NO177461B - Triodobenzene compounds and contrast agents containing these - Google Patents

Triodobenzene compounds and contrast agents containing these Download PDF

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NO177461B
NO177461B NO892189A NO892189A NO177461B NO 177461 B NO177461 B NO 177461B NO 892189 A NO892189 A NO 892189A NO 892189 A NO892189 A NO 892189A NO 177461 B NO177461 B NO 177461B
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NO892189L (en
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Michel Schaefer
Maryse Dugast-Zrihen
Michel Guillemot
Didier Doucet
Dominique Meyer
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Guerbet Sa
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Priority claimed from FR8900762A external-priority patent/FR2643077B1/en
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Publication of NO892189L publication Critical patent/NO892189L/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21H—OBTAINING ENERGY FROM RADIOACTIVE SOURCES; APPLICATIONS OF RADIATION FROM RADIOACTIVE SOURCES, NOT OTHERWISE PROVIDED FOR; UTILISING COSMIC RADIATION
    • G21H5/00—Applications of radiation from radioactive sources or arrangements therefor, not otherwise provided for 
    • G21H5/02—Applications of radiation from radioactive sources or arrangements therefor, not otherwise provided for  as tracers

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  • High Energy & Nuclear Physics (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Production Of Liquid Hydrocarbon Mixture For Refining Petroleum (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to new nonionic compounds of formula <IMAGE> These compounds can be employed as contrast agents.

Description

Foreliggende oppfinnelse vedrører trijodbenzenforbindelser og kontrastmidler inneholdende disse for anvendelse ved radio-graf i . The present invention relates to triiodobenzene compounds and contrast agents containing these for use in radiography.

Jodbenzenforbindelser inneholdende flere jodatomer i benzen-ringen, vanligvis tre jodatomer pr benzenring, og forskjellig andre substituenter er i lang tid blitt anvendt som kontrastmiddel. Disse andre substituenter er farmakologisk tålbare grupper som gjør at forbindelsene kan tilføres til mennesker og dyr. Generelt, velges disse substituenter, på den ene side, for å gi forbindelsene tilstrekkelig oppløselighet i vann slik at de kan tilføres i .vandig løsning og, på den annen side, for å gi disse forbindelser tilstrekkelig toleranse slik at de Iodobenzene compounds containing several iodine atoms in the benzene ring, usually three iodine atoms per benzene ring, and various other substituents have for a long time been used as contrast agents. These other substituents are pharmacologically tolerable groups which enable the compounds to be administered to humans and animals. In general, these substituents are chosen, on the one hand, to give the compounds sufficient solubility in water so that they can be supplied in aqueous solution and, on the other hand, to give these compounds sufficient tolerance so that they

tolereres av den humane organisme. tolerated by the human organism.

For dette formål har man foreslått ikke-ioniske strukturer, For this purpose, non-ionic structures have been proposed,

dvs jodbenzenderivater med ikke-ioniske substituenter. i.e. iodobenzene derivatives with non-ionic substituents.

Således ble det i FR patent 2.053.037 foreslått karba-moyljodbenzenforbindelser inneholdende totalt minst en N-hydroksyalkylgruppe og minst to hydroksygrupper. Thus, in FR patent 2,053,037 carbamoyl iodobenzene compounds were proposed containing a total of at least one N-hydroxyalkyl group and at least two hydroxy groups.

En forbindelse som illustrerer denne gruppen er metrizamid som imidlertid har vist seg å ha begrenset stabilitet. A compound that illustrates this group is metrizamide which, however, has been shown to have limited stability.

Formålet med den foreliggende oppfinnelse er å tilveiebringe The purpose of the present invention is to provide

nye ikke-ioniske forbindelser som tolereres godt av den humane organisme, som er svært stabile i vandig løsning og som har en høy oppløselighet i vann og som utviser lav viskositet til løsning. new non-ionic compounds which are well tolerated by the human organism, which are very stable in aqueous solution and which have a high solubility in water and which exhibit low viscosity in solution.

Den foreliggende oppfinnelse vedrører således forbindelser med The present invention thus relates to compounds with

formel I: formula I:

hvori in which

R-L er en gruppe med formel R-L is a group with formula

hvori R5 er C1 - C4-alkyl, C1 - C4-hydroksyalkyl eller C1 - C4-polyhydroksyalkyl, og wherein R5 is C1 - C4 -alkyl, C1 - C4 -hydroxyalkyl or C1 - C4 -polyhydroxyalkyl, and

R6 er hydrogen, C-l - C4-alkyl, Cx - C4-hydroksyalkyl eller R 6 is hydrogen, C 1 - C 4 -alkyl, C 1 - C 4 -hydroxyalkyl or

Cx - C4-polyhydroksyalkyl, Cx - C4-polyhydroxyalkyl,

eller R-j^ er en gruppe med formel or R-j^ is a group of formula

hvori R7 er - C4-hydroksyalkyl eller Cx - C4-polyhydroksy-alkyl, og wherein R7 is - C4-hydroxyalkyl or Cx - C4-polyhydroxy-alkyl, and

R8 er hydrogen eller C1 - C4-alkyl, R8 is hydrogen or C1 - C4 alkyl,

R2 er hydrogen, C-^ - C4-hydroksyalkyl eller Cx - C4-poly-hydroksyalkyl, R 2 is hydrogen, C 1 - C 4 -hydroxyalkyl or C 1 - C 4 -polyhydroxyalkyl,

R3 er hydrogen eller Cx - C4-alkyl, og R3 is hydrogen or Cx - C4 alkyl, and

R4 er valgt fra hydrogen, Cx - C4-alkyl, Cx - C4-h<y>droksyalkyl eller C1 - C4^polyhydroksyalkyl. R4 is selected from hydrogen, Cx - C4 alkyl, Cx - C4 hydroxyalkyl or C1 - C4 polyhydroxyalkyl.

Med en polyhydroksyalkylgruppe menes det, i henhold til foreliggende oppfinnelse, en rettkjedet eller forgrenet polyhydroksyalkylgruppe. By a polyhydroxyalkyl group is meant, according to the present invention, a straight-chain or branched polyhydroxyalkyl group.

En foretrukket forbindelse med formel I er forbindelsen med formel I hvori A preferred compound of formula I is the compound of formula I wherein

Rx = -CO-NH-CH2-CH2OH, R2 = -CH2CH2OH, R3 = H Rx = -CO-NH-CH2-CH2OH, R2 = -CH2CH2OH, R3 = H

R4<=> -CH2-CHOH-CH2OH. R 4 <=> -CH 2 -CHOH-CH 2 OH.

En foretrukket gruppe av forbindelser med formel I er den gruppen som utgjøres av forbindelser av den symmetriske diaminotype, dvs forbindelser med formel: A preferred group of compounds of formula I is the group consisting of compounds of the symmetrical diamino type, i.e. compounds of formula:

hvori R2, R3 og R4 har den ovennevnte betydning. Forbindelsene med formel I kan fremstilles på vanlig måte, særlig ved acylerings- og/eller alkylerings-reaksjoner med utgangspunkt i kjente«forbindelser. wherein R2, R3 and R4 have the above meaning. The compounds of formula I can be prepared in the usual way, in particular by acylation and/or alkylation reactions starting from "known" compounds.

Således kan forbindelsene av den symmetriske diaminotype (forbindelser med formel II) fremstilles ved Thus, the compounds of the symmetrical diamino type (compounds of formula II) can be prepared by

å) acylering av en diaminoforbindelse med formel: å) acylation of a diamino compound of formula:

hvori R2' representerer en R2-gruppe hvis hydroksygrupper er beskyttet, wherein R2' represents an R2 group whose hydroxy groups are protected,

med et syreklorid med formel: with an acid chloride of formula:

hvori R representerer gruppe, hvis hydroksygruppen er beskyttet, b) alkylering av den oppnådde forbindelse, om nødvendig, med et alkylerende reagens med formel: in which R represents group, if the hydroxy group is protected, b) alkylation of the obtained compound, if necessary, with an alkylating reagent of formula:

hvori R'4 har betydningen som angitt over med unntak av hydrogen og Z representerer en labil gruppe slik som et klor-, brom- eller jodatom, i nærvær av en base slik som natriummetylat, natriumetylat, natriumhydrid eller wherein R' 4 has the meaning given above with the exception of hydrogen and Z represents a labile group such as a chlorine, bromine or iodine atom, in the presence of a base such as sodium methylate, sodium ethylate, sodium hydride or

natriumhydr oksyd, sodium hydroxide,

c) avbeskyttelse. c) deprotection.

Forbindelser med formel III er beskrevet i FR patentsøknad Compounds of formula III are described in the FR patent application

FR-A-2.614.299. FR-A-2,614,299.

De andre forbindelser med formel III kan fremstilles på analog måte idet man særlig utgår fra et alkyl-3,5-dinitrobenzoat med formel: The other compounds of formula III can be prepared in an analogous manner, particularly starting from an alkyl-3,5-dinitrobenzoate of formula:

hvori R' er en C1 - C4-alkylgruppe slik som metyl. wherein R' is a C1-C4 alkyl group such as methyl.

Asymmetriske diaminoforbindelser kan også fremstilles ved å utgå fra en forbindelse med formel VI ved: Asymmetric diamino compounds can also be prepared starting from a compound of formula VI by:

a) Reaksjon med et amin med formel: a) Reaction with an amine of formula:

for fremstilling av forbindelser med formel: b) reduksjon ved hjelp av ammoniumsulfid for fremstilling av forbindelser med formel: c) acylering av forbindelsen med formel IX med et syreklorid med formel RC0C1 (IV) for fremstilling av en forbindelse med formel: d) reduksjon og jodering av forbindelsen med formel X for fremstilling av forbindelsen med formel: for the preparation of compounds of formula: b) reduction with ammonium sulphide for the preparation of compounds of formula: c) acylation of the compound of formula IX with an acid chloride of formula RC0Cl (IV) for the preparation of a compound of formula: d) reduction and iodination of the compound of formula X to prepare the compound of formula:

e) alkylering, om nødvendig, av forbindelsen med formel XI med et alkylerende reagens med formel V for fremstilling e) alkylating, if necessary, the compound of formula XI with an alkylating reagent of formula V for preparation

av forbindelsen med formel: of the compound with formula:

f) avbeskyttelse av forbindelsen med formel Xli f) deprotection of the compound of formula Xli

g) acylering av den oppnådde avbeskyttede forbindelse med et g) acylation of the obtained deprotected compound with et

syreklorid med formel: acid chloride with formula:

hvori R'5 representerer en R5-gruppe hvis hydroksygruppe er beskyttet, hvorpå man etter avbeskyttelse oppnår en forbindelse med formel: in which R'5 represents an R5 group whose hydroxy group is protected, whereupon after deprotection a compound of formula is obtained:

idet trinn med f og g om nødvendig kan gjennomføres i motsatt rekkefølge, since steps f and g can be carried out in the opposite order if necessary,

h) alkylering for fremstilling av forbindelser med formel I hvori R6 har betydningene som angitt over, unntatt h) alkylation for the preparation of compounds of formula I in which R 6 has the meanings given above, except

hydrogen. hydrogen.

Symmetriske forbindelser av isoftalsyre-typen (forbindelser Symmetric compounds of the isophthalic acid type (compounds

med formel I hvori of formula I wherein

kan fremstilles ved can be produced by

a) acylering av et amin med formel: a) acylation of an amine of formula:

med et syreklorid med formel RC0C1 (IV) for fremstilling av with an acid chloride of formula RC0C1 (IV) for the preparation of

forbindelser med formel: compounds with formula:

b) reaksjon av forbindelsen med formel XVI med et amin med formel (VII) for fremstilling av forbindelser med formel: b) reaction of the compound of formula XVI with an amine of formula (VII) to produce compounds of formula:

og, om ønsket, enten and, if desired, either

c) alkylering av forbindelsen med formel XVII med et alkylerende reagens med formel R'4Z slik som det som er c) alkylating the compound of formula XVII with an alkylating reagent of formula R'4Z such as

angitt over og til slutt stated above and finally

d) fjerning av beskyttelsesgruppene fra -CH (CH2H) 2-gruppen, eller e) fjerning av beskyttelsesgruppen fra -CH (CH2OH) 2-gruppen og, om ønsket f) alkylering av den avbeskyttede forbindelse med et alkylerende reagens R'4Z. d) deprotecting the -CH(CH2H)2 group, or e) deprotecting the -CH(CH2OH)2 group and, if desired f) alkylating the deprotected compound with an alkylating reagent R'4Z.

De asymmetriske forbindelser av isoftalsyre-typen The asymmetric compounds of the isophthalic acid type

(forbindelser med formel I hvori (compounds of formula I wherein

med R7 / R2 og/eller R8 ? R3) kan fremstilles ved a) acylering av et amin med formel: with R7 / R2 and/or R8 ? R3) can be prepared by a) acylation of an amine with formula:

med et syreklorid med formel RC0C1, with an acid chloride of formula RC0C1,

b) alkylering, om ønsket, med et alkylerende reagens med formel R'4Z og c) fjerning av beskyttelsesgruppene fra -CH-(CH2OH) 2-gruppen. b) alkylation, if desired, with an alkylating reagent of formula R' 4 Z and c) deprotection of the -CH-(CH 2 OH) 2 group.

Forbindelsen med formel XVIII kan oppnås som beskrevet i EP-O-015.867. The compound of formula XVIII can be obtained as described in EP-O-015,867.

Alternativt, kan de asymmetriske forbindelser av isoftalsyre-typen fremstilles ved Alternatively, the asymmetric compounds of the isophthalic acid type can be prepared by

a) acylering av et amin med formel: a) acylation of an amine of formula:

hvori R'7 representerer en R7-gruppe hvori hydroksygruppen er wherein R'7 represents an R7 group in which the hydroxy group is

beskyttet, protected,

med et syreklorid med formel RC0C1 (IV) for fremstilling av en forbindelse med formel: with an acid chloride of formula RC0C1 (IV) to produce a compound of formula:

b) reaksjon av forbindelsen med formel XX med et amin med formel: for fremstilling av en forbindelse med formel: b) reaction of the compound of formula XX with an amine with formula: for the preparation of a compound of formula:

og, om ønsket, enten and, if desired, either

c) alkylering av forbindelsen med formel XXI med et alkylerende reagens med formel R'4Z slik som det som er c) alkylating the compound of formula XXI with an alkylating reagent of formula R'4Z such as

angitt over, og til slutt stated above, and finally

d) fjerning av beskyttelsesgruppene fra -CH-(CH2OH)2-gruppen, eller e) fjerning av beskyttelsesgruppene fra -CH-(CH2OH)2-gruppen, og om ønsket, f) alkylering av den avbeskyttede forbindelse med et alkylerende reagens R'4Z. d) removing the protecting groups from the -CH-(CH2OH)2 group, or e) removing the protecting groups from the -CH-(CH2OH)2 group, and if desired, f) alkylating the deprotected compound with an alkylating reagent R' 4Z.

Et annet formål med den foreliggende oppfinnelse er kontrastmidler, som inneholder minst en forbindelse med generell formel I. Another object of the present invention is contrast agents, which contain at least one compound of general formula I.

Disse kontrastmidler anvendes i mennesker og dyr for radiologiske formål. These contrast agents are used in humans and animals for radiological purposes.

Den foretrukne farmasøytiske type kontrastmidler i henhold til oppfinnelsen består av vandige løsninger av forbindelsene. The preferred pharmaceutical type of contrast agents according to the invention consists of aqueous solutions of the compounds.

De vandige løsninger inneholder vanligvis totalt fra 5 - 100 g forbindelser med formel I pr 100 ml og volumet som skal injiseres av en slik løsning varierer vanligvis fra 1 - 1000 ml. The aqueous solutions usually contain a total of from 5 - 100 g of compounds of formula I per 100 ml and the volume to be injected of such a solution usually varies from 1 - 1000 ml.

Den vandige løsning av forbindelsene med formel I kan også inneholde tilsetningsmidler slik som: natriumklorid i konsentrasjoner mellom 0,1 og 10 mM/1 dinatrium EDTA i konsentrasjoner mellom 0,1 og 2 mM/1 natriumcitrat i konsentrasjoner mellom 0,1 og 10 mM/1 heparin i doser mellom 10 og 100 enheter pr 100 ml The aqueous solution of the compounds of formula I can also contain additives such as: sodium chloride in concentrations between 0.1 and 10 mM/1 disodium EDTA in concentrations between 0.1 and 2 mM/1 sodium citrate in concentrations between 0.1 and 10 mM /1 heparin in doses between 10 and 100 units per 100 ml

løsning. solution.

Disse forbindelser kan tilføres på alle vanlig anvendte måter for joderte ikke-ioniske kontrastmidler. Således kan de tilføres enteralt eller parenteralt (intravenøs tilførsel, intra-arteriell tilførsel, opasifisering av hulrom) og de kan særlig tilføres i det subarachonoide hulrom. These compounds can be added in all commonly used ways for iodinated non-ionic contrast agents. Thus, they can be administered enterally or parenterally (intravenous administration, intra-arterial administration, opacification of cavities) and they can especially be administered in the subarachnoid cavity.

Et eksempel på middelet i henhold til oppfinnelsen er gitt i det følgende. An example of the agent according to the invention is given below.

Følgende eksempler illustrerer fremstillingen av forbindelsene med formel I. The following examples illustrate the preparation of the compounds of formula I.

EKSEMPEL 1 EXAMPLE 1

Fremstilling av 5-[3-hydroksy-2-(hydroksymetyl)-N-(2,3-dihydroksypropyDpropionamido] -N' ,N'' -bis- (2-hydroksyetyl) - 2,4,6-trijodoisoftalamid. a) Fremstilling av 5-[ 2- isopropyl- l, 3- dioksan- 5- karboks-amido]- 2, 4, 6- trijodisoftaloyldiklorid. Preparation of 5-[3-hydroxy-2-(hydroxymethyl)-N-(2,3-dihydroxypropylDpropionamido]-N',N''-bis-(2-hydroxyethyl)-2,4,6-triiodoisophthalamide. a) Preparation of 5-[2-isopropyl-1,3-dioxane-5-carboxamido]-2,4,6-triiododisophthaloyl dichloride.

137 g 5-amino-2,4,6-trijodisoftaloylklorid (0,23 mol) oppløses i 460 ml DMAC hvortil det tilsettes 110 g (0,57 mol) 2-isopropyl-1,3-dioksan-5-karboksylsyreklorid. Reaksjonsblandingen omrøres under argon ved omgivelsestemperatur i fire døgn. DMAC fjernes i vakuum. Den oppnådde olje ekstraheres med 3 1 etylacetat og vaskes to ganger med 1 1 isvann. Den 137 g of 5-amino-2,4,6-triiododisophthaloyl chloride (0.23 mol) are dissolved in 460 ml of DMAC to which 110 g (0.57 mol) of 2-isopropyl-1,3-dioxane-5-carboxylic acid chloride are added. The reaction mixture is stirred under argon at ambient temperature for four days. DMAC is removed in vacuo. The oil obtained is extracted with 3 1 ethyl acetate and washed twice with 1 1 ice water. It

organiske fase tørkes og konsentreres til tørrhet. Produktet krystalliseres fra 200 ml CH2C12. Etter filtrering, oppnås 110 g fast stoff: organic phase is dried and concentrated to dryness. The product is crystallized from 200 ml of CH2C12. After filtration, 110 g of solid are obtained:

Utbytte: 64 % Yield: 64%

TLC: Si02 CH2C12 Rf: 0,13 (60 F 254) Si02 eter/petroleumseter 50/50 TLC: SiO2 CH2C12 Rf: 0.13 (60 F 254) SiO2 ether/petroleum ether 50/50

Rf: 0,52 Rf: 0.52

b) Fremstilling av 5-[ 2- isopropyl- l, 3- dioksan- 5- karboks-amido]- N', N''- bis-( 2- hvdroksvetyl)- 2, 4, 6- trijodisoftalamid b) Preparation of 5-[2-isopropyl-1,3-dioxane-5-carboxamido]-N',N''-bis-(2-hydroxymethyl)-2,4,6-triiododisophthalamide

130 g av produktet oppnådd i a (0,173 mol) oppløses i en løsning av 750 ml DMAC og 75 ml (0,534 mol) trietylamin. 130 g of the product obtained in a (0.173 mol) are dissolved in a solution of 750 ml of DMAC and 75 ml (0.534 mol) of triethylamine.

33,7 g etanolamin (0,552 mol) tilsettes dråpevis til reaksjonsblandingen. Reaksjonsblandingen omrøres deretter i tre timer ved omgivelsestemperatur. Trietylaminhydrokloridet fjernes ved filtrering og DMAC fjernes i vakuum. Den oppnådde olje krystalliseres fra 1 liter vann. Produktet avfiltreres og tørkes i vakuum. 33.7 g of ethanolamine (0.552 mol) are added dropwise to the reaction mixture. The reaction mixture is then stirred for three hours at ambient temperature. The triethylamine hydrochloride is removed by filtration and the DMAC is removed in vacuo. The obtained oil is crystallized from 1 liter of water. The product is filtered off and dried in a vacuum.

Utbytte: 95 % Yield: 95%

TLC: Si02 Rf: 0,25 CH2C12/metanol 9/1 TLC: SiO 2 Rf: 0.25 CH 2 Cl 2 /methanol 9/1

(60F254) Si02 Rf: 0,67 CH2Cl2/metanol 8/2 (60F254) SiO2 Rf: 0.67 CH2Cl2/methanol 8/2

% I : 45,6 (funnet) - 47,6 (teoretisk) % I : 45.6 (found) - 47.6 (theoretical)

Hypersil C8 5 Jim 15 cm HPLC-renhet: 97 % 0,01 M NaH2P04 = 50 Hypersil C8 5 Jim 15 cm HPLC purity: 97% 0.01 M NaH2PO4 = 50

Metanol - 50 Methanol - 50

c) Fremstilling av 5-[ 3- hydroksy- 2- hydroksymetvl- N-( 2, 3-dihvdroksypropyl)- propionamido]- N', N''- bis-( 2- hydroksyetyl)-2, 4, 6- trijodisoftalamid. c) Preparation of 5-[3-hydroxy-2-hydroxymethyl-N-(2,3-dihydrohydroxypropyl)-propionamido]-N',N''-bis-(2-hydroxyethyl)-2,4,6-triiododisophthalamide .

Til en suspensjon av 100 g av produktet oppnådd i b (0,125 mol) i 350 ml etylenglykol tilsettes dråpevis 125 ml (0,5 mol) 4 N metylen ved 60°C etterfulgt av 65 g (0,625 mol) 1-klor-2, 3-propandiol. Etter en time ved 60°C har massen i reaksjonsblandingen økt. 100 ml (0,4 mol) 4 N metylat og 55,2 g (0,5 mol) l-klor-2,3-propandiol tilsettes. Blandingen holdes over natten ved 60°C. En ytterligere tilsetning av 31 ml (0,125 mol) 4 N metylat og 20,7 l-klor-2,3-propandiol gjennomføres. Omrøring opprettholdes i 4 timer ved 60°C.. Mineralsaltene fjernes ved filtrering. Etylenglykol avdampes i vakuum. To a suspension of 100 g of the product obtained in b (0.125 mol) in 350 ml of ethylene glycol is added dropwise 125 ml (0.5 mol) of 4 N methylene at 60°C followed by 65 g (0.625 mol) of 1-chloro-2, 3 -propanediol. After one hour at 60°C, the mass in the reaction mixture has increased. 100 ml (0.4 mol) of 4 N methylate and 55.2 g (0.5 mol) of 1-chloro-2,3-propanediol are added. The mixture is kept overnight at 60°C. A further addition of 31 ml (0.125 mol) of 4 N methylate and 20.7 l of chloro-2,3-propanediol is carried out. Stirring is maintained for 4 hours at 60°C. The mineral salts are removed by filtration. Ethylene glycol is evaporated in a vacuum.

Destillasjonsresten opptas i 800 ml 10 N HC1 og løsningen omrøres over natten ved omgivelsestemperatur. Reaksjonsblandingen konsentreres til tørrhet og resten opptas i 300 ml etanol. Mineralsaltene fjernes ved filtrering. Etanolen avdampes i vakuum og resten krystalliseres fra 1 liter isopropylalkohol. Presipitatet avfiltreres og renses ved HPLC (RP 18) (eluering med vann). The distillation residue is taken up in 800 ml of 10 N HCl and the solution is stirred overnight at ambient temperature. The reaction mixture is concentrated to dryness and the residue is taken up in 300 ml of ethanol. The mineral salts are removed by filtration. The ethanol is evaporated in vacuo and the residue is crystallized from 1 liter of isopropyl alcohol. The precipitate is filtered off and purified by HPLC (RP 18) (elution with water).

Totalt utbytte (alkylering-avbeskyttelse-rensing): 52 % Total yield (alkylation-deprotection-purification): 52%

1) TLC (silika 60F254) : CH2C12/metanol 7/3 Rf: 0,4 1) TLC (silica 60F254) : CH2C12/methanol 7/3 Rf: 0.4

2) HPLC Hypersil C8 5\ im 15 cm 2) HPLC Hypersil C8 5 µm 15 cm

Buffer 0,01 M NaH2P04 .. 97 Buffer 0.01 M NaH2P04 .. 97

metanol .. 3 methanol .. 3

Renhet: 97 % Purity: 97%

3) % I : 45,8 (funnet) - 46,4 (teoretisk) 3) % I : 45.8 (found) - 46.4 (theoretical)

4) NMR (DMSO) 4) NMR (DMSO)

Dårlig oppløst multiplett sentrert ved 3,5 ppm (18 H); multiplett sentrert ved 4,5 ppm (OH) utbyttbar med D20 (6 H) ; bred topp ved 8,4 ppm (NH) utbyttbar med D20 (2 H) . Poorly resolved multiplet centered at 3.5 ppm (18 H); multiplet centered at 4.5 ppm (OH) exchangeable with D 2 O (6 H); broad peak at 8.4 ppm (NH) exchangeable with D 2 O (2 H) .

EKSEMPEL 2 EXAMPLE 2

Framstilling av 5-glykolamido-3-[3-hydroksy-2-hydroksymetyl-N-(2,3-dihydroksypropyl)-propionamido]-2,4,6-trijod-N-hydroksymetylbenzamid Preparation of 5-glycolamido-3-[3-hydroxy-2-hydroxymethyl-N-(2,3-dihydroxypropyl)-propionamido]-2,4,6-triiodo-N-hydroxymethylbenzamide

a) Fremstilling av 3, 5- dinitro- N-( 2- hvdroksvetyl)- benzamid 750 g (3,32 mol) metyl-3,5-dinitrobenzoat suspenderes i 2 a) Preparation of 3,5-dinitro-N-(2-hydroxymethyl)-benzamide 750 g (3.32 mol) methyl-3,5-dinitrobenzoate is suspended in 2

liter metanol i nærvær av 222,7 g (3,65 mol) etanolamin. Reaksjonsblandingen kokes med tilbakeløp i 48 timer inntil esteren har forsvunnet. Etter 4 timer ved romtemperatur, avfiltreres det krystallinske produkt, vaskes med 500 cm<2 >metylenklorid, og tørkes deretter i en ovn ved 60°C og i vakuum i 4 timer. Denne prosedyre fører til utvinning av 718 g produkt i et utbytte på 85 %. liter of methanol in the presence of 222.7 g (3.65 mol) of ethanolamine. The reaction mixture is refluxed for 48 hours until the ester has disappeared. After 4 hours at room temperature, the crystalline product is filtered off, washed with 500 cm<2 >methylene chloride, and then dried in an oven at 60°C and in vacuum for 4 hours. This procedure leads to the recovery of 718 g of product in a yield of 85%.

Smeltepunkt: 140°C. Melting point: 140°C.

TLC (toluen/metyletylketon/maursyre (60/25/25) Rf: 0,5. TLC (toluene/methyl ethyl ketone/formic acid (60/25/25) Rf: 0.5.

b) Fremstilling av 3- nitro- 5- amino- N-( 2- hvdroksvetvl)-benzamid. b) Preparation of 3-nitro-5-amino-N-(2-hydroxyhydroxy)-benzamide.

Til en suspensjon av 25,5 g (0,5 mol) 3,5-dinitro-N-(2-hydroksyetyl)-benzamid i 135 cm<2> vann tilsettes ved 70°C 12,25 g (0,18 mol) ammoniumsulfid. Ved endt tilsetning er blandingen homogen, men represipitering skjer etter en halv time ved 70°C. Reaksjonsblandingen får avkjøle til omgivelsestemperatur og omrøringen fortsettes i to timer. Presipitatet avfiltreres, vaskes med metanol (70 cm<2>) og tørkes i en ovn (60°C). At 70°C, 12.25 g (0.18 mol ) ammonium sulfide. At the end of the addition, the mixture is homogeneous, but precipitation occurs after half an hour at 70°C. The reaction mixture is allowed to cool to ambient temperature and stirring is continued for two hours. The precipitate is filtered off, washed with methanol (70 cm<2>) and dried in an oven (60°C).

Oppnådde masse : 15,1 g - Utbytte 67 % Mass obtained: 15.1 g - Yield 67%

TLC (toluen/metyletylketon/maursyre 60/25/25). Rf : 0,3 TLC (toluene/methyl ethyl ketone/formic acid 60/25/25). Rf : 0.3

% NMR (DMSO): 3,4 ppm (multiplett; 4H, CH2 alifatisk); 4,65 ppm (multiplet, H utbyttbar med D20, NH2); 5,9 ppm (singlett, H utbyttbar med D20, OH) ; 7,4 - 7,7 ppm (2 multipletter; 3H, aromatiske protoner); 8,6 ppm (multiplett, 1H, NH). % NMR (DMSO): 3.4 ppm (multiplet; 4H, CH2 aliphatic); 4.65 ppm (multiplet, H exchangeable with D 2 O, NH 2 ); 5.9 ppm (singlet, H exchangeable with D 2 O, OH) ; 7.4 - 7.7 ppm (2 multiplets; 3H, aromatic protons); 8.6 ppm (multiplet, 1H, NH).

c) Fremstilling av 3- nitro- 5-[ 2- isopropyl- l, 3- dioksan- 5-karboksamido]- N- hvdroksvetylbenzamid 40 g (0,177 mol) 3-nitro-5-amino-N-(2-hydroksyetyl)-benzamid oppløses i 400 cm<2> DMAC. Tilsetningen av 74,9 g (0,389 mol) 2-isopropyl-l,3-dioksan-5-karboksylsyreklorid i nærvær av trietylamin (54,6 cm<2>) gir en eksotermisk reaksjon. c) Preparation of 3-nitro-5-[2-isopropyl-1,3-dioxane-5-carboxamido]-N-hydroxymethylbenzamide 40 g (0.177 mol) 3-nitro-5-amino-N-(2-hydroxyethyl) -benzamide is dissolved in 400 cm<2> DMAC. The addition of 74.9 g (0.389 mol) of 2-isopropyl-1,3-dioxane-5-carboxylic acid chloride in the presence of triethylamine (54.6 cm<2>) gives an exothermic reaction.

Reaksjonsblandingen holdes under argon i 18 timer ved omgivelsestemperatur. Blandingen filtreres og filtratet fortynnes med vann og ekstraheres med etylacetat. Resten som oppnås etter avdamping av løsningsmidlet behandles med kaliumkarbonat (12 g) i 300 cm<2> metanol. Etter omrøring ved omgivelsestemperatur i 48 timer, konsentreres blandingen, og ekstraheres deretter med etylacetat. Det urene produkt oppnådd etter behandling rekrystalliseres fra en blanding av en eter/etylacetat 80/20. 37,8 g produkt isoleres i et utbytte på 56 %. The reaction mixture is kept under argon for 18 hours at ambient temperature. The mixture is filtered and the filtrate is diluted with water and extracted with ethyl acetate. The residue obtained after evaporation of the solvent is treated with potassium carbonate (12 g) in 300 cm<2> of methanol. After stirring at ambient temperature for 48 hours, the mixture is concentrated, and then extracted with ethyl acetate. The impure product obtained after treatment is recrystallized from a mixture of an ether/ethyl acetate 80/20. 37.8 g of product is isolated in a yield of 56%.

TLC (etylacetat Rf: 0,48). TLC (ethyl acetate Rf: 0.48).

HPLC Hypersil C8 5|lm 15 cm HPLC Hypersil C8 5|lm 15 cm

Buffer: 0,01 M NaH2P04 50 % Buffer: 0.01 M NaH2PO4 50%

MeOH 50 % MeOH 50%

Renhet: 94 % Purity: 94%

d) Fremstilling av 5- amino- 3-[ 2- isopropyl- l, 3- dioksan- 5-karboksamido]- 2, 4, 6- triiod- N- hvdroksvetylbenzamid. d) Preparation of 5-amino-3-[2-isopropyl-1,3-dioxane-5-carboxamido]-2,4,6-triiodo-N-hydroxybutylbenzamide.

En metanolisk løsning (1,4 1) av 40 g 3-nitro-5-[2-isopropyl-1,3-dioksan-5-karboksamido]-N-hydroksyetylbenzamid omrøres under en hydrogenatmosfære (5 • IO<5> Pa) i fem timer ved 50°C i nærvær av 4 g palladiumholdig kull. Katalysatoren avfiltreres deretter og filtratet avdampes under redusert trykk. Den oppnådde forbindelse suspenderes i 950 cm<2> vann. Blandingen gjøres homogen ved tilsetning av 20 cm<2> 2 N saltsyre. 63 cm<2 >jodklorid (70 % i jod) tilsettes deretter dråpevis under kraftig omrøring. Etter 24 timer ved omgivelsestemperatur avfiltreres presipitatet, vaskes med vann opptas i eter.'Etter tørking, oppnås 32 g produkt i et utbytte på 42 %. A methanolic solution (1.4 1) of 40 g of 3-nitro-5-[2-isopropyl-1,3-dioxane-5-carboxamido]-N-hydroxyethylbenzamide is stirred under a hydrogen atmosphere (5 • 10<5> Pa) for five hours at 50°C in the presence of 4 g of palladium-containing charcoal. The catalyst is then filtered off and the filtrate is evaporated under reduced pressure. The compound obtained is suspended in 950 cm<2> of water. The mixture is made homogeneous by adding 20 cm<2> of 2 N hydrochloric acid. 63 cm<2 >iodine chloride (70% in iodine) is then added dropwise with vigorous stirring. After 24 hours at ambient temperature, the precipitate is filtered off, washed with water and taken up in ether. After drying, 32 g of product are obtained in a yield of 42%.

TLC (diklormetan/metanol 90/10) Rf: 0,8 TLC (dichloromethane/methanol 90/10) Rf: 0.8

e) Fremstilling av 5- amino- 3-[ N-( 2, 3- dihvdroksvpropyl)- 2-isopropvl- 1, 3- dioksan- 5- karboksamido1- 2, 4, 6- trijod- N-hydroksyetylbenzamid. e) Preparation of 5-amino-3-[N-(2,3-dihydroxpropyl)-2-isopropyl-1,3-dioxane-5-carboxamido-1-2,4,6-triiodo-N-hydroxyethylbenzamide.

Til en løsning av forbindelsen oppnådd i d) (20 g, 0,027 mol) i en blanding av etylenglykol-dimetylformamid v/v (160 ml) tilsettes dråpevis 84 cm<2> (0,337 mol) 4 N natriummetylat. Blandingen oppvarmes ved 60°C i en halv time og 36,1 cm<2 >(0,432 mol) l-klor-2,3-propandiol tilsettes ved denne temperatur. Reaksjonsblandingen holdes ved 60°C under nitrogen i 60 timer. Mineralsaltene fjernes ved filtrering. Etylenglykol og DMF avdampes i vakuum. Det oppnådde urene produkt renses på silanisert silika (eluering med vann, etterfulgt av vann/metanol 50/50). 16,5 g produkt isoleres. Ubytte 76 %. To a solution of the compound obtained in d) (20 g, 0.027 mol) in a mixture of ethylene glycol-dimethylformamide v/v (160 ml) is added dropwise 84 cm<2> (0.337 mol) of 4 N sodium methylate. The mixture is heated at 60°C for half an hour and 36.1 cm<2 >(0.432 mol) of 1-chloro-2,3-propanediol is added at this temperature. The reaction mixture is kept at 60°C under nitrogen for 60 hours. The mineral salts are removed by filtration. Ethylene glycol and DMF are evaporated in a vacuum. The impure product obtained is purified on silanized silica (elution with water, followed by water/methanol 50/50). 16.5 g of product is isolated. Untraded 76%.

TLC (diklormetan/metanol 80/20). Rf: 0,8 TLC (dichloromethane/methanol 80/20). Rf: 0.8

f) Fremstilling av 5- amino- 3-[ 3- hydroksy- 2-( hvdroksvmetyl)-N-( 2, 3- dihydroksypropvl)- propionamidol- 2, 4, 6- trijod- N-hydroksyetylbenzamid. 16 g (0,02 mol) av produktet oppnådd i e) avbeskyttes i nærvær av 80 cm<2> 10 N saltsyre i 48 timer ved omgivelsestemperatur. Etter nøytralisering og avdamping under redusert trykk, presipiteres resten med en blanding av metanoleter (9/1), avfiltreres og renses deretter ved HPLC (RP 18) (eluering med vann, deretter med vann/metanol 90/10). 4 g produkt isoleres i et totalt utbytte (avbeskyttelse, rensing) på 30 %. f) Preparation of 5-amino-3-[3-hydroxy-2-(hydroxymethyl)-N-(2,3-dihydroxypropyl)-propionamidol-2,4,6-triiodo-N-hydroxyethylbenzamide. 16 g (0.02 mol) of the product obtained in e) is deprotected in the presence of 80 cm<2> 10 N hydrochloric acid for 48 hours at ambient temperature. After neutralization and evaporation under reduced pressure, the residue is precipitated with a mixture of methanol ether (9/1), filtered off and then purified by HPLC (RP 18) (elution with water, then with water/methanol 90/10). 4 g of product is isolated in a total yield (deprotection, purification) of 30%.

TLC (diklormetan/metanol 80/20). Rf: 0,25 TLC (dichloromethane/methanol 80/20). Rf: 0.25

HPLC Hypersil C8 5|lm 15 cm. HPLC Hypersil C8 5|lm 15 cm.

Buffer: 0,01 M NaH2P04 90 % Buffer: 0.01 M NaH2PO4 90%

MeOH 10 % MeOH 10%

Renhet: 97 %. Purity: 97%.

g) Fremstilling av 5- N- glvkolamido- 3- f3- hvdroksv- 2-( hvdroksvmetyl)- N-( 2, 3- dihvdroksypropyl)- propionamidol- 2, 4, 6-triiod- N- hydroksvetylbenzamid. g) Preparation of 5-N-glucolamido-3-f3-hydroxy-2-(hydroxymethyl)-N-(2,3-dihydroxypropyl)-propionamidol-2,4,6-triiodo-N-hydroxybutylbenzamide.

5,5 g O-acetylert glykolsyreklorid (0,04 mol) tilsettes dråpevis ved omgivelsestemperatur til en løsning av 3 g av forbindelsen oppnådd i trinn f (0,004 mol) i 30 cm<2> vannfri DMAC. Reaksjonsblandingen oppvarmes ved 40°C i 12 timer, og helles deretter over i 250 cm<2> isvann. Det oppnådde presipitat avfiltreres og ekstraheres med etylacetat. Etter behandling etterfulgt av avdamping,, avbeskyttes det oppnådde produkt oppløst i 50 cm<2> metanol i nærvær av 10 cm<2> 1 N natriumhydroksyd. Løsningen omrøres ved omgivelsestemperatur i 14 timer, og avsaltes deretter ved påfølgende passeringer gjennom H+ (IRN77) og 0H- (IRN78) harpikser. Etter avdamping til tørrhet, opptas resten i etyleter, filtreres og tørkes. Oppnådd masse: 1,5 g. Totalt utbytte: 47 %. 5.5 g of O-acetylated glycolic acid chloride (0.04 mol) is added dropwise at ambient temperature to a solution of 3 g of the compound obtained in step f (0.004 mol) in 30 cm<2> of anhydrous DMAC. The reaction mixture is heated at 40°C for 12 hours, and then poured into 250 cm<2> of ice water. The precipitate obtained is filtered off and extracted with ethyl acetate. After treatment followed by evaporation, the product obtained is deprotected dissolved in 50 cm<2> methanol in the presence of 10 cm<2> 1 N sodium hydroxide. The solution is stirred at ambient temperature for 14 hours, and then desalted by successive passes through H+ (IRN77) and 0H- (IRN78) resins. After evaporation to dryness, the residue is taken up in ethyl ether, filtered and dried. Mass obtained: 1.5 g. Total yield: 47%.

Renhet i jod: 99 % Purity of iodine: 99%

TLC (etylacetat/metanol/ammoniakk 60/40/1). TLC (ethyl acetate/methanol/ammonia 60/40/1).

Rf: 0,25 Rf: 0.25

HPLC Hypersil C8 5\ lm 15 cm HPLC Hypersil C8 5\ lm 15 cm

Buffer: 0,01 M NaH2P04 90 % Buffer: 0.01 M NaH2PO4 90%

MeOH 10 % MeOH 10%

Renhet: 89 % Purity: 89%

EKSEMPEL 3 EXAMPLE 3

Fremstilling av 3,5-bis- (3-hydroksy-2-hydroksymetyl) -propionamido-2 , 4,6-tri j od-N- (2 , 3-dihydroksypropyl) -benzamid Preparation of 3,5-bis-(3-hydroxy-2-hydroxymethyl)-propionamido-2,4,6-triiodo-N-(2,3-dihydroxypropyl)-benzamide

a) Fremstilling av 3, 5- diamino- 2, 4, 6- triiod- N-( 2, 3-diacetoksvpropyl)- benzamid a) Preparation of 3,5-diamino-2,4,6-triiodo-N-(2,3-diacetoxypropyl)-benzamide

301,5 g (0,5 mol) 3,5-diamino-2,3,6-trijod-N-(2,3-dihydroksy-propyl) -benzamid suspenderes ill vannfri pyridin avkjølt til 15°C. Etter tilsetning av 2.450 ml eddiksyreanhydrid, omrøres blandingen i 18 timer ved omgivelsestemperatur og helles deretter i surgjort vann. Etter ekstrahering med etylacetat, tørking av den organiske fase og avdamping, oppnås 270 g produkt i et utbytte på 78,5 %. 301.5 g (0.5 mol) of 3,5-diamino-2,3,6-triiodo-N-(2,3-dihydroxy-propyl)-benzamide are suspended in anhydrous pyridine cooled to 15°C. After adding 2,450 ml of acetic anhydride, the mixture is stirred for 18 hours at ambient temperature and then poured into acidified water. After extraction with ethyl acetate, drying of the organic phase and evaporation, 270 g of product are obtained in a yield of 78.5%.

Renhet i jod: 98,3 % Purity of iodine: 98.3%

TLC toluen/metyletylketon/HCOOH 60/25/35. Rf: 0,70 TLC toluene/methyl ethyl ketone/HCOOH 60/25/35. Rf: 0.70

b) Fremstilling av 3, 5- bis-( 2- isopropyl- l, 3- dioksan- 5-karboksamido) - 2, 4, 6- triiod- N- ( 2 , 3- diacetoksypropyl) - benzamid b) Preparation of 3,5-bis-(2-isopropyl-1,3-dioxane-5-carboxamido)-2,4,6-triiodo-N-(2,3-diacetoxypropyl)-benzamide

114,5 g (0,166 mol) av forbindelsen oppnådd i a) oppløses i 350 ml vannfri DMAC. Tilsetning av 128 g (0,66 mol) 2-isopropyl-1,3-dioksan-5-karboksylsyreklorid gjennomføres ved 0°C. Etter omrøring over natten helles reaksjonsmassen i en blanding av is og vann. Presipitatet avfiltreres, vaskes med vann og tørkes deretter i vakuum ved 50°C. 114.5 g (0.166 mol) of the compound obtained in a) are dissolved in 350 ml of anhydrous DMAC. Addition of 128 g (0.66 mol) of 2-isopropyl-1,3-dioxane-5-carboxylic acid chloride is carried out at 0°C. After stirring overnight, the reaction mass is poured into a mixture of ice and water. The precipitate is filtered off, washed with water and then dried in a vacuum at 50°C.

c) Fremstilling av 3, 5- bis-( 2- isopropyl- l, 3- dioksan- 5-karboksamido)- 2, 4, 6- trijod- N-( 2, 3- dihvdroksypropyl)- benzamid c) Preparation of 3,5-bis-(2-isopropyl-1,3-dioxane-5-carboxamido)-2,4,6-triiodo-N-(2,3-dihydroxypropyl)-benzamide

175 g av forbindelsen oppnådd i b) suspendert i 2,5 1 metanol omrøres ved omgivelsestemperatur i nærvær av 45 g kaliumkarbonat over natten. Etter avdamping av reaksjonsblandingen, krystalliseres produktet fra vann. Etter filtrering og tørking, anvendes krystallene oppnådd i et utbytte på 85 % direkte i neste trinn. 175 g of the compound obtained in b) suspended in 2.5 l of methanol is stirred at ambient temperature in the presence of 45 g of potassium carbonate overnight. After evaporation of the reaction mixture, the product is crystallized from water. After filtration and drying, the crystals obtained in a yield of 85% are used directly in the next step.

d) Fremstilling av 3, 5- bis-( 3- hydroksy- 2- hvdroksvmetyl-propionamido)- 2, 4, 6- triiod- N-( 2, 3- dihvdroksypropyl)- benzamid d) Preparation of 3,5-bis-(3-hydroxy-2-hydroxymethyl-propionamido)-2,4,6-triiodo-N-(2,3-dihydroxypropyl)-benzamide

Forbindelsen oppnådd i c) oppløses i 2 1 5 N HCl ved 50°C. Etter omrøring i 18 timer, filtreres den oppnådde suspensjon. Filtratet konsentreres i vakuum og resten opptas i iso-propanol. The compound obtained in c) is dissolved in 2 1 5 N HCl at 50°C. After stirring for 18 hours, the obtained suspension is filtered. The filtrate is concentrated in vacuo and the residue is taken up in iso-propanol.

108 g krystallinsk produkt oppnås i to mengder i et utbytte på 94 %. 108 g of crystalline product is obtained in two amounts in a yield of 94%.

TLC Si02 Butanol 60, vann 25, CH3COOH 11 : Rf : 0,2 TLC SiO2 Butanol 60, water 25, CH3COOH 11 : Rf : 0.2

Produktet renses ved preparativ HPLC på Si02 RP18 15,25 fim med vann som elueringsmiddel i et utbytte på 47 %. The product is purified by preparative HPLC on SiO2 RP18 15.25 µm with water as eluent in a yield of 47%.

Renhet i jod: 99,6 % Purity of iodine: 99.6%

HPLC-renhet: 99,1 % (Hypersil C8 5\ lm 15 cm 0,01 M HPLC purity: 99.1% (Hypersil C8 5\ lm 15 cm 0.01 M

NaH2P04, MeOH 5) . NaH 2 PO 4 , MeOH 5).

<X>H NMR 200 MHz (DMSO) <X>H NMR 200 MHz (DMSO)

8.5 ppm (m, 1H utbyttbar med D20, O-CONH) 8.5 ppm (m, 1H exchangeable with D20, O-CONH)

9,9 ppm (t, 2H utbyttbar med D20, O-NH-CO) 9.9 ppm (t, 2H exchangeable with D2O, O-NH-CO)

4.6 ppm (m, 6H utbyttbar, OH) 4.6 ppm (m, 6H exchangeable, OH)

3-4 ppm (m, 13H, CH) 3-4 ppm (m, 13H, CH)

2.7 ppm (m, 2H, NH-CH2) 2.7 ppm (m, 2H, NH-CH2)

EKSEMPEL 4 EXAMPLE 4

Fremstilling av 5-(3-hydroksy-2-(hydroksymetyl)-N-(2-hydroksyetyl)-propionamido]-N-(2-hydroksyetyl)-N'-(2,3-dihydroksypropyl)-2,4,6-trijodisoftalamid Preparation of 5-(3-hydroxy-2-(hydroxymethyl)-N-(2-hydroxyethyl)-propionamido]-N-(2-hydroxyethyl)-N'-(2,3-dihydroxypropyl)-2,4,6 -triiododisophthalamide

a) Fremstilling av 5-( 2- isopropyl- l, 3- dioksan- 5- karboks-amido)- 2, 4, 6- trijod- 3- N'-( 2- acetoksyetyl)- karbamoylbenzoyl-klorid a) Preparation of 5-(2-isopropyl-1,3-dioxane-5-carboxamido)-2,4,6-triiodo-3-N'-(2-acetoxyethyl)carbamoylbenzoyl chloride

5,36 g 2-isopropyl-l,3-dioksan-5-karboksylsyre (0,0308 mol) oppløses i 18 ml DMAC. Reaksjonsblandingen avkjøles til 5°C og 2,55 ml (0,0350 mol) S0C12 tilsettes dråpevis slik at temperaturen forblir under 15°C. Når tilsetningen er fullstendig, får reaksjonsblandingen stå i tre timer ved omgivelsestemperatur. 5.36 g of 2-isopropyl-1,3-dioxane-5-carboxylic acid (0.0308 mol) are dissolved in 18 ml of DMAC. The reaction mixture is cooled to 5°C and 2.55 ml (0.0350 mol) SOCl 2 is added dropwise so that the temperature remains below 15°C. When the addition is complete, the reaction mixture is allowed to stand for three hours at ambient temperature.

Deretter tilsettes 6,0 g (0,00906 mol) 5-amino-2,4,6-trijod-3-(N-2-acetoksyetyl)-karbamoylbenzoylklorid. Reaksjonsblandingen holdes under argon i fire døgn ved omgivelsestemperatur. 6.0 g (0.00906 mol) of 5-amino-2,4,6-triiodo-3-(N-2-acetoxyethyl)-carbamoylbenzoyl chloride are then added. The reaction mixture is kept under argon for four days at ambient temperature.

DMAC fjernes i vakuum. Den oppnådde olje opptas i etylacetat; den organiske fase vaskes med vann, tørkes og konsentreres til tørrhet. Produktet krystalliseres fra 100 ml eter. Etter avfiltrering og tørking, oppnås 1,8 g produkt i et utbytte på 24 %. DMAC is removed in vacuo. The oil obtained is taken up in ethyl acetate; the organic phase is washed with water, dried and concentrated to dryness. The product is crystallized from 100 ml of ether. After filtration and drying, 1.8 g of product are obtained in a yield of 24%.

TLC (silika 60F 254) : TLC (silica 60F 254) :

Etylacetat/petroleumseter 80/20 - Rf = 0,83 Ethyl acetate/petroleum ether 80/20 - Rf = 0.83

b) Fremstilling av 5-( 2- isopropyl- l, 3- dioksan- 5- karboks-amido) - 2, 4, 6- triiod- N-( 2- acetoksyetvl)- N'-( 2, 3- dihvdroksy-propyl) - isoftalamid 1 g (0,00122 mol) av produktet oppnådd i a) oppløses i 100 ml DMAC, deretter tilsettes 0,26 ml trietylamin (0,00189 mol). 0,18 g (0,00196 mol) 3-amino-l,2-propandiol tilsettes dråpevis til reaksjonsblandingen. Etter fullstendig tilsetning, omrøres reaksjonsblandingen under argon ved omgivelsestemperatur i 24 timer. b) Preparation of 5-(2-isopropyl-1,3-dioxane-5-carboxamido)-2,4,6-triiodo-N-(2-acetoxyethyl)-N'-(2,3-dihydroxy- propyl) - isophthalamide 1 g (0.00122 mol) of the product obtained in a) is dissolved in 100 ml of DMAC, then 0.26 ml of triethylamine (0.00189 mol) is added. 0.18 g (0.00196 mol) of 3-amino-1,2-propanediol is added dropwise to the reaction mixture. After complete addition, the reaction mixture is stirred under argon at ambient temperature for 24 hours.

Trietylaminhydrokloridet avfiltreres, hvorpå DMAC avdampes. Den således oppnådde olje krystalliseres fra 20 ml eter. The triethylamine hydrochloride is filtered off, after which the DMAC is evaporated. The oil thus obtained is crystallized from 20 ml of ether.

Etter avfiltrering og tørking, oppnås 0,8 g produkt i et utbytte på 75,5 %. After filtering off and drying, 0.8 g of product is obtained in a yield of 75.5%.

TLC (silika 60F254) : CHCl3/MeOH/NH4OH 53/30/10 TLC (silica 60F254) : CHCl3/MeOH/NH4OH 53/30/10

Rf = 0,77. R f = 0.77.

c) Fremstilling av 5-[ 3- hydroksy- 2-( hvdroksvmetyl)- N-( 2-hvdroksyetyl)- propionamido]- N-( 2- hydroksyetyl)- N' -( 2, 3-dihvdroksvpropyl)- 2, 4, 6- trijodisoftalamid c) Preparation of 5-[3-hydroxy-2-(hydroxymethyl)-N-(2-hydroxyethyl)-propionamido]-N-(2-hydroxyethyl)-N'-(2,3-dihydroxypropyl)-2,4 , 6-triiododisophthalamide

0,4 g (0,000458 mol) av produktet oppnådd i b) oppløses i 0,7 ml etylenglykol og 0,69 ml (0,00275 mol) av en 4 N løsning av natriummetylat. Til denne løsning tilsettes 0,18 ml (0,0027 5 mol) kloretanol. Reaksjonsblandingen oppvarmes ved 40°C i fem timer. 0,34 ml 4 N natriummetylat og 0,1 ml kloretanol 0.4 g (0.000458 mol) of the product obtained in b) is dissolved in 0.7 ml of ethylene glycol and 0.69 ml (0.00275 mol) of a 4 N solution of sodium methylate. 0.18 ml (0.0027 5 mol) of chloroethanol is added to this solution. The reaction mixture is heated at 40°C for five hours. 0.34 ml of 4 N sodium methylate and 0.1 ml of chloroethanol

tilsettes. Blandingen holdes ved 40°C over natten. pH i reaksjonsblandingen bringes til 7,00 ved tilsetning av fortynnet saltsyre. Etylenglykol avdampes i vakuum. Resten etter destillering opptas i 6 ml vann og 5 ml konsentrert saltsyre, og omrøres over natten ved omgivelsestemperatur. is added. The mixture is kept at 40°C overnight. The pH of the reaction mixture is brought to 7.00 by adding dilute hydrochloric acid. Ethylene glycol is evaporated in a vacuum. The residue after distillation is taken up in 6 ml of water and 5 ml of concentrated hydrochloric acid, and stirred overnight at ambient temperature.

Reaksjonblandingen konsentreres og renses deretter ved preparativ HPLC (RP 18, eluering med vann). Etter avdamping og tørking, oppnås 0,1 g produkt i et totalt utbytte (alkylering The reaction mixture is concentrated and then purified by preparative HPLC (RP 18, elution with water). After evaporation and drying, 0.1 g of product is obtained in a total yield (alkylation

- rensing) på 27 %. - purification) of 27%.

TLC (silika 60F254) : CH2Cl2/metanol/7/3 - Rf = 0,33 TLC (silica 60F254) : CH2Cl2/methanol/7/3 - Rf = 0.33

HPLC: kolonne av Hypersil C8 5|im 25 cm HPLC: column of Hypersil C8 5 µm 25 cm

Buffer: 0,01 M NaH2P04/MeOH : 95/5 Buffer: 0.01 M NaH 2 PO 4 /MeOH : 95/5

Renhet: 95 % Purity: 95%

^■H NMR (Bruker - 200 MHz) i DMSO: i overensstemmelse med forventet struktur. ^■H NMR (Bruker - 200 MHz) in DMSO: consistent with expected structure.

Claims (7)

1. Forbindelse, karakterisert ved at den har formelen: hvori Rx er en gruppe med formelen hvori R5 er Cx <-> C4-alky<l>( Cx - C4-hydroksyalkyl eller Cx - C4-polyhydroksyalkyl, og R6 er hydrogen, Cx - C4-alkyl, C-l - C4-hydroksyalkyl eller C1 - C4-polyhydroksyalkyl, eller Rx er en gruppe med formel: hvori R7 er - C4-hydroksyalkyl eller C1 - C4-polyhydroksy, og R8 er hydrogen eller Cx - C4-alkyl, R2 er hydrogen, Cx - C4-hydroksyalkyl eller C-l - C4-polyhydroksyalkyl, R3 er hydrogen eller Cx - C4-alkyl, R4 er hydrogen, C1 - C4-alkyl, C± - C4-hydroksyalkyl eller C1 - C4-polyhydroksyalkyl.1. Connection, characterized in that it has the formula: in which Rx is a group with the formula wherein R5 is Cx <-> C4-alkyl<l>( Cx - C4 -hydroxyalkyl or Cx - C4 -polyhydroxyalkyl, and R6 is hydrogen, Cx - C4 alkyl, C1 - C4 hydroxyalkyl or C1 - C4 polyhydroxyalkyl, or Rx is a group of formula: wherein R 7 is - C 4 -hydroxyalkyl or C 1 - C 4 -polyhydroxy, and R8 is hydrogen or Cx - C4 alkyl, R2 is hydrogen, Cx - C4-hydroxyalkyl or C-1 - C4-polyhydroxyalkyl, R3 is hydrogen or Cx - C4 alkyl, R4 is hydrogen, C1-C4-alkyl, C±-C4-hydroxyalkyl or C1-C4-polyhydroxyalkyl. 2. Forbindelse som angitt i krav 1, karakterisert ved at den har formelen: hvori R2, R3 og R4 har betydningene som angitt i krav 1.2. Compound as stated in claim 1, characterized in that it has the formula: wherein R2, R3 and R4 have the meanings given in claim 1. 3. Forbindelse som angitt i krav 1, karakterisert ved at den er 5-[3-hydroksy-2- (hydroksymetyl) -N- (2 , 3-dihydroksypropyl) -propionamido] - N' ,N''-bis-(2-hydroksyetyl)-2,4,6-trijodisoftalamid.3. Compound as stated in claim 1, characterized in that it is 5-[3-hydroxy-2-(hydroxymethyl)-N-(2,3-dihydroxypropyl)-propionamido]-N',N''-bis-( 2-hydroxyethyl)-2,4,6-triiododisophthalamide. 4. Forbindelse som angitt i krav 1, karakterisert ved at den er 5-N-glykolamido-3- [3-hydroksy-2- (hydroksymetyl) -N- (2,3-dihydroksypropyl) - propionamido] -2,4, 6-trijod-N-hydroksyetylbenzamid.4. Compound as stated in claim 1, characterized in that it is 5-N-glycolamido-3-[3-hydroxy-2-(hydroxymethyl)-N-(2,3-dihydroxypropyl)-propionamido]-2,4, 6-triiodo-N-hydroxyethylbenzamide. 5. Forbindelse som angitt krav 1, karakterisert ved at den er 3,5-bis-(3-hydroksy-2-hydroksymetyl)-propionamido-2,4,6-trijod-N-(2,3-dihydroksypropyl)-benzamid.5. Compound as stated in claim 1, characterized in that it is 3,5-bis-(3-hydroxy-2-hydroxymethyl)-propionamido-2,4,6-triiodo-N-(2,3-dihydroxypropyl)-benzamide . 6. Forbindelse som angitt i krav 1, karakterisert ved at den er 5-[3-hydroksy-2-(hydroksymetyl)-N-(2-hydroksyetyl)-propionamido]-N-(2-hydroksyetyl)-N'-(2,3-dihydroksypropyl)-2,4,6-trijodisoftalamid.6. Compound as stated in claim 1, characterized in that it is 5-[3-hydroxy-2-(hydroxymethyl)-N-(2-hydroxyethyl)-propionamido]-N-(2-hydroxyethyl)-N'-( 2,3-dihydroxypropyl)-2,4,6-triiododisophthalamide. 7. Kontrastmiddel, karakterisert ved at det omfatter en effektiv mengde av minst en forbindelse som angitt i krav 1-6.7. Contrast agent, characterized in that it comprises an effective amount of at least one compound as stated in claims 1-6.
NO892189A 1988-06-02 1989-05-31 Triodobenzene compounds and contrast agents containing these NO177461C (en)

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