DE2229360A1 - NEW ROENTHY CONTRAST AGENT AND PROCESS FOR ITS PRODUCTION - Google Patents

Description

49 l

BRACCO INDUSTRIA CHIMICA Socleta per Azionl , Milan (Italy)

New X-ray contrast medium and process for its production

The present invention relates to a new X-ray contrast medium, which is used as the shading component 3- (N-β, γ propyl-acetylamino ^ w ^ -acetylaininoinethyl - ^^ Ato-trijQd-l the formula

COOI

CO-CH ₃

whose physiologically well-tolerated water-soluble alkali metal and / or amine salts contain »

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The new shading component according to the present invention is characterized by its good general tolerance and its particularly good tolerability by the central nervous system (CNS). Your intracerebraia, and especially your intracisternal toxicity, is much less than that comparable related compounds »

The new "X-ray contrast agent containing the compound of formula I is therefore an optimal vasography agent and particularly suitable for cerebral angiography _o for this use it is clearly superior to the previously known X-ray contrast agents"

The following table shows the values for vascular contrast media (vasography agents) authoritative and in particular the most important for depictions of blood vessels in the area of the central nervous system pharraacodynamic parameters of the new shading component Λ, the constitutionally next known connection B and one of the best vascular contrast media used today (C), which has also proven to be optimal as a cerebral angiography agent

The values were determined in all cases using identical methods and under the same external conditions, in each case in parallel and simultaneously. They are therefore among themselves directly comparable · bar ·

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Bs mean:

A: 3 "(N ~ ß j f-Dihydroxypropyl acetylinino) -5" acetylamlncanethyl = 2,4,6-triiodo * benzoic acid

[Examples 1 - 3]

B; 3 »(Ν ™ β- Hydroxyethyl · * acetyl amino) » S ^ acetylarainomethyl-2,4 _S 6-triiodo-benzoic acid

[German Offenlegungsschrift Wr Io928,838, example 5]

C; 3-acetylaraino-5-acetylaminoinethyl-2 »4,6» triiodo-benzoic acid [IODAMIDE (E)]

[German patent specification No. 1 273.747] [American patent specification \ hs 3.360.436}

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Tabel

O (O OO ro oo

ο cn

I. link ι
I. A. i B. Toxicity DL SO Intravenously 12 days
mgJ / 'kg intracerebral 12 days
mgJ / kg I. Rabbit ^ 12 days
mgj / kg C. 24 hours
mgJikg 6600 4S h
mgJ / 'kg intracistemel OO A I Mouse: 6600 285 48 h
ragJ kg I. N / A;
7400 5700 285 39 21 y \ 5800 56OG 120 38 20 y
ι i 6600 97

N) N> N) CO CO

Purification °

IvO nothing else is noticed, the connections were made in Torrn their N-methylglucamine salÄ solutions aagev / ends,

Intra venous toxicity; Concentration of the injection solutions:

300 mg iodine / ml, injection rate ** age? 20 g iodine / kg / 60 "o

Intracerebral toxicity; 2 ml / kg were always administered

The concentrations were varied

In tracistereal toxicity concentration of the solutions:

280 mg iodine / ml c

The table clearly shows:

The compound A obtained according to the invention surpasses the structurally closest previously known compound B and also the IODAMIDE (E) (C) , which has proven itself particularly for cerebral angiography, with regard to the most important property - that is, the tolerance by the CNS - by far, and both after intracerebral and after intracisternal application

The general compatibility corresponds at least to that of the well-established IODAMLDES (C) _β

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The new connection ¹ . ¹ ^; xrlrd usually in the form of their physiologically well-tolerated, visually-; Easily water-soluble * injectable alkali metal jr.d Ainins used as solutions.

As an alkali metal all s el: za korusen iv <Batr-eight: The sodium al 2 and in a few special cases also the lithium salt, which may have a small addition of calcium modar magnesium salt,

The amine salts used are preferably salts of alkanolamines, for example of N-methylglucamine, N-methylxylaiain (- · 1 methylamino-1-deoxy - [D] -xylitol), 1-methylamines - ^, 3-propanediol, diethanolamine, monoatlianolaxnin , Tris (hydroxymethyl) ^ aminomethane Uc a m

Mixtures of the salts mentioned can also be used

The production of the new Schattengebendan 3 * (N * β «y-Dihydroxy propyl acetylaiaiuo) ■ 5- ■ acefcylamincmethy 1 - ■ '.'. . ■ ': -. 6 tri jod- benzo ^ s euve is keratized by “that men

3 "Acetylamino ° 5-acetylaminomethyl ~ 2" 4,6-triiodo benzoic acid in strongly alkaline solution with

an alkylating agent consisting of a reactive one Strong acid ester of the formula

X - CH ₉ - CH - CFi ₉ - OH

¹ II «

wherein X is a halogen atom, chlorine, bromine or iodine ₅ or a sulfonate radical, alkyl-SO ₀ -C or aryl SO ₉ -C *, or with a corresponding epoxide
implements,

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The UüiseUasung takes place preferably ία alcoholic solution and in the presence of an alkali alcoholate "

All alkylating agents can be considered, for example :

1-chloro-propanediol-2,3 (3-chloro-1,2-propanediol, nc-glycerol chlorohydrin), 1-bromo-propanediol-2,3, 1-iodopropanediol-2,3, xlienzenesulf crnyloxy-propanediol-2,3, 1-toluenesulfonyloxy · »prop-ndiol-2,3, 1-methanesulfonyioxy-propanediol-2,3, glyceryl glycide (2,3-epoxy ~ 1-propanoi ₉ glycidol), epichlorohydrin (1-chloro -2 »3-epoxy-propane) ₃ l-benzenesulphonylcxy-2,3-epoxy · * propane and 1-methanesulphonyloxy-2,3-epoxy-propane

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VERFAHRENS · 'and SUBSTZiNZB ₁ SISFIE ₁ LEt

3 * (Ν- ß, ν-dihydroxypropyl-acecylaaiino) 5-acatylaminoinethyl-2 _t 4,6-triiodo-benzoic acid

example 1

50.2 g 3 "Acetylajnino = 5-acetylaiij.nomethyl -2,4,6-triiodo-benzoic acid (0 _s 08 mol) in 400 ml methanol and 128 ml 2 * 5 molar sodium methylate solution (0 _s 32 mol ) are mixed with 13 * 4 ml of 1 = chlorine * propanediol »2.3 (0.16 mol) and stirred for 24 hours at room temperature. Another 32 ml of 2.5 molar sodium diethylate solution (0..08 mol) are added and 6 _r 7 ml of l-chloro-propanediol-2,3 zn and stir for a further 24 hours

The reaction solution is diluted with 400 ml of water, evaporated with ethyl «acid neutralisier t _t to half its volume and acidified with hydrochloric acid after stirring overnight, the precipitated product is abgenutschto

Yield: 49 ^ 5 g "d, s, 83% of theory"

Melting point after recrystallization from approx. 40% aqueous ethanol); 195 197 ° C _:

C ₁₅ H ₁₇ J ₃ N ₂ O ₆ calc, C 25.66% J 54 * 23% f- C 25 ^ 65% J 53.637. _O equivalent weight? her, 702 ;, gef "709 ₀

TLC, on silica gel with butanol / water / glacial acetic acid - 3; 2: l _o R _f »0.57,

Solubilities j Soluble in 40 parts of boiling water _s 7 parts

cold and 3 parts of boiling methanol _s 50 parts

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cold and 5 parts boiling ethanol5 insoluble in chloroform- ^v

Sodium salt and N-methylglulcamine salt (MGA-Salz); <~ 100 g / 100 itil water at 20 ° C,

Example 2

By reacting 25.1 g of S-acetylamino-S-acetylaminomethyl 2,4,6-triiodo "benzoic acid, dissolved in 380 ml of O ₈ 5 molar methanolic sodium ethoxide solution, with 18.6 g of 1-bromo" propanediol ~ 2, 3 _s 24 g of 1-iodo-propane diol-2,3, 20 gl ~ onyloxy propanediol methanesulfonic £ = 2 ".3 or with 28 g of 1-benzene sulphonyl oxy -propanediol" 2 ₁ 3 bine under door · ¹ for 60 hours is obtained one also 3 "(N" ß, γ-dihydroxypropyl-acetylamino) * 5-acetylaminomethyl-2 ₉ 4 _S 6 "triiodobenzoic acid with a melting point of 194-198 ° C, yield; 75-90% of theory c

Example 3

12.55 g of 3-acetylamino-5-acetylarainomethyl-2,4,6 "triiodo * benzoic acid (0 _sec 02 mol) in 80 ml of O ₉ 5 molar methanolic sodium methoxide solution are mixed with 4 g of glyceryl glycide, while 1 Stirred for hour and then left to stand for 60 hours at room temperature _o

After the work-up carried out analogously to Example 1, 10 _s 5 g ( ^e 74j, 7% of theory) S-CN-βsY-'Dihydroxypropyl ^ acetylami ¹ = no) * 5 acetylarainoraethyl ~ 2 _> 4 _s 6 "triiodo" benzoic acid with a melting point 196 - 198 ° C preserved *

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FORHJM GSBEISPIe-E

3 »(N ~ ßc ν-dihydroxyoropyl-ac:; t> isirJuio) 5- sicetylaiuinomathyl'- 2 <4 * 6-triiodo ^ benzoic acid \ Λ.τά corresponded- · ;! Their use as a vasographic agent is usually processed into saline solutions that can be used or infundlerable

Be:.; O «idev: s well aqueous solutions of sodium or alkanol amines as aisers, in particular mono-, di- and poly-hydroxy-alkylamine salts like a.-B- the N- ^ iethylglukandn- * N * methyl xylamine, 1-methyl amino-2,3-propanediol, ethanol ainine * or di ethanolamine salt, these solutions usually contain around 140 600 mg iodine / ml *

Composition of 2 typical solutions:

example 1

a ₀ 3- (N-ß _f t'-Dihydroxypi-cpyl- & C3 ty I amino) 5 ~

acetyl aiainoine thy I- 2 * 4,6 - tri jod benssoes äure 553 g

bo N'-methylglucamine 136.7 g

Co sodium hydroxide 3, .6 g

do Ethylenediamine-tetra-acetic acid-di-sodium salt 0.01 g

e _o water (double distilled) to 800 ml

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BATHROOM ORIGINAL

Prepare the salt solution v-irl jre.'ir.ss of the above recipe * by dissolving substance d in a little i, 'as3er, adding substances a, b and c one after the other and adjusting the solution obtained by stirring to pH 7 _y l Oji , finely filtered. filled into ampoules of 10 and 20 ml and then sterilized

Iodine content; 375 mg / ml,

Example 2

a 3 '- (N-β, r ^fj dihydroxypropyl acetylamino) ~ 5- acetyl »

aminomethyl 2,4,6-triiodo-benzoic acid 553 g

b sodium hydroxide 31.5 g

c Ethylenediarain tetra acetic acid disodium salt 0.02 g d water (double distilled) to 1000 ml

The salt solution is prepared according to the above recipe, to pH 7.1

! O ₄ 2 set «in ampoules of 20 ml or in vials of

100 and 200 ml bottled and sterilized iodine content; 300 mg / ml

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BAD OBfQINAL

Claims (1)

PATENT CLAIMS 3- (N-ß, γ-dihydroxypropyl-acetylainino) "5-ecetylamlnomethyl-2,4,6-triiodo-benzoic acid the formula OH ^ CH ₇ -CH-CH ₉ -OH CH ^ -CO-NH-CH ₉ '"V ^ N and their physiologically well- tolerated water-soluble metal and / or amine salts. X-ray contrast medium, particularly suitable for vascular division, characterized in that it contains 3- (N-ß, Y-dihydroxypropyl-acetylamino) -5-acetylaminomethyl-2,4,6-triiodo-benzoic acid of the formula I in claim 1 or which contain physiologically well-tolerated, easily water-soluble alkali metal οάβ-τ alkanolamine salts A09828 / 1057