRP-UHFFFAOYSA-N 2-[(3,5-diacetamido-2,4,6-triiodobenzoyl)amino]acetic acid Chemical compound CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C(=O)NCC(O)=O)=C1I ZMMSWDCZEHRVRP-UHFFFAOYSA-N 0.000 description 1
- OOUHUXLLFPJKIE-UHFFFAOYSA-N 2-[(3,5-diaminobenzoyl)amino]acetic acid Chemical compound NC1=CC(N)=CC(C(=O)NCC(O)=O)=C1 OOUHUXLLFPJKIE-UHFFFAOYSA-N 0.000 description 1
- MIVUDAUOXJDARR-UHFFFAOYSA-N 2-[(3,5-dinitrobenzoyl)amino]-2-phenylacetic acid Chemical compound C=1C=CC=CC=1C(C(=O)O)NC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 MIVUDAUOXJDARR-UHFFFAOYSA-N 0.000 description 1
- PJZXWXFIUIDMBP-UHFFFAOYSA-N 2-[(3,5-dinitrobenzoyl)amino]acetic acid Chemical compound OC(=O)CNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 PJZXWXFIUIDMBP-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 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
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- XBPNQSRYUZTHDA-UHFFFAOYSA-N OC(CNC(C(C(I)=C(C(I)=C1NC=O)NC=O)=C1I)=O)=O Chemical compound OC(CNC(C(C(I)=C(C(I)=C1NC=O)NC=O)=C1I)=O)=O XBPNQSRYUZTHDA-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- ZGUNAGUHMKGQNY-UHFFFAOYSA-N alpha-phenylglycine Chemical compound OC(=O)C(N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D233/22—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Structures Of Non-Positive Displacement Pumps (AREA)
Description
Røntgenkontrastmidler inneholdende N-acylderivater av (3,5-diamino-2, 4, 6-trijodbenzoyl)-aminosyrer og fremgangsmåte til fremstilling av sådanne X-ray contrast agents containing N-acyl derivatives of (3,5-diamino-2, 4, 6-triiodobenzoyl)-amino acids and method for producing such
acylderivater. acyl derivatives.
I US patentskrift 2 680 133 er beskrevet In US patent 2 680 133 is described
fremstilling av N-acylerte aminosyrer hvis production of N-acylated amino acids if
aminogruppe er acylert med 3-amino-2,4,6-trijodbenzoyl-resten. I dette patentskrift amino group is acylated with the 3-amino-2,4,6-triiodobenzoyl residue. In this patent document
anbefales også anvendelse av slike forbindelser som skyggedannende bestanddel i the use of such compounds as a shadow-forming component is also recommended
røntgenkontrastmidler, idet der særlig X-ray contrast agents, in particular
fremheves visse fordelaktige egenskaper for certain advantageous properties are highlighted for
dette anvendelsesformål, som god oppløse-lighet av visse salter og relativt liten gif-tighet. this intended use, such as good solubility of certain salts and relatively low toxicity.
Øyensynlig var imidlertid ikke disse However, these were not obvious
fordelaktige egenskaper så utpreget at de beneficial properties so distinct that they
kunne føre til anvendelse i praksis av de could lead to their application in practice
nevnte kontrastmidler. Følgelig vil en for-sterkning av de nevnte egenskaper bety et mentioned contrast agents. Consequently, a strengthening of the aforementioned properties will mean a
ytterligere teknisk fremskritt. further technical progress.
Det ble nå funnet at et slikt fremskritt It was now found that such an advance
oppnåes ved å føre inn en ytterligere aminogruppe i 3-amino-2,4,6-trijodbenzoylres-tens fri 5-stilling sammen med mono-acy-lering av én eller begge aminogruppene i is achieved by introducing a further amino group into the free 5-position of the 3-amino-2,4,6-triiodobenzoyl residue together with mono-acylation of one or both amino groups in
3-stillingen og 5-stillingen. Man får da de The 3 position and the 5 position. Then you get them
forbindelser hvis anvendelse i røntgenkon-trastmidler og fremstilling danner foreliggende oppfinnelses gjenstand, nemlig N-acylderivater av (3,5-diamino-2,4,6-trijod-benzoyl)-aminosyrer med følgende generelle formel: compounds whose use in X-ray contrast agents and preparation form the object of the present invention, namely N-acyl derivatives of (3,5-diamino-2,4,6-triiodo-benzoyl)-amino acids with the following general formula:
I denne generelle formel betegner X en metylengruppe, en polymetylengruppe eller en substituert metylen- eller polymetylengruppe hvis substituenter kan være alkylradikaler, fenylradikaler, Ac betegner syreradikalet av en alifatisk karbonsyre, fortrinnsvis en lavere til middels høy alifatisk karbonsyre og R betegner hydrogen eller syreradikalet i en alifatisk karbonsyre, fortrinnsvis en lavere til middels høy alifatisk karbonsyre. In this general formula, X denotes a methylene group, a polymethylene group or a substituted methylene or polymethylene group whose substituents may be alkyl radicals, phenyl radicals, Ac denotes the acid radical of an aliphatic carboxylic acid, preferably a lower to medium high aliphatic carboxylic acid and R denotes hydrogen or the acid radical of a aliphatic carboxylic acid, preferably a lower to medium high aliphatic carboxylic acid.
Slike forbindelser og deres salter med organiske og/eller anorganiske baser er, Such compounds and their salts with organic and/or inorganic bases are,
særlig på grunn av deres meget lavere gif-tighet, betydelig fordelaktigere til anvendelse som skyggedannende stoffer i rønt-genkontrastmidler enn forbindelsene ifølge det foran nevnte amerikanske patentskrift. particularly because of their much lower toxicity, significantly more advantageous for use as shadow-forming substances in X-ray contrast agents than the compounds according to the above-mentioned American patent document.
Førstnevnte forbindelser er særlig godt egnet for røntgenundersøkelser for urogra-fiske formål. The former compounds are particularly well suited for X-ray examinations for urographic purposes.
Forbindelsene ifølge foreliggende opp-finnelse er ikke tidligere beskrevet. De kan fremstilles ved at man først 3,5-dinitrobenzoyliserer aminogruppen i den ønskede ami-nosyre på vanlig måte, fortrinnsvis ved omsetning med 3,5-dinitrobenzoylklorid etter Schotten-Baumann, hvorpå man reduserer acyleringsproduktet til den tilsvarende 3,5-diaminobenzoylforbindelse. Sistnevnte forbindelse tri-j oder es derpå hensiktsmessig ved hjelp av monoklorjod i saltsur oppløs-ning hvorpå den herved erholdte forbindelse N-acyleres helt eller delvis på i og for seg kjent måte. The compounds according to the present invention have not been previously described. They can be prepared by first 3,5-dinitrobenzoylizing the amino group in the desired amino acid in the usual way, preferably by reaction with 3,5-dinitrobenzoyl chloride according to Schotten-Baumann, after which the acylation product is reduced to the corresponding 3,5-diaminobenzoyl compound. The latter compound is then suitably tri-iodinated with the aid of monochloroiodine in hydrochloric acid solution, whereupon the compound thus obtained is N-acylated in whole or in part in a manner known per se.
Eksempler på fremstilling av skyggedannende stoffer ifølge oppfinnelsen. Examples of the production of shadow-forming substances according to the invention.
Eksempel 1: Example 1:
58,7 g 3,5-diamino-2,4,6-trijodhippur-syre med smeltepunkt 186° C (spaltning) oppvarmes med 400 ml eddiksyreanhydrid til 120° C inntil alt er gått i oppløsning, hva der kreves 15 minutter. Oppløsningen av-kjøles derpå og røres inn i 3 1 vann. Etter spaltning av overskudd av eddiksyreanhydrid bringes acetyleringsproduktet til å skille seg ut ved tilsetning av saltsyre. Pro-duktet renses ved å oppløses i sterkt for-tynnet vandig ammoniakk, behandling av oppløsningen med animalsk kull, svak sur-gj øring av filtratet med eddiksyre og ytterligere behandling med animalsk kull. Etter filtrering tilsettes saltsyre hvorved ren 3,5-bis- (acetylamino) -2,4,6-trijodhippursyre 58.7 g of 3,5-diamino-2,4,6-triiodohippuric acid with a melting point of 186° C (decomposition) is heated with 400 ml of acetic anhydride to 120° C until everything has dissolved, which takes 15 minutes. The solution is then cooled and stirred into 3 1 water. After cleavage of excess acetic anhydride, the acetylation product is caused to separate by addition of hydrochloric acid. The product is purified by dissolving in highly diluted aqueous ammonia, treating the solution with animal charcoal, slightly acidifying the filtrate with acetic acid and further treating with animal charcoal. After filtration, hydrochloric acid is added, whereby pure 3,5-bis-(acetylamino)-2,4,6-triiodohippuric acid
skiller seg ut som et fargeløst bunnfall. Smeltepunktet er 263° C (spaltning). Ut-byttet er 55 g tilsvarende 82 % av det teoretiske. stands out as a colorless precipitate. The melting point is 263° C (decomposition). The yield is 55 g corresponding to 82% of the theoretical.
Ved intravenøs anvendelse på rotter må der brukes doser på over 13,6 g pr. kg legemsvekt for å få en dødelighet på 50 % For intravenous use in rats, doses of more than 13.6 g per kg of body weight to obtain a mortality rate of 50%
(LDbo). (LDbo).
3,5-diamino-2,4,6-trijodhippursyre som anvendes som utgangsmateriale i dette eksempel kan fremstilles av 3,5-dinitrobenzoylklorid og glykokoll etter Schotten-Baumann hvorved man får 3,5-dinitrohippur-syre med smeltepunkt 176° C. Ved reduksjon av sistnevnte forbindelse får man 3,5-diaminohippursyre med smeltepunkt 170° C som sluttelig joderes med 3 mol monoklorjod i saltsur oppløsning. 3,5-diamino-2,4,6-triiodohippuric acid, which is used as starting material in this example, can be prepared from 3,5-dinitrobenzoyl chloride and glycocoll according to Schotten-Baumann, whereby 3,5-dinitrohippuric acid with a melting point of 176° C is obtained. By reducing the latter compound, 3,5-diaminohippuric acid with a melting point of 170° C is obtained, which is finally iodinated with 3 mol of monochloroiodine in hydrochloric acid solution.
Eksempel 2: Example 2:
64,3 g 3,5-diamino-2,4,6-trijodbenzoyl-N-d,l-leucin med smeltepunkt 167—168° C (fremstillet ved jodering av 3,5-diamino-benzoyl-N-d,l-leucin som kan erholdes ved reduksjon av 3,5-dinitrobenzoyl-N-d,l-leu-cin med smeltepunkt 199° C) oppvarmes 15 minutter med 300 ml eddiksyreanhydrid på vannbad hvorpå oppløsnnigen opparbeides videre som angitt i eksempel 1. Man får med et utbytte på 58 g tilsvarende 80 % av det teoretiske bis-(3,5-acetylamino)-2,4,6-trijodbenzoyl-N-d,l-leucin med smeltepunkt 249—250° C (spaltning). 64.3 g of 3,5-diamino-2,4,6-triiodobenzoyl-N-d,l-leucine with melting point 167-168° C (produced by iodination of 3,5-diamino-benzoyl-N-d,l-leucine which can obtained by reduction of 3,5-dinitrobenzoyl-N-d,l-leucine with a melting point of 199° C) is heated for 15 minutes with 300 ml of acetic anhydride in a water bath, after which the solvent is worked up further as indicated in example 1. A yield of 58 g is obtained corresponding to 80% of the theoretical bis-(3,5-acetylamino)-2,4,6-triiodobenzoyl-N-d,l-leucine with melting point 249-250° C (decomposition).
Eksempel 3: Example 3:
58,7 g 3,5-diamino-2,4,6-trijodhippur-syre og 400 ml propionsyreanhydrid oppvarmes i 15 minutter til kokning. Etter avkjø- 58.7 g of 3,5-diamino-2,4,6-triiodohippuric acid and 400 ml of propionic anhydride are heated for 15 minutes to boiling. After cool-
ling røres den klare oppløsning inn i vann hvorpå den opparbeides videre som angitt i eksempel 1. Man får på denne måte med godt utbytte bis-(3,5-propionylamino-)-2,4,6-trijodhippursyre som ved oppvarmning til 275—280° C spaltes under avspaltning av jod. ling, the clear solution is stirred into water, after which it is worked up further as indicated in example 1. In this way, bis-(3,5-propionylamino-)-2,4,6-triiodohippuric acid is obtained in good yield, which when heated to 275— 280° C decomposes during the decomposition of iodine.
Eksempel 4: Example 4:
58,7 g 3,5-diamino-2,4,6-trijodhippur-syre suspenderes i 300 ml maursyre og sus-pensjonen tildryppes ved romtemperatur og under omrøring 80 ml eddiksyreanhydrid. Herved oppvarmes blandingen hvor-under hippursyren går i oppløsning. Den klare oppløsning omrøres ytterligere 2 ti-mer på vannbad, hvorpå den avkjøles og helles i 2 liter vann. Etter 24 timers henstand suger man væsken bort fra bunnfallet som renses således som angitt i eksempel 1. Man får herved svakt gulfarget 3,5-bis- (f ormylamino) -2,4,6-trijodhippursyre som spaltes ved oppvarmning til 250° under avspaltning av jod. 58.7 g of 3,5-diamino-2,4,6-triiodohippuric acid are suspended in 300 ml of formic acid and the suspension is added dropwise at room temperature and with stirring to 80 ml of acetic anhydride. The mixture is thereby heated, during which the hippuric acid dissolves. The clear solution is stirred for a further 2 hours in a water bath, after which it is cooled and poured into 2 liters of water. After a 24-hour standstill, the liquid is sucked away from the precipitate, which is purified as indicated in example 1. This gives faintly yellow-coloured 3,5-bis-(formylamino)-2,4,6-triiodohippuric acid, which decomposes when heated to 250° under separation of iodine.
Eksempel 5: Example 5:
60,1 g 3,5-diamino-2,4,6-trijodbenzoyl-N-d,l-alanin med smeltepunkt 170—172° C (spaltning) (fremstillet ved jodering av 3,5-diaminobenzoyl-N-d,l-alanin som kan fåes ved reduksjon av 3,5-dinitrobenzoyl-N-d,l-alanin med smeltepunkt 170—172° C) oppvarmes til ca. 120° C under omrøring med 400 ml eddiksyreanhydrid og noen drå-per konsentrert svovelsyre inntil alt er gått i oppløsning. Overskudd av eddiksyreanhydrid og eddiksyre som har dannet seg av-destilleres i vakuum og det halvfaste resi-duum omrøres med 300 ml vann inntil det går over i fast tilstand. Det erholdte produkt underkastes en rensning således som angitt i eksempel 1. Man får herved fargeløst 3,5-bis-(acetylamino)-2,4,6-trijodbenzoyl-N-d,l-alanin. Etter tørring ved romtemperatur inneholder denne forbindelse 1 mol krystallvann og smelter under spaltning ved 269—270° C. 60.1 g of 3,5-diamino-2,4,6-triiodobenzoyl-N-d,l-alanine with melting point 170-172° C (decomposition) (prepared by iodination of 3,5-diaminobenzoyl-N-d,l-alanine as can be obtained by reduction of 3,5-dinitrobenzoyl-N-d,l-alanine with melting point 170-172° C) is heated to approx. 120° C while stirring with 400 ml of acetic anhydride and a few drops of concentrated sulfuric acid until everything has dissolved. Excess acetic anhydride and acetic acid that has formed are distilled off in a vacuum and the semi-solid residue is stirred with 300 ml of water until it turns into a solid state. The product obtained is subjected to a purification as indicated in example 1. This gives colorless 3,5-bis-(acetylamino)-2,4,6-triiodobenzoyl-N-d,l-alanine. After drying at room temperature, this compound contains 1 mol of crystal water and melts during decomposition at 269-270° C.
Eksempel 6: Example 6:
34,4 g N-(3,5-dinitrobenzoyl)-a-aminofenyleddiksyre med smeltepunkt 230—232° C (fremstillet ved omsetning av 3,5-dinitrobenzoylklorid med a-aminofenyleddiksyre i alkalisk oppløsning) behandles med en opp-løsning av 136 g tinnkloryr i 500 ml konsentrert saltsyre i varme inntil alt er gått i oppløsning. Den klare oppløsning avkjøles, fortynnes med 3 liter vann, og den fortyn-nede oppløsning tilsettes dråpevis 49 g monoklorjod i 50 ml 20 %'s saltsyre. Der utskiller seg herved et gult voluminøst bunnfall fra hvilket væsken trekkes bort etter 1 times henstand. Bunnfallet vaskes derpå med svovelsyrling og vann. Man får hervedN-(3,5-diamino-2,4,6-trijodbenzoyl)-a-aminofenyleddiksyre som spaltes under avspaltning av jod ved 180° C. 34.4 g of N-(3,5-dinitrobenzoyl)-α-aminophenylacetic acid with a melting point of 230-232° C (produced by reacting 3,5-dinitrobenzoyl chloride with α-aminophenylacetic acid in alkaline solution) is treated with a solution of 136 g stannous chloride in 500 ml concentrated hydrochloric acid in heat until everything has dissolved. The clear solution is cooled, diluted with 3 liters of water, and 49 g of monochloroiodine in 50 ml of 20% hydrochloric acid is added dropwise to the diluted solution. A voluminous yellow precipitate is thereby separated from which the liquid is drawn off after 1 hour's rest. The precipitate is then washed with sulfuric acid and water. This gives N-(3,5-diamino-2,4,6-triiodobenzoyl)-a-aminophenylacetic acid, which is decomposed during the elimination of iodine at 180°C.
Acetyleringen skjer ved å oppvarme syren med fire ganger dens mengde eddiksyreanhydrid inntil alt er gått i oppløsning. Oppløsningen omrøres med ti ganger sitt volum vann for å spalte overskuddet av eddiksyreanhydrid hvorpå acetyleringsproduktet bringes til å skille seg ut kvantita-tivt ved tilsetning av saltsyre. Rensningen av råproduktet utføres som angitt i eksempel 1. Man får nesten fargeløs N-[3,5-bis-(acetylamino)-2,4,6-trijodbenzoyl]-a-aminofenyleddiksyre som ved 280° C be-gynner å spaltes under langsom avspaltning av jod. The acetylation takes place by heating the acid with four times its amount of acetic anhydride until everything has dissolved. The solution is stirred with ten times its volume of water to split the excess of acetic anhydride, whereupon the acetylation product is caused to separate quantitatively by the addition of hydrochloric acid. The purification of the crude product is carried out as indicated in example 1. Almost colorless N-[3,5-bis-(acetylamino)-2,4,6-triiodobenzoyl]-α-aminophenylacetic acid is obtained which at 280° C begins to decompose under slow release of iodine.
Eksempler på fremstilling av bruksferdige kontrastmidler. Examples of the production of ready-to-use contrast agents.
Eksempel 1: Man oppløser 65 g bis-(3,5-acetylamino-)2,4,6-trijodhippursyre samt 18,9 g metylglukamin i vann og fyller opp til et volum på 100 ml. Man får herved en farge-løs oppløsning som inneholder 369 mg jod pr. ml. 20 ml av denne oppløsning gir ved intravenøs anvendelse i urografi optimale røntgenbilder 10—15 minutter etter inn-sprøytningen. Example 1: 65 g of bis-(3,5-acetylamino-)2,4,6-triiodohippuric acid and 18.9 g of methylglucamine are dissolved in water and filled to a volume of 100 ml. This results in a colorless solution containing 369 mg of iodine per ml. 20 ml of this solution when used intravenously in urography gives optimal X-ray images 10-15 minutes after the injection.
Eksempel 2: En oppløsning med følgende sammen-setning er egnet til bronkografi: 16,8 g metylglukaminsalt av bis-(3,5-acetylamino-) 2,4,6-trij odhippur-syren 8 mg Titripleks 3 64 mg natriumcitrat brakt på et totalvolum på 20 ml ved tilsetning av vann. Example 2: A solution with the following composition is suitable for bronchography: 16.8 g methylglucamine salt of bis-(3,5-acetylamino-) 2,4,6-triiodhippuric acid 8 mg Titriplex 3 64 mg sodium citrate brought to a total volume of 20 ml by adding water.
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62696567A | 1967-03-30 | 1967-03-30 | |
| US639315A US3888846A (en) | 1967-03-30 | 1967-05-18 | Process for 2(2-(1,3-diazacycloalk-2-enyl))benzophenone derivatives and 1,3-diazacycloalkenyl(2,1-a)isoindole derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO127239B true NO127239B (en) | 1973-05-28 |
Family
ID=27090306
Family Applications (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO1212/68A NO124111B (en) | 1967-03-30 | 1968-03-29 | |
| NO03753/71*[A NO127239B (en) | 1967-03-30 | 1971-10-12 | |
| NO03754/71*[A NO127350B (en) | 1967-03-30 | 1971-10-12 | |
| NO03755/71*[A NO127351B (en) | 1967-03-30 | 1971-10-12 | |
| NO03752/71*[A NO127238B (en) | 1967-03-30 | 1971-10-12 |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO1212/68A NO124111B (en) | 1967-03-30 | 1968-03-29 |
Family Applications After (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO03754/71*[A NO127350B (en) | 1967-03-30 | 1971-10-12 | |
| NO03755/71*[A NO127351B (en) | 1967-03-30 | 1971-10-12 | |
| NO03752/71*[A NO127238B (en) | 1967-03-30 | 1971-10-12 |
Country Status (8)
| Country | Link |
|---|---|
| JP (2) | JPS4843360B1 (en) |
| ES (1) | ES352173A1 (en) |
| IE (1) | IE31999B1 (en) |
| IL (1) | IL29651A (en) |
| MY (1) | MY7300459A (en) |
| NO (5) | NO124111B (en) |
| SE (1) | SE346318B (en) |
| YU (1) | YU33929B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS50125392U (en) * | 1974-03-30 | 1975-10-14 |
-
1968
- 1968-03-18 IL IL29651A patent/IL29651A/en unknown
- 1968-03-27 SE SE4081/68A patent/SE346318B/xx unknown
- 1968-03-29 IE IE366/68A patent/IE31999B1/en unknown
- 1968-03-29 NO NO1212/68A patent/NO124111B/no unknown
- 1968-03-29 YU YU717/68A patent/YU33929B/en unknown
-
1969
- 1969-05-19 ES ES352173A patent/ES352173A1/en not_active Expired
-
1970
- 1970-08-03 JP JP45067352A patent/JPS4843360B1/ja active Pending
-
1971
- 1971-10-12 NO NO03753/71*[A patent/NO127239B/no unknown
- 1971-10-12 NO NO03754/71*[A patent/NO127350B/no unknown
- 1971-10-12 NO NO03755/71*[A patent/NO127351B/no unknown
- 1971-10-12 NO NO03752/71*[A patent/NO127238B/no unknown
-
1973
- 1973-02-09 JP JP48016353A patent/JPS5017479B1/ja active Pending
- 1973-12-30 MY MY459/73A patent/MY7300459A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPS4843360B1 (en) | 1973-12-18 |
| IE31999L (en) | 1968-09-30 |
| IL29651A (en) | 1972-07-26 |
| YU71768A (en) | 1978-02-28 |
| NO127351B (en) | 1973-06-12 |
| JPS5017479B1 (en) | 1975-06-20 |
| SE346318B (en) | 1972-07-03 |
| IE31999B1 (en) | 1973-03-07 |
| NO124111B (en) | 1972-03-06 |
| NO127238B (en) | 1973-05-28 |
| ES352173A1 (en) | 1969-10-01 |
| YU33929B (en) | 1978-09-08 |
| NO127350B (en) | 1973-06-12 |
| MY7300459A (en) | 1973-12-31 |
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