DE1928838A1 - X-ray contrast media and process for their preparation - Google Patents

Description

Dr. F. Zumsteln sen. - Dr. E. Assmann Dr ₀ R. Koenigsberger - Dipl. Phys. R. Holzbauer .. Dr. F. Zumstein jun.

O Patent attorneys

25.90-968 ⁸ ** önchen 2, BräuhavMhwßo 4 / IH

Kyegaard and Go. A / S, Oslo 4, Norway.

X-ray contrast media and processes for their production,

The invention "relates to new triiodobenzoic acid derivatives for use as X-ray contrast media, in particular for visualizing the cardio-vascular system and the cavities which the Contains cerebrospinal fluid.

When x-raying relatively extensive regions of the human body, e.g. of the cardiovascular system or the cavities that which contain cerebrospinal fluid, very large amounts of X-ray contrast medium must be injected in order to achieve sufficient To achieve opacity in the region concerned. As a result, the toxicity of the contrast agent is at high concentrations of great importance. To make the cardiovascular system visible, a large number of compounds are used as contrast agents has been suggested, and although many have been used successfully, their loxicity, albeit causing them often very minor, some undesirable side effects. To make the cavities that contain the eerebrospinal fluid visible, the compounds used to visualize the vascular system are often far too toxic, "as follows is performed.

The space that contains the cerebrospinal fluid consists of several different cavities, d / ie with the central nervous system are connected and includes the ventricles of the brain, the cisternae and both the subarachnoid space around the brain around as well as the vertebral column. The radiological

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Booking these cavities can be divided into three main groups: ventriculography, cisternography and myelography. Myelography is the radiological examination of the spinal subarachnoid space, which can be divided into two zones; the radiological examination of the lowest part of the Y-vertebral column is called radiculography and the examination of the remaining part is called lumbar myelography.

The compatibility of these areas with e.g. water-soluble X-ray contrast media is very different, an approximate order decreasing tolerance is: radiculography, ventriculography, lumbar myelography and cisternography. These * Different areas cannot, however, be considered separate areas considered v / o since communication exists through the whole system, v / o by leaking from one area to the neighboring areas is made possible. Lumbar myelography, for example, is particularly demanding with regard to the tolerance of the contrast medium, but the higher cavities are even more demanding in this regard. One reason for this is the risk of leakage into the cisterns, an area that is much more sensitive than e.g. the ventricles.

Funds for use in this area should ideally sure to be useful in all areas, but an ideal medium has not yet been found. Iodized oils, used as such or as aqueous emulsions, are water-soluble Sodium iodomethanesulfonate and gas (oxygen) are examples for media that are commonly used. One of the disadvantages of the oils is that they remain in the system, without being absorbed and excreted, while radiologists nowadays generally use contrast media that are extremely long Remaining time in the organism, not acknowledging it. In addition, the use of these oils in hyelography can be aseptic Cause meningitis which is considered very serious complication. Gases such as oxygen, which / in many cases are good contrast media, give a so-called negative contrast, this is not sufficient in many cases. ·

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If a positive contrast is required and the contrast agent must not remain in the system (even if most of the Oil can be removed mechanically), so it is water-soluble Sodium iodomethanesulfonate is the main medium used. These Substance, however, is far from ideal; it is commonly used for radiculography, however, the simultaneous use of an anesthetic is required, and its use is for lumbar myelography contra-indexed.

It has now been found that triiodobenzoic acid, which has at least one group -IT-R ¹ in the molecule, "in which R ^{1 represents} a hydroxyalkyl group, viewed from the standpoint of compatibility with the tissue in question and also from the standpoint of water solubility and viscosity, Properties which are important for the use of very concentrated aqueous solutions are generally more useful than the corresponding compounds which do not carry a hydroxyalkyl group for use in making the cardiovascular system and the cavities containing the cerebrospinal fluid visible. (β-Hydroxyethyl) -acea-uamido-5-acetamido-2,4,6-triiodobenzoic acid, 3,5-bis ~ K- (β-hydroxyethyl) -acetamido-2,4,6-triiodobenzoic acid, and 3-IT - (ß ~ Hydro: cyäthyl) -acetamido-2,4-, 6-triiodobenzoic acid and 3- (lT-ß-nydroxyäthylacetamido) -? - (lT-ß-hyaroxyäthylacetamido) -niethyl-2,4,6-triiodo bezoic acid previously used as a cardiovascular X-ray contrast medium but no other hydroxyalkyl-triiodobenzoic acids have been described.

According to the invention, 2,4-, 6-triiodobenzoic acids are created which ^{carry at least one group of the formula -IT-R 1} in which. R ^{1 is} a hydroxyalkyl group, with no iI- (β-hydroxyethyl) acetamido group being in the 5-position when a hydrogen atom or an amino group, acetamido or H - (β-hydroxyethyl) acetamido group is in the ^ -position ; and their salts.

The new compounds can, largely under the following general Porael can be summarized:

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ι
χ ·

COOH

N-Ac R ¹

where Ac is an acyl group,

R represents an ¥ hydrogen atom or an alkyl group which is unsubstituted can be, or one or more substituents, e.g. hydroxyl groups or groups of the formula:

COOH

I X

Ii-Ac ι

wearing,

X is a hydrogen atom, an amino group, an acylaminomethyl

2 2

group, a group of the formula -N-Ac means in which Ac is a

^l o

the ^R ₁

Represents acyl group which can be the same as Ac or different of Ac can be and

2
R denotes a hydrogen atom or an alkyl group which can be unsubstituted or which bears one or more substituents, for example hydroxyl groups, or
X is a group of the formula:

-COF

¹ ZA

wherein Br and R ⁴ , which can be the same or different, water

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Substance atoms or alley groups that can be unsubstituted

or,
or carry one / more substituents, mean, or together with the adjacent nitrogen atom form a heterocyclic ring, with at least one M-hydroxyalkyl group in the molecule

1 1

is, R has at least 3 carbon atoms when Ac is Acetyl group and X. a hydrogen atom, an amino group, an acetamido group or an N- (ß-hydroxyethyl) acetamido group is.

The salts of the new acids of the invention are special useful because many of them are generally more water-soluble are than the corresponding acid and have the advantage that they are neutral. Salts for radiological purposes must of course be physiologically compatible with the body system in which they are intended to be used. However, other salts can be used for cleaning etc. of the acids. Particularly useful salts include the sodium salt, calcium and magnesium salts and the salts with alkanolamines such as ethanolamine or N-methylglucamine a.

Those compounds of the formula I are particularly preferred

■ ι
in which R is a hydroxyalkyl group and X is an acylamino group or a Η-substituted acylamino group. Another particularly useful class comprises those compounds of the formula I in which X represents a group COlTR R ^ and at least one of the radicals R-, R- ^ and R ^ "is a hydroxyalkyl group."

1 2
The acyl groups Ac and Ac are preferably lower alkanoyl groups with 1 to 4 carbon atoms, in particular acetyl and propionyl groups. ·. ":

Most preferred hydroxyalkyl group. is the ß-hydroxyethyl group. Other hydroxyalkyl groups of particular interest include the 2,3-dihydroxypropyl group and the 2- and 3-hydroxypropyl groups. R> Ά t R -and. ^ Rt.,; en thai- -;

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Preferably 1 Ms 6 carbon atoms. “In general, preference is given to a total number of carbon atoms” in the ITAc R ^{1 group} greater than 4, in particular when X is an amino group or acetamido group or a hydrogen atom. Where R and R form part of a heterocyclic ring, this is vorzugsweise.ein 5- or 6-membered saturated ring (the other ^{Heteroatome-:} may contain as oxygen), for example a piperidine, or morpholine Methylpxperidin-. . .. "■ -....

Particularly useful compounds of the invention include:

3- (N-ß-Hydroxyethyl-acetamido) -5-N'-me thy lace tamidö-2,4, β-tri- ' iodobenzoic acid; .., ._- ■ "/-.· ,;

3- (U-ß- γ- dihydroxypropyl-acetamido) -5-1ί'-methylacetamido-2,4,6-triiodobenzoic acid; ... ■ ^; '·

5- (K " ^f - £ Hydroxyethyl-acetamido) -2,4,6-triiodo-ri-methylisophthalic acid amide;. \ -". . .'__ ■.; jw)

3- (IT-ß-Hydroxyethyl-propionamido) -5-IT ^! -methylacetamidO- ^, 4i 6 ^ ^e - ^: triiodobenzoic acid; ■ · * '' ■, '■ ·' · ■ - '

3- (K-ß-Hy dr oxyäthy 1-acet ami do) -5-H ^f -methy 1-pr opi onami'do-gj 4, 6-triiodobenzoic acid and its salts. ..;. ·;. · ';>:

In the table below, the LDj-QV / erte arig'e ^ ge ^ ben-, 'be- * ) determined by intracerebral and intravenous injection ^' - b'ei- ßauseh, expressed in mg tf / kg for several relatives Contrast media. *.,

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Acute Toxicities "in mice.

link

intracere-
bral
mgJ / kg intravenous
mgJ / kg 425 9500 425 8300 400 345 9500 340 290 210 195 130 8700 210 120

3- (N-ß-Hydroxyethyl-acetainido) -No

^ y

iodobenzoic acid

3- (N-β, / -dihydroxypropyl-acetamido) -5-li ^l -metliylacetamido-2,4,6-triiodobenzoic acid

5- (N'-ß-Hydroxyethyl-acetamido) -2,4,6-tri iod-IT-niethyl-isophthalic acid amide

3- (N-.beta.-hydroxyethyl-propionamido) 5-Hi_methylacetamido-2,4,6-tri i odbenzoesäure

3- (N-ß-Hydroxyethyl-acetamido) .- 5-N'-methyl-propionamido-2,4,6-trij odbenzoic acid

3- (lf-ß-Hydroxyethyl-acetamido) -5- (N'-ß-hydroxyethyl-propionamido) -2,4,6-trij odbenzoic acid

3- (N-ß-Hydroxyethyl-acetamido) -5-acetamidonethyl-2,4,6-tri3odben- zoic acid

Iodomethanesulfonic acid

N-Methy 1-3, ^r 5-diacetanido-2,4,6-triiodobenzoic acid

5-Acetamido-2,4,6-trij od-R-methyl-isophthalic acid amide

3-Acetaiaido- ^r 5-acetainidomethyl-2,4,6-trijocibanoic acid ⁱ e

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BATH ORIGINAL

According to the invention, a radiological composition is also created that contains at least one acid according to the invention or contains one of their physiologically acceptable salts together with a radiological carrier.

The concentration of the X-ray contrast medium according to the invention in an aqueous medium varies according to the particular field of application. In general, lower concentrations are required for yentriculography than for myelogography, while even lower concentrations are required for radiculography. The preferred concentration and dosage ranges of the compounds are for these three applica- tions W, the following:

Concentration dose

Radiculography 150-250 mg J / ml 6-12 ml

Ventriculography 250-350 mg J / ml. 3 - 7 ml myelography 350 - 450 mg J / ml 4-9 ml

The preferred concentration range for visualizing the cardiovascular system is 150 to 450 mg J / ml. The amount of contrast agent to be administered is preferably such that it remains in the system for only about 2 to 3 hours, although both shorter and longer residence times are normally acceptable. "The active material can therefore be formulated for cerebrospinal purposes, conveniently in vials or ampoules, which contain 5 to 15 ml of an aqueous solution thereof, but for cardiovascular wakes amounts of 10 to 500 ml are given.

In Belgian patent 645 634 the applicant describes compositions which contain liatric salts of X-ray contrast acids, the toxicity of which is due to the inclusion of relatively small amounts of substance, which release calcium and / or magnesium ions, favorably

took 70 ο

Modified “Man / an that this effect is related to the ion equilibrium connected in the vascular system. It has now been found that

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- Q -

in the cerebrospinal fluid, although the sodium salts of X-ray contrast acids given intracerebral are much more toxic than given intravenously, these toxicities due to the inclusion of CrX-

Next
cium and / or magnesium ions / ITodium ions are modified favorably and are the same as those which have been observed for the vascular system.

The ratio of calcium to sodium ions is preferably at least 0.00025, preferably at least 0.0005. Are If magnesium ions are present, these are also preferably at least with the above minimum ratios. The relationship from calcium ions to sodium ions is actually preferred in the range of 0.005 to 0.10, while the ratio of magnesium ions to sodium ions is preferably in the range of 0.002 to 0.05. Both calcium and magnesium ions are preferred present.

The calcium and / or magnesium ions can by adding a Calcium and / or magnesium salt of X-ray contrast acid or by adding or in situ forming another physiologically and chemically compatible water-soluble calcium or magnesium salt to be delivered. The metal ions should of course be in the free state and ions formed by chelating Agents bound, such as ethylenediaminetetraacetic acid, are not effective and they should not be included in the calculation of the appropriate Ionic ratios are used. Particularly useful calcium and magnesium salts as additives to the compositions are the chlorides. Another possibility is to add one or more bases to a solution of the acid, which supply the sodium ions on the one hand and the calcium and / or magnesium ions on the other hand.

The new compounds of the invention can be based on a suitable Way to be made, some- procedure are below specified:

a) Implementation of a compound "of the general formula:

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COOH

HH-Ac

II

with a hydroxyalkylating agent, Tim a compound of To produce formula I, in which R is a hydroxyalky! Group. The hydroxyalkylating agent can, for example, be a reactive one Be monoester derivative of a glycol or polyol, e.g. a halide such as a chloride or bromide, or a hydrocarbon sulfonate. To introduce a hydroxyethyl group 2 ~ chloroethanol is a useful reagent. The responsive one Derive, is preferably made with the acylamido starting material reacted under basic conditions, e.g. in an aqueous alkaline medium, for example an alkali metal hydroxide such as sodium or potassium hydroxide, or in a non-aqueous solution Medium, e.g. in an alkanol such as methanol or ethanol, the base conveniently being an alkali metal alcoholate such as Is sodium methylate. One can also use the acylamido compound an epoxy, e.g. ethylene oxide, propylene oxide, glycid etc., to implement, also advantageously under the same conditions, such as those used for the reactive esters.

b) reacting an amide of formula II with an allylating agent such as a reactive ester of a Allylalkoholes, z _# as allyl chloride or bromide, to a H-aliy! grouping introduce, which is then subjected to the oxidation of the double bond, for example using a Permanganate oxidizing agent to form a glycol moiety, thereby forming a compound of formula I in which R is a dihydroxyalkyl group.

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c) For the preparation of monohydroxyalkyl bisacylamido compounds can be a compound of the general formula:

AIkOH

III

(in which Ac has the oMge meaning and AIkOH is a mono- or poly (hydroxyalkyl) group) with an acylating agent reacted v / ground to acylate both the primary amino group and the hydroxyl group or groups, then the ester grouping or grouping thus formed is hydrolyzed, for example under basic conditions to form a monohydroxyalkyl compound of the general formula:

Ac ² IIH.

COOH

AlIcOH

N-Ac t

12th

wherein Ac, Ac and 'AIkOH die. have the meanings given above, to surrender.

The acylating agent can, for example, be an acid anhydride (which can also serve as a solvent) together with catalytic Amounts of a mineral acid, for example sulfuric acid or perchloric acid, or an acid halide, preferably in a polar solvent such as dimethylformamide or dimethylacetamide, acid halides are preferred because they are lower Forming quantities of by-products. The basic hydrolysis of the

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O-acyl grouping can, for example, using aqueous Alkali metal hydroxide, e.g. sodium hydroxide the reaction is preferably carried out at room temperature. In addition, depending on the acylating agent used other products are formed that need to be separated. Becomes an acyl anhydride like acetic anhydride with concentrated sulfuric acid Used as a catalyst, the primary amino group is often partially bisacylated, although the bis-acylamino group very easily under mild basic conditions to acylamido is hydrolyzed, whereas if a substituted amide or imide is used as a solvent such as dimethylacetamide or dimethylformamide is present, the hydroxyl group is acylated while the primary amino group remains unaffected. Used However, one acyl halide in a substituted amide or Imide as solvent, the reaction with formation of the N, O-bis-acyl compound is strongly predominant and this method is preferred. .

Pas starting material, the formula III can of course according to the method a) and b) above using compounds in which X represents an amino group.

d) Another process for the preparation of H-alkylated monohydroxyalkyl-bis-acylamido compounds comprises the reaction of a compound of the general formula:

COOH

- I.

IV

AIkOH

with an alkylating agent, e.g. a reactive ester of an alkanol, e.g. -an allyl chloride, -bromide, iodide, tosylate or mesylate or a dialkyl sulfate, whereby

909850/1769. . '.

a corresponding compound of the formula I is formed in which X is an N-alkyl-acylamino group.

The compounds of formula II used as starting materials can be prepared by conventional methods described by the nature of group X are dependent.

The compounds of the formula II in which X is HEL, a A particularly important group of intermediates, can be prepared by acylation of 3-amino-4-nitro-benzoic acid, under subsequent reduction of the nitro group to the amino group, for example by catalytic hydrogenation, for example using of palladium or platinum and subsequent iodination, for example with 'sodium iodine chloride. Compounds of formula II, in which X represents an N-alkyl-acylamido group, can by Alkylation of 3-nitro-5-sulfaminobenzoic acid produced v / earth, as described in the applicant's South African patent specification 68/6797, for example a reactive Ester of an alkanol used, preferably in the presence of an acid-binding agent, then the sulfamino group acid hydrolyzed to produce an alkylamino group which can then be acylated as previously described, to form an S-N-alkyl-acylamido - ^ - nitrobenzoic acid, the on reduction, for example hydrogenation, gives the 5-amino compound; this can then be iodized, for example with NaIClp and acylated by the above procedure to introduce an acyl group which may be the same as that pre-existing or different from pre-existing to form the desired 5-acylamido compound.

e) For the preparation of compounds of the formula I in which X is a COlTR ^ R group and in which at least one of the groups R, R "^ and R is hydroxyalkyl, a 5-nitro-isophthalic ester halide can be used with ammonia or a primary or secondary Amiη NHR R (where R and R ^ have the above meanings own) are implemented in order to achieve the desired 3-carb

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amoy! grouping, wherein the ester grouping is then hydrolyzed, for example under basic conditions, for example using aqueous alkali, and the nitro group is reduced to an amino group, for example by catalytic hydrogenation using, for example, palladium or platinum; iodized, for example using an iodinating agent such as HaJCl ₂ , the corresponding 2,4,6-iriiodobenzoic acid being obtained, which can then be subjected to acylation, for example using an acylating agent such as an anhydride or acid chloride. The product is

1 1

thus a compound of the formula I in which Ac is acyl, R Is hydrogen and X is COlTR R and it is possible that one hydroxyalkyl group or even two hydroxyalkyl groups are present in the carbamoyl moiety rather than the acetamido moiety in the molecule by using an amine in which zi ndest one of the radicals R and R ^ is hydroxyalkyl. If desired, the product of a further hydroxyalkylation can be used dura. Subjected to reaction with a hydroxylating agent

5 4-will ^ n and if none of the radicals R and R is hydroxyalkyl, such a further reaction is indeed necessary in order to prepare a compound of the formula I. \! o one or both

° 5 A-

Radicals R ^ and R represent hydroxyalkyl, the starting product, in which R represents hydrogen, umgesetzi; in order to introduce an alkyl group which does not carry any hydroxyl groups.

The nitro compound, which is catalytically reduced in the above synthesis, can also be obtained by reacting a half ester of the 5-NI
the.

3 a 5-nitro-isophthalic acid can be produced with the compound NHR R

f) In a further manufacturing process for compounds of Formula I in which X is the COITR R * "group, in which R and R can have the meanings given above, a half-ester of 5-nitro-isophthalic acid to the corresponding 5-amino compound are reduced, for example by catalytic hydrogenation, then, as described above, the corresponding

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■ - 15 -

2,4,6-triiodophthalic acid ester is iodized, which is then also formed the corresponding 5-acylamino compound can be acylated; this is then converted into the ester halide, for example by Uinsetsung with a reagent that is responsible for the conversion a carboxyl group in an acid hair enid group, e.g. a sulfony halide or phosphorus halide. That Ester halide can then be reacted with the compound IiHR R finally the esterified carboxyl group is converted into carboxyl, e.g. by aminolysis. V / o none of the remains R, R and R are hydroxyalkyl, the product must then be reacted with a hydroxyalkylating agent in order to a hydroxyalkyl group in the 5-acylamino group and / or the carbamoyl group when one or both of the radicals R and R are hydrogen, to introduce. If one of the leftovers or both radicals R and R represent hydroxyalkyl, can Product can be alkylated as described above to form the corresponding 5-N-alkyl-acylamido compound.

g) Would you like R to be an alleyl group that has a substituent the formula:

0OH

carries, the compound of formula II can be bifunctional with a Alkane derivative, such as an oc, 6? -Dihaloalkane or a bis-epoxyalkane, e.g. 1,3-butadiene-diepoxide.

Isolation of the hydroxyalkylated product from others water-soluble products v; ie inorganic salts can To cause difficulties. In cases where the desired

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• - 16 -.

If the product is particularly soluble, the residue of the reaction mixture can be dissolved in water and extracted with phenol, preferably several times, for example 3 to 4 extractions with 1/10 to 1/5 volume of 90% aqueous phenol. The combined extracts _Λ phenol can then be extracted again with V / ater, remove inorganic salts to, and be diluted with a water-immiscible liquid such as diethyl ether. Upon further extraction with water, the desired product is taken up in the aqueous phase, which can be evaporated to dryness after removing the remaining phenol.

The following examples explain the invention without, however, restricting it.

Descending paper chromatography was performed on "Whatman" paper No. 1 in a solvent system of butanol- (1) / ethanol / concentrated ammonia / water = 4: 1: 2: 1 (A). Thin-layer chromatography was performed on silica gel 'G ^ 5 4 S ^emä ß "Stahl in a solvent system of chloroform / diethyl ether / methanol / formic acid = 55: 25: 10: 10 (B). The spots were observed under ITV light (Hannovia Chromatolite). The IR spectra were Taken in KBr pellets with a Perkin Elmer Model 237. The melting points are not corrected. All temperatures are given in ⁰ C. ... -

example 1

3-Amino-5- (rT-ß-hydroxyethyl-acetamido) -2,4,6-triiodbenzoic acid.

Method 1: 3-Acetamido-5-amino-2,4,6-tz-i-i-odbenzoic acid (5.72 g) was obtained by adding 5N iSodium hydroxide (8 ml) in 16 ml v / ater dissolved. Then 1.35 ml of 2-chloroethanol were added vigorous stirring at room temperature. ! Laughs 6 hours the solution neutralized and treated with charcoal at room temperature over! The charcoal was filtered off and the Acid by adding 6N hydrochloric acid in freedom. Yield: 5.7 g (93 #).

C '...'.:! '':., 909850/17 69

Procedure ^: ■ '- ■' ■■ ■ - "■■ .- ·:. · -.. ■ -.- ■■■■. ■":

5-Äcetamido-5-aiüino-2,4 _i 6-triiodobenzoic acid (1036 g) were in 3.1 ltr. Suspended in water and dissolved by adding 740 ml of 1N sodium hydroxide. The solution was heated to 70 ° (in a reaction flask) and 250 ml of 2-chloroethanol were added over the course of one hour. The mixture was heated to 70 ° for an additional half hour, after cooling the solution was neutralized and stirred with charcoal overnight. The charcoal was filtered off, after diluting the reaction solution with 9 ltr. In water, the acid was precipitated by adding 6N hydrochloric acid, yield: 1048 g (94 ).

Procedure 3:

3-Acetamido-5-amino ~ 2,4,6-tri, 3odbenzeesäure- (57,2 -g) was in 150 ml of solvent (see. Table I) as the sodium salt Addition of sodium hydroxide or sodium methylate dissolved. then the ethylene oxide was introduced through a feed pipe into the bottom of the cylindrical reaction vessel. Table I describes multiple fabrications using this process, under different conditions.

. Table I.

N-alkylation of 3 ~ acetamido-5-amino-2,4,6-trijodbenzoic acid with ethylene oxide.

Solution mi 11 e1 MeOH MeOH .MeOH MeOH- -H ₂ OH ₂ O H ₂ O H ₂ O base NaOMe NaOMe ITaOMe NaOH NaOH NaOH NaOH Equiv. 1 1 1 1 1 . 1 pH'-v base 12-13 Equiv. Ethy
lenoxyd 1.0 1.5 2.0 2.0 1.0 .. 2.0 2.5 Re alft ions temp.
OC 20th 20th 20th 20th 20th 20th 2.0 reaction time
in days 2-3 3 2 1 3-4 ' 3-4 2-3 fo unchanged
Starting material 3.1
25th 5 . ■ 5 5. · 70 30-40 traces

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Me oliromatograms showed low ester levels. .- '·

4 '- ■■' ■ * -

Example 2 ■ -. ■ '

N ~ (β-hydroxyethyl) -3,5-diacetamido-2,4,6-triiodobenzoic acid.

Method 1: '_. - .----. -. ·. ■ - ■■ --—

3-Amino-5- (N-ß-hydroxyethyl-acetamido) -2,4 »6-triiodobenzoic acid; ) (462 g) was dissolved in a mixture of acetic anhydride (1400 ml) and _: concentrated sulfuric acid (14 ml) and heated on a steam bath for 45 minutes. Then 185 ml of water were added _. , add a dropping funnel. When the anhydride was hydrolyzed, ·: ψ the solution was concentrated in vacuo to about half its volume. The mixture was diluted with 4 ltr. Water and, acidified with 6N hydrochloric acid. The next day, the Mi-. Schung decanted and the precipitate dissolved in 900 ml of water by adding 1On-Natriumhydroxj'd up to about pH 7. Man. added more 1On sodium hydroxide (265 ml) and heated that. Solution on a steam bath for 45 minutes. After cooling down ^; ; the acid was liberated with the help of chlorine acid. puts. Yield: 326 g. The product was dissolved in methanol (650-m3.) "By heating on the steam bath, each cooling the ammonium salt was precipitated by adding concentrated ammonia. (ST ml). The mixture was cooled down. -20 and filtered, - Yield: 138 g. The salt was suspended in 280 ml of water. Acidified with ön hydrochloric acid. Yield: 127 g. This process was repeated three times. Yield: 76 g. The product was then recrystallized from dioxane (activated charcoal). Yield: 66 g the procedure with precipitation of the Ammoniuinsalzes «^ 'of methanol and liberate the acid in the aqueous solution was ¹ .-; repeated three times. yield:. 52 g the acid was dissolved by from 10n- ^ Nätriumhydroxyd in water as iiatriumsalz. Treated activated charcoal, filtered and the acid precipitated by adding, 6N-hydrochloric acid. Yields 37 g (7 #) »Pp-. = 247 to 263 ° (decomposition)

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Analysis: C ₁ ^ H ₁ 7J7II 2 ° 5 ι Η 1 , $ 99 J 57, 9 1 ° H 4, 26 fo ■ Ä 658 Calculated: C. 23, 73 5S 2 , 30 56, 3 4, 36 • ι 665 Found: 24, 18th - Procedure 2:

3-Amino-5- (l <"- ß-hydroxyethyl-acetamido) -2,4,6-triiodobenzoic acid (62 g) was dissolved in 150 ml of Ιί, Ιί'-Diinetliylacetamid and 34 ml Acetyl chloride was added. ITAfter 1 hour "at room temperature the solution was diluted with 20 ml of water. Then the solution evaporated in vacuo and the residue by adding 1Onliatriumhydroxyd (10 ml excess) dissolved in 50 μl of water. One heated the solution on the steam bath for 1/2 hour, then refrigerated off and neutralized with glacial acetic acid; 22 g of ammonium chloride were added and stirred the mixture overnight. The precipitate was suspended in 500 ml of water and the acid released by adding 6N hydrochloric acid. Yield: 45 g. This acid was dissolved in 90 ml of methanol and concentrated by adding 11 ml Precipitated ammonia. The precipitate was suspended in water and the acid with the aid of hydrochloric acid released. Yield: 34 g. This procedure was repeated once. Yield: 30 g. After recrystallization from dioxane the acid melted at 252 to 263 ° (decomposition). Yield: 24 g (£ 36). A Hiscli melting point of the substances from the two procedures showed no depression. The IR spectra were identical.

Example 3

N, Ii '-di (β-hydroxyethyl) -3 _} 5-dibutyramido-2,4,6-tri 3 odbenzoic acid.

Dissolved 3.5 ~ dibutyrar.iido-2,4,6-triiodobenzoic acid (13.4 g, 0.02 hol) Chew in 120 nl methanol by adding 5N sodium methylate (16 ml,

'Ip, 08 Hol). Then 2-chloroethanol (2.8 ml, 0.04 mol) was added Room temperature all at once with vigorous stirring. jJach 24 hours gave 5N-liatrium methylate (8 ml, 0.04 mol) and 2- ^ chloroethanol (2.8 ml, 0.04 hol). The mixture was allowed to stand for 24 hours before repeating the latter addition. The next day, the reaction mixture was diluted with 120 ml of water and neutralized with acetic acid and applied in vacuo

909850/1769

Half of the original volume. The reaction product was precipitated off by adding 6N hydrochloric acid. After filtration, the acid was redissolved in water (120 ml) by addition of 10n-lTatriumhydro / "dissolved ^y and with activated carbon. _·:. Treated over spurred on at room temperature The product mi was" t "by means of 6N hydrochloric acid released yield. .: the product 12, "2" g (81 io) was dissolved again in 50 ml of water as the sodium salt, treated with Alctivkohle overnight and precipitated the acid by addition of 6N hydrochloric acid from yield:.. 11 g; Pp = 203 up to 270 ^° C. (decomposition).

Analysis: ^c -iq ^H 25 ^J 3 ^ 2 ^O 6

Calculated: C $ 30.10 N $ 3.25 J 50.21 % N $ 3.70 Neutr. X

(r '■ "758

Found:

29.63

3.38

49.2

3.86 ITeutr.Äv 771

Example 4 '^;

3- (N-ß-Hydroxyäthyl-ace tamido) ~ 5-pröpiOnainido-2,4,6-trij * odben ^ · zoic acid.

3-Amino-5- (II-ß-hydroxyethyl-acetamido) -2, 4, 6-triiodobenzoic acid (138 g) was added to a mixture of propionic anhydride (4.1.5 ml and concentrated acidic acid (4.1 ml ) and heated on the steam bath for 1 hour. Then 56 ml of water were added from a dropping funnel. The solution was concentrated in vacuo: to about half the volume and water was added to the residue until further addition resulted in no additional precipitation and the mixture -was with 6N-Chlorv .angesäuert ^r asserstoffsäure the residue was dissolved in v / ater (~ 50 mL) by addition of 10n-lTatriunhydro;... up to about pH 7 dissolved cyd, then was added more 10n -Uatrium hydroxide (138 ml) was added and the solution was heated on a steam bath for 45 minutes. After cooling, the solution was neutralized with glacial acetic acid and treated with activated charcoal overnight After decanting, the precipitate was in Water as ITatrium

909850/1769

salt · "dissolved and: again with the help of 6N-Ghrorv / hydrogen acid" failed. Yield: 87 g. This substance was made from 700 ml Diöxan 'crystallized, yield: '64 g. The substance was through Add concentrated ammonia (16 ml) by heating dissolved in 130 ml of ethanol in a steam bath. After cooling it fell the ammonium salt "off" and was filtered off. "The salt v / urde through Addition of 10N-Efatriiimhydroxyd dissolved in 340 ml of water and through Addition of 6N-hydrochloric acid precipitated. This method was repeated twice. Yield: 40 g ($ 27), m.p. = 246

up to 259 C (Decomposition). 2, 25 i ° 'J 56, 7 io "N 4 , 17 5 ί 1 672 Analysis: C ₁₄ H ₁₅ J ₅ H ₂ O ₅ ' 2, 29 56, 9 . 4th , 22 665 Calculated: G-25.02 io H. Found: 24.76

Example 5

3-Acetamidometllyl-5- (H-ß-hydroxyethy 1-acetamido) -2,4,6-triiodo-benzoic acid. "'' _ ' '. '

3 Acetamido-5-acetamidomethyl-2,4,6-triiodobenzoic acid (62.8 g, 0.1 mol) - was dissolved in 500 ml of methanol by adding 5m sodium methylate (80 ml, 0.4 mol). Then 2-chloroethanol (14 ml \ 0.2 mol) was added at room temperature with stirring. After 24 hours you gave 5m-Liatfiummethylät (20 ml, 0.1 mol) and. 'Add 2-chloroethane oil (7 ml, 0.1 mol). After 24 hours, the reaction mixture was diluted with water (600 ml), neutralized with glacial acetic acid and reduced to about half of its volume in a vacuum. "The acid was released by adding 6N hydrochloric acid. After stirring over Hacht \ rarde, the product was filtered off and redissolved in water (600 ml) as the sodium salt by adding 10N sodium hydroxide. The solution was kept for 1 day at room temperature Treated activated charcoal. 'If the ϊϋ-trating the' product was precipitated by adding 6N hydrochloric acid. Yield: 59.5 'g (SO' ^ j, Tp. = 232; up to 245 ° ('decomposition;). '''"-''"'' ^k '',

909850/1769

Analysis: C ^ / R ^ JJ. Calculated: J 56.7 Found: 56.2

Example 6

Neuter 1. ■ 672 668

triiodobenzoic acid.

3- (N-methyl-acetamido) -5-propionamido-2,4,6-triiodobenzene acid% ^: "^ (420 g) was dissolved in a mixture of water (800 ml) and" tön- "V sodium hydroxide (260 ml ) and heated, with stirring, to 70 ° in an electric flask, V. 2-oleoethanol (88 ml) was then added from a pressure funnel over the course of 1 hour After cooling, the solution was acidified with glacial acetic acid and treated with activated charcoal. The acid was precipitated ^Λ with 6N-hydrochloric acid. Yield: 401 g (89 fb). The crude product (39O g) was dissolved in 780 ml of ethanol by adding 50 ml of concentrated ammonia. The "acid" was then released with 6N hydrochloric acid. This procedure was repeated once. This acid, which held amsionium chloride '> eh ^; &->, was dissolved in water as the' sodium salt by adding 1On-sodium hydri ' - - · -.;. Xyd added, treated over! Laughs-with activated charcoal and precipitated oxtM-ej acid, by adding 6N hydrochloric acid. Yield: 210 g. Pp. = 235 to 242 ° (decomposition). ■; · s ^ .tzzl? - :.

Calculated: C '26.26 $ SH 2.50 <fo Ϊ &quot; 55.5% F 4.08 ^ X' 6SS - ^

Found:

25.12

2.69

'54, O

'4.08

,;? cöX

Example 7 - · s ^j;) - ■:. ■ .-.,. , - ,,. _{:; ri} - _ ._., _: - _Λ -

3- (lf-Hethy.l-propionamldQ) ^ 5-nitrobenzoic acid., ..

3 -. (H-.Methylamino) -5-nitrobenzoic acid (56Q g) -yurde - dissolved - in ^ .Q propionic anhydride by heating - in an aem-Daiapfbad- .. ... _x , after 1/2 hour ΐ / The solution was cooled to room temperature.

9 8 5 Ö / ff 6 § ^{;: >:} · - ■ ^

After stirring it over! laughs - you diluted the mixture with ether and filtered. Aiis yield: 627 g ($ 87). Haeh the recrystallization from ethyl acetate the product melted at 163 ° to 169 °.

Ii 11.11 % Ä 252 11.29 258

Analysis: C-j-iH 12 * 2 ^night 5 io η 4th , 80 Calculated: C. 52 , 28 4th , 52 Found: 52 , 41 Example 8

3-Amino-5- (1-4 -methyl-propionamido) -benzoic acid.

3- (H-diethyl-propioiianido) -5-nitrobenzoic acid (25.2 g) Dissolved in 200 ml of hot 1-ethanol, a catalyst was added Add 5 # palladium on charcoal (.2 g) and hydrogenate the hot Solution in a low pressure apparatus (Parr). As soon as the calculated Amount of hydrogen was absorbed, the solution was in vacuo concentrated to 75 ml, then diluted with water (150 ml) and acidified with glacial acetic acid. Yield: 17.4 g (78 $$) ·. liach the recrystallization from "water the product melted at 160 to 166 °.

N 12.60 $ S Ä 222 12.53 224

Analysis: C j. AL · .Ii ₉ 0 " H 6, 55 Calculated: G 59 .45 5- 6, 54 Found: 59 , 59 Example 9

3-Amino-5- (li-methyl-propionaniido) -2,4,6-triiodobenzoic acid.

3-Anino ~ 5-Cr-rietli3'l-propiona: r.ido) -benaoic acid (177.6 g) was dissolved in 460 μl V / water by adding 82 ml of 10N-lithium hydroxide, acidified with 540 μl of glacial acetic acid and heated to 70 ° in the reaction flask with stirring. I-Ian added 5.44M KaJCl ₂ (935 ml) from a dropping funnel over the course of 1 hour. The addition was heated for 3 1/2 hours after which the mixture was cooled and filtered. The product was suspended twice in acidified water. Yield: 238 g (50%).

909850/1769 6A _D

Example 10 """.. ■ ~

3- (IT-ß-II-hydroxyethyl-acetamido) -5 ~ (i-methyl-propionamid.o) -2.4, triiodobenzoic acid. "-. ■ - .. - ·

3-Acetamido-5- (IT-methyl-propionamido) -2,4,6-triiodo-benzoic acid was obtained by acetylation of 3-amino-5- (IT-methyl-propionamido) 2,4,6-triiodobenzoic acid with acetic anhydride, with concentrated Sulfuric acid as a catalyst.

3-Acetamido-5- (lT-ß-hydroxyethyl-propionamido) -2,4,6-triiodobenzoic acid (987 g) was in 2.6 ltr. Suspended water and dissolved by adding 10N -l sodium hydroxide (6JO ml) and heated to 70 ° with stirring. Then 2-chloroethanol '(213 ml) was added from the dropping funnel over the course of 1 hour. Half an hour after the addition, the solution was cooled to room temperature, acidified with glacial acetic acid and labeled "-Active-" overnight. coal treated after the activated carbon was filtered off, the product is precipitated by the addition of Gn Chlorwasserstoffßäure ■ - out. Yield: 950 g (90 ^c / j). The product was in 1.5 Itr. What water dissolved by adding 10n4Iatriumhydroxyd and treated over Hacht at about pH 6 with activated charcoal. The acid was then released with ön hydrochloric acid. This procedure was repeated once. Yield; 890 g, pp. = 227., Up to 231 °. ·

Analysis: C. •
• 15 ^H. 17 ^y 3IT ₂ O ₅ H 2 , 50 fo J 55 , 5 IT 4, 08 1 686 Calculated C. 26th , 26 «ο 2 , 82 55 , 0 4, 08 -697 Found: 26th , 67

Example 11 - ■ - '

K- (ß-hydroxyethyl-) - li ^l -methyl-3,5-diacetamido-2,4,6-triiodobene-

zoic acid.

Procedure _; 1: ·

IT-iiB-Hydroxyathy-l) ^, 5-diacetamido-2,4,6-triiodobenzoic acid (6.6 g) was in a mixture of 20 ml of water and 4 ml of 1On sodium hydroxide solved. Then the solution was cooled in ice water

9 0 9 8 5 0/1769

BATH

ser and added 1.9 ml of dimethyl sulfate in portions. Half an hour after the addition, the reaction solution was neutralized and heated on a steam bath for 15 minutes. After cooling, the mixture was acidified with 6N hydrochloric acid, yield: 4.4 g (65 ^a J>) .

Before heating, the paper chromatogram of the reaction solution showed three spots with R ^ values of 0.35; 0.48 and 0.58 increase in a ratio of about 5: 5: 1 in the order of the R ^ values. The paper chromatogram of the heated reaction solution showed the same three spots in a ratio of about 3; 7 ι 1 in the order of increasing R _f values. The paper chromatogram of the precipitated product showed two spots, with R ^ values of 0.48 and 0.58 in a ratio of about 9: 1 in the order of increasing R ^ values. Dissolved the precipitate as Ammoniumsala in water and the solution 20 minutes long heated on the steam bath, the spot appeared with R "- ¥ ert of 0.35 again in an amount of about 15 ^cp. It should be mentioned that the starting material has the R ^ value of 0.35 «, -

Method 2:. . '.

1 · T ~ methyl-'3J5-diacetamido-2,4> β-tr2iodobenzoic acid (6.3 g) was dissolved in a mixture of 10 ml of water and 6 ml of 10N sodium hydroxide. 2.1 ml of 2- The solution was left to stand for 5 hours and then acidified with 6N hydrochloric acid .. Yield: 5.6 g (82 ^c / b) · The paper chromatogram of the product showed a spot with R ^ - Value of 0.48. ·....

The IR spectra. of the products produced by the method 1 land ^ 'were identical and their spectra were identical to the IR spectrum of K- (ß-hydroxyethyl) -N ^l -methyl-3,5-diacetamido-2,4,6-trijQdbenzoic acid, which are manufactured by a different process ^: A- / ar. ■ ". ....-..-. ■

909850/1769 '

1120838

» 26 - Method 3: *

3- * Acetamido-5- "N-methylacetamido-2,4» β-trijodbehzoic acid (TÖOÖ g, 1.59 mol) was suspended in 200OmI of water and by adding 6.4 mol of sodium hydroxide in water (1300 ml ) dissolved «The resulting solution was heated to 70 ° and 2-chloroethanol (213 ml, 3.18 mol) was added dropwise with stirring over the course of T hour. The mixture was stirred for a further 30 minutes at this temperature. The pH was then adjusted to 5.9 with 6N hydrochloric acid (240 ml) and acetic acid (20 ml), one treated with activated charcoal (10 g) and stirred over ITachii.ITach, .dem- '· .->, “Filtration, the piltrate was brought to pH <0.5 by adding 200 ml of hydrochloric acid. A white crystalline material precipitated out. The resulting suspension was stirred for 4 hours at room temperature, left to stand ^: '- ■ filtered and the solid material' with water which had been acidified with a few drops of hydrochloric acid, -gewasshejl ·. The substance weighed 1065 g (99 ^) after drying in vacuo t 70 °, mp = 238 to 241 ° (decomposition). . -.

The material (1060 g) was suspended in 2000 ml · ethanol. 0.88 m / (1pu ml) was added until the pH was −7. Man fil * - ^; A little undissolved material trotted off, the filtrate was stirred with 5 g of activated charcoal for 30 minutes, filtered and acidified to pH <0.5 by adding 250 ml of hydrochloric acid. The suspension of the white crystalline material was stirred for 1 hour, left to stand overnight and filtered. In order to remove the precipitated ammonium chloride, the material was suspended in 1000 ml of water containing a few drops of hydrogen chloride and filtered again. This material weighed ν 843 g (79 ^c ß>) after drying in vacuo at 70 °, mp = - 2.41. _; ; bi _; s 243 ° (decomposition).

For the purpose of analysis, this material was once recrystallized from water ¹ , again ^! as ammonia salt - dissolved in Kethanpl- ^ e, 'precipitated by acidification - uiid good ^! washed with water _{; f} pp. = 241 to 243 ° (decomposition).

Analysis:

Calculated: C 25.00 f = H $ 2.25 J $ 56.70 > .IT 4.17 <fo Found: ■ 25.14 2.34 "" 56.44 4.09

Example 12

lI- (2,5-3ihydro>: ypropyl) -iI ^f -methy 1-5, 5-diacetamido-2,4,6-tri, iodobesic acid.

(100 g) vmrde

suspended in 160 ml of methanol and through. Addition of 1ii-methano ~ Iisch.Q.r ijatriurnnetliylailösung (160 ml, 1 iiquiv.) Dissolved. Ilan gave glycid (20ial, 2 equiv.) liinsu and left the homogeneous solution Stand at liaum temperature for 2 days. The solution is in a vacuum Concentrated to about half of the volume, with water diluted the original volume and added concentrated "hydrogen chloride" acid acidified to etv / a pH 0.5. ! laugh at stirring over freight vmrde the precipitated product is filtered off, in with Hydrochloric acid acidified water (80 ml) suspended and stirred etv / a for 1 hour, filtered and in vacuo at Dried about f? 0 ° C. Yield: 79.0 g (£ 72) .. '. '.. V

The product was purified by double precipitation with hydrochloric acid from a solution, the ammonium salt in a 1: 1 mixture of ethaiiol / water and subsequent crystallization from diethyl alcohol / water, melting point = 244 to 246 ⁰ C.

Analysis: C ₁ -H ...- J-Ii ₂ Og

Bereclonet: J 34.3 ^ IT £ 3.99 equiv. 702 Found: T-2.7 4.10 710

JSine halbqu £ ix "citative Äquivalentgev / ichtsbestiminung assuming a Terjodadoxydation gave 642 (! Confirmation of the positions of the hydroxy groups of) paper chromatography in n-Bu0Ii. ΙίΙϊ, ΟΗ (-25 £): H ₂ O (4: 1: 2: 1); R _f value: 0.37 ..

909850/1769 BAD ORIÖJNAL

5-N- (2, 3 - dihydroxy-propyl) -cicetamido-2,4, 6-tri, iodobenzoic acid and IT, IT'-Ms- (2, 3 ~ DJhyd.ro :: -: yproT) yl) -3, 5-diacetamido-2,4 <6-tri _t i * odbenzoic acid were prepared as described above. The R «values in the above system were 0.52 and 0.20, respectively.

Example 13

N- (2,3-Dihydroxypropyl) -IT '~ -raethyl ~ 3,5-diacetamido-2,4,6-triiodobenzoic acid via the corresponding li-allyl derivative.

1. Allylation.

IT ~ Methy1-3j5 diacetamido-2,4,6-triiodobenzoic acid (6.3 g) was suspended in 15 ml of water, dissolved by addition of 10n-lTatriumhydroxydlösung (6 ml) and the solution was heated to 5O ⁰ C before 4 ml of allyl bromide were added with stirring. Stirring was continued at 50 ° until the solution became clear (about 30 minutes). The solution was cooled to room temperature and acidified with hydrochloric acid (1: 1) to a pH of about 0.5. The precipitated product was filtered off, resuspended in water (about 50 ml) and iiatrium bicarbonate up to about pH 7 was added. The non-dissolved love product (0.4 g) (possibly ester) was filtered off and the desired IT-allyl compound was precipitated with concentrated hydrochloric acid, filtered off, washed with water and dried ^{at about 60 ° C. in vacuo.} Output: 4.8 g, 72 a; Pp = 220 to 224 ° C; $ J calculated: 57.0; found: 55.7 1 °. Paper chromatography in the solvent system n-BuOH: EtOH: IJH, OH (25 ^c £) : H ₉ O = 4: 1: 2: 1; R. value: 0.66.

2. Oxidation:

The IT-allyl compound (200 g) obtained above under point 1 was suspended in water and sodium carbonate was added, to obtain a clear, alkaline solution, to which potassium permanganate solution (2.6 ml, 0.3 mKol / ml) was then added. The hangan dioxide was filtered off and the piltrate was acidified with concentrated hydrochloric acid to about pH 0.5. The precipitated product was filtered off, washed with water

90 9850/1769

BAD ORiGtNAL

see and dried. A paper chromatogram showed about 50 the desired dihydroxypropyl compound.

Example 14

3 ~ Amino-5-H- (ß-hydroxyethyl-propiona.mido) -2,4 »6-triiodobenzoic acid.

3 ~ Amino-5-propionamido-2,4,6-triiodobenzoic acid (117 g) is suspended in 300 ml of water and dissolved by adding 1On sodium hydroxide solution (80 ml). They gave 27 ml of 2-chloroethanol dropwise with stirring at 7O ⁰ C in the course of 30 minutes added. After stirring a total of 11/2 hours, the solution was cooled to room temperature and the pH adjusted to about 6 by the addition of concentrated hydrochloric acid. The solution was treated with activated carbon (3 g of activated carbon), filtered and acidified to about pH 0.5 with concentrated hydrogen chloride. The precipitated product was filtered off with

egg
te: 117 g ( $ 93), m.p. = 150 to 155 °.

Washed with water and dried in vacuo at about 50%. Exertion

Example 15. ·

5- (II-ß-Hydroxyethyl acetamido) -2,4, 6-triiodo-IT, methyl isophthalic acid amide.

5-Acetamido-2,4,6-trij od-li-methyl-isophthalic acid amide (122.8 g, 0.2 mol) v / urde in 1200 ml of methanol by adding 5m-liatrium methylate (160 ml, 0.8 mol) dissolved. Then 2-chloroethanol was added (28 ml, 0.4 mol) with stirring. After 24 hours, 5m sodium methylate (40 ml, 0.2 mol) and 2-chloroethanol (14 ml, 0.2 mol) was added with stirring. After 24 hours, the reaction solution was diluted with 700 ml of water and neutralized with Glacial acetic acid and evaporated to about 1/3 of the volume in vacuo. The product was obtained by adding 6N hydrochloric acid failed,! times that. The product was redissolved in filtration 1.2 Itr. Water as the sodium salt, by adding 10n-1ta.trium hydroxide and treated «overnight with activated charcoal, then v / urde

9098S0 / 1769 ^ _{0 ORIS1NAL}

the product was first precipitated from acid with 6ii ~ hydrochloric acid. Yield: 11.5 g (87 ^), Ep. = 258 to 280 ° (decomposition).

Analysis: CL ~ IL., J ₁₅ NpO ₁ -

Calculated: J 57.9 # 1 658
Found: 57.4 666.

R _f ~ value: 0.26.

Example 16

3 ~ acetamido-2,4, 6-tri _t iodo- (LT-ß-hydroxyäth.yl) -isophthalsL; .ureamid.

a) Me tho>: yc arb ony 1 ~ '"■ -ni tr ob cn π oy 1 chi or id was according to the method described by Hoey et al., J, l <Ied.Ghem. 6 ^ 24 (1963) manufactured.

b) 5-Ni tr o ~ (IT-ß-hy dr oxyäthy 1 ) ~ is orihthalami dsäurene thy lest cr

The product obtained above under point a) (100 g, 0.41 kol) was at 0 to 5 ° in the course of 45 minutes to a well-stirred solution of ethanolamine (27.5 g, 0.45 kol) and sodium bicarbonate (69 , 0 g, 0.82 Hol) in 580 ml of water. After stirring at 0-5 ° for 2 hours, the reaction mixture was allowed to reach room temperature. Stirring was continued for 1 hour. After standing overnight, the reaction mixture was filtered, and the undissolved material was washed with the sodium bicarbonate solution and then with water and finally dried. Yield: 88 g (80 ^c / o), pp. = 124 to 129 °.

c) 5-nitro- (IT-ß "h7 / dro: c7 / ethyl ) -iso- ^> meththalic acid - anide.

29.6 g of sodium carbonate were added in portions to a heated mixture of the product obtained above under point b) (75 g) in 180 ml of methanol and 900 ml of v / water. After filtration and acidification with hydrochloric acid, crude product III precipitated. The product was isolated, washed and dried. Yield: 51.8 g (73 ^c / o), I ¹ P. = 135 to 138 °. .

9 09850/1769
- -. .. :: ^ W: ■ fiAD ORIGINAL "

A sample of the crude product was crystallized from ethanol; S ¹ P. = 169 to 17 '
calculates: 254.2).

I ¹ P. = 169 to 170 °. Today rali sat i ons equivalent = 256.6 (be

d) 5-A - ni3iο- (IT- ⁿ '-liy (\ ro>: y? - ;. thy 1) -isorhthalsuure-ainid.

The crude product (20 g) obtained above under point c) was hydrogenated at atmospheric pressure in a ethanolic solution (500 ml) with PotO / C (2 g, 10 ^c / j) as a catalyst, and the solid material was filtered off at the end of the reaction , extracted with methanol, "the ExtraktionsIosun. ;; combined with dom FiItrat and the solution guessed el removed under reduced pressure, whereby a white residue of IV was obtained; l ^? p. (crude product) = 188 to 190 °. Heut rali sat ion equivalent ~ 222 (calculated: 224.2).

e) 5-Ar; ·, no-2, · \ , · ~ -tri; i od- (IT-? -iiV (lro :: Y; lthy I) -I, ^ ophthalr- ^: 'itre-aniid. The above lint or ei) obtained product (8, - ;, O, ü' ^ 56 Hol) was dissolved in gn-chloro / aqueous acid (approx. 10%) and diluted with 575 ml of water. The solution was heated to 50.degree. And, with stirring, over the course of 20 _{minutes for 3 s,} 56m liaJClp solution (32.2 ml, 0.1V; i-Iol) was added. Add 20 ml of hydrochloric acid and raise the temperature to 85 to 90 °. After a few hours at this temperature, the reaction mixture was left to stand over at room temperature. The product was filtered and dried in vacuo. Yield: 9.73 g. Found: J 62.5 ^c /> (bereclmet: 63.2 ^), neutralization equivalent = c ^: 00 (bereclmet: 601.9).

The filtrate was stirred at 90 for a total of 9 hours. During this period, he added 3.56 ml of IVa / Clp solution (16.1 ml). A further 4.86 g of dried product could be isolated by v. ^r earth. Total iuiD '-. C-ute: 14.59 g (69 ^).

f) ^ -Acct-ar.u.do-2.4, 6-tri; iod - ('i ~ ß-hyaroxvätlr / l) -isophthalic acid arud.

For the I-iischling of the product obtained above under e) (715 g, 0.0125 mol) and dimethylformamide (15 ml) were slowly added

9 0 9 8 5 0/1769

β * ⁰ original

Stir 2.5 ml of acetyl chloride (0.06 Hol) at room temperature. The reaction mixture was stirred for 4 hours and allowed to stand for 60 hours. 5 ml of water were added and the solution was evaporated in vacuo to a thick oil. The acid was dissolved as the sodium salt with water and sodium bicarbonate and the product was precipitated by adding hydrochloric acid up to about pH 1, filtered, washed and dried in vacuo. Yield: 5.8 g (72 Ji). Found: J $ 58.7 £; N 4.29 #; calcd-J 59.1 ^c / o ', H 4.35 / β; . Neutralization equivalent = 646 (calculated: 644).

Analysis: O 22 38 ^r / o H 1.72 io J 59, - (O nl
I tL / 0 N 4, 35 Calculated: 22 90 2.11 60, 31 4, 62 Found:

Example 17

N, Ii ¹ -di (ß-hydroxyethyl) -3-acetamido-5-propionamido-2,4,6-triiodobenzoic acid.

3-Acetamido-5-propionamido-2,4,6-triiodobenzoic acid (62.8 g, 0.1 Hol) was dissolved in 600 ml of ethanol by adding ^; of 5N-1 sodium methylate (80, ml, 0.4 Hol) dissolved. Then 2-oloroethanol (14 ml, 0.2 hol) was added in one portion at room temperature with stirring. After 24 hours, 5N-ITriuric diethylate (40 ml, 0.2 hol) and 2-chloroethanol (14 ml, 0.2 hol) were added with stirring. The latter addition is repeated after 24 hours. The next day, the reaction mixture was diluted with 600 ml of water, neutralized with glacial acetic acid and concentrated in vacuo to half the original volume. The reaction product was first precipitated out of acid by adding 6n-chloro-vass. The product was redissolved in 600 μl of water by adding liatric hydroxide, treated with activated charcoal overnight and precipitated with bn hydrochloric acid. After filtering, the latter procedure was repeated. Yield: 48 g (67 io). Mp = 234-276 ° (decomposition).

909850/1769

Analysis: C ^ glLgJ ^ HpOg

Calculated: G $ 26.83 H $ 2.67 J $ 53.2 N $ 3.91 HG 716 Found: 26.37 2.87 51.4 3.89 727

N, IT · -di (β ~ hydroxyethyl) -3, 5-dipropionamido ~ 2,4,6-triiodobenzoic acid.

3,5-Dipropionamido-2,4,6-triiodobenzoic acid (64.2 g, 0.1 mol) was hydroxyethylated and purified as described above. Yield: 52 g ($ 71), m.p. = 193 to 275 ° (decomposition).

Analysis: C. _} ^ H- J ₃ K ₂ Og

Calculated: 0 27.97 '$ H. 2.90 $ J 52.1. $ IT 3.84 ■ $. lieut.Ä Found: 27.17 3.07 50.5 3.89

Example 18

3-Acetamido-5- (N-methyl-N- (β-hydroxyethyl) carbamyl) -2,4,6-tri-3odbenzoic acid.

a) 3-Amino-5-niethoxycarbony / benzoic acid.

3-Methoxyca.rboxyl-5-nitrobenzoic acid (25 g) was hydrogenated in 500 ml of methanol using palladium oxide on carbon (2.5 g, $ 10) at atmospheric pressure. Served as the exothermic reaction ended, the catalyst was filtered off! Times 2 1/2 hours long cooling to -20 ⁰ O 12.7 g product were isolated. An additional 6.5 g was isolated by concentrating the mother liquor. In thin-layer chromatography (silica gel, GHOl,: EtpO: MeOH .: HCOOH = 55: .25: 10: 10) the product (100 jig) showed only one spot (R ^ = 0.4).

b) 3 ~ amino ~ 5-methoxycarbonyl-2,4,6-triiodobenzoic acid,

The amino compound (12, θ "g) obtained under a) was suspended in 280 ml of water and dissolved by adding concentrated hydrochloric acid (7.1 ml) and glacial acetic acid (28.5 ml). At 60 to 70 ^° C., the mixture was added a NaJCl ₂ solution (73 ml, 58.7 g JCl / t00 ml)

909 8 5 0/1769

- Add 34 dropwise with stirring over the course of about 3 hours. The reaction mixture was v / urther 3 hours with stirring a "uf 80 ms 90 ⁰ C heated. Skilled the -Abkühlen to room temperature, the mother liquor was decanted and the residue was dissolved as an ammonium salt in 80 ml of v / ater. The Ammoniuiüsalz was prepared by adding BH ^ Cl. ( 'g 2.4) and cooling to O precipitated ⁰ C. the ammonium salt v / urde filtered off and dissolved in 140 ml of water, twice at 80 ⁰ C treated with activated charcoal, and the acid was quenched by adding hydrochloric acid at room temperature precipitated and filtered off, Ken dissolved the crude product in ethyl acetate (100 ml) and washed the solution three times with hydrochloric acid (2N).

Evaporation of the solvent isolated 19 g of the encoded product. Thin-layer chromatography on silicates! using BuOH: EtOH: H ₂ O: ITFW = 30: 5 ', 5:10 showed only one spot - with R- = 0.35 (starting material: R- = 0.27), pp. = 170 to 176 °.

c) 3-Amino-5-methoxycarbonyl-2,4,6-triiodobenzoyl chloride.

A mixture of 3-amino-5 ~ nethoxycarbonyl-2,4,6-triiodobenzoic acid (198 g) and thionyl chloride (400 ml) was heated with stirring for 16 hours at 70 ⁰ C. The solid material slowly dissolved.

The thionyl chloride was evaporated off in vacuo, - the residue was dissolved in chloroform (1000 ml), the solution was washed with 80 ml of water each time, twice with saturated lithium bicarbonate, then five times with 2N sodium hydroxide solution and finally with water until neutral " The solution was dried with CaCIr ,, filtered and evaporated to dryness. The product was ^{dried at 50 °} C. in a vacuum. Yield: 203 g, pp = 55-60 °.

d) J-ethamido-S-methoxycarbonyl ^^ sö-triiodobenzoyl chloride.

106 ml of acetic anhydride were added to the acid chloride (53 g) obtained under point c). After stirring for 20 minutes at room temperature the insoluble material was filtered off (3 "to ,, 4 g)

^:; 909850/1769

BAD OBiGiWAL

Tin filter passed through 0.3 nl concentrated sulfuric acid, v / o a yellowish product began to precipitate. The [temperature reached etv / a 50 °. The producer was isolated after it was over That night in the Kühln-chraiüc. Yield: 39 g, "m.p. = 210 to 215 °

Analysis; C ₁₁ Ur ₇ ClJ-IiO.
. iii 3 4

Calculated: Cl £ 6.62
Found: 5.4ö

e) 5-Acetamido-2, A. 6-tri j öd- (II-methyl-17- (ß-hydroxyethyl)) isophth; i lcurii d nl '.u :: e— ne thy Io s I er.

The acetylated product (36 g) was dissolved in a mixture of dioxane (400 ml) and dinethylformamide (20 nl). In the course of 2 hours this solution was added dropwise to a solution of IT-Hu t; iylUthaiioliunin (5.0 nl, 10 ^c / j excess) and triethylu :: iin (8.7 vl ) in Dioiian. LJcn rattled for hours. A sticky Kiedersciilag v / urdc- filtered off. The fiItrate ViUrde in Yakuuni: ur dryness cingecu ".r.: Pft. The residue is triturated with aqueous 1, atrium bicarbonate, filtered off and mixed with the crcteii Fra.roioii. iv / ll -.- ri ^ em iiatrium bicarbonate suspended, filtered off, geti-oclaiet with Viassor {; ev / acc :: fii and in vacuum. Yield: 23 E, melting point = 201 bio 212 °.

Ajialyre: C ₁ , H _{1 r} _ J ./A _r 0 _r -

Bereclinet: J "-6.65 ^C , O
Feelings: 54.4

f)? -Acetanico-2,4,6-tri iod- (iT-iaetiiyl-L ^r - (ß-hydroxyethyl)) - isophthalic anide.

The isophthalanic acid ester obtained above under e) (21.8 g) is mixed with freshly distilled ethanolamine. (4 ml), mixed and stirred at 70 ° for 9 hours. The excess ethanolamine was removed in vacuo at 50 to 60 ⁰ C. The residue was

909 8 5 0/1769

BAD ORfGINAL.

dissolved in water and treated with activated charcoal at pH 5 Ms 5.5. The crude product was precipitated with hydrochloric acid (pH 0.5) and, after stirring for 2 hours at ⁰ ° C., filtered. 7.6 g of this acid were suspended in 13.3 ml of ethanol and dissolved by adding 1.54 ml of concentrated ammonia . The ammonium salt began to precipitate over the course of about 30 minutes and was isolated after stirring for 2 hours. The salt was dissolved in 30 ml of water, filtered, and the acid was precipitated with hydrochloric acid (pH 0.5). After stirring for 2 hours at ⁰ ° C., the product was filtered off and dried in vacuo. Yield: 5.7 g.

Analysis; C. ^ iL ₇ N ₀ O ₁ -

Calculated: J 57.86 <fo today. Ä. 664 (theoretical 658) Found 55.8

5-Acetamido-2,4,6-triiodo- (lT,] i-di- (β-hydroxylthyl)) isophthalic acid amide.

Was made from 3-acetamido-5-carboxymethyl-2,4,6-triiodobenzoyl chloride by reaction with diethanolamine according to that described above Process made.

g) 5- (lT-13-Hydroryä "bhyl) -acetamido-2,4.6-triiodo- (ίΤ-ß-hydroxyethyl) -isophthalic lureamide.

5-Acetamido-2, 4, 6-triiodo- (li ^r -β-hydroxyethyl) -isophthalamic acid. (34.0 g) was suspended in 295 ml! -! Ethanol and dissolved by adding 70.5 ml of 3N-liatriuranetylate. 7.05 ml of 2-chloroethanol were added to this solution and the mixture was left to stand at room temperature for 4 days. After it had been neutralized, the solution was concentrated to 150 ml and acidified to about pH 0.5. After stirring at ⁰ ° C., the precipitated product was isolated by filtering off (28.18 g). 10 g of this product were suspended in 50 ml v / water, dissolved by adding sodium bicarbonate (2 g), treated with activated charcoal, filtered and acidified (pH 0.8). After stirring at ⁰ ° C.,

909850/1769

"■ '" "" · BAD ORIGINAL

3 g were isolated. (Calculated: J 55.34 fr; found: 54.24 neutralization equivalent = 681 (theoretical 688).

Analysis: ( Ί4 ^Η 1 5 ^J 3 IT ₂ ( fr H 2, 20th Io N 4, 07 # J 55, 34 fr Calculated: C. 24, 44 2, 86 3, 67 54, 32 Found: 27, 34

Example 19

li -. (3-Acetaniido-5-car'boxy-2,4,6-trijodbenzoyl) -N ~ methyl-glucamine ,,

a) l · Γ- (3-metho ^ '■ car ^^ onyl-5-nitrΌ ■ bellZoyl) -l ^λ ί · -nethylglucarain.

N-methylglucamine (13.9 g) was added to 400 ml of DtD? dissolved, then 7.14 g of triethylamine were added. 2 ~ methoxycarbonyl-5-nitrobenzoyl chloride (14.4 g) dissolved in 50 ml of dioxane, was added in ₁ over 45 minutes with stirring dropwise. After 3 hours the solution was evaporated to Troclaie in talc. The residue, a yellow oil, was extracted twice with ether and then dissolved in 80 ml of ethanol and 2 ml of water. After leaving to stand at -20 0 for 16 hours, 22.6 g (86 ^c / o) were isolated.]? P. = 144 Ms 146 ⁰ C; recrystallization from MeOH / H ₂ O: p. = 158 up to 164 ° E.

Analysis: C ₁ gHg ₂ H ₂ 0 .j _Q

Calculated: C 47.77 H 5.51 fr fr fr Έ 6.97 Found: 47.91 5.38 7.12

b) W- (3-amino-5-carboxybenzoyl) -IT-methylglucamine.

The Hitroester (4.02 g) was suspended in 50 ml water heated to 60 ⁰ C and under stirring, 1.06 g of sodium carbonate in the course of 30 minutes, added in portions. After all of the substance was dissolved, stirring was continued for 10 minutes. The solution was hydrogenated at room temperature at pH 4 using Pd / C as a catalyst (1 to 4 atmospheres are normal). After the catalyst had been separated off, the solution was extracted five times with 10 ml of phenol each time. The United

909850/1769

BATH

Phenol extracts were washed three times with water (10 ml each time), then diluted with 150 ml of ether tend five times with each 1b ml of water extracted. The combined aqueous solution was washed three times with 15 ml of ether each time and in vacuo to Evaporated to dryness. The residue (0.5 g) melted at 94 ms 97 ° C.

c) N- (3-Amino-5-carboxy-2, 4, 6-triiodobenzoyl) -li-methyl-glucamine.

The nitroester (20.1 g) was hydrolyzed and hydrogenated as described above. However, the product was not yet isolated. After removal of the catalyst, the solution was treated with charcoal, and acidified with HOl (2n, 25 ml) was heated to 50 ⁰ C. 41 ml of NaClp solution (4N, 3.3 equiv.) Were added with stirring over the course of 1 hour. The mixture was stirred <3 1/2 hours further, in the last two hours, the temperature was 80 ⁰ C. The solution "was treated with Na ₂ SpO, at 50, was maximum to discoloration achieved with phenol (1 χ 100 ml + 3 x 50 ml). The phenol phase was diluted with 750 ml of ether and extracted with 4 x 70 ml of water. The aqueous solution was washed with ether and evaporated to dryness. Residue: 22.6 g ($ 61)> pp = 138 to 147 ° C. After Uuik crystallization from ethanol (activated charcoal) the white product melted at 94 to 140 ° (crystallized from EtOH).

Analysis; C ₁₅ H ₁₉ N ₂ O ₃ J ₅ * CH ₅ CH ₂ OH

Calculated: J 48.7 fi
Found: 48.1

d) N- (3-carboxy-5-diacetylamino-2,4,6-triiodobenzoyl) "lT-ynethyl ~ glucamine pentaacetate.

The amino compound (21 g) was prepared by suspending it in acetic anhydride (63 ml) at 60 ° using 0.2 ml more concentrated HpSO, peracetylated as a catalyst. The solution was 1 hour stirred for a long time at 80 ° before evaporating to dryness. Dex * residue was dissolved in 200 ml of ethyl acetate, with 3 x 15 ml of v / water

909850/1769

-XMi ^ r * · -. ::; BATH ORIGINAL

washed, dried with CaClp and evaporated to dryness in vacuo. Yield: 27.2 g (91 #), melting point = 126 to 142 ^° C.

e) H- (3-acetamido-'3-carbo; o / -2,4,6-triiodobenzoyl) -IT-methylglucarnine.

The peracetylated compound (26.2 g) is suspended in water and added dropwise! of 2N sodium hydrochloride: dissolved in solution up to pH 10 constant v.-urde (60 C). The solution is extracted with phenol as described above at room temperature and pH 1. _{13 5} 3 g (67 ^C J>) of a light brown product were isolated from the final aqueous solution by evaporation to dryness, melting point = 174 to 180 ^° C .; recrystallized (EtOH), m.p. - 195 to 205 °.

Analysis: C ₁ ^ i ^ J ₅ Ii ₂ O ₉ • CH ₅ CH ₂ OH

Calculated: J 46.3
Found: 46.0

This product is dissolved in Y'acser and treated with activated charcoal at 100.degree. The solution vmrde to "dryness. Mp. = 1T9 to 194 ^0C

Analysis: C ₁₇ Ii _0. , J-IT ₂ O ^

Calculated: C 26.23 Ά ü 2.72 ^C A 17 3.59 ^C , O J 48.93 # Found: 26.77 2.80 3.63 48.5

According to method a) to e), the corresponding glutamine derivative is also vmrde manufactured.

Stage a: Yield 95 # ₉ mp = 159 to 17O ⁰ C (H ₂ O)

Analysis: ^G -] ^ 20 ^ 2 ° 10

Calculated: C 46.38 £ H 5.19 & ■ IT 7.21 ^c / o Found: 48.84 5.15. 7.09

909850/17 6 9

BATH ORIGINAL

Level b: Pp. = 82 to 92 ⁰ C.

Stage c: Yield: 78 56, pp. = HO to 145 ⁰ C Stage d: Yield: 65 $, pp. = 125 to 135 ⁰ C Stage e: Yield: 91 $ (crude), pp. = 184 to 192 ⁰ C.

Anal?, Rse: CgH. "J ^ H ₂ Oq

Calculated: C 25.15 # H 2.51 % IT $ 3.67> J 49.8 fo ^ Found: 24.92 2.57 3.49 49.4

Example 20

IT- (3-carboxy-5-IT-methylacetamido-2,4,6-trijodbenzoyl) -IT-methyl-

glucamine.

a) 3-Hethoxycarbon3 ^r l-5-IT-meth3 ^ 1acetamido-2,4,6-triiodobenzoic acid,

3-Amino-5-methoxycarbonyl-2,4,6-triiodobenzoic acid (200 g) was acetylated with acetic anhydride at 70 ° 4OO ml using concentrated sulfuric acid as a catalyst. The excess anhydride was distilled off, the residue was suspended in 500 ml of water, and 10N sodium hydroxide solution was added until the pH was stable at 10 (60 °). The solution was at pH 7.5

treated with activated charcoal at 80 °, cooled to room temperature and precipitated the product with concentrated hydrochloric acid. Yield: 212.6 g (98%), pp = 160-168 °.

Analysis: C _1. , H ₀ J

Calculated: J 62.3 ? °
Found: 61.7

This compound (61.5 g) was IT-methylated in an aqueous alkaline solution with dimethyl sulfate, whereby 59.5 g of the desired th product received. Pp. = 160 to 165 °.

909850/1769

Analysis: O. 2H ₁₀ J ₃ ITO ₅ ok J- 60.6 % Calculated: C 22.90 fo H. 1.61 io N 2, -23 59.6 Found: 23.00 1.97 2.33 6-tri ") odbenzoyl- b) 3-methoxycarbonyl-5-H-methylacetamido-2, Chloride.

The H-methyl derivative (48.0 g) was suspended in 96 ml of thionyl chloride and heated to 60 °, stirring for 30 minutes, after the acid has dissolved (total 2 1/2 hours). Excess thionyl chloride was distilled off and the residue crystallized from toluene. Yield: 38.8 g ($ 78), Ep. = 205 to 230 °. Recrystallized from toluene, Ep. = 208 bis 233 °. . ..

Analysis: O ₁₂ HqCU.

Calculated: Cl 5.48 % -

Found: 5,39 '.,., -.'-

c) H- (3-methoxy carbonyl-H-me thylac etami d.o-2,4,6-tri j odbenz oy 1) H-methyl-glucamln.

The acid chloride (22.7 g »0.035 mol) was dissolved in 220 ml of dioxane and 45 ml of water and 3.86 g of potassium bicarbonate (0.039 mol) were added. H-methyl glucamine (8.2 g, 0.042 mole) was added in portions over 30 minutes. The mixture was left to stand at room temperature for 40 hours with stirring (after stirring for 16 hours, 45 ml of water were added). The solution turns to dryness in a vacuum; evaporated, the residue dissolved in 50 ml of hot water and 14.9 g of product, pp. =. 120 to 160 °, isolated after standing at 3 °. The mother liquor was extracted with phenol, the phenol solution washed with water, diluted with ether, extracted with water, 'the aqueous solution, washed with ether and finally. Evaporated to dryness in vacuo. Yield: 10.4 g,]? P. = 111 to 140 °. Total yield: 25.3 g (89 ^c / o). The product was crystallized from water, Ep. = 170 to 180 °. 909850/17 ^ 9 '

d) F- (3-Carboxy-5-N-methylacetamido-2,4,6-triiodo-bezoyl) -N-. methyl glucamine.

In accordance with c) ester (prepared 30 g) was aminolysed by the addition of 60 ml of ethanolamine by 'under-stirring "4 ^STUN. Long heated under nitrogen at 70 ⁰ C The ethanolamine was distilled under high vacuum, the residue in 20Ö ^ml; dissolved ^<water, acidified to pH 1, "long treated with activated carbon at room temperature for 1 hour, and (x 50 ml 5) extraliiert with phenol. The phenol layer was washed with water (6 × 50 ml), diluted with 600 ml of ether and extracted with water (4 x 70 ml). The aqueous solution obtained was washed with ether (2 × 30 ml), treated with activated charcoal at room temperature for 16 hours and evaporated to dryness. The residue (24.4 g, $ 83, m.p. = 145 to 155 °) was crystallized from isopropyl alcohol / ethyl acetate, then dissolved in water, treated with activated charcoal for 20 minutes at 100 ° and reduced in vacuo Evaporated to dryness.

M.p. = 150 to 18 ^H. 170 0
• 2, 92 io ■ " Si 54? 5 J 48.0 Analysis: Ό. IO
C. 3, 13th 3, 54 47.6 Calculated: 27 j c- y
.30 5έ Η Found: 27 , 77 Example 21

2- (F-ß, V -dihydroxypropyl-acetamido) -5-H'-methylacetamido-2,4,6-triiodobenzoic acid (36.85 g) is suspended in water for injection corners (about 70 ml) and titrated by adding strong sodium hydroxide solution in solution. Calcium disodium ethylenediamine tetraacetate (15 mg), calcium chloride dihydrate (68 mg) and magnesium chloride hexahydrate (62 mg) were dissolved in the solution, the volume was adjusted to 100 ml and the pH to 7.4, the solution was filtered, filled into ampoules and 20 ^{Placed in the autoclave at 120 0} O for a long time, this resulted in a composition which contained 200 mg J / ml and the ratios of calcium ions and magnesium ions to matrium ions were

909850/1769:

0.015 and 0.006, respectively.

The intracerebral LDrn of this solution was included in mice 625 mg J / kg body weight compared to 425 mg J / kg, if none Calcium and magnesium was added.

Example 22

5- (H'-β-Hydroxyethyl-acetamido) -2,4,6-trijod-N-methyl-isophthalamidic acid, (34,6 g), calcium oxide (25 rag), magnesium oxide (12 mg) and calcium dinatriunethylenediamine tetraacetate (15 mg) suspended one in Yfasser for injection wakes (about 70 ml). The remaining Acid that is not neutralized by the alkaline earth oxides was made by adding a strong sodium hydroxide solution neutralized. The resulting solution was treated as above, a composition was obtained which, in terms of the iodine concentration and the ionic ratios of those described above was equivalent.

The intracerebral LD ^ ₀ in ilice was 580 mg J / kg, compared to 400 mg J / kg when no calcium and no magnesium were added.

909850/1769

BAD OSIGlNAt

Claims (1)

- 44 claims 1. / experienced for the production of connections of the general COOH in which Ac is an acyl group, R denotes a hydrogen atom or an alkyl group which
can be unsubstituted or can carry one or more substituents, e.g. hydroxyl groups or groups of the formula: COOH X is a hydrogen atom, an amino group, an acylammomethyl 2
group, a group of the formula -Il - Ac y ρ
in which Ac represents an acyl group which may be the same as or different from Ac and R denotes a hydrogen atom or an alley group which can be unsubstituted or one or more substituents
can carry, for example Hj ^ droxylgruppen, or Ί. means a group of the formula: 909850 / 176.9 3 4- in which R and R, which can be the same or different, are hydrogen atoms or denote alkyl groups which can be unsubstituted or which can carry one or more substituents, or together with the "adjacent nitrogen atom" a heterocyclic atom Form a ring, at least one li-hydroxyal-icy in the molecule ! group is present, R contains at least 3 carbon atoms sits when Ac is an acetyl group and X is a hydrogen atom, an amino group, an Acetamidog.ru.ppe or an N- (ß-Hydroxyätliyl) -acetamido group represents, and their salts, characterized in that a) a compound of the general formula :. . . . . COOH II X ^ C ^ - NH-Ac reacting with a hydroxyalkylating agent to produce a compound of Formula I in which R is a hydroxyalkyl group; b) an amide of the formula II, as defined above, is ^{reacted with an allylating agent in order to introduce an M -} -AlIy! grouping which is then subjected to the oxidation of the double bond in order to form a glycole grouping, whereby a compound ^ of the formula I is formed in which R is a hydroxyalkyl group; c) a compound-the general formula "· ' 909850 / T789 COOH •1 in which Ac is as defined above and AlIcOH is a mono- or polyhydroxyalkyl group represents, with an acylating reagent converts to both the primary amino group and the hydroxyl group acylate or groups, the ester group or groups formed in this way are then hydrolyzed to form a monohydroxyalkyl compound the general formula: Ac ² HH COOH IV AIkOH 12th in which Ae, Ac and AlkOH have the meanings given above, to surrender; . . ; ,: .. ■ d) a compound of the general formula IV, as defined above under c), is reacted with an alkylating agent; through which a corresponding connection of the üOrmel I is formed in the X represents an F-alkylaeylamino group; e) a 5-liter nitro-isophthalic acid ester halide with ammonia or * ~ * Λ '2 A a primary or secondary amine ITHR ^ R, in which R and R ' have the meaning given above, to form the desired 3-carbamoy! grouping, then the ester grouping hydrolyzed, the ITitro group to the amino group 909850/1769 reduced, the nucleus triiodinated and the corresponding 2,4,6-TrIjOdbenzoic acid H-acylated, a compound of formula I being formed in which X represents a group COIlFt IT ", R is hydrogen means and Ac has the meaning given above, then, if none of the radicals R, R and R is hydroxyalkyl, reacted with a hydroxyalkylating agent to form a hydroxyalkyl group on the 5-acylamino group and (where one of the Rests or both radicals R and R represent hydrogen) on the To introduce carbamoyl group GOIIR R; f) a halbestex of the 2-l-nitro-isophthalic acid to the corresponding 5-amino compound is induced, triiodinated, the corresponding 2,4,6-iriiodophthalic acid ester is acj'lated to form the 5-acylamino compound, is converted into the corresponding acid halide, with a compound HHIrR , in which R and R have the meanings given above, then converts the esterified carboxy group into a carboxyl group and then, if none of the radicals R, li ^J and R ^{r represents} a hydroxyalkyl group, reacts with a hydroxyalkylating agent to form a hydroxyalkyl group the 5-acylamino group and (v / o one of the radicals or both radicals R and R ^ represent hydrogen) to the carbamoyl group COiTR R eiiizufüirenjund g) the compounds of the formula II with a functional alkane derivative reacted to produce compounds of the general formula I in which R represents an alkyl group, the one Substituents of the general formula: COOH 909850/1769 - 48 carries, in which Ac and X are as defined in formula I. 2. The method according to claim t, characterized in that the 'hydroxyalkylating agent used is a reactive monoester derivative of a glycol or polyol, or is an epoxy. 5. The method according to claim 2, characterized in that the reactive Monoester derivative is a halide or hydrocarbon sulfonate. 4. The method according to claim 3, characterized in that the Halide is the chloride or bromide. 5. The method according to any one of claims 2 Ms 4, characterized in that that the reaction is carried out under basic conditions. 6. The method according to claim 1, characterized in that the derivative used in method g) is an α, CJ -dihaloalkane. 7. The method according to claim 1, characterized in that the Mfunctional derivative used in method g) is a bisepoxyalkane is. 8. The method according to claim 1, characterized in that the 'Allylation reagent of method b) a reactive ester of an allyl alcohol. 9. The method according to claim S, characterized in that the reactive ester is allyl bromide or allyl chloride. 10. The method according to claim 1, characterized in that the acylation agent of method c) together an acid anhydride with catalytic amounts of a mineral acid or an acid halide is. 11. The method according to claim 10, characterized in that the 909850/1769 - 49 τ
Mineral acid is sulfuric acid or perchloric acid. 12. The method according to claim 10, characterized in that a Halide is used in a polar solvent. 13. The method according to claim 12, characterized in that the Solvent is a substituted amide or imide. 14. The method according to claim I ^ characterized in that the reactive ester of the alkanol in method ¹ d) an alkyldiiiörid- bromide -iodide tosylate or mesyiate or an I) IaI-kylsulfät is; ' 15. The method according to claim i ^ characterized in that the Hydrolysis of the ester groups in process ej under basic Conditions is carried out. 16. The method according to claim i or 15 ^, characterized in that that the reduction of the Hitrögruppe in process e) by catalytic Hydrogenation is carried out. 17. The method 'according to claim 1, 15 or 16, characterized in that the tTodierung in method e) using -is carried out". 1 * 8. Method according to one of Claims 1 or 15 to .1TV thereby characterized in that a product of the formula I, in which one or 1 3 4 several of the radicals R, R and R denote hydrogen. the other Hydroxyalkylation by reaction with a hydroxyalkylating agent is subjected. 19. The method according to claim 1, characterized in that the Carboxyl group into an acid halide group through conversion with a sulfonyl halide or phosphorus halide converted v; ird. 909850/1769 ORIGINAL BATHROOM 20. The method according to any one of claims 1, 15 "to 17 and 19, characterized in that the starting product of the" method e) or f), in which R is hydrogen and one or both of • 3 4 ■ R and R radicals represent hydroxyalkyl, with an alkylating agent is implemented in order to introduce an unsubstituted AUry! respectively, 21. 2,4; 6-iri; fodbenzoic acid which ^{carries at least one group "of the formula -HR 1} in which R ^{1 is} a hydroxyalkyl group, -no H- (β-hydroxyethyl) -acetamido group is in the 3-position , vrenii there a hydrogen of fat on or an amino, acetamido or "= 'H- (ß-hydroxyethyl) -aetamido group is in the 3-3 position ·} tifid' their salts. ...; -'-.-. 22. Compounds of the general formula t according to; Claim 1 and their Salts. - - ' 23. Compounds according to claim 21 or 22 in the form of their ITatriüm-, Calcium or magnesium salts or their salts with Alkänölaü'ihenv 24. Compounds according to claim 23, in which the AUranolämin iithanolamin or N-methylglucamine. 25. Compounds according to a ^ m ^l 'of claims 22 to 24, in which 1 - ■ R is a hydroxyalkyl group and X is is li-substituted acylamino group. R is a hydroxyalkyl group and X is an acylsmino group or a 26. Compounds according to any one of claims 22 to 24 ^ in d X is a group COR R and at least one of the radicals R, Vr and "R is a Hydroxyallcylgruppe., .---- ■ ■ -, - 27. Compounds according to any one of claims 22 to 26, in which ■■ - .; ■. '... · · 1 2 ■ "■■ - ■ ·" the acyl groups Ac and Ac lower alkanoyl groups Eüt 1 to 4 Are carbon atoms. . . , .90 9850/1769 28. Compounds according to claim 27, in which the groups Ac and 2 ■ ■■ '"··> ■ Ac are acetyl or propiony! Groups. 29. Compounds according to any one of claims 22 to 28, in which the hydroxyl group is the β-hydroxyethyl group. 30. Compounds according to any one of claims 22 to 28, in which the Hydroxyall-iylgruppe the 2,3-dihydroxypropyl group or the Is 2- or 3-hydroxypropyl group. 31. Compounds according to any one of claims 22 to 30, in which 1 1 the total number of carbon atoms in the ITAc R group is greater than is 4. 32. Compounds according to any one of claims 22 to 31, in which the groups R, R, R ^ and R ^ 1 to 6 carbon atoms each contain. 33. Compounds according to any one of claims 22 to 31, in which R and R together form part of a 5- or 6-membered saturated heterocyclic ring which may contain other heteroatoms. 34. Compounds according to claim 33 »in» .dene the heterocyclic Ring is a piperidine, methyl piperidine or corpholine ring. 35. 3- (H-ß-Hydrojcyäthyl-acetaraido) -5-1I'-methylacetamido-2,4,6-triiodobenzoic acid. ' 36. 3- (li-ß, i -Dihydroxypropyl-acetainidoJ - ^ - IT'-methylacetamido-2,4,6-trijodbensoesliure. 37. 5- (II'-ß-IIyärox3 ^r ethyl-acetamido) -2,4,6-triiodo-II-methyl-isophthalic acid-amiu. 38. 3- (H-ß-hydroxyethyl-propioiiamido) -5- ΪΓ -methylacetamidc-2,4,6-triiodobenzoic acid. 909850/1769 BATH ORIGINAL 39. 3- (N-ß-Hydroxyethyl-acetamido) -5-N ^l -methyl-propionamido-2,4j6-triiodobenzoic acid. 40. Salts of the compounds according to any one of claims 35 to 41. Iladiological composition, characterized in that they-.at least one acid according to claim 21 or a physiolo-! gically acceptable salt thereof together with a radiological carrier. 42. A composition for injection according to claim 41 'characterized overall W indicates that the carrier is sterile, germ-free water. 43. Composition according to claim 42, characterized in that it contains calcium and / or Magnesiuiaionen. 44. Composition according to claim 43 »characterized in that that the ratio of calcium or magnesium ions to sodium ions is at least 0.00025. 45. Composition according to claim 44 ». characterized, that the ratio is at least .0.0005. 46. Composition according to claim 45, characterized in that the ratio voj
0.005 to 0.10. that the ratio of calcium to Hatriuniionen in the range of 47. Composition according to claim 45, characterized in that that the ratio of magnesium to sodium ions is in the range of 0.002 to 0.05. 48. Composition according to one of claims 43 to 47, characterized characterized in that the calcium and / or magnesium! ons of a calcium and magnesium salt of contrast acid or supplied by another physiologically and chemically compatible, water-soluble calcium or magnesium salt. BATH 909850/1769 49. Composition according to claim 48, characterized in that that the water-soluble salt is calcium or magnesium chloride ". 50. Composition according to one of claims 41 "to 49 for the Radiculography, characterized in that the concentration of the contrast agent is 150 to 250 mg J / ml-, in one dose unit Clay 6 to 12 ml. 51. Composition according to one of claims 41 to 49 for veiitriculography, characterized in that the concentration of the contrast agent is 250 to 350 mg "J / ml, in one dose unit from 3 to 7 52. Composition according to one of claims 41 to 49 for Myelography, characterized in that the concentration of the Contrast agent is 350 to 450 mg J / ml, in one dose unit from 4 to 9 ml. 53. Composition according to one of claims 41 to 49 for making the cardiovascular system visible, characterized in that the concentration of the contrast agent in the range from 150 to 450 mg J / ml, in a dose unit of 10 to 500 ml. 9098 50/17 69