DD204476A5 - METHOD FOR PRODUCING HALOGEN-CONTAINING, AROMATIC CARBONIC ACID AMIDES - Google Patents

Abstract

The present invention relates to a process for the preparation of bromine-iodine-benzene compounds, which can be used as contrast agents in radiography and have a better tolerance than analogous poly-iodine compounds, with contrast values of the same order of magnitude as the poly iodo-compounds.

Description

ν _ AP C 07 C / 242 885 6 ~ 61 359/11 4. 4. 1983

Process for the preparation of mixed bromine-iodine-benzene compounds

Field of application of the invention

The present invention relates to a process for the preparation of mixed bromine-iodine-benzene compounds. The compounds according to the invention are used as contrast agents for radiography.

Characteristic of the known technical solutions

For a long time, iodine-benzene compounds have been used as contrast agents, which in the benzene nucleus have been found to stain several iodine atoms, generally 3 iodine atoms per benzene nucleus, as well as various other substituents. These other substituents are pharmacologically acceptable groups which allow administration of the compounds to humans and animals , The substituents are generally chosen in order to provide the compounds with sufficient water solubility for aqueous solution administration.

Several solutions have heretofore been proposed to increase the tolerance of the iodobenzene compounds used as contrast agents. A first type of solution is to synthesize structures having two or three triiodo benzene nuclei (see, for example, US Pat ÜS-PS 3 290 366 and GB-PS 1 346 795).

A second type of solution is to select substituents other than iodine atoms in order to obtain a particular

0 λ \ .107 -10 2 1 * n> 7 <Λ'Ί Ό ~

Jiuuu Iw w _, V *. i xj ι u J

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to obtain their tolerance. In particular, it is based on non-ionic structures, d. h) that they have no ionic substituents such as carboxyl groups (see ζ B. B. DE-PS 2 031 724 and PR-PS 2 253 509).

A third type of solution is to synthesize polyiodided di- or tribenzene asymmetric compounds having a single ionic group (see, for example, U.S. Patent No. 4,014,986).

Object of the invention

The aim of the invention is to provide new compounds which have an increased tolerance and the same contrast effect.

Explanation of the essence of the invention

The invention is based on the object, the problem of ToIeranzerhöhung in the iodine-benzene compounds in a fundamentally new, different from the "previously known solutions by replacing a portion of the iodine atoms in the core of the known iodine-benzene compounds To dissolve bromine atoms.

Not only does the tolerance of the compounds increase, but also the contrast effect of the same order of magnitude is maintained.

This last fact is particularly surprising, since it was normally expected that the exchange of iodine atoms by bromine atoms would result in a marked reduction in contrast effects.

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The atomic number of an atom on X-rays is proportional to the activity of its atomic number (J · Duheiz, V · Bismuth, M., Laval-Jeantet - Traite de radiodiagnostic, vol. 1 L-image radiologique, Masson et Cie, 1969) · The atomic number bromine is 35 and that of iodine 53. The contrast effect conferred by bromine should therefore be three to four times weaker, and it might therefore be expected that the replacement of a part of the iodine atom by bromine atoms would lead to a considerable reduction of the contrast effect However, by the partial exchange of iodine atoms by bromine atoms, one can achieve a contrast effect of the same order of magnitude as is known from corresponding poly-iodine compounds economic benefit, because bromine is currently far less expensive than iodine »

Therefore, the present invention relates to providing mixed bromine-iodine-benzene compounds which can be used as contrast agents in radiography and have a greater tolerance than the poly-iodine compounds used as contrast agents in radiography, their contrast effect in the same order of magnitude as the poly-iodine compounds.

In the compounds, the number of core bromine atoms is advantageously 1: 2 to 2: 1 in number. Preferably, the number of bromine atoms is equal to that of the iodine atoms in the compounds. Ss may be, in particular, compounds with two benzene nuclei whose one core is triiodinated and whose other core is tribrominated.

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The mixed compounds provided by the present invention may be, in particular, the following compounds:

I - Compounds of the formula I

(D,

in the 2L. , 2U ^ ¹¹ ^ ^ 3 are selected under Jo ^ d-bromine,

where J and Br are present at the same time and

Q ₁ , Q ₂ and Q- pharmacologically acceptable groups are II compounds of formula II

in the

X, X ₂ * ^Σ 3 ^»X A is> ² 5 ¹ ^ d ² ^ ^{un" ter Jo (3} x ^ ¹¹¹ ^ bromo selected, wherein J and 3r are simultaneously present and Qj 'Q2' Q3 '^ 4 » ^ 1 » ^Y 2 ^ * ¹ ^ ^P P ^{narmaIs: olo} s ^are acceptable groups.

Among the compounds of the formula II, an advantageous class of compounds has the formula II a

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Y- -P-

(II a),

in the

Q> j »Q2» Q3 »Q4» ^Y -pen are ·

4 » ^Y -j

^{un <i} - ¹ * ¹ ο log is an acceptable group

III - Compounds of Pormel III

in the

and Zg are selected from iodine and bromine, Z., Zc, where J and Br are present at the same time and

Q ₁ , Q ₂ . Q3 »Q4» Q

5 »

» ^Y 2» ^Y 3 » ^Y 4»

2 » ^Y 3» ^Y 4 ologi sch

are acceptable groups.

IT - compounds of the Pormel IV

- P

(IV),

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in the

Χ .., X ₂ , X ^, X ,, Xc, Xg, Χγ, Xg and Xg are selected from iodine and bromine, wherein J and Br are present simultaneously and

Ji Q-Q ₂ 'Q3' Q4 'Q5 "Qg" ^Y j ^"Y _2" Y3 v d. P pharmaceutically acceptable groups are

The following are examples of groups of types Q, Y, Z and? given.

1 · Groups of type Q

a) hydrogen

b) hydrophilic amino groups

as © of the groups Ä of the formula

in the

m is 0, 1 or 2, η is 0 to 6,

and the radicals R ^, R ₂ , R ₂ and Rg are groups of the formula

- (CHZ) _a T with a = 0 to 5

ZaH or OH

T = H, OH or COOH

^{b = 1 to 5} d = 1 to 5

ρ = 1 to 5 and

- mean sugar residue.

L ⁴ ί L Ö Ö ü O

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As typical examples of such groups, one can specify groups of the following formulas:

CH ₀ OH CH ₀ -CH ₀ -OH

t 2 y 2

ι -IT f.

-NH-CH; -IT \ ; -HC-CH-;

"T tr J

CH ₂ OH CH ₂ CH ₂ -OH CH ₃

NC (CHOH) ₅ H; -HH-

(^) Groups of the formula C-A

1 '

(CH ₂ ) _n H

in the η same. 0 to 3 and A represents a nitrogen group as defined above.

- Groups of the formula

(CHZ) _a1 T

SO ₃ H

in the Z = H or OH T = H or OH

a ^ = 0 to 3 are ·

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c) ether or ester groups such as

Q alkoxy groups having 1 to 6 carbon atoms, optionally substituted, in particular by carbon or amino groups, such as the group A defined above;

© Groups of formula - 0 -

in the m = 0, 1 or 2 η = 0 to 6

a = 0 to 6

Z = H, OH or ₂

T _{1 is} SH, OH or NH ₂ ;

£) groups of the formula - 0 - C - Ar,

Ar is an aromatic radical;

φ groups of the formula

- 0 - C - A or - O - C - C - A

I! U I

0 0 0

in which A is as defined above.

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d) sulfonyl groups such as the group -SO ^ H,

the groups of the Pormel - SQ ₀ -A, in which A is as defined above

e) carbon-linked groups such as Q groups of the Pormel

in the a - O to 6

TaH or OH T = H or OH ·

(^ Groups of the Pormel - (CHg) -O-Ar,

in which Ar represents an aromatic radical,

ζ) groups of the Pormel

OH

- (0Η ₂ ) _η -σ-Η or - (CH ₂ ) _n -CHi

S OH

- (CH ₂ ) _n -C-OH 0

- (0H ₂ ) _n -CA

in the η = 0 to 6 and

A as defined above

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^ Groups of the formula -C-O- (CHZ) T,

in the a = 0 to 6

Z = H or OH

T = H or OH.

Q groups of the formula -C = HH

0 (CHZ) ₀ T,

in the a = 0 to 3

Z = H or OH T = H or OH

are·

ügroup -c am

2 groups of Ttp Y (bivalent)

a) groups linked to carbon

TCHZ)

Q groups of the Ponael

- η

in which a, b = 0 to 6, η = 1 to Z = H or OH T = H or OH,

ζ / the groups -C-

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£) groups of formula -CH-

0 (CHZ) ₀ T,

El

in the a = 0 bi3 6

Z * H or OH

T = H or OH,

Qthe group -CH-

SH

b) Groups of a different type-like

Group -S-O

φ groups of the formula -S-

0 (CH ₂ ) _n1H

with n-a 1 to 6

(?) the Ozy group - OQ Grrtppen the Pormel -

(CHZ) T,

in the a = O to 3

Z,! »Η or OH,

φGroups of Formal

(CHZ) _b T

(CHZ) ₀ T

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in the a, b = 0 to

Z, T = H or OH are ·

3 · groups of type P

The divalent groups P may correspond to the following formula

(CHZ) ₀ T

- (CHU) _f - (CHY) _g -

or -

SO.

(CHB) -D,

in which d, e, h, j = 0,1 or 2 a, f, g, i β 0 to 6 Z, U _t B, VH, OH, Br, (CH ₂ ) _n C00H

with η = 0 to 3, T, D a H or OH ·

Other residues may be inserted into the bridges, such as the groups of the Pormel

-0-, -S-, -CH «- S"

Ä,

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The trivalent groups P may be groups of the following formula:

-co (CH ₂ ) _k -ir

with k = 0 to 4.

A preferred group of the mixed compounds provided by the invention are compounds of formula V.

J-CO-CCH ^ -BH-

(CHZ) _n3 H

HH-CO-

in the X, Z ₂ ^UI1 ^ · ^ 3 represent bromine or iodine,

where at least one of the other two is different,

Q ₁ is a group -COOH or a group of the formula

-CON

where R-3 and H _{A are} independent

is a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxylated, lower alkyl radical or a lower carboxyalkyl radical,

Q represents a hydrogen atom, a CH ₂ OH radical, a cyano radical or a radical of the formula

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-COU, where R _q and Rs are independent

each is a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxylated, lower alkyl radical or lower alkanoyl, lower oxyalkyl, an amino group or a radical of the formula

-N- CORy, where R ~ is a lower

Alkyl radical, lower hydroxyalkyl radical or lower alkoxy lower alkyl radical and R _{Q represents} a hydrogen atom, a lower alkyl radical or lower hydroxyalkyl radical,

Q and Qi independently represent a hydrogen atom, a cyanoradical, a CH ₂ OH radical, a radical of the formula

- COH, la the H ₉ and E ₁₀ the for

R ₁ - and R ^ have given meanings, an amino group or a radical of the formula

- COR-J ₁ , where R _{11 is} the one given for R ^

»12

Meaning and R _{12 have} the meaning given for Rg,

Q4 represents an amino group, a cyanoradical or a group

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-H-COR-c, wherein IL ₁ - a

is a lower alkyl radical, a mono- or polyhydroxylated, lower alkyl radical or a lower alkoxy-lower-alkyl radical,

R _{1 is} a hydrogen atom, a lower alkyl radical, a lower hydroxyalkyl radical or a lower alkanoyl radical,

Z is H or OH n- and n "are equal to 1 to 5 n-, is 0 to 3, and b is 0 or 1, and their pharmaceutically acceptable salts,

In the present application, the term "lower" generally refers to radicals having 1 to 6 carbon atoms ·

To produce the compounds of formula V can proceed, as described in U.S. Patent 4-014986 describes in such a way, one DAB the condensation of an amine of formula VI

 ^ 1 HH • oo ^Q 3 - Λ * N-C0 (CH _{2) a1} - Tqt (CHZ) _n3 H ^s NHCO (CH _{2) n2} HH acid chloride with a the formula VII

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Cl-CO

(VII)

carried out, in particular in a polar solvent at a temperature of 20 to 60 ⁰ C and in the presence of an acid acceptor

More generally, it can be seen that the mixed bromine-iodine-benzene compounds can be obtained by the same procedures as those used for the analogous poly-iodo compounds, by carrying out, in particular, reactions such as halogenation, Alkylation, acylation (by condensation of an acid chloride with an amine or alcohol) or salt formation, which have been described extensively for the analogous poly-iodo compounds.

Therefore, for example, compounds of general formula VIII

(VIII)

COST (CLL,) -UCO ι * - "· ι

I R-iT R-I o

If IO

in the X. Bromine and X ₂ ^ ⁰ ^ or X-. Iodine and X _{2 are} bromine, Q and Q independently represent an amino radical or a radical of the formula

in which

a lower alkyl radical,

61 359/11 - 17 -

represents a mono- or polyhydricated, lower alkyl radical or a lower alkoxy-lower alkyl radical and R ₂ Q is a hydrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical,

Qg and Q independently represent a hydrogenato, a CHgOH eadical, a radical of the formula

-CO-N, where R ₅ and R _{0 are} a hydrogen

atom, a lower alkyl radical, a mono- or polyhydroxylated lower alkyl radical or lower alkanoyl lower oxyalkyl, an amino group or a radical of the formula

where R- is a lower alkyl radical, mono- or polyhydroxylated, lower alkyl radical or lower alkoxy-lower-alkyl and Rg is a hydrogen atom, a lower alkyl radical or lower hydroxyalkyl radical,

and R-γ and R-g are independently a hydrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical, and

η is an integer from 1 to 5, in which the condensation of an amine of the formula ΓΣ

C03- (CH ₉₎ -NH (IX)

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with an acid chloride of the formula X.

Gl-CO ^^^ - ^ "^ ⁿ ^

optionally followed by an acylation reaction to this reaction.

The process conditions may be the same as described in FR-PS 2,313,018.

In the same way, compounds of the formula XI

3OiIH (CH ₀ ) -COlJ ^ Sn ^ n 'I ^Q i R ₂₁ ^X 1

in which X _{1 is} bromine and X _{2 is} iodine or X _{1 is} iodine and X _{2 is} bromine,

Q ₁ is a group COOH

Q ₂ represents a hydrogen atom, a CHgOH radical or

Radical of the formula

-CO-B, where E and

a hydrogen, a lower alkyl radical, a mono- or polyhydroxylated, lower alkyl radical or lower alkanoyl lower-alkyl, an amino group or a

Radical of the formula

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Represent -N-COR, where R _{7 is} a lower ι 7 ι

"8th

Alkyl radical, lower hydroxyalkyl radical or lower alkoxy lower alkyl, and Rg represents a hydrogen atom, a lower alkyl radical or lower hydroxyalkyl radical, Q 1 means a radical of the formula

R ₁

in which R _{11 is} the one for R ₇

Ί2

given meaning and R _{12 have} the meaning given for Rq. R ₂₁ represents a hydrogen atom, a lower alkyl radical or lower hydroxyalkyl radical, and η is an integer of 1 to 5, and their pharmaceutically acceptable salts are prepared by subjecting the condensation of an amine of formula ZII

Q-

(XII)

with an acid dichloride of the formula ZIII

(ZIII)

optionally followed by an acylation and / or salt formation reaction to this reaction.

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The process conditions may be the same as described in PR-PS 2,347,339.

Ausführungsbei3piel

Examples of the preparation of the mixed bromine-iodine-benzene compounds are given below.

In these examples, the products are characterized by their Rf value from thin layer silica gel layer chromatography using the following eluents:

- Eluant 1: benzene / methyl ethyl ketone / formic acid

(60/25/20)

- Eluant 2: n-butanol / acetic acid / water

(50/11/25).

example 1

Preparation of 2,4,6-tribromo-3-H-hydroxyethylcarbamoyl- (2,4,6-triiodo-H-methylcarbamoyl-H-methyl-S-H-acetylaminobenzoyl) -5-glycylamino-benzoic acid (Compound 1

COOH CH ₃ -H-COCH ₃

Br I Br ill

HO-CH ₂ CH ₂ IiHCO ' T HHCOCH ₂ HH-CO

I - Preparation of 2,4,6-tribromo-3-H-hydroxymethylcarbamoyl-5-amino-benzoic acid

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A suspension of 1 mole of N-hydroxy-3-ethylcarbamoyl-5-amino-benzoic acid in 4 liters of water and 820 ml of conc. Hydrochloric acid. Then add dropwise 230 ml (9 mol) of bromine. Stirring is then continued for 24 hours at ambient temperature. It is centrifuged, the precipitate is washed with 2 l of water at 90 ^° C. and dried at 110 ^° C. for 24 h.

Yield: 96.5% purity control:

- CCM with sluant benzene / methyl ethyl ketone (MSC)

Formic acid (60/25/20) Rf of the starting product: 0,05 Rf of the brominated product: 0,55

- purity according to bromine determination: 100%

II - Preparation of 2,4,6-tribromo-3-? T-hydroxyethylcarbamoyl-5-aminoacetamido-benzoic acid

a) Preparation of 2,4,6-tribromo-3-ii-phthalamido-acetoxyethyl-carbamoyl-S-phthalimidoacetylaminobenzoic acid

COOH

NCEUCOOOt ₀ OT ₀ NHCO- ^ NV * sNHCOOT ₉ IT.

^ά CO

Dissolve 322 g (0.7 mol) of 2,4,6-tribromo-3-N-hydroxyethylcarbamoyl-5-amino-benzoic acid in 60 ml of dimethylacetamide.

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Then added in portions 392 g (1.75 mol) of phthalyl-glycine acid chloride.

After 48 hrs. Stirring at ambient temperature, the solution is poured into 2 1 of water at 70 ⁰ C. There is a precipitate, after which it is stirred for a 1/2 hour and then centrifuged.

The product is used without drying and cleaning in the following stage ·

Control:

CCM with sluant benzene / MEC / formic acid

(60/25/20): Rf 0.7 (starting product: Rf 0.55).

b) Preparation of 2,4,6-tribromo-3-N-hydroxyethylcarbamoyl-5-aminoacetamido-benzoic acid

HIGH ₂ CH

A suspension of the product obtained above in 2.4 l of water and 204 ml of hydrazine hydrate is prepared. The mixture is heated for 1 hr. At 90 ⁰ C and then stirred for 48 hrs. At ambient temperature. Ss gives a crystallization.

Then you centrifuged and clarified with water. A product containing 10 to 15% phthalhydrazide is obtained. The product is concentrated in 1 liter of water and 100 ml of conc. Absorbed sulfuric acid.

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The mixture is heated to 90 ^° C. and the mixture is separated. The insoluble fraction is separated by filtration and the pH is then adjusted to 3-4 with ammonia.

Then one can crystallize over Hacht at ambient temperature.

After centrifuging, washing with water and drying in a drying oven, 175 g of product are obtained, which corresponds to a yield of 48.5%.

Purity control:

1) GCM with sluant benzene / MSC / formic acid (60/25/20): Rf

0.05 (orange-yellow spot after development with hinhydin) ·

Bs remain about 1 % phthalhydrazide with Rf 0.75.

2) Purity according to iodine determination: 98 % *

III- Preparation of 2,4,6-tribromo-3-N-hydroxy

ethylcarbamoyl- (2,4,6-triiodo-3-ii-methylcarbamoyl-N-.

methyl-S-N-acetylamino-benzoylj-S-glycylaminobenzoesäure

a) condensation

provides a suspension of 75 g (0.145 mol) of 2,4,6-tribromo-H-hydroxyethylcarbamoyl-S-aminoacetamido-benzoic acid in a mixture of 75 ml of dimethylacetamide and 56 ml (0.4 mol)

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Triethylamine. Then, 103 g (0.159 mol) of 2,4,6-triiodo-3-S'-methylcarbamoyl-1-methyl-5-JiT-acetyl-aminobenzoic acid chloride are added. The mixture is stirred for 3 hours at 45 ⁰ C and checks the end of the reaction by CCM.

The solution obtained is concentrated in 500 ml of water and 40 ml of conc. Hydrochloric acid poured, forming a precipitate. It is allowed to stir for 15 hours at ambient temperature. After centrifugation, the product is taken up in 300 ml of water and dissolved by the addition of 5N sodium carbonate solution (pH = 7.8), then again precipitated by 5-K ^- salic acid.

It is centrifuged, washed with water and dried in an oven at 60 ⁰ C.

This gives 114.5 g of crude product, which corresponds to a yield of 70 % »

b) Cleaning

It is made by crystallization from the 7 / arms in abs. Ethanol carried out ·

114 g of the product are absol with 125 ml. Ethanol brought into suspension. Then it is heated under reflux, after which the solution and then the crystallization occur. The heating is continued for a further 24 hours and then allowed to cool.

centrifugation and drying, the product is dissolved in 250 ml of water and soda. The pH is adjusted to 4-5 with acetic acid and filtered twice over charcoal 3SA. It is filtered and then acidified with conc. Hydrochloric acid on.

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After centrifugation, washing with water and drying in a drying oven at 60 ⁰ C to obtain 54.5 g of the pure product, which corresponds to a yield of 47.5 % .

Hein tightness control:

a) CCM with eluant benzene (methyl ethyl ketone / formic acid) (60/25/20): Rf 0.15.

CCM with eluant butanol / acetic acid / water (50/11/25): Rf 0.3 and 0.8.

2) purity as determined by methylate: 97 %

3) Purity according to iodine determination: 100 %, according to bromine determination: 100 %.

Example 2

Preparation of 2,4,6-triiodo-3-N-hydroxyethylcarbamoyl- (2,4,6-tribromo-3-N-methylcarbamoyl-N-methyl-5-N-acetylamic-2-benzoyl) -5-glycylamino-benzoic acid ( Connection 2)

COOH CH ₃ -Ii-COCH ₃

HIGH ₀ CH ₀ HHCO ^ T HH-COOCh ₀ NH-CO ^ χ ^ CONHCH ^{ά ά} J Br

I - production of 2 ^, o-

methyl-5-N-acetylamino-benzoic acid

COOH

CH ₃ NHCO ^ \ N-COCH ₃ ³

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1) Preparation of 2,4,6-tribromo-3-methylcarbamoyl-5-aminobenzoic acid

A suspension of 194 g (1 mol) of 3-N-methylcarbamoyl-5-aminobenzoic acid in 4 l of water and 820 ml of conc. Hydrochloric acid is then added dropwise 230 ml (9 mol) of bromine. Mq ρ continues stirring for 24 hours at ambient temperature. Then it is centrifuged, the precipitate is washed with 2 l of water at 90 ^° C. and then dried at 110 ^° C. for 24 h.

This gives 410 g of crude acid, which corresponds to a yield of 95 % .

Purity control:

1) CCM with Eluant Benzo1 / MSC / formic acid (60/25/20) Rf of the starting product: 0.1 Rf of the brominated product: 0.7

2) purity according to bromine determination: 98 %,

3) Preparation of 2,4,6-tribromo-3-methylcarbamoyl-5-N-acetylaminobenzoic acid

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CH ^ IiHCO

a) condensation

A suspension of 230 g (0.5 mol) of 2,4,6-tribromo-3-N-methylcarbamoyl-5-aminobenzoic acid in 200 ml of acetic anhydride and 100 ml of acetic acid is prepared. Then, dropwise, 60 ml of conc. Sulfuric acid added, the temperature may not rise higher than 55 to 60 ⁰ C. The mixture is stirred for 1 hr. At 55 ⁰ C and then added sulfuric acid. The resulting solution is then poured into 1 liter of ice-water. There is a precipitate, and one, stirring for 24 hours, at ambient temperature. Then centrifuged and washed with 7 / ater and then dried for 16 h. At 80 ⁰ C in a drying cabinet ·

240 g of crude acid are obtained, which corresponds to a yield of 100%.

b) Cleaning

Purification takes place by crystallization via the ammonium salt.

A suspension of 42 g of crude acid in 45 ml of 7 / acid is prepared. Then add 10 μl ammonia solution until dissolved (pH = 7-8). It is stirred for 24 hrs.

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Application temperature · Ea crystallization is carried out, centrifuged and clarified by 10 ml of water. The precipitate is dissolved in 500 ml of water of 90 ⁰ C. Then "treated twice with coal 3SA within 2 hrs. At 80 ⁰ C. The product is precipitated by hydrochloric acid 1/10 · Man centrifuged, washed with water and dried overnight at 80 ⁰ C,

This gives 30 g of the product, which corresponds to a yield of 71 % .

Purity control:

1) CGM - with eluant benzene / MEC / formic acid (60/25/20)

Rf of the starting product: 0.7 Rf of the acetylated product: 0.35 - with eluant butanol / acetic acid / water (60/11/25) Rf of the starting product: 0.75 Rf of the acetylated product: 0.3

2) Purity According to Bromine Mood: 100 %

3. Purity as determined by S _o da: · 99 % ·

3) Preparation of 2,4,6-tribromo-3-N-methylcarbamoyl-N-methyl-5-N-acetylaminobenzoic acid

a) Methylation

CH ₃ NHCO I N-GOGH ₃

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189 g (0.4 mol) of 2,4,6-tribromo-3-N-methylcarbamoyl-5-H-acetylaminobenzoic acid are dissolved in 184 ml of 5 N sodium carbonate solution (0.92 mol). Then add 32.4 ml (0.52 mol) of methyl iodide and stirred for 24 hrs. At ambient temperature. The end of the reaction is monitored by CCM, Sluant: butanol / acetic acid / water (50/11/25). The solution is poured into 300 ml of water and 75 ml of conc. Hydrochloric acid, after which the precipitation takes place. "The mixture is allowed to crystallize for a further 5 hours and then centrifuged. The precipitate is taken up in 500 ml of water and 1Q-JI-soda solution is added until it is dissolved, then the pH is restored to 4 by addition of acetic acid. To decolorize the solution, add 1 ml of sodium bisulfite solution. It is precipitated in an acidic medium, centrifuged, washed with water and dried at 80 ^° C. for 24 hours.

This gives 157 g of the product, which corresponds to a yield of 81 % for the methylation.

b) Cleaning

The purification is carried out by recrystallization from an ethanol-water mixture.

A suspension of 100 g of the crude acid in 500 ml of water is prepared. It is heated to 30 ⁰ C and slowly added 130 ml of ethanol (95%) until complete dissolution. It is filtered and allowed to crystallize with stirring for 24 hours. It is centrifuged, clarified by a V / asser-ethanol mixture and dried in a drying oven for 24 hrs. At 80 ⁰ C.

This gives 62.8 g of the product, which is dissolved in 200 ml of 7 / acid and soda. The pH is adjusted to 4-5 with acetic acid

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The mixture is treated twice with charcoal, then filtered and acidified with concentrated hydrochloric acid, centrifuged, washed with water and dried for 24 hours at 80 ^° C. to give 50 g of the pure product, which gives a yield of 50 %. equivalent ·

Purity control:

1) CCM with eluant butanol / acetic acid / water (50/11/25) Rf of the egg product: 0.3 Rf of the methylated product: 0.25 and 0.35.

2) purity as determined by methylate: 97 %

3) purity according to bromine determination: 97 %

II - Preparation of 2,4,6-tribromo-3,2-ethylcarbamoyl-II-myyl 1-5-IT-acyl-amino-benzoic acid chloride

COCI

CCH .3HC0

A suspension of 296 g (0.59 mol) of 2,4,6-tribromo-3-ii-niethylcarbamoyl-1-methyl-5-2r-acetylamino-benzoic acid in 600 ml of thionyl chloride is prepared. The mixture is heated for 3 hours with stirring to 80 ⁰ C. A solution is obtained and the excess thionyl chloride evaporated in a vacuum. The pasty residue is taken up in 500 ml of isopropyl ether and the mixture is stirred for 24 hours at ambient temperature. The crystallization is carried out, after centrifuging and clarification with isopropyl ether, the precipitate is washed with stirring for 24 hours at ambient temperature in 250 ml of acetone. One centric

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61 359/11 - 31 -

fugates, clarified with 50 ml of acetone and the product is then dried under vacuum.

150 g of a clear, beige product are obtained, which corresponds to a yield of 50.5 % ,

Purity control: ·

1) CCM (after reaction with monoethanolamine in excess,

in dimethylacetamide)

with sluant benzene / methyl ethyl ketone / formic acid (βθ / 25/20):

Rf of the starting product: 0.57

Rf of monoethanolamine condensed product: 0.35 x

2) .Determination of the acid chloride by propylamine: 105%

III - Preparation of 2 ^, 6-Iiiodo-O-li-hydroxyethylcarbamoyl-2,4,6-tribromo-3-5 ^ -methylcarbamoyl-2I-methyl-5-N-acetylaminobenzoyl) -5-glycylaminobenzoic acid

The 2,4,6-triiodo-3-Sr-hydroxyethylcarbamoyl- (2,4,6-tribromo-3-U-methylcarbamoyl-1-niethyl-S - ^ -acetylamino) -benzoyD-S-glycylamino- benzoic acid is prepared as in example 1-III, starting from 2,4,6-triiodo-3-ii-hydroxyethylcarbamoyl-5-arainoacet _a mido-benzoic acid and 2,4,6-tribromo-3-N-methylcarbamoyl-2I- methyl-5 - ^ - acetylamino-benzoe3äure "

Yield crude: 55 % - Yield global: 21%.

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- 31 -

Purity control:

1) CCM

- with Bluant benzene / MEC / formic acid (60/25/20): Rf 0.3

- with eluate butanol / acetic acid / water (50/11/25): Rf 0.2 - 0.3.

2) Purity by determination of methylate: 99.6 %.

3) purity by iodine determination: 98.3 %

by bromine removal: 99 »4 % ·

Example 3

Preparation of 2,4,6-tribromo-3-H-hydroxyethylcarbamoyl-2,4,6-triQo-3-3 "-hydroxyethylcarbamoyl-1-methyl-5-N-acetylaminobenzoyl) -5-glycylamino benzoic acid (compound 3)

HIGH ₀ CH ₉ HHCCr (HHCOCH ₉ IiHCO ^ T COHHCH ₉ CH ₉ Oh

I - Preparation of 2 ^, ö-TriiJod ^ -H-acetoxyethylcarbamoyl-H-methyl-5-H-acetylamino-benzoic acid

COOH

j I j

CH 2 CO-H T ^ COHHCH ₉ CH ₉ OCOCh

61 359/11 - 33 -

900 g (1.38 mol) of 2,4,6-triiodo-3-N-hydrosyethylcarbamoyl-N-methyl-5-N-acetylaminobenzoic acid are suspended in 1500 ml of dioxane. Then add dropwise 198 ml of acetyl chloride. After 4 hours of heating to 80 ⁰ C to obtain a clear solution. After cooling, this solution is poured into 4.5 1 isopropyl ether. This gives white crystals, which are centrifuged, washed with water and dried in a drying oven at 70 ⁰ C.

Yield: approximately 100 % · CCM, with Sluant 1: Rf 0.45.

II - Preparation of 2,4,6-triiodo-3-N-acetoxyethylcarbamoyl-N-methyl-S-N-acetylaminobenzoic acid chloride

CH 1 CO-N J CONHCH ₀ CH ₀ OCO CH ^J ' ¹ J ^d *

96O g of the above acid are refluxed in 2080 ml of thionyl chloride for 6 hrs. The acid chloride crystallizes in thionyl chloride and, after cooling, is centrifuged and washed with isopropyl ether.

Yield: 55 %

Purity control:

- Determination of organic chlorine: 101 %

- CCM with 31uant 1: Rf 0.6 after condensation with isopropylamine.

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61 359/11 34 -

III - condensation

The 2,4,6-tribromo-3-II-hydroxydiaminocarbamoyl- (2,4,6-tri3od-3-N-acetoxyethylcarbamoyl-N-metyl-5 - ^ -acetyl-amino-benzoyl) -5-glycyl-aminobenzoic acid of the formula

CH ₃ -IT-COCH ₃

HIGH ₂ CH ₂ HHCCr ηΤ ^ IiHCO CH ₂ ITHCO ^ J ^ COIiHCH ₂ CH ₂ OCOCH ₃

is prepared as in Example 1, starting from 2,4,6-tribroin-3-IT-hydroxyethylcarba-inoyl-5-amino-acetamido-benzoic acid and 2,4,6-tri3o-3-IT-aceto-2-methylcarbamoyl-II-methyl-5 -IT-acetylamino-benzoic acid.

Condensation yield: 70 %, S unit control by CCM with Sluant 1: Rf 0.1.

IY - saponification

The above product is dissolved in 320 ml of 23% soda solution. The mixture is heated for 2 hours at 50 ⁰ C and then the product is precipitated with hydrochloric acid, then centrifuged, washed with water and dried in a drying oven at 70 ⁰ C.

Yield; 65%

V - cleaning

It is carried out via the crystallization of the methylamine salt in stanol. The purified product is centrifuged

61 359/11

35 -

and then washed with propanol for 2 hrs. At 80 ⁰ C

The methylamine al ζ is then dissolved in Sodalö'sung and then treated with charcoal 3SA 3 hours at 60 ⁰ C to decolor it.

The purified, centrifuged product is washed with water until the absence of chloride and methylamine traces.

Purity control:

1) CCM

with sluant 1: Rf 0.1,

with Eluant 2: Rf 0.25 and 0.3.

2) purity according to iodine determination: 97 %

3) Purity according to bromine determination: 96 % *

Example 4

Preparation of 2,4,6-tribromo-3-N-hydrozyethylcarbamoyl

benzoyl) -glycyl-5-N-methylaminobenzoic acid (Compound 4)

NHCOCH ₃

HIGH ₂ CH ₂ HHCO 3 Y 1 N-COCH ₂ JCOHCOX Y'SCONHCHGCH ₂ OH

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I - Preparation of 2,4,6-tribromo-3-H-hydroxyethylcarbamoyl-S-chloro-acetamido-benzoic acid

HOGH ₂ CH ₂ HHCO

To a suspension of 1 mole (461 g) of 2,4,6-tribro-3-H-hydroxyethylcarbamoyl-5-aminobenzoic acid in 1 liter of dioxane is added dropwise 3 moles of chloroacetyl chloride *

Map heated to 80 ^° C. for 3 hrs. The product dissolves and then crystallizes. "The amidated product esterified by acetyl chloride is centrifuged and washed with water. Then saponify the ester function by 2 moles of sodium carbonate in water at ambient temperature. The product obtained is precipitated with hydrochloric acid, centrifuged and washed with water.

Yield: 78 %,

CCM, Eluant 1: Rf 0.35, Eluant 2: Rf 0.5

% Cl. Found: 6.55 % Cl theoretical: 6.60 % 3r found: 44.6 5% Br theoretical: 44.65.

II - Preparation of 2,4,6-tribromo-3-H-hydroxyethylcarbamoyl-iodo-5-IT-methyl-acetamido-benzoic acid

COOH

HIGH ₂ CH ₂ HHCO

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0.75 mole of the above acid is dissolved in 2.23 moles of 5N soda solution and 1.5 moles of CH ₃ I. After 4 hours. Heat to 40 ⁰ C, the solution is poured into 400 ml of industrial hydrochloric acid, which was diluted with ice water 1: 2, and the resulting clear, yellow precipitate was centrifuged and washed with water

Yield: 85 %

Determination of acidity: 97.8 % Determination of iodine: % I found 19.35

% I theoretical 19.75 Bromine: % Br found 36.66

% Br theoretical 37.30 CCM, Eluant 1: Hf 0.4

III - Preparation of 2,4,6-tribromo-3-N-hydroxyethylcarbamoyl-amino-5-n-methyl-acetamido-benzoic acid

COOH

HIGH ₂ CH ₂ NHCO

0.517 mole of the above product are heated in 1.5 1 10 N-ammonia solution for 2 hrs. At 60 ⁰ C.

Thereafter, the ammonia is evaporated under water jet pump vacuum. 35Og of an equimolar mixture of the ammonium salt of the expected product and of ammonium are obtained; CCM, Eluant 1: Rf ν 0.05 This product is used without purification.

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IV condensation

The 2,4,6-tribromo-3-N-hydroxyethylcarbamoyl- (2,4,6-triiodo-3-U-aco-oxyethylcarbamoyl-5-aminobenzoyl) -glycyl-5-H-methylthiaminol benzoic acid of the formula

HIGH ₂ CH ₂ NHCO COOH Y _N NHp j br L Br ^ \ THCO ^- ^ CONHCH ₂ CH ₂ OCOCH ₃ Y ^ n-cocio • ι * - Br ", τ j

Starting from 2,4,6-tribromo-3-2I-hydroxyethylcarbamoylamino-5-N-methyl-acetamido-benzoic acid and 2,4,6-triiodo-3-2iacetoxyethylcarbamoyl-5-B.mi.no- benzoic acid chloride, prepared, yield of condensation: 81 %

CCM, eluant 1: Rf 0.1

This product will continue to be used without purification.

V - acetylation

COOH

ITHCpCH.

CH ₃ OCOCH ₂ CH ₂ UHCo

N-COCH ₀ UHCO

COIIHCh ₂ CH ₂ OCOCH ₃

357 g of the above crude acid are dissolved in 330 ml of dimethylacetamide. Then, 1.23 moles of acetyl chloride are added dropwise. The resulting solution is stirred for 4 hrs. At ambient temperature and then poured into water. The resulting precipitate is centrifuged and washed with water.

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The product obtained is used as it is without purification or drying.

VI - saponification of the ester function

The above crude acid is dissolved in 1.23 mol of 251-soda solution. The resulting solution alkaline is stirred for 2 hr. At ambient temperature, then adjusted to pH with acetic acid and treated twice with charcoal 3SA at 70 ⁰ G. The filtered, well-discolored solution is then poured into a hydrochloric acid solution.

The expected product precipitates, it is separated by centrifugation and washed with water.

Yield: 53.5 % for acetylation and saponification. Purification via the ammonium salt.

The product is purified by two successive ammonium salts, then washed with water to obtain chlorides and ΝΉ. ⁺ - to remove ions.

Determinations: Acidity: 101.50 %

BroEL: found: 20.4% theoretical: 20.7 % iodine: found: 32.5 % theoretical: 32.9%

CGM, eluant 1: Rf 0.05

Eluant 2: 2 isomers, Rf 0.17 and 0.27.

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example 5

Preparation of a compound of the formula

CH ₃ -Si-COCH ₂ OCH.

Br ^ 1 Jr "Jw"

HIGH ₂ CH ₂

COCH ₂ IiHCO - ^ Y ^ COHHCH ₃

HOOH ₂ CH ₂

(Compound 25)

I - condensation of diethanolamine with 2, 4, 6-tribromo-aminoisophthalsäuredichlorid

leads to a connection of the formula

CH ₂ CH ₂ OH

COH

^ CH ₀ CH ₂ OH

.CH ₂ CH ₂ OH

'CH ₂ CH ₂ OH

To a solution of 1.18 moles of diethanolamine in 100 ml of water and 1.18 moles of KHCO _{3 is} added dropwise 184 g (0.4 mol) of 2,4,6-amino-isophthalic acid dichloride in solution of 185 ml of acetone.

The white product gradually falls out. By centrifuging and subsequent drying in a drying oven

61 359/11

isolated 278 g of a crude product which gives an Rf value of 0.1 with eluant 1 and which contains 9.7 % KCl and 26 % KHCCU according to the determinations of bromine, chlorine and acidity,

Purification by crystallization in ethanol:

The 278 g of the crude product are heated to boiling in 1 liter of ethanol (absolute). 97 g of the insoluble mineral are removed by centrifuging in the heat. The pure product crystallizes gradually, and after two days has elapsed, 110 g of the well-crystallized white product are centrifuged,

Purity control:

98% purity according to bromine determination

0 % acidity to methylate

no Cl "/

CCM with Eluant 1: a single spot Rf 0.1 Yield: 46.5 % for condensation and purification.

II - Chloroacetylation

leads to a compound of the formula

CH ₀ CH ₀ OCOCH ₀ Cl

con

CH ₂ Ch ₂ OCOCH ₂ Cl

To this solution of 35 g of the above amine (crystallized in ethanol) in 100 ml of dioxane is added dropwise 80 ml of chloroacetyl chloride. After 1/4 hour, the resolution is complete. The solution is stirred overnight at ambient temperature and then poured into 500 ml of ice-water.

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- 42 -

sen. You get a gum. The supernatant solution is transferred and replaced twice with 500 ml of ice-water. »This gives a white, crystallized product. CGM, Eluant 1: Rf 0.6.

III - Saponification of the ester functions leads to a compound of the Pormel

HIGH ₂ CH ₂

HIGH ₂ CH ₂

COH

HCO

br

CH ₂ CH ₂ OH

NHCOCH ₂ CL

The above product is dissolved in 1.144 mol of 2U soda solution and the resulting solution is stirred for 3 hrs. At ambient temperature.

It is then acidified to pH 2 and extracted from the

Saponification-derived monochloroacetic acid with 3 σ 250 ml

Ethyl acetate to a neutral pH in the two phases. Man, after evaporation to dryness 95 g of a white,

crystalline pesticide. CCM, Sluant 1: Rf 0.1

Determination of bromine and organic chlorine: 95 % ·

Z4ZÜÖD ο

61 359/11

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IV - amination

leads to a compound of the formula

, GH ₂ CH ₂ OH

GON

HIGH ₂ CH ₂

HIGH ₂ CH ₂

The 95 g of the above product are dissolved in 600 ml of ΙΟΝ-ammonia solution. The mixture is heated for 3 hours at 60 ⁰ C and then evaporated to dryness. An almost white solid containing 1 mol of NH.Cl per mole is obtained. CCM, Sluant 1: Rf 0

CCM, isopropanol / ethyl acetate / NH ₄ OH (35/35 / 4O) / Rf 0.7 CCM, Sluant 2: two spots, Rf 0 and 0.1. The spots are visible under UV light and after treatment with ninhydrin.

V - condensation

0.154 mole of the above product are condensed with 0.154 moles of 2,4,6-triiodo-3-N-methylmethoxy-acetamido-methyl-5-carbamoylbenzoesäurechlorid in the presence of 0.23 mol of triethylamine in DMAC at 45 ⁰ C. Thereafter, the DMAC is extracted with sthyl acetate and the nonionic product is continuously extracted with phenol and the resulting aqueous solution is added

evaporated.

Yield (global): 35 % CCM, Eluant 1: Rf 0.05 Eluant 2: Rf 0.3 and 0.45

61 359/11

Example 6 Preparation of a compound of the formula

Br _N INOC ' CO-NHCH ₂ COOH "Br J" * NH-COCh ₂ NH-OC " CH ₃ -N-COCH ₃ CH ₃₁ 26) br J (Connection

I - Preparation of a compound of the formula

To a suspension of 80 g (0.60 mol) of glycine ethyl ester Hydro chiorid in 500 ml of anhydrous DMAC and 200 ml of triethylamine are added in portions 176 g (0.39 mol) of tribromo-5-aminomethyl-isophthalaminsäurechlorid. After stirring at ambient temperature, the reaction solution is poured into 2 l of water.

The precipitate is centrifuged, washed with water and dried.

I69 g of the product are obtained in a yield of 84% purity (determination of bromine): 97 %

242 8öS 6

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II - Preparation of a compound of the formula

CO-UH-CH ₂ COOH

br

CH ₃ HTiOC

155 g of the ester (0.30 mol) are stirred at ambient temperature in 1 1 N sodium carbonate solution.

The acid gets through. Obtained with hydrochloric acid. The resulting white crystals are centrifuged and washed with water.

Yield: 68.5 %

Purity (-COOH): 100.6%.

III - Preparation of a compound of the formula

CO-NH-CH ₂ COOH

12.2 g of the above product (0.025 mol) are dissolved in 40 ml of anhydrous DMAC and 6.7 ml of triethylamine. Then added in portions with stirring 9 g (0.04 mol) of phthalylglycine acid chloride. The reaction mixture is poured into water and the expected derivative crystallized. Yield: 50 % Purity (bromine): 102.8 %

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- 46 - 61 359/11

17 - Preparation of a compound of the formula

CO-NH-CH ₂ COOH

CH.HNOC * ^ NH NH-COCH, Br

24 g (0.03 mol) of the above product are heated to 70 ^° C. in 50 ml of water and 5 ml of hydrazine hydrate for 8 hours.

The resulting pesticide is filtered and dried. Yield: 50% purity (bromine); 99%.

V - condensation

2.2 g (0.004 mol) of the above amino-acetylated acid are dissolved in 3 ml of DMAC, 1.4 ml of triethylamine and 1 ml of water, and 2.7 g (0.004 mol) of 2,4,6-triiodo-5-methyl -acetamidoisophthalaminsäure-chloride added in small portions · After 8 hrs. after heating "at 50 ⁰ C the acid (61% yield =) Rf CCM fails · After filtration and drying, the expected compound (eluant 2) 0.65

At 3OJel 7

Preparation of N- (2,4,6-triiodo-3-N-hydroxy-ethylcarbamoyl-5-N-gluconylaminobenzoyl) -N ^f - (2,4,6-tribromo-3-N-methylacetamido 5-N-gluconylaminobenzoyl) -1,2-diaminoethane (compound 28)

61 359/11

- 47 -

CO-IJH-CH ₂ -Ch ₂ -IIH-CO

N-COCH,

HO-CH ₂ -CH ₂ (CHOH) ^ Έ. (CHOH)

I - Preparation of (2,4,6-triiodo-3-ii-acetoxy-ethylcarbamoyl)

5-amino) benzoylamino-ethylamine

The 2,4,6-triiodo-3-ff-acetoxy-ethyl-carbamoyl-5-arriino-benzoic acid chloride (216 g, 0.325 mol) is suspended in 250 ml of water. »Then 250 ml of ethylenediamine are added and the mixture is cooled the way that the temperature does not exceed 20 ⁰ C. The complete dissolution is reached after 2 hours of stirring, after which it is stirred for a further 15 hours. The product crystallizes. After centrifugation and methanol with methanol, 131 g of product are obtained, which corresponds to a yield of 58.7 % . CCM (eluate 1) R f 0.12

II - Preparation of 2,4,6-tribromo-3-N-diethyl-acetamido-5

amino-benzoic acid

20 g of the corresponding acid are heated in 40 ml SOCIp for 2 hrs. At 80 ⁰ C »After evaporation of the thionyl chloride, the oil is precipitated in 100 ml of isopropyl ether. After stirring for 1 h, centrifuging, washing with ethyl acetate, centrifuging and drying, 17 g of the compound are obtained, which corresponds to a yield of 81.5 %

 CClI (eluate 1): Rf 0.75

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III - Preparation of H- (2,4,6-triiodo-3-H-acetoxy-diethylcarbamoyl-5-amino-benzoyl) -N '- (2,4,6-tribromo-3-H-methylaceta-inido-5- a-inino-benzoyl) -1, 2-diaminoethane

CONH-CH ₂ -CH ₂ -2H-CO

CH ₂ -CH ₂ OA ₀

The compound obtained according to I (100 g, 0.145 mol) is dissolved in 100 ml of DMAC in the presence of triethylamine (100 ml, basic pH). The 2,4,6-tribromo-3-H-methylacetamido-5-aminobenzoic acid chloride (80 g, 0.168 mol) is added to the solution in powder form.

The mixture is heated to 50 ^° C. for 7 hours and then stirred for 8 hours at ambient temperature. Hach precipitation with 1 1 of water, centrifuging and drying gives 170 g of the compound, which corresponds to a yield of 100%

 CCM (Eluant 1): Rf 0.46

IV - Preparation of N- (2,4,6-triiodo-3-H-acetoxyethylcarbamoyl-H-penta-acetoxygluconyl-S-aminobenzoyl) -2I '- (2,4,6-tribromo-3-H-methyl- acetamido-H-pentaacetoxygluconyl-5-amino-benzoyl) -1,2-diaminoethane

CH ₂ OAc CH ₂ OAc

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Dissolve 10Og (0.089 mol) of the compound obtained above in 180 ml of DMAC. Then add 0.445 mole of pentaacetylgluconic acid chloride in powder form, which dissolve accordingly.

After stirring for 20 h at ambient temperature, the mixture is precipitated by 1.3 l of ice water. The stirring is then continued overnight. After centrifugation, the gummy product is taken up in 300 ml of CH ₂ Clp. The bicarbonate (5%) and then washed with water organic phase is then evaporated. This gives 126 g of a beige product, which corresponds to a yield of 75%.

V - Cleavage of the protecting groups

The cleavage of the acetyl protecting groups is carried out by transesterification of 100 g (0.053 mol) of the compound obtained in 250 ml of methanol in the presence of 6.2 ml (0.1 mol) of ethanolamine and using a catalyst. After heating to 35 ^° C. (48 h) and then stirring at ambient temperature (48 h), the reaction mixture is added via Resin H ⁺ . After concentration of the Piltrats and precipitation with 7 / asser obtained 26.6 g of the still impure product. This is dissolved in warm 'Yasser. After removal of the insoluble fraction is obtained from the concentrated filtrate 4 g of the expected compound, which corresponds to a yield of 5.3 % .

CCiI Eluant 2, starting material Rf: 0.70 0.86 -'- 'product obtained: 0.35 0 * 40

Eluant 1, starting material Rf: 0.72 product obtained: 0.05

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In the following Tables I and II, the characteristic data of the compound of Examples 1 to 7 and of other compounds of the general Porrnel V are listed, as well as those of the compounds of the formula III, which were prepared by analogous methods #

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Table I

N-CO-CCH _{2) n1} -NH-CO (CHZ) _n2 H

(V a)

Q-

connection

Br J -COOH -CONHCH ₂ CH ₂ OH -CONHCH

Cock-

2 J br It If it It -NHCOCH ₃ CHOOH 3 J It It -CONHCH ₂ CH ₂ OH " «*" ^GH 3 ^ COCH ₃ 4 br J It It Il It 5 J br It -CONHCH 3 ^H It 6 br J It It It CH ₃ 7 br J It H -CONHCH ₃ ^X ^ COCH ₂ OCH 8th J br η η It It CH ₃ ^S COCH ₃ 9 br J It -CONHCH ₂ CH ₂ OH " CH-, 10 11 J J Br Br If It η It -COMCH ₂ CH ₂ OH COCH ₃ 12 J br COOH H -CONHCH ₃ tt It 13 J br COOH -CONHCH ₂ CH ₂ 0H -CONHCH ₃ 14 J br If -CONHCH It 15 J br It -COITHCH οCHOH-CONHCHo '

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61 359/11

Continuation Table I

Verb. X ₁ X ₂ Q ₁

Q ₃ Q ₄

16 Br J -COOH -CONHCH.

-IJHCOCH.

-N,

'COCH.

GH.

17 Br J ⁿ -IV

-CONHCH

-: ihcoch

J Br

CH-

13 20 J J Br Br ti -COOH -1HCOCH ₃ ^ CH ₂ CH ₂ OH * ^ CH ₂ CH ₂ OH -N ^ "COCH-, CH- -CONHCH-, -N ^ ^ ^ ^ COCH ₃ ti it 21 J br η -CONHCH ₂ CH ₂ OH -CONHCH ₂ CH ₂ OH -NHCOCH ₂ OCH ₃ ^ H ₉ CH ₀ OH ^ ^{ά ά} -CONHCH ₃ 22 br J Il ti ti ti 23 J br π ti _CH, ti _jj ^^ -5 COCH ₃ 24 br J π It 25 br J -CON ^ , CH ₀ CH ₀ OH ^{ά ά} -conhC 'CH ₂ CH ₂ OH

26 Br J -COOHTHCH ₂ COOH -CONHCH ₃ -CONHCH ₃

-IV

CH.

COCH.

CH.

27 J Br-COOH-CH ₂ OH

-CONHCH.

* r

COCH.

28 -Br J -COOH -CONCE ₂ CH ₂ OH 7CONHCH ₃ -CN

Z4ZÖÜ0

61 359/11

Continuation Table I

Yerborg _e ^Q 1 Z ⁿ 2 Sation yield yield%% condensate saponification Yield % global u. U , 5 U Rf RF Eluant Eluam: 1 2 0.3 and 0.38 1 1 _ O 70 33 0.15 0.2 u. 0.3 2 Il - It 55 21 0.3 0.25 u. 0.3 3 η - π 70 65 , 5 U 0.1 0.17 u. 0.27 4 11 H 1 81 AC + verse. 53.5 0.05 0.3 and 0.4 5 tr - O 76 16 , 5 0.45 0.35 u. 0.45 6 tt - Il 88 60 0.50 0.55 0,4 u. 0.5 7 U - 11 66 50 0.45 8th ti - 11 83.7 48 0.55 0.25 9 Il - Il 87 23 0.05 0 0.25 10 "1 - 11 47 20 0.1 0.45 u. 0.55 11 It - Il 90 51 12 0.1 0.45 u. 0.6 12 2 - H 93 56 0.4 0.2 u. 0.25 13 3 - π 72 45 0.5 0.2 u. 0.3 H 3 - Il 84 41 0.13 0.2 u. 0.27 15 ^H 1 H 1 85 AC + verse. 61 20 0.05 0.35 u. 0.40 16 η - O 77.5 Acelylation 51 25 0.20 'O', 25 17 tt - It 0.25 18 It - H 0.15 0.20 and 0.30 19 jl - ii 82 acetyl. 55.5 20 0,10 .0,15 0.15 u. 0.23 20 1 - O 61.5 13 0.1 0.1 u. 0.17 21 It - 11 0.03 0.1 u. 0.17 22 It - It 0.05 0.1 u. 0.2 23 Il H 1 0.05 0.1 u. 0.2 24 H H 1 0.05 0.3 and 0.45 25 Il - t o 35 0.05 0.65 26 It - H 61 0.3 and 0.4 27 It - 11 0.25 .0.30

_ Il

70

0.15 0.4

Table II Compounds of the formula III

Verb.

Chemical formula Rf Rf Eluant 1 Eluant

COOH COOH

br

OHCH ₂ CH ₂ NHCO

NHCOCH ₂ NHCo

br

CONHCHgCONH

br

0.65 0.050

br

CONHCH ₉

CH ₉

OH

,COOK

, CONHOiL

CHoNHCO

NHCOCH ₂ NHCo

HCOCH ₂ NHCO

0,050

COOH J I J

NHCOCH

OHCH ₂ CH ₂ NHCO

COCH ₂ NHCO

COOH

CONHCH ₂ CO

CONHCH

I '

CH,

I ^t

OH

0.30 u. 0.35

0.10

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In the following, comparative test results of the mixed bromine-iodine-benzoin compounds are given.

1- contrast effect

The contrast effect was measured indirectly by means of an impression produced by a bundle of X-rays on a photographic panel, the rays being previously passed through a cuvette containing the test compounds in aqueous solution. The transparency of the PiLm after development was measured by means of an optical densitometer. In each pail, the measurement was performed on the same plate and with the same source of radiation (70 kV) as compared with a contrast agent which served as the reference point.

Hexabrix was used as a comparison product, which is a solution of the sodium salt and the methylglucamine salt of joxaglic acid (32 % iodine) »

The mixed compounds were assayed in the aqueous solutions of their liethylglucamine salts containing the same number of moles of compounds as Hexabrix.

The results are listed in the following Table III.

Table III

Compound relative contrast effect / Hexabriz

1 0.91

2 0.92

3 0.92

242885 6

61 359/11 - 56 -

It can be seen that the contrast effect of the mixed compounds is close to that of Hexabrix, a single encoded compound of similar structure to the test compounds. To obtain the same contrast effect with the blended products as with the only coded products, only 1.09 times more moles of compounds are required.

2- activation; of the complement

The work of Elliott C. Lasser (Investig. Hadiol, 1974, 414a) has shown that the contrast agents activate the complement, that is, the set of serine proteins whose activation can lead to severe anaphylactic reactions.

The measurement of this activation is carried out by determining the hemolytic concentration 50, designated CH50. It is believed that the products have less complement activators, i. H. have an increased CH50, and thus cause fewer secondary effects of the anaphylactic type, so have a better tolerance.

The results are listed in Table IV.

242885 6

- 57 - 61 359/11 Table IV test compound CH 50 mol / ml 1 20.2 2 1 and 2 20.8 corresponding additional iodination of the compound 17.9

5 7.4

corresponding supplementary

Iodination of compound 5 3.8

7 10.0

8 11.5

12 11.0

13 15.3

- Acute intracisternal toxicity

The acute intracranial toxicity was measured in the rat according to the method of E. Melartin, P. Tuohimaa, R. Dabb, (Investigate Radiology, 1970, vol. 5, Hr. 1, 13-21).

The results are listed in Table V.

Table V

connection complementary connection 2 acute toxicity IG rat 5 7 2 Corresponding iodination of complementary connection 5 170 - 7-5 5 Corresponding iodination of 10, 3,

61 359/11 - 58 -

The mixed compounds (brominated and iodinated) of the present invention may also be used as specific products for radiological purposes.

The preferred pharmaceutical form is represented by aqueous solutions of one or more of the above-defined mixed compounds.

The aqueous solutions generally contain from 5 to 100 g of mixed compound, and the injection amount of these solutions may generally vary between 5 and 100 ml.

Claims (1)

Z4Z885 Β 61 359/11 - 59 - invention claim 1 · Process for the preparation of compounds selected under 1- compounds of the formula V S-CO- (CH _{2) n1} -3SH UH-CO- (CH ₂ ) In which X ₁ , X ₂ and X represent-, bromine or iodine, wherein at least one of the other two is different, Q is a group -CjOOH or a group of the formula CoII where H ^ and ^Λ 4 independently of one another, a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxylated, lower alkyl radical or a lower carboxyalkyl radical i3t, Q ₂ represents a hydrogen atom, a CHgOH radical, a cyanoradical or a radical of the formula 242885 6 61 359/11 60 - -CON, where R, - and R ^ independently represent a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxylated, lower alkyl radical or lower alkanoyl, lower oxyalkyl, an amino group or a radical of the formula means, where R 4 is lower alkyl radical, lower hydroxyalkyl radical or lower alkoxy lower alkyl radical, and R q represents a hydrogen atom, lower alkyl radical or lower hydroxyalkyl radical; Q 1 and Qo 'independently represent a hydrogen atom, a cyanoradical, a CH ₂ OH radical , a radical of the formula -CON in which Rg and R _10, the ^R 10 for Rc and R ^ given meanings, an amino group or a radical of the formula I ¹¹ , in the R ₁₁ the for Kj given meaning and R _{12 have} the meaning given for Rq, Z4Z8ÖD (j 61 359/11 61 - Q. represents an amino group, a cyanoradical or a group " wherein R ₁ , - a ^R 16 is a lower alkyl radical, a mono- or polyhydroxylated, lower alkyl radical or a lower alkoxy-lower alkyl radical, R.sub.jg is a hydrogen atom, a lower alkyl radical, a lower hydroxyalkyl radical or a lower alkanoyl radical, Z is H or OH n. «And no are equal to 1 to 5 η-, is 0 to 3, and b is 0 or 1, and their pharmaceutically acceptable salts, 2 - compounds of Pormel VIII VIII, in the. Χ. Bromine land Xp is iodine or X _{1 is} iodine and X _{2 is} bromine, Q ₁ and "Q ₁ " independently represent an amino radical or a radical of the formula Q dar, in the R ^ q 242885 6 61 359/11 - 62 - lower alkyl radical, a mono- or poly-hydroxylated lower alkyl radical or a lower alkoxy-lower alkyl radical, and RpQ eis. Is hydrogen, a lower alkyl radical or a lower hydroxyalkyl radical, Qp and Q ^ each independently represent a hydrogen atom, a CHgOH radical, a radical of the formula -CO - Ή , wherein R ₁ - and IL-V 5 "b ^R 6 a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxylated, lower alkyl radical or lower alkanoyl-lower oxyalkyl, an amino group or a radical of the formula · Mean, where is a lower alkyl radical, mono- or polyhydroxylated lower alkyl radical or lower alkoxy-lower alkyl, and Rg is a hydrogen ion, a lower alkyl radical or lower hydroxyalkyl radical, and R-γ and R ₁ O independently represent a hydrogen atom, a lower alkyl radical or a lower one Hydroxyalkyl radicals, and η is an integer from 1 to 5, 3-compounds of the formula U Z4ZÖÖ3 61 359/11 ICO (CH ₉ ) -NHCO R ₂₁ CONH (CH ₉ ) -COST J ^ _n an., Ι ^ ₂ R ₂₁ ^Χ 1 (XI) in which X _{1 is} bromine and X _{2 is} iodine or X _{1 is} iodine and X _{2 is} bromine, Q ₁ is a group COOH Q ₂ represents a hydrogen atom, a CH ₂ 0H radical or a radical of the formula -G0-1I V, wherein R ₁ - and R a 'hydrogen atom, a lower alkyl radical, a mono- or polyhydroxylated, lower alkyl radical or lower alkanoyl-lower-oxyalkyl, an amino group or a radical of the formula represent, wherein is a lower alkyl radical, lower hydroxyalkyl radical or lower alkoxy-lower alkyl and Rg represents a hydrogen atom, a lower alkyl radical or lower hydroxyalkyl radical, 242885 6 61 359/11 - 64 - Q-5 "means a radical of the formula -N-COR 11 , in the the for given meaning and R _{1 2 have} the meaning given for Rg, R ₂₁ represents a hydrogen atom, a lower alkyl radical or lower hydroxyalkyl radical, and η is an integer from 1 to 5, and their pharmaceutically acceptable salts, characterized by preparing said compounds by halogenation, alkylation, acylation, and salt formation reactions » 2 · Process according to item 1 for the preparation of compounds of the formula V, characterized in that the condensation of an amine of the formula VI with an acid chloride of formula VII (VII) 242885 61 359/11 - 65 - carried out, in particular in a polar solvent at a temperature of 20 to 60 ⁰ G and in the presence of an acid acceptor, 3 "" Process according to item 1 for the preparation of compounds of the formula VTII, characterized in that the condensation of an amine of the formula IX COU- (CH ₀ ) -NH (ΙΣ) with an acid chloride of the formula X. (X) which is followed, if appropriate, by an acylation 3 reaction * 4. The method according to item 1 for the preparation of compounds of formula XI, characterized in that the condensation of an amine of formula XII 2428 61 359/11 - 66 - with an acid dichloride of Pormel XIII * 2 Cl-C COCI * 2 (XII) (XIII) optionally followed by an acylation and / or salt formation reaction to this reaction ·