DD205892A5 - PROCESS FOR PREPARING BROM COMPOUNDS USE IN CONTRASTING AGENTS - Google Patents

Abstract

THE INVENTION HAS A METHOD FOR PRODUCING BROM-BENZOLE COMPOUNDS OF THE SUBJECT THAT CAN BE USED IN CONTRASTING AGENTS.

Description

2/9 P Q K / Berlin, 11.2.1983

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Process for the preparation of bromine compounds useful in contrast agents

Field of application of the invention

The present invention relates to a method for the preparation of compounds which can be used as contrast agents in radiography.

Characteristic of the known technical solutions

For a long time used as a contrast agent iodine-benzene compounds, which have several iodine atoms in the benzene nucleus, generally 3 iodine atoms per benzene nucleus, as well as various other substituents. These other sub-items are pharmacologically acceptable groups that 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 been proposed so far to increase the tolerance of the iodine-benzene 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. PS 32 90 366 and GB-PS 13 46 795).

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

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To get tolerance. In particular, it is based on non-ionic structures, ie, that they have no ionic substituents such as carboxy groups (see, for example, DE-PS 20 31 724 and PR-PS 22 53 509) ₀

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)

So far, very few bromine-benzene compounds have been described which are analogous to iodine-benzene compounds and can be used as contrast agents.

Elliot C. Lasser in Amer. J. of Roentg. 1962, 8J, 2, 338-360, refers in a comparative study to the brominated analog of sodium acetrizoate (Urokon), namely the 2,4, δ-tribromo-S-acetamido-sodium benzoate.

In addition, the PR-PS 11 72 953 describes halogenated aminoisophthalic acid compounds. Although the PS refers essentially to iodinated derivatives, it also describes two brominated derivatives, namely 2,4t6-tribromo-3-aminoisophthalic acid and 2,4,6-tribromo-3-acetamido-isophthalic acid _o

Object of the invention

The aim of the invention is the provision of new compounds, with which the problem of tolerance increase in the iodine-benzene compounds can be solved in a fundamentally new, different from the previously known solutions way.

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Explanation of the essence of the invention

The invention is based on the object by the use of a portion of the iodine atoms in the core of the known iodine-benzene compounds by bromine atoms not only to increase the tolerance of the compounds, but also to obtain the contrast effect in the same order of magnitude.

It is particularly surprising that the desired effect is achieved according to the invention, since it would normally have been expected that the partial replacement of iodine-benzene compounds with bromine-benzene compounds would lead to a marked reduction in the contrast effect. It is actually known that the contrast effect of an atom on X-radiation is proportional to the effectiveness of its atomic number (J · Duheix, V, Bismuth, M. Laval-Jeantet-TraitS de radiodiagnostic, vol. 1-L ¹ image radiologique, Maason et Cie The atomic number of bromine is 35, that of iodine 53. The contrast effect conferred by bromine should therefore be three to four times weaker. It could therefore be expected that the presence of bromine atoms instead of a portion of the iodine atoms leads to a significant reduction in the contrast effect. According to the invention, however, the partial exchange of iodine-benzene compounds by bromine-benzene compounds can achieve a contrast effect of contrast agents which is of the same order of magnitude as known from corresponding compositions containing only iodine-benzene compounds.

There is also a significant economic benefit, as bromine is currently far less expensive than iodine.

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In accordance with the invention, analogous new bromobenzene compounds are made available to the iodobenzene compounds.

The present invention accordingly provides compounds selected from 1-compounds of the formula Ia

(Ia)

in the .

Q _{1 is} a group -COOH or a group -COOH salted with a pharmacologically acceptable base,

Q ₂ represents a radical of the formula

- 00 - -N

where R is a

Is hydrogen, lower alkyl radical, lower hydroxyalkyl radical or lower alkanoyl lower oxyalkyl and Rg is lower hydroxyalkyl radical or lower alkanoyl lower oxyalkyl,

Q, represents an amino group or a radical of the formula

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-N-

^E 8

where R "a

lower alkyl radical, lower hydroxyalkyl or lower alkoxy-lower alkyl and R iat _ß represents a hydrogen atom, an alkyl radical or a lower hydroxyalkyl radical niederea mean?

2-compounds of the formula I ¹ a

ql

ι α

(I'a),

in the

Q.sup.- is a group -COOH or a group-COOH which has been bonded with a pharmacologically acceptable base as a salt,

Q ¹ P represents an amino group or a radical of the formula

- N - CORq, where R _Q

I ^{9 9}

^R 10

is a lower alkyl radical, a lower hydroxyalkyl radical or lower alkoxy lower alkyl, and R _{10 is} a hydrogen

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represents a nitrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical,

3a ^ ⁸ * ^ * ^e ^ - ^ne amino group or a radical of formula ₁ are wherein R ₁ a ^

is lower alkyl radical, lower hydroxyalkyl radical or lower alkoxy lower alkyl, and R- denotes a hydrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical,

3-compounds of the formula I "a

Q ".

in the

Q "- is a group -00OH or a group -000H salted with a pharmacologically acceptable base,

Q ^M 2 _{a represents} a hydrogen atom, Q "o represents a radical of the formula

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- N - CO - R. J3, where R ₁₃

^E 14

is a lower alkyl radical, a lower hydroxyalkyl radical or lower alkanoyl lower oxyalkyl, and R _{14 represents} a lower alkyl radical or a lower hydroxyalkyl radical,

4-compounds of formula Ib

Q.

br

(Ib)

in the

Q ₁ - a radical of the formula

- N - CO - R ₁₅ , where R _{1 is} C

^R '15

is a polyhydroxylated, lower alkyl radical and R ¹ ^ ₁ - represents a hydrogen atom or a lower alkyl radical,

Q ₂ I _{3 is} a radical of the formula

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- 00 - IT represents, in ^R 17

R ^ g and R "represent a hydrogen atom, a lower alkyl radical, a lower hydroxyalkyl radical or lower alkanoyl-lower oxyalkyl,

Qo _{b is} a radical of the formula

- OO - N is, in R ₁₈ and R ₁₉

^R 19

a hydrogen atom, a lower alkyl radical, a lower hydroxyalkyl radical or lower alkanoyloxy-oxyalkyl or a radical of the formula

- N - CO - Rort mean, in the ι you

^R 21

R _{20 represents} a lower alkyl radical, a lower hydroxyalkyl radical or lower alkoxy-lower alkylate, and R _{21 represents} a hydrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical,

5-compounds of the formula Ic

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(Ic)

in the

Q _{1 represents} a radical of formula - COHH-R ₂₂ in which R _{22 is} a Zuckerreat or a polyhydroxyliertea, lower alkyl radical,

Q _{2c is} a radical of the formula

- CO - R ₂ O means in the

a lower alkyl radical, a lower hydroxyalkyl radical or lower alkoxy-lower alkylate and R ₂ * represents a hydrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical and

Q- a radical of the formula

- CO - H ^ represents, in the ^R 26

R ₂ c and R ₂ g represent a hydrogen atom, a lower alkyl radical, a lower hydroxyalkyl radical or lower alkanoyl lower-oxyalkyl or a radical of the formula

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-K-CO

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mean,

In which R 1 is a lower alkyl radical, a lower hydroxyalkyl radical or lower alkoxy lower alkyl and R p is a hydrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical,

6 compounds of formula Ha

N-CO- (CH _{2) n1} CO-KH

(CHZ)

(Ha),

N2H

in the

a group is -COOH or a group -COOH which is linked to a pharmacologically acceptable base as a salt,

and Qj _{d is} a hydrogen atom, a radical of the formula

- CO -

29

where Ron and R ^ _{0 are} a hydrogen atom,

30

is a lower alkyl radical, a lower hydroxyalkyl radical or lower alkanoyl lower oxyalkyl, an amino group

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or a radical of the formula

Mean -N-CO-Ro ₁ , where R _{01 is} 31 '31

is a lower alkyl radical, a lower hydroxyalkyl radical or lower alkoxy lower alkyl, and R ^ _{2 represents} a hydrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical, where Q ₂ ^ may also be a radical,

Q., a group -NH ₂ or a radical of the formula -N-CO-Ro3

^R 34 represents, in the R "

is a lower alkyl radical, a lower hydroxyalkyl radical or lower alkoxy-lower alkyl and R ^. represents a hydrogen atom, a lower alkyl radical, a lower hydroxyalkyl radical or a lower alkanoyl radical,

Z is H or OH,

n .. is equal to 1 to 5,

n ₂ is 0 to 6;

7-compounds of the formula H ^

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in the

br

- CO - (CHg) _n - CO

(Lib),

- _{θ is} a group -COOH or a group -COOH which is linked to a pharmacologically acceptable base as a salt,

Q _{2e is} a hydrogen atom, a radical of the formula -CO-H

wherein R ^ c and R ^ r are a hydrogen atom, a lower alkyl radical, a lower hydroxyalkyl radical or lower alkanoyl-lower-oxyalkyl, an amino group or a radical of the formula

Represents -N-CO-R07, where * 38

R is a lower alkyl radical, a lower hydroxyalkyl radical or lower alkoxy lower alkyl and R ™ is a hydrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical,

8-compounds of the formula III

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B CO - CH ₂ - N

"(CHZ) _n H

br

br

CH ₂ CO

CH ₂ CONH

6f

in the

Q is a group -COOH or a group -COOH which is bound with a pharmacologically acceptable base as a salt,

Q ₂ f »

the formula

"Q, _f

^a hydrogen atom, a radical

- CO - N

, in which

and R.Q

A hydrogen atom, a lower alkyl radical, a lower hydroxyalkyl radical or lower alkanoyl-lower-oxyalkyl, an amino group or a radical of the formula

Represent -N-CO R..j, where

42

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Is R. j is a lower alkyl radical, lower Hydroxyalkylradi "kal or lower alkoxy-lower alkyl and R ₂ means ⁿ ei Wasserstoffatoni, a lower alkyl radical or a lower hydroxyalkyl radical,

Z is H or OH and η is 0 to 6,

9 - Compounds of the formula IV

0 - N - (CH _{2) n3} - N - CO

( ₂ ) _n3 (GHZ ₁ ) _n1 H (CHZ ₂ ) _n H

(C

3g

(IV),

in the

a radical of the formula

- CO - R

43

represents, where

R _{43 is} a polyhydroxylated, lower alkyl radical and R '~ represents a hydrogen atom or a lower alkyl radical,

Q ₂ and Q _{3 are} independently a radical of the formula

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C » ^being 45

R ₄ . and R _{4 is a} hydrogen atom, a lower alkyl radical, a lower hydroxyalkyl radical or lower alkanoyl lower oxyalkyl, an amino group or a radical of the formula

Represent -N- GOR.c , where Rr is 4o 4o

A ₄₇

is a lower alkyl radical, a lower hydroxyalkyl radical or lower alkoxy lower alkyl, and R represents R , a hydrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical,

Z 1 and Z ₂ are H or OH,

n ^ and n «are 0 to 6,

n ^ is 0 to 4,

10 - Compounds of the formula V

in the

Q ₁ . , Q ₂ . and Qou a group - COOH, a group -GOOH who

bound with a pharmacologically acceptable base as a salt

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is, or a group of the formula

48 - OO - N, in which

^R 49

Mean R. _Q and R ^ g a Wasaerstoffatom, a lower alkyl radical, lower hydroxyalkyl or lower Alkanoylniederes-oxyalkyl.

In the definitions above, the term "lower" as used in the radicals alkyl, alkoxy or alkanoyl refers to radicals having from 1 to 6 carbon atoms and "hydroxyalkyl radical" refers to a mono- or polyhydroxylated alkyl radical.

The novel bromobenzene compounds can be obtained by the methods used for the preparation of the analogous polyiodo compounds. For this purpose one can perform the classical reactions of bromination, alkylation, acylation (by condensation of an acid chloride with an amine or alcohol) and salt formation, as they are are described in detail for the analog polyiodide compounds.

Therefore, the compounds of the formulas Ia, I'a and I "a can be prepared in particular by alkylation and / or acylation of the corresponding compounds which have an amino- or monosubstituted amino group»

The compounds of formula Ib can be prepared by reacting with an acid chloride of the invention

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Formula Cl-GO-R-c »whose hydroxyl groups are preferably slit, which may be followed by the removal of the protective groups and an alkylation of the corresponding compounds having an amino group, follow.

The process conditions may be the same as described in FR-PS 22 53 509.

The compounds of the formula I can be prepared by carrying out the acylation of an amine of the formula NHo-Rp? with a corresponding acid chloride, that is. with a compound of the formula

CO-Cl

Br 1 Br

The process conditions may be the same as described in FR-PS 20 53 037.

The compounds of formula Ha can be prepared by subjecting the acylation of an amine of formula

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2'η1

N - CO (CH ₀₎ ^ - HH (CHZ) _n2 H

with an acid chloride of the formula

br

CICO

durchfuhrt.

The process conditions may be the same as described in US Pat. No. 4,014,986.

The compounds of formula Hb can be prepared by subjecting the condensation of an amine of formula

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with a diacid chloride of the formula Cl - C0 (CHg) _n - CO - Cl

durchfuhrt.

The process conditions may be the same as described in US Pat. No. 3,290,366.

The compounds of formula III can be prepared by reacting an amine of formula

with a chlorinated derivative of the formula

Br JC Br

Cl-CH ₂ -CONH

converts *

The process conditions may be the same as described in FR-PS 22 72 640.

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The compounds of formula IV can be prepared by subjecting the acylation of an amine of formula

br

CO-W- (CH ₂ ) n _{3 -N} -CO

) _n1 H CCHZ ₂ ) _n2 H Br

with an acid chloride of the formula

Cl-CO-R ₄₃

whose hydroxy groups are preferably protected, which optionally followed by the removal of the protective groups

The process conditions may be the same as described in FR-PS 23 13 018.

With regard to the compounds of the formula V, starting from 2,4,6-tribromo-5-cyano-isophthalic acid, they can, by hydrolysis of the amide, optionally followed by conversion of the amide into an acid chloride, reacting with an amine of the formula HMR ₄₈ R ₄ Q connected, manufactured v / earth.

embodiment

The following examples illustrate the preparation of the bromine-benzene compounds.

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Beiapiel 1

Preparation of 2,4o6.-tribromo-3-N-hydroxy-ethylcarbamoyl-5-N'-acetylaminobenzoic acid

COOH

HIGH ₂ CH ₂ NHOo

N - COCH

I ^J

1) Preparation of 2,4, 6-tribromo-3-N-hydroxyethylcarbamoyl-5 : aminobenzoic acid

COOH

HIGH ₂ CH ₂ NHC

ΙίΗ,

A suspension of 1 mole of 3-N-hydroxyethylcarbamoyl-5-aminobenzoic acid in 4 liters of water and 820 ml of conc. Hydrochloric acid is added. Then, 9 moles of bromine are added dropwise. Continue stirring for 24 more hours at ambient temperature. It is centrifuged, the precipitate is washed with 2 liters of water at 90 ^° C. and then dried at 110 ^° C. for 24 hours.

Yield: 96.5 %

Purity control:

- COM with El ant benzene / MEC / formic acid (60/25/20)

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Rf of the starting product: 0.05 Rf of the brominated product: 0.55

- purity according to bromine determination: 100 %

2) Preparation of 2,4t6-tribromo-3-N-hydroxyethylcarbamoyl-5; N-acetylamino-benzoic acid

COOH

HIGH ₂ GH ₂ NHCO

COGH,

a) condensation

A suspension of 0.5 mole of 2,4,6-tribromo-3-N-hydroxyethylcarbamoyl-5-amino-benzoic 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 55 to 60 ⁰ C should not exceed. After addition of the sulfuric acid is stirred for 1 hr. At 55 ⁰ C C. The resulting solution is poured into 1 1 of ice water. There is a precipitation. It is stirred for 24 hours at ambient temperature. Then, centrifuge and wash with water. It is dried for 16 hours at 80 ^° C. in a drying oven.

Yield: 75.5 %

b) Cleaning

Purification takes place by crystallization of the ammonium

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salt »Prepare a suspension of 42 g of the crude acid in 45 ml of the crude acid in 45 ml of water. Then add 10N ammonia until dissolved (pH = 7 to 8). Stir at room temperature for 24 h. There is Krostallisation. It is centrifuged and clarified with 10 ml of water. Then the precipitate is dissolved in 500 ml of water of 90 ⁰ C. Two treatments are carried out with carbon 3SA at 80 ^° C. within 2 hours. Then the product is precipitated with 1/10 hydrochloric acid. It is centrifuged, washed with water and dried overnight at 80 ⁰ C,

Purity control:

- CCM with Bluant Benzene / MEC / formic acid (60/25/20)

Rf of the starting product: 0.55

Rf of the acetylated product: 0.25

- purity according to bromine determination: 101%

Purity as determined by methylate: 100 %

Example 2

H e rstellung of 2 ^ 4 »6-tribromo-3-N-hydroxyethylcarbamoyl-N-methyl - ^ - iJ-acetylamino-benzoic acid

COOH Br JL Br

HIGH ₂ CH ₂ NHCO

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a) Methylation

Dissolve 0.4 mol of 2,4,6-tribromo-3-N-hydroxyethylcarbamoyl-5-N-acetylaminobenzoic acid in 184 ml of 5 N sodium carbonate solution (0.92 mol), then add 32.4 ml ( 0.52 moles) of methyl iodide and stirred for 24 hours, at ambient temperature. The end of the reaction is monitored by CCM with eluant: butanol / acetic acid / water (50/11/25). The solution is poured into 300 ml of water and 75 ml of conc. Hydrochloric acid, precipitation takes place, the mixture is allowed to crystallize for 5 hours, then centrifuged. The precipitate is taken up in 500 ml of water. Add 10N soda to dissolution and then adjust the pH to 4 by adding acetic acid. To decolorize the solution is added 1 ml of sodium sulfite solution. Then it is precipitated in an acidic medium, centrifuged, washed with water and dried for 24 hours, at 80 ⁰ C.

b) Cleaning

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

A suspension of 100 g of the crude acid in 500 ml of water is prepared. Then it is heated to 80 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, long, centrifuged, clarified with a water-ethanol mixture and dried for 24 hours at 80 ^° C. in a drying oven. 62.8 g of the product are obtained ml of water and soda dissolves, the pH is adjusted to 4 to 5 by addition of acetic acid and treated twice with charcoal, filtered and acidified

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afterwards, with concentrated hydrochloric acid. Then centrifuged wäacht with water and dried 24 h. At 80 ⁰ C.

Yield global (methylation and purification): 20 % Purity Control:

GCM with eluant benzene / MEC / formic acid (60/25/20)

Rf of the starting product: 0.25 Rf of the methylated product: 0.25

GCM with eluant butanol / CH 2 COOH / water (50/11/25)

Rf of the egg product: 0.20 Rf of the methylated product: 0.18 to 0.32

Purity as determined by methylate: 98 %

- purity according to bromine determination: 104%

Example III

Herat ell us from 2 _f 4 ^ 6 ~ tribromo-N ~ methyl - 3 ~ N-acetylaminobenzoic acid

br

K-COGH ₃

br

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1) Preparation of 2 ₁ 4t6 tribromo-3-amilo-ben2oeaäare

COOH

The 2,4 »6-tribromo-3-amino-benzoic acid is, as in Example I.

1, prepared starting from 3 aminobenzoic acid.

Yield »95 _t 2% purity control:

CCM with eluant benzene / MEC / formic acid (60/25/20)

Rf of the starting product: 0.2 Rf of the brominated product: 0.85 purity in accordance with bromine determination: 99%

2) Preparation of 2,4-tribromo-β-N-acetyl-2-aminobenzoic acid

COOH

MHCOCH

The 2,4,6-tribromo-3-diacetylaminobenzoic acid is prepared as described in Example 1-2 starting from 2,4,6-tribromo-3-aminobenzoic acid *

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Yield: 84.5% purity control:

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

Rf of the starting product: 0.85 Rf of the acetylated product: 0.6

Purity according to determination of sodium methylate: 97 %

3) Preparation of 2 _t 4 _{t of} 6-tribromo-1: 1-methyl-3-N-acetylaminobenzoic acid

N-COCH ₃

The 2,4,6-tribromo-N-methyl-3-N-acetylamino-benzoic acid is prepared as described in Example II, starting from 2,4,6-tribromo-3-N-acetylamino-benzoic acid yield globally (Methylation and purification):

64.5% "purity control:

-CCM with eluant benzene / MEC / formic acid (60/25/20) Rf of the starting product: 0.6 Rf of the methylated product: 0.75

-CCM with eluant butanol / CH 2 COOH / waaser (50/11/25) R f of the starting product: 0.45

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Rf of the methylated product: 0.55

Purity as determined on methylate: 98 % purity according to bromine determination: 99%

Example IV

Preparation of 2,4 "6- ^f Jribrom'-3 ~ amino ~ N ~ methyl-5 ~ IJ acetylaminobenzoeaäure

Ό00Η

-COCH ₃ Br CH ₃

) Preparation of 2- _t 4-tribromo-3-amino-5-N-acetylaminobenzoic acid

COOH

br

MHCOCH ₃

The 2 _{t of} 4,6-tribromo-3-amino-5-N-acetylaminobenzoic acid is prepared as described in Example 1-1, starting from 3-amino-5-H-acetylaminobenzoic acid _o

Yield! 95 % purity control:

- CCM with elixant benzene / MEC / formic acid (60/25/20)

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Rf of the starting product: 0.07 Rf of the brominated product: 0.65

- purity according to Brombestimentj 97 %

2) Preparation of 2- _t 4-tribromo-3-amino-N-methyl-5-N-acetylaminobenzoic acid

COOH Bp ..

Γ-GOGH ₃

br

The 2,4,6-tribromo-amino-1-methyl-SN-acetylaminobenzoic acid is prepared as described in Example II starting from 2,4,6-tribromo-3-amino-5-N acetylaminobenzoic acid _e

Yield: 81 % purity control:

CCM with eluant butanol / acetic acid / water (50/11/25): Rf of the starting product: 0.4 Rf of the methylated product: 0.32 and 0.47

- purity according to bromine determination: 98 %

- purity as determined at methylate: 101%

Example V

Preparation of 5.5 ^L bis-adipoyldiimino- (2,4 ₎ -6-tribromo-5-amino-N-methylisophthalanoic acid

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COOH

CH ₃ IiHCO

br

br

UH-COCCH ₀ ), COUH

CONH,

a) condensation

Dissolve 150 g (0.348 mol) of 2,4,6-tribromo-3-N-methylcarbamoyl-5-amino-benzoic acid in 520 ml of dimethylacetymide. 25.5 ml (0.2 mol) of adipolychloride are then added dropwise while maintaining the temperature between 20 and 25 for 12 hours at ambient temperature.

C. One stirs

The end of the reaction is controlled by CCM. The solution is poured into 900 ml of water and the precipitation is carried out. The stirring is continued for 16 hours. After centrifuging, washing with water and drying at 60 ^° C. for 24 hours, 135 g of the product are obtained, which corresponds to a yield of 80 % ,

b) Cleaning

Purification takes place by crystallization of the ammonium salt. A suspension of 135 g of the product in 135 ml of water is prepared and 10N ammonia is added until it is dissolved (pH a 7 to 8). The mixture is then stirred for a further 24 hours. It is the crystallization. After centrifugation and clarification with 20 ml of water, the precipitate is dissolved in 500 ml of water and treated with 3SA coal

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by. It is filtered and then acidified with conc. Hydrochloric acid on. It is centrifuged, washed with water and dried for 16 hrs. At 80 ⁰ C in 'frockenschrank. This gives 58.9 g of the pure product, which corresponds to a yield of 43 »5% for the purification.

Re inhe control:

- CCM with eluant benzene / MEC-formic acid (60/25/10)

Rf of the starting product: 0.7 Rf of the condensed product: 0.45

- purity according to bromine determination: 104%

Purity as determined by methylate: 93 %

Purity as determined by tetrabutylammonium: 104%

Example VI

Preparation of 5'5'-biB-adipoyldiiniino- (2,4,6-tribromo-3-amino-benzoic acid)

COOH Br JL Br

NHCO (

The 5,5'-bis-adipoyldiimino (2,4,6-tribromo-3-amino-benzoic acid) is prepared as described in Example V, starting from 2,4> 6-tribromo-3-amino-benzoic acid ,

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Condensation yield: 100% purification yield; 56%

Reinheitakontrolle:

- CCM with eluant benzene / MEC / formic acid (60/25/10)

Rf of the starting product: 0.85 Rf of the condensed product: 0.5

- purity according to bromine determination: 99%

Purity as determined by methylate: 101 %

Example VII

Preparation of 2- _t 4 -6-tribromo-3-N-hydroxy-ethylcarbamoyl - (2 _f 4 -6-tribrpm-3-N-methyl-carbamoyl-H-methyl-5-N-acetyl-n-n- benzoyl) ^ -glycylaminp-benzoic acid

COOH CH ₃ -N-COCH ₃

HHCOCH ₂ NHCo

1) Preparation of 2,4,6-tribromo-3-N-hydroxy-ethyl-carbamoyl-5-aminoacetamido-benzoic acid

a) Preparation of 2 _> 4 »6-tribromo-3-N-phthalimido-acetoxyethyl-carbamoyl-S-phthalimido-acetylamino-benzoic acid

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COOH

- Br ^ Br CO COOCh ₂ CH ₂ NHCO ' ^ NHCOCH ₂ Ny

Dissolve 322 g (0.2 mol) of 2,4,6-tribromo-3-N-hydroxy-ethylcarbamoyl-5-amino-benzoic acid in 600 ml of dimethylacetamide. Then added in portions 392 g (1.75 mol) of phthalyl-glycinsäurechlorid added. After 48 hours, stirring at ambient temperature, the solution is poured into 2 1 of water at 70 ^° C. It is precipitated, the stirring is continued for 1/2 hour and then centrifuged.

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

Control:

CCM with eluant benzene / MEC / formic acid (60/25/20) logo CNRS logo INIST

Rf 0.7 (starting product = Rf 0.55)

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

COOH Br ^ ^^ * V ^^ Br

HIGH ₂ CH ₂ NHCO

NHCOCH ₂ NH ₂

A suspension of the product obtained as above is obtained

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Product in 2.4 l of water and 204 ml of hydrazine hydrate. The mixture is heated 1 St d _e at 90 ⁰ G and stirred for 48 hours at ambient temperature ₀ · There is crystallization. Then centrifuged and clarified with water. A product is obtained which contains 10 to 15% phthalhydrazide · The product 1 of water and 100 ml of concentrated sulfuric acid is added and · the mixture to 90 ⁰ G held in the first The insoluble fraction is separated off by filtration and the pH is then adjusted to 3 to 4 with ammonia. Then allowed to crystallize overnight at ambient temperature.

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

Purity control:

1) COM with eluant benzene / MEC / formic acid (60/25/20) = Rf 0.05 (orange-yellow spot after development with ninhydrin)

There remains about 1 % phthalhydrazide with Rf 0.75.

2) purity according to bromine determination: 98 %

2) Preparation of 2 _t 4 _t 6-tribromo-3-N-methylcarbamoyl-N- methyl-5-N-acetylamino-benzoic acid chloride

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COCI

CH ₃ NHCO

br

A suspension of 296 g (0.59 mol) of 2,4,6-tribromo-3-N-methylcarbamoyl N-methyl-5-N-acetylaminobenzoic acid in 6OO ml of thionyl chloride ago. The mixture is then heated with stirring for 3 hrs. At 80 ⁰ C to give a solution from which the excess thionyl chloride is evaporated in vacuo. The pasty residue is taken up in 500 ml of isopropyl ether and the mixture is stirred for 24 hours at ambient temperature. There is crystallization. After centrifugation and clarification with isopropyl ether, the precipitate is washed with stirring for 24 hours at ambient temperature in 250 ml of acetone. It is centrifuged, clarified with 50 ml of acetone and the product is then dried under vacuum.

This gives 150 g of a pale, beige product, which corresponds to a yield of 50.5%.

Purity control:

1) CCM (after reaction with monoethanolamine in excess in dimethylacetamide) with eluant benzene / methyl ethyl ketone /

Formic acid (60/25/20):

Rf of the starting product 0.57

Rf of product condensed with monoethanolamine 0.35

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2) Determination of Acid Chloride by Propylamine: 105 %

3) Preparation of 2 _! 4 _y 6-tribromo-3-N-hydro: gy -ethylcarbamoyl (2 1 4.6 ~ tribromo-3-H-met hyl-carbamoyl-N-methyl-5-N-acetylaminobenzoyl) -5-Klycylamino-benzoic acid

a) condensation

A suspension of 135 g (0.296 mol) of 2,4,6-tribromo-3-N-hydroxyethylcarbamoyl-5-N-aminoacetamido-benzoic acid in a mixture of dimethylacetamide (300 ml) and triethylamine (107 ml) corresponding to 0, 74 mol) ago. 150 g (corresponding to 0.296 mol) of 2,4,6-tribromo-N-methyl-S-carbamoyl-N-methyl-SN-acetylaminobenzoic acid chloride are added to this suspension. The mixture is stirred at 45 ^° C. for 3 hours. The end of the reaction is monitored by CGM: less than 3 % of the starting product remains

The solution is poured into 1 1 of water and then acidified with conc. Hydrochloric acid is formed. A slight precipitate forms and stirring is continued for 8 more days at ambient temperature

After centrifuging, washing with water and drying at 60 ^° C. for 25 hours, 68.2 g of the product are obtained, which corresponds to a yield of 24%.

b) Cleaning

Dissolve 68.2 g of the product in 130 ml absol. Ethanol at reflux · Then allowed at ambient temperature

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Crystallize for 24 StcL. The mixture is centrifuged and clarified. Then the product is dissolved in 200 ml of water and soda. The pH is adjusted to 4 to 5 with acetic acid and treated twice with charcoal. Then filtered and then acidified with conc. Hydrochloric acid on.

After centrifuging, washing with water and drying for 24 hours, long at 60 ⁰ C to give 43 g of the product, which corresponds to a yield of 63 % for the purification.

Purity control:

- COM with eluant benzene / MEC / formic acid (60/25/20) Rf of the amine: 0.07

Rf of the acid corresponding to the acid chloride: 0.7 Rf of the condensed product: 0.4

- purity according to bromine determination: 100%

Purity as determined by methylate: 97 %

Example VIII

Preparation of 2,4i6-tribromo-3-Ifl-hydroxyethylcarbamoyl- (2 ₁ 4 _< 6-tribromo-3-N-hydroxy-yl-carbamoyl-N-methyl-5-N-acetylaminobenzoyl) -5 --Klycylamino-benzoic acid

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COOH

CH ₃ -N-COOH ₃

HIGH

MHOOOHgläHCO

CONHCH ₂ CH ₂ OH

1) Preparation of 2,4i6-tribromo-3-N-acetoxy-ethylcarbamoyl-N-methyl-SN-acetylamino-benzoic acid

COOH

CH ₃ CO-

CONHCh ₂ CH ₂ OCOCH ₃

A suspension of 270 g (0.52 mol) of 2,4,6-tribromo-3-N-hydroxyethylcarbamoyl-N-methyl-SN-acetylaminobenzoic acid in 1.3 l of dioxane is prepared. Then 78 ml (1.04 mol) of acetyl chloride are added and the mixture is heated for 8 hours at 80 ⁰ C ₀ Daa dioxane is removed by evaporation under vacuum. This gives 290 g of product which corresponds to a yield of 98.6 % . "This product is used without purification ₀

Purity control:

- CCM with eluant benzene / MEC / formic acid (60/25/20) Rf of the starting product: 0.25 Rf of the O-acetylated product: 0.40

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2) Prod RECOVERY of 2 ₁ 4 "6 ~ Tribrotn - 3» N-acetoxy-ethyl l -carbamoyl-N-methyl - ^ - 'IT acetylacaino-benzoeaäiirechlorid

COCI

CH ₃ CO-

C0NHCH ₂ CH ₂ 0C0CH ₃

A suspension of 290 g (0.52 mol) of 2,4,6-tribromo-3-N-acetoxyethyl-carbamoyl-N-methyl-5-N-acetylaminobenzoic acid in 500 ml of thionyl chloride is prepared. The mixture is then heated at 80 ^° C. for 4 hours. The excess thionyl chloride is removed by evaporation under reduced pressure.

After drying, 300 g of dea product are obtained, which corresponds to a yield of 100 % . This product will continue to be used without purification.

3) condensation

COOH

HIGH ₂ CH ₂ MHCO

KHCOCHgMCO

CH ₃ -N-COCH ₃

br

The production of 2,

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^^, ß-tribromo ^ -N-acetoxyethyl-carbamoyl-1-methyl -. ^ - N-acethylamino-benzoyl) -5-glycylamino-benzoic acid is carried out as described in Example VII, starting from 2,4,6 Tribromo ^^ N-hydroxyethylcarbamoyl-S-amino-acetoamido-benzoic acid; and 2,4,6-tribromo-3-li-acetoxy-ethylcarbamoyl-N-methyl-5-N-acetylamino-benzoic acid chloride.

Yield of condensation: 62.5%

This product is not used without cleaning ·

4) saponification

Dissolve 146 g (0.138 mol) of 2,4,6-tribromo-3-N-hydroxyethylcarbamoyl- (2,4,6-tribromo-3-N-acetoxyethylcarbaraoyl-N-diethyl-5-N'-acetylaminobenzoyl) - 5-glycylaminobenzoic acid ⁱⁿ 270 ml 2N sodium carbonate solution. Then you heat 2 St d. long to 45 ^° C. Adjust the pH to 6-7 with hydrochloric acid and carry out two treatments with charcoal. It is filtered and then precipitated in an acidic medium (pH = 1), then centrifuged, clarified and dried for 20 hrs. At 60 ⁰ C in a drying oven »This gives 54 g of the product, which corresponds to a yield of 24 % .

purity control

- GCM with eluant benzene / MEC / formic acid (60/25/20) Rf of the starting product: 0.1

Rf of saponified product: 0.05

5) Cleaning

It is carried out by crystallization in isopropanol.

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A suspension of 54 g of the crude product in 54 ml of isopropanol is then prepared. The mixture is then heated at 80 ° C. for 2 hours. The mixture is stirred at ambient temperature overnight, during which time the crystallization takes place. It is centrifuged, clarified with isopropanol and then the product is washed with water. After drying at 80 ⁰ C, 16 hours, long in the oven, to give 21 g of the product, which corresponds to a yield of 34 % for the purification.

purity control

-GGM with eluant benzene / MEC / formic acid (60/25/20):

Rf 0.05 - CCM with eluant butanol / acetic acid / water (50/11/25): Rf 0.2 and 0.3

Example IX Preparation of 2 _{t of} 4-tribromo-3-N-methyl-carbamoyl- (2,4,6

tribromo-N ~ methyl-3-i'j-acetylamino-benzoyl) -5-glycylamino

benzoic acid

- COOH br Br, CH ^ -N-COCH- br I ν. > Av ^ Br et ^S NH-COCH ₂ NHCO * CH ₃ NHCO ^y V

br

br

1) Preparation of 2 «4-tribromo-3-N- methylcarbamoyl-5- aminoacetylaminobenzoic acid

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The compound is prepared as described in example VII-1 starting from 2,4,6-tribromo-3-im-methyl-carbamoyl-5-amino-benzoic acid.

Yield: 45 %

Reinheitakontrolle:

-CGM with eluant benzene / MEC / ameiaic acid (60/25/20): Rf 0.1 -CGM with eluant butanol / EAAAA / Wasaer (50/11/25):

Rf 0.07 purity according to bromine determination: 96 %

2) Preparation of 2,4,6-tribromo-N-methyl-3-N-aoetylaminobenzoic acid chloride

The compound is prepared as described in Beiapiel VII-2 using 2,4,6-tribromo-1-methyl-3-N-acetylaminobenzoic acid.

Yield: 85%

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Purity control:

CCM (after reaction with monoethanolamine in excess, in dimethylacetamide)

with eluant benzene / methyl ethyl ketone / formic acid (60/25/20)

R _{f of the} starting product: 0.7 Ro. Dea with monoethanolamine condensed product: 0.5

3) production; of 2 _{t of} 4 * 6-tribromo-3-N-methyl-carbamoyl- (2- _t, 4- trichloro-N-methyl-3 - (- acetylamino-benzoyl) -5-glycyl- aminobenzoic acid

br

CH ₃ NHCO

Im-COCH ₂ NHC

br

The 2,4,6-tribromo-3-N-methylcarbamoyl- (2,4,6-tribromo-N-methyl-3-N-acetylamino-benzoyl) -5-glycylamino-benzoic acid is as described in Example VII prepared from 2,4,6-tribromo-3-N-methylcarbamoyl-5-amino-acetamidobenzoic acid and 2,4,6-tribromo-N-methyl-3-N-acetyl-amino-benzoic acid chloride

Condensation yield: 85 %. Purification yield: 13.5 %.

Purity control:

CCM with eluant benzene / MEC / formic acid (60/25/20)

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Rf dea amine 0.05

Rf of acid corresponding to acid chloride 0.85

Rf of the condensed product: 0.5

- purity according to bromine determination: 96 %

Purity as determined by methylate: 103 %

Example X

H, he at RECOVERY of 2 ₁ 4 »6-tribromo-3 ~ PIP" N-methyl ~ oarbamoyl- 'l _(2.4> e ~ ~ tribromo 3' 5 ~ to ~ (M-'hydroxy -. Ethylcarbamoyl ) - > phenyl-1-ocarbamoyl-methyl-S-ataino-acetamido-benzoic acid

COOH

CH ₃ NHCO

IIHOOCH ₂ N-CH ₂ CO

br

HOGH ₂ CH ₂ NHCO

ONHCH ₂ CH ₂ OH Br

CONHGH ₂ CH ₂ OH

CONHCH ₂ CH ₂ OH

1) Preparation of 2 _{t of} 4 "tribromo-3" 5-bis (hydroxyethyl) carbamoyl) -chloroacetanilide

2 Λ 2 8 8 6

HOGH ₂ CH ₂ WHCO

-45-

NHGOCH ₂ Gl Br

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COHHCH

a) Preparation of 2,4,6-tribromo-5-amino-i-butylphthalic acid

Me

HOOC

Gooh

The acid is prepared as described in Example 1-1,

starting from 3-amino-isophthalic acid

Yield: 86.5% purity control:

- CGM with eluant benzene / MEC / formic acid (60/25/20) Rf of the starting product: 0.1

Rf of the brominated product: 0.8

- purity according to bromine determination: 99 %

b) Preparation of 2,4 »6 ~ tribromo-5 ~ agiiQO-isophthalic acid chloride

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GlCO

'Gogl

A suspension of 729 g of ateilt (1.73 mol) of 2,4,6-tribromo-5 ~ amino-iaophthalaäure in 1800 ml of thionyl chloride forth »· then heated 8 hrs. At 80 ⁰ C. then removed the überschiisaige Thionyl chloride by evaporation under vacuum, The concentrate is taken up in 1 1 isopropyl ether, and it is crystallized, it is centrifuged and clarified with Iaopropylether, After drying under vacuum to obtain 465 g, which corresponds to a yield of 60 % .

Reinheitakontrolle:

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

Rf of the starting acid: 0.8

Rf dea products after condensation with monoethanolamine: 0.4

Purity according to acid chloride with propylamine: 105 9

c) Preparation of 2 _{t of} 4i6-tribromo-3'5-bia ~ (hydroxyethylcarbamovD-aniline

HIGH ₂ CH ₂ IIHGo

CONHCH ₂ GH ₂ Oh

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Dissolve 184 g (0.404 mol) of 2,4,6-tribromo-5-amino-isophthalic acid chloride in 180 ml of dimethylacetamide. Then added dropwise 145 ml (2.4 mol) of monoethanolamine, keeping the temperature between 20 and 25 ° C, "Man stirred for 16 hrs. At ambient temperature. Then the solution is poured into 1 liter of ice-water, whereby the precipitation takes place. The mixture is stirred for a further 24 hours at ambient temperature, centrifuged, washed with water and dried for 16 hours at 80 ⁰ C, giving 168 g of the product, which corresponds to a yield of 84 % .

purity control

CGM with eluant benzene / MEC / formic acid (60/25/20): Rf 0.4

- purity according to bromine determination: 98 %

d) Preparation of 2,4, 6-tribromo-3, 5-bis- (hydroxyethylcarbamoyl) -chloroacetanilide

- condensation

515 g (1.02 mol) of the product obtained according to c) are dissolved in 775 ml of dimethylacetamide. Then added dropwise 377 ml (4.7 mol) of chloroacetyl chloride, keeping the temperature between 20 and 30 ⁰ C. The mixture is stirred for 16 hrs. At ambient temperature and the mixture is poured into 4.5 1 of ice water, whereby the precipitation takes place. It is centrifuged and clarified with water. This product will continue to be used without drying,

Purity control:

- COM with eluant benzene / MEC / formic acid (60/25/20) Rf of the starting product: 0,4

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Rf of the condensed product: 0.85

- saponification

A suspension of the above product is prepared in 1750 ml of 2N soda solution. Then it is stirred for 16 hrs. At ambient temperature and acidified with hydrochloric acid (pH = 1) · It is centrifuged, washed with water and dried for 16 hrs d. long at 80 ⁰ C.

This gives 215 g, which corresponds to a yield of 36%.

Purity control:

CCM with eluant benzene / MEC / ameiaic acid (60/25/20) Rf of the starting product: 0.4

Rf of the chloroacetylated product: 0.2

- purity according to bromine determination: 99 %

- purity according to chlorine determination: 105%

2) Preparation of 2 _{t of} 4-tribromo-3-N-methylcarbamoyl-bis-L (2 _> 4 _{t of} 6-tribromo-3-bis (N-hydroxyethylcarbamoyl) -phenyl) -carbamoyl-methyl amino-acetamido-ben2oesäure

a) condensation

A solution of 10 g (0.02 mol) of 2,4,6-tribromo-3-N-methylcarbamoyl-5-amino-acetamido-benzoic acid in 18 ml of 1N soda is mixed with a solution of 23.2 g (0.04 mol) of 2,4,6-tribromo-3,5-bis (hydroxyethylcarbamoyl) -chloroacetanilide in 40 ml of 1N sodium carbonate

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After 1 hr. Heating at 85 ⁰ C is added 18 ml of 1-N-soda and the mixture for a further 20 hrs. On 85 ⁰ G. Then the solution is cooled to 20 ⁰ C and acidified with conc. Hydrochloric acid to pH = 1 to ₀ A gum forms, which crystallizes after 16 hours at ambient temperature. It is centrifuged, washed with water and dried for 24 hours in a drying oven at 60 ⁰ C.

29 g of the crude acid are obtained,

b) Cleaning

Make a suspension of 29 g of the crude acid in 60 ml of water and adjust the pH by adding soda on. Then the insoluble portion is filtered and then acidified with conc. Hydrochloric acid to a pH of or below. Centrifuge the precipitate and wash it with water. Suspend the precipitate in 10 ml of water in suspension and add ammonia until neutral. Then 2 g of ammonium chloride are added as well. The mixture is stirred for 48 hrs. At ambient temperature, wherein the crystallization takes place. It is centrifuged and the precipitate is dissolved in 50 ml of water. Then treat twice with charcoal and precipitate with hydrochloric acid. After centrifuging, washing with water and drying, 5.2 g of the purified product are obtained »

purity control

CGM with eluant / butanol / acetic acid / water (5011/25) Rf of the chlorinated starting product: 0.65

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Rf of the starting aminated product: 0.07 Ef of the condensation product: 0.2

Purity according to bromine mood: 98.7%

Purity as determined by sodium methylate: 95 %

Example XI

Preparation of 2 _→ 4-tribromo-3- (N-methylacetamido) -5 · (N-hydroxyethyloarbamoyl-N-cluconyl-aniline

NHOO (CHOH) ₅ H

CH ₃ OON

CONHCH ₂ CH ₂ OH

1) Preparation of 2 _{t of} 4,6-tribromo-N-methyl-3-N-acetylamino-5-amino-benzoic acid chloride

COCl Br

CH ₃ CO:

A suspension of 200 g (corresponding to 0.446 mol) of 2,4,6-tribromo-N-methyl-3-N-acetylamino-5-aminobenzoic acid in 200 ml of isopropyl ether is prepared. 200 ml of thionyl chloride are then added dropwise. It is stirred for 4 more hours

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80 ⁰ C and overnight at ambient temperature, then the mixture is evaporated on a rotary evaporator until a residue is obtained, which in turn is taken up in 400 ml of isopropyl ether. The mixture is stirred for 24 hours at ambient temperature, whereby the crystallization takes place. After centrifuging, clarifying and drying for 24 hrs. At 40 ⁰ C to obtain 165 g of the product, which corresponds to a yield of 79.3%.

Reinheitakontrolle

- CCM with eluant benzene / MEO / formic acid (60/25/20) Rf of the starting product: 0.7 to 0.8

Rf of acid chloride: 0.5

(after condensation with monoethanolamine)

Purity as determined by propylamine: 90.5%

2) production; of 2 _{t of} 4 ^ 6-tribromo-3-N-hydroxy-ethylcarbamoyl-N-methyl-5-N-.acetylamino-aniline

CIiHCH ₀

br

Dissolve 65.3 g (0.140 mol) of 2,4,6-tribromo-N-methyl-3-.M-acetylamino-5-amino-benzoic acid chloride in 100 ml of dimethylacetamide. Then added dropwise 25.2 ml (0.140 mol) of ethanolamine, where appropriate, cooling, so that the temperature does not exceed 25 ⁰ C. It is stirred for another 2 days

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at ambient temperature. Then the solution is poured into a mixture of 400 ml of water and 80 g of ice. It is precipitated, then stirred for another 48 hrs. Wach Zentrifugieren, washing, clarifying and drying gives 56.4 g of the product, which corresponds to a yield of 82.5 '/ q *

Reinheitakontrolle

- GGM with eluant benzene / MEC / formic acid (60/25/20) Rf of the starting product: 0.7 to 0.8

Rf of the condensed product: 0.55

3) Herateilung of 2 ^ 4 ^ 6-3-U-acetoxyethyl-carbamoyl-CT-methyl 5-N-acetylamino-aniline o

CH-CO

A suspension of 56.4 g (0.115 mol) of 2,4,6-tribromo-3-3! I-hydroxyethylcarbamoyl-ίί-methyl-5-N-acetylaminoaniline in a mixture of 74.8 ml of acetic acid and the like is added 0.78 ml of sulfuric acid are then stirred at 80 ^° C. for 3 hours and then at ambient temperature for 12 hours. The solution is poured into 260 ml of permuted water containing a few pieces of ice and crystallized. After iilärung and drying gives 46 g of the product, which corresponds to a yield of 75.4%.

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Purity control:

GCM with eluant benzene / MEC / formic acid (60/25/20) Rf of amine OH: 0.55

Rf of the amine O-acetylated: O, 75

4) Preparation of 2 _{t of} 4i6-tribromo-3- (N-methylacetamido) -5- (N-acetoxyethylcarbamoyl) N-pentaacetoxygluconylaniline

MCO (CHOCOCH _{3) 5} H

CONHCH ₂ CH ₂ OCOCh ₃

br

A suspension of 28 g (0.0573 mol) of 2,4,6-tribromo-3-N-acetoxyethylcarbamoyl-N-methyl-SN-acetylaminoaniline in 36 ml of dimethylacetamide is prepared and added portionwise to 36.5 g of pentaacetyl-gluconic acid chloride ( 0.086 mol). Then stir for 48 hrs. At ambient temperature. Add 78 ml of water and stir for 30 minutes. The aqueous phase is extracted with 4 × 150 ml dichloroethane. Then the organic phase is washed with 4 × 250 ml of a 5% sodium bicarbonate solution and with 2 × 500 ml of water,

After drying over calcium chloride, the mixture is filtered and the dichloroethane is evaporated off under vacuum. This gives 30.5 g of the product.

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waa corresponds to a yield of 63 % .

Reinheitskontro11e:

CCM with eluant butanol / acetic acid / water (50/11/25) Rf of amine OH: 0.2

Rf of the amine O-acetylated: 0.65

Rf of the condensed product before saponification: 0.5

5) Preparation of 2,4j6-tribromo ~ 3 ~ _{(N-methyl-acetamido):} - 5-- (N-hydrpxy et hylcarbamoyl) ~ N ~ gluconyl · -aniline

KHGO (CHOH) ₅ H

CH CON ^ ^ ** < ^ CONHCH ₂ CH ₂ OH

br

30.5 g (0.033 mol) of 2,4,6-tribromo-3- (N-methylacetamido) -5- (N-acetoxyethylcarbamoyl) -N-pentaacetoxy-gluconyl-aniline are dissolved in a mixture of 83 ml of Y. / carcasses, 13 ml of hydrazine hydrate and 15 ml of methanol. Then rlihrt 6 h · at 45 ⁰ C and 12 hrs. at ambient temperature. Then, it transmits in the mixture 40 ml of water and 36 g of phthalic anhydride, and stirred for 4 hrs, long at 70 ^° C and 48 hours at ambient temperature »

After centrifugation, treating the mother liquor at 60 ⁰ C with charcoal 3SA, concentrated by evaporation to one third of its initial volume, and extracted with 200 ml 6 χ

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Ethyl acetate. After evaporation to dryness, 13 g of the product are obtained, which corresponds to a yield of 60 % .

Reinheitakontrolle:

- GGM with eluant benzene / MEC / ameoic acid (60/25/10) Rf of the product before saponification: 0,05 Rf of the product after saponification: 0,55

Examples XII and XIII

The procedure is as described in Examples VII and VIII, and the following compounds are obtained:

example

formula

Rf

Eluant 1 ^X 0.1

Rf

Eluant 2 ^J 0.25

COOH

HIGH ₂ CH ₂ NHCO ^ f NHCOCHgNHCO

br

HIGH ₂ CH ₂ MCO

br

-COCH ₂ BHCO

CH ₃ N-COCH ₂ OCH ₃

CONH.

0.2 and 0.25

CONHCH ₂ GH ₂ OH

^x Eluant 1: Benzene / methyl ethyl ketone / formic acid (60/25/20)

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Bluant 2: n-butanol / acetic acid / water (50/11/25)

Example XIV

Preparation of ÜR 'N ^t ~ bis - (2 _t ~ 4i6 tribromo-3 ~ N ~ ~ N -methylacetamido 5-gluconylamino-benzoyl) ~ 1,2-diamino-ethane

CH ₃ CON

NHCO (CH 2 OH) _C H

COKHCH

NHCO (CHOH) ₅ H

br

NCOCH

a) Preparation of 2,4-tribromo-3-N-methyl-aoetaniido-5-amino-benzoic acid chloride

20 g of the corresponding acid, dissolved in 40 ml SOCl _2, are heated to 80 ⁰ C for 2 hrs.. After evaporation of the thionyl chloride, the oil is precipitated with 100 ml of isopropyl ether. The mixture is stirred for 1 h, centrifuged, washed with ethyl acetate, centrifuged again, dried, and 17 g of the compound are obtained, which corresponds to a yield of 81.5%.

b) Preparation of !!, N'-bis ^ »~ 4.6 tribromo-3 ~ N - methylacetamido" 5-amino ~ benzoyl) ₁ -I 2 _{t-diamino-ethane}

100 g of the acid chloride (0.215 mol) obtained in a), dissolved in 190 ml of DMAC, are added to 10 ml (0.15 mol) of ethylene oxide.

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diamine and 30 ml of triethylamine. After 4 days of stirring at ambient temperature, the insoluble fraction is removed by centrifuging and the filtrate is precipitated with 950 ml of water. After centrifuging, washing and drying, 85.3 g of the product are obtained, which corresponds to a yield of 44 % .

- CCM benzene / MEC / formic acid (50/20/30) acid chloride + ethanolamine Rf: 0.70 to 0.74 product obtained R f: 0.90

c) Preparation of H _t N'-bis (2 ₁ 4 "6-tribromo-N-meth ~ 3: ylacetamido" 5 ~ ~ N-pentaacetoxy Rlüconyl-amino ~ benzoyl) ~ 1 _T 2-diamino-ethane _

Dissolve 0.089 mol of the compound obtained above in 180 ml of DMAC. Then 0.445 moles of pentaacetylgluconic acid chloride are added in powder form, which dissolves accordingly. After stirring for 20 h at ambient temperature, the mixture is precipitated with 1.3 l of ice water. The stirring is continued overnight. After centrifugation, the crude product is taken up in dichloroethane. The washed with NaHCOo (5%) and then washed with water organic phase is evaporated. The oil crystallizes in petroleum ether _o

Yield: 40%

- CCM benzene / MEC / formic acid (60/25/20) Rf 0.38 (starting material Rf 0.46)

d) Cleavage of the protecting groups

The deprotection is carried out by means of sodium

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Methylate / methanol performed.

COM butanol / water / acetic acid (50/25/20) Rfs 0.34 to 0.40

Example XV

Preparation of 2y4-6-tribromobenzene-1,3-tricarboxylic acid and its derivatives

a) Herateilung of 2,4;; 6-tribromo-5-cyano-isophthalic acid

232 g (0.555 mol) of 2,4,6-tribromo-5-amino-isophthalic acid were dissolved in 500 ml of conc. Sulfuric acid and the solution is then cooled with the aid of an ice bath to a temperature between 0 and 5 ⁰ O. It is added within 1 hr. Gradually 77 g (1.11 mol) of sodium nitrite, the temperature to 0 to 5 ⁰ G. is held for at least 2 hours at this temperature. The mixture is then poured slowly onto ice while stirring and the excess sodium nitrite removed by a sufficient amount of urea solution. While maintaining a temperature of 0 to 5 ° C, the suspension is then neutralized with 5-N-soda to pH «6. The mixture is then added to a solution of 69 g (0.694 mol) of copper chloride and 89 g (1.82 mol ) Sodium cyanide in 1 liter of water and the solution stirred at ambient temperature overnight. The pH of the solution is adjusted to 3 by addition of hydrochloric acid, the copper salt precipitate is centrifuged off and the pH is brought to 1 by the further addition of hydrochloric acid. The solution is cooled using an ice bath and stirred for 16 hours. long. Then the precipitate formed is centrifuged off and taken up in 400 ml of water.

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and a quantity of soda necessary for the dissolution and for reaching a neutral pH. To decolorize the solution, it is stirred for 1 hr. With 3 SA coal, then the coal is filtered off and precipitated with dilute hydrochloric acid.

After centrifuging and washing with a little water, 130 g of the white product are obtained.

Yield: 55 %

After recrystallization in 400 ml of ethanol, 77.5 g of the purified product are obtained,

Melting point higher than 300 ⁰ C.

b) Preparation of 2 _{t of} 4i6-tribromo-5-carbamoyl-i3ophthalic acid

JONH ₂

HOOC '^ gS ^ 00OH

60 g (0.140 mol) of 2,4,6-tribromo-5-cyano-isophthalic acid are dissolved in 120 ml (0.6 mol) of 5-N-soda. The solution is then stirred for 3 hrs. At 50 ⁰ C and then added at ambient temperature 50 cm conc. Hydrochloric acid added. Cool with the help of an ice bath and stir for 2 hrs. After centrifuging off the low

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Hitting and washing with a little Eiswasaer obtained after drying 60 g of the white product.

Yield: 96%, melting point higher than 300 ⁰ G.

- CCMs benzene / MEG / formic acid (60/25/20) RF: 0,3

°) Preparation of 2 _f 4 »6-tribromobenzene-1,3t5- tricarboxylic acid

~~~ · COOH

HOOC ⁴ ^ ^ y ^ COOH Br

The 2,4,6-tribromobenzene-1,3,5-tricarboxylic acid can be prepared from 2,4,6-tribromo-5-carbamoyl-isophthalic acid by reaction with a nitrosating agent such as sodium nitrite in sulfuric acid or hydrochloric acid or as an alkyl nitrite or nitrosonium Tetrafluoroborate in an organic solvent. 52.5 g (0.123 mol) of 2,4 _J 6-tribromo-5-carbamoyl-isophthalic acid in a mixture of 700 ml of water and 700 ml of conc. Hydrochloric acid brought into suspension. Then the suspension is heated to 90 ⁰ C and gradually added within 7 Stdo a solution of 41 g (0.595 mol) of sodium nitrite in 700 ml of water. After the addition, the mixture is stirred for 1 hr. And the resulting solution is evaporated to dryness. you

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receives 90 g of residue which is taken up in 500 ml of ether with stirring for 2 hrs. Remove the insoluble itfatrium chloride by filtration. The etheris before phase is evaporated to dryness, and you get 49 g of a white powder,

Yield: 93 % $ melting point higher than 300 ° c.

- CCM: benzene / MEC / formic acid (60/25/20) Rf: 0.4

d) Preparation of 2 _> 4 »6-» tribromobenzene-1,3,5-tricarboxylic acid trichloride

A suspension of 45 g (0.1 mol) of 2,4,6-tribromobenzene-1,3,5-tricarboxylic acid in 80 ml (1.1 mol) of thionyl chloride is prepared. Then 2 ml of dimethylformamide are added and the mixture is stirred for 2 hours under reflux. The mixture is allowed to cool and a white pesticide is crystallized. It is centrifuged, washed with a little cyclohexane and after drying gives 43 g of the product in the form of white needles,

Yield: 85 %, melting point: 202 ^° C.

e) Preparation of 2 _t 4 _{»6-tribromo-1>} 3i5-tris (2 ₁ 3 ~ dihydroxypropyl-carbamoyl) benzene

25 g (0.05 mol) of 2,4,6-tribromobenzene-1,3,5-tricarboxylic acid trichloride are dissolved in 50 ml of dimethylacetamide. Then, a solution of 30 g (0.33 mol) of aminopropane-2,3-diol in 60 ml of dimethylacetamide is added little by little. Man stirs

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the reaction mixture at 50 ⁰ C for 3 hrs., After it has been adjusted by addition of hydrochloric acid to a neutral pH and then evaporated to dryness. "The residue is taken up in a minimum of water and extracted with phenol. After treatment of the phenolic phase with ethyl ether and extraction with water, the aqueous phase is evaporated in vacuo. 25 g of a white product are obtained,

Yield: 76 %

- COM: benzene / MEC / formic acid (60/25/20) Rfs 0.05

- GGM: isobutanol / isopropanol / ammonia (30/30/40)

Rf: 0.55 to 0.60

f) Preparation of 2,4,6-tribromo-i.3-5-tria- (2 _t 3,4,5,6-N-methylpentahydroxyhexylcarbamoyl) benzene

The compound is prepared in the same manner as the product (e) described above,

- GGM: benzene / MEC / formic acid (60/25/20) R f: 0,05

- CCM: laobutanol / iaopropanol / ammonia (30/30/40) R f: 0.10 and 0.15

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g) Preparation of 2- _t 4 -6-tribromo-1,3-tris (bis-hydroxyethyl-oarbamoyl) -benzene

The connection is made in the same way as under e) »

- CCM: benzene / MBC / formic acid (60/25/20) R f: 0.05

- CCM: isobutanol / isopropanol / ammonia (30/30/40) R f: 0.45

The following are the results of comparative studies carried out with the mixtures of the bromine-benzene compounds and with the iodine-benzene compounds.

1, contrast effect

The contrast effect was measured indirectly by means of an impression produced by a bundle of X-rays on a photographic film, the rays being previously passed through a cuvette containing an aqueous solution of the compounds to be investigated. The transparency of the film after development was measured by means of an optical densitometer. In each case, the measurement was performed on the same film and with the same radiation source (70 kV) as compared with a contrast agent serving as a reference.

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AIb reference compound was Hexabrix used, which is a solution of the sodium salt and the methylglucamine salt of ioxaglic acid (32 % iodine content).

The mixtures were tested in the form of the aqueous solutions of mixtures of the methylglucamine salts of the iodinated and the brominated compounds, which contained the same number of moles as was the Pall in Hexabrix. The results are given in Table I below.

Table I

Contrast agent relative contrast / Hexabrix

Ä'quitnolar mixture of methylglucamine salt

loxaglin acid and 0.905

of the brominated analogue product (Example VII)

It is found that the contrast effect of the mixture is very close to that of Hexabrix. In order to achieve the same contrast effect with the mixtures as with one mole of the only 30-diert product, only 0.55 mol of the encoded product and 0, 55 moles of the brominated product,

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2 * Acute intracranial toxicity

The acute intracisternal toxicity was measured in the mouse according to the method of E. Melartin, P. Tuohimaa, R. Dabb, Investigative Radiology, 1970, vol. 5, No. 1, 13-21. The results are listed in Table II.

Table II

Contrast agent acute toxicity IC mouse

^DL 50 ^{s E} q

Telebrix 0.2

Equimilar mixture Telebrix + brominated analog product

(Methylglucamine salt of Yer-0.35

binding of Example 1-2) 3 proteinaceous binding

The degree of interaction with proteins is an indication of the tolerance of contrast agent products. The smaller these interactions, the better "is the tolerance.

Proteinaceous binding was assayed according to the technique described by Brodersen (J. of Clinical Investigation, 1974, vol 4, 1353-1364). ^;

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The results are listed in Table III.

Table III

Contrast agent protein. binding

Mole "* ¹

Methylglucamine Ioxaglate 122

Equimolae Mixture Methylglucamine Ioxaglate + Brominated Analog Product (Methyl Glucamine Salt 102

the compound of Example VII)

Methylglucamine adipiodone 12,800

equitnolar mixture methylglucamine adipiodone + brominated analog product (methylglucamine 8 100

Salt of the compound of Example VI

The mixtures of iodinated and brominated compounds can thus be used as contrast agents for radiological purposes.

The aqueous solutions generally contain from 5 to 100 g of the mixture of iodinated and brominated compounds, and the injectable amount of these solutions may generally vary between 5 and 1000 ml.

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In addition, the brominated compounds are useful on their own in diagnostic techniques such as regiatring angiography.

Claims (3)

24 2 8 86 4 -68- n.2.1983 AP C 07 C / 242 886/4 61 360/11 Inventive claim Process for the preparation of bromine compounds, selected from 1 - Compounds of the formula Ia ^ a br (Ia) in the Q _{1 is} a group -COOH or a group -COOH, ι a which is bound with a pharmacologically acceptable base as a salt, Q _2a is a radical of the formula -GO-IT, where R _{5 is} a Is hydrogen, a lower alkyl radical, a lower hydroxyl radical or lower alkanoyl-lower oxyalkyl, and Rg represents a lower hydroxyalkyl radical or lower alkanoyl-lower oxyalkyl, Q ~ represents an amino group or a radical of the formula 2 - Compounds of the formula I ¹ el br in the Q is a group -COOH or a group -COOH which is bound with a pharmacologically acceptable base as a salt, Q 2 represents an amino group or a radical of the formula -N-COR ₉ where Rq is 10 a lower alkyl radical, a lower hydroxyalkyl radical or lower alkoxy-lower alkyl, and R 242886 4 -70- 11.2.1983 AP C 07 G / 242 886/4 61 360/11 a hydrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical, Q ¹ Oq represents an amino group or a radical of Formula -Kf-GO-R ₁₁ where R _{11 is} a 12 ⁿ is lower alkyl radical, lower hydroxyalkyl radical or lower alkoxy lower alkyl and R _{12 is} a hydrogen atom, lower alkyl radical or lower hydroxyalkyl radical, 3 - Compounds of the formula I , br "" 2a in the Q "is a group -GOOH or a group -GOOH which is bound with a pharmacologically acceptable base as salt, Q " _{2a represents} a hydrogen atom, Q" _3a represents a radical of the formula where R-. 242886 02/11/1983 AP G 07.C / 242 886/4 61 360/11 is a lower alkyl radical, a lower hydroxyalley 1-radical or lower alkanoyl-lower-oxyalkyl, and R ₁ - represents a lower alkyl radical or a lower hydroxyalkyl radical, 4 - Compounds of the formula (Ib) (Ib) in the Q ₁ . a radical of the formula -If-CO-R 15 R ' represents, where is a polyhydroxylated, lower alkyl radical and R 'is _{1 (} - a hydrogen atom or a lower alkyl means radical a radical of the formula -CO-N ⁴ and 16 represents, in the 17 a hydrogen atom, a lower alkyl 24 2 8 86 4 -π- "· * · AP G 07 C / 242 886/4 61 360/11 radical, a lower hydroxyalkyl radical or lower alkanoyl-lower-oxyalkyl, Q ^ is a radical of the formula _{iat> ln r <iq and} ^R 19 a hydrogen atom, a lower alkyl radical, a lower hydroxyalkyl radical or lower alkanoyl lower oxyalkyl or a radical of the formula -N-GO-R ₂₀ I mean in the R ₂₁ R _{20 is} a lower alkyl radical, a lower hydroxyalkyl radical or lower alkoxy-lower-altcyl and Rp _{1 is} a hydrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical, 5 - Compounds of formula Ic (Ic) in the Q _{1 represents} a radical of the formula -CONH-R ₂₂ , 242886 4 ~ ⁷³ - ¹¹ · ² · AP C 07 C / 242 886/4 61 360/11 R _{22 is} a sugar residue or a polyhydroxylated, lower alkyl radical, Q _{2 is} a radical of the formula -U-CO-R ₂₃ means in the 24th R _{23 is} a lower alkyl radical, a lower hydroxyalkyl radical or lower alkoxy lower alkyl and R _{2 /} , a hydrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical, and Qj _Λ a radical of the formula Represents -CO-N, in the ^R 26 R ₂ c and R ₂ g represent a hydrogen atom, a lower alkyl radical, a lower hydroxyalkyl radical or lower allcanoyl-lower oxyalkyl or a radical of the formula -K-CO-R ₂₇ (C ₁
mean, ^R 28 in the Rp _{7 is} a lower alkyl radical, a lower hydroxyalkyl radical or lower alkoxy-lower alkyl 242 8 86 -74- 11.2.1983 AP G 07 G / 242 886/4 61 360/11 RgQ is a hydrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical, 6 - Compounds of the formula Ha ? 3d <2d N-CO- (GH _2: Br (GHZ) _n2 H (Ha), in the Q _{1d is} a group -COOH or a group -COOH which is salt-bound with a pharmaceutically acceptable base, and Q ₀ , a hydrogen atom, a radical of formula 3d ^ ^R 29
-CO-N _f where R _2g and R ₃₀ ^R 30 is a hydrogen atom, a lower alkyl radical, a lower hydroxyalkyl radical or lower alkanoyl lower mono-oxyalkyl, an amino group or a radical of the formula -N-GO-R 31 mean, where £ 4 l ~ O 8 6 4 -75- 11.2.1983 AP C 07 C / 242 886/4 61 360/11 R 1 is a lower alkyl radical, a lower hydroxyalkyl radical or lower alkoxy lower alkyl and R _{2 is} a hydrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical, where Q _{24 may} also be a radical CHpOH, I. , a group -NH ₂ or a radical of the formula -N-CO-R. RoΛ represents, in the R " is a lower alkyl radical, a lower hydroxyalkyl radical or lower alkoxy lower alkyl and Ro _{4 represents} a hydrogen atom, a lower alkyl radical, a lower hydroxyalkyl radical or a lower alkanoyl radical, Z is H or OH, n- is equal to 1 to 5 n ₀ is equal to 0 to 6 \ 7 - Compounds of the formula Hb 1c br : -co- (CH ₂ ) _n - CONH 242886 k -76- 11.2.1983 AP C 07 G / 242 886/4 61 360/11 in the Q _{1c is} a group -COOH or a group -COOH, which is salt-bound with a pharmacologically acceptable base, Q _{2 is} a hydrogen atom, a radical of the formula -CO-N, where Ro is _C and R -, / - is a ^ io .Jb ^R 36 Hydrogen atom, a lower alkyl radical, a lower hydroxyalkyl radical, or lower alkanoyl lower-oxyalkyl, an amino group or a radical of the formula -N-OOR N-OOR ₃₇ I represents, where ^W 38 R "is a lower alkyl radical, a lower hydroxyalkyl radical or lower alkoxy lower alkyl, and R _{38 represents} a hydrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical, 8 - Compounds of the formula III 242 8 86 k 02/11/1983 AP C 07 G / 242 886/4 61 360/11 CO-CH ₂ -N CH ₂ COM ' III, in the Q is a group -COOH or a group -COOH which is a pharmacologically acceptable base as a salt is bound ^a wafer atom, a radical of the formula -CO-N where Roq and R ^ _{0 are} one 40 242 8 86 4 - ^TO - 02/11/1983 AP C 07 G / 242 886/4 61 360/11 A hydrogen atom, a lower alkyl radical, a lower hydroxyalkyl radical or lower alkanoyl-lower-oxyalkyl are an amino group or a radical of the formula -Ii-COR, represent, wherein R 1 is a lower alkyl radical, a lower hydroxyalkyl radical or lower alkoxy-lower alkyl and R.sub.o is a hydrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical, Z is H or OH and η is 0 to 6, 9 - Compounds of the formula XV (IV), CO-N- (GH ₀ V v-lM CCHZ _{1) nl} H (CHZ _{2) n2} H in the Q _{1 is} a radical of formula 'S OQQC Λ * " ⁷⁹ " ^{11 # 2φ} L 0 0 UH "AP C 07 C / 242 836/4 61 360/11 -N-GOR ₄₃ I is where ^R 43 R is a polyhydroxylated, lower alkyl radical 43
and R ¹ Λ3 ^{e: Ltl is} hydrogen atom or a lower alkyl radical, Q ₂ and Q _{3 are} independently a radical of the formula 44 4.R is a hydrogen atom, a lower alkyl radical, a lower hydroxyalkyl radical or lower alkanoyl-lower-oxyalkyl, an amino group or a radical of the formula -N-COR ₄₆ I, where R _A r R ₄₇ 46 is a lower alkyl radical, a lower hydroxyalkyl radical or lower alkoxy lower alkyl and R.rj represents a hydrogen atom, a lower alkyl radical or a lower hydroxyalkyl radical, Z ₁ and Z ₂ are H or OH, n and n ₂ are equal to 0 to 6, n-i is equal to 0 to 4, AP G 07 C / 242 886/4 242 8 86 4 10 - Compounds of the formula V br   br in the Q ₁ ,, Q ₂ ^ and Qo-u are a group - COOH, a group
-GOOH containing a pharmacologically acceptable base
iat as a salt, or a group of the formula / - ^R 48
Represent -CO-N, in the R. and R.q represent a hydrogen atom, a lower alkyl radical, a lower hydroxyalkyl radical or lower alkanoyl-lower oxyalkyl, characterized in that the compounds are prepared by one or more of the following reactions:
Bromination, alkylation, acylation, salt formation, hydrolysis, conversion of an amide into the acid and conversion of an acid into the amide by reaction in the acid chloride and subsequent reaction with an aniine. Process according to item 1 for the preparation of compounds of formula Ia, I'a and I "a, characterized in that one carries out an alkylation and / or acylation of corresponding compounds which have an amino group or a mono-substituted amino group. 242886 -81- 11.2.1983 AP G 07 C / 242 806/4 61 360/11 3. A process according to item 1 for the preparation of compounds of the formula Ib, characterized in that an acylation is carried out by means of an acid chloride of the formula Cl-CO-, the hydroxy groups of which are preferably protected, optionally followed by splitting off the protecting groups and alkylating the corresponding compounds having an amino group 4 · Process according to item 1 for the preparation of compounds of formula Ic, characterized in that one carries out the acylation of an amine of the formula NHp ~ ^R 22 ¹ ^ ^einl corresponding acid chloride, d, h »with a compound of formula CO-Cl 5 · Process according to item 1 for the preparation of compounds of the formula Ha, characterized in that the acylation of an amine of the formula Br ^ ^ * S ^ ^ Br j _2d J J-OOCOH ₂ ) _nl -NH ₂ 242886 4 -82- 11.2.1983 AP C 07 C / 242 886/4 61 360/11 with an acid chloride of the formula glGo performs · 6. The method according to item 1 for the preparation of compounds of formula Hb, characterized in that the condensation of an amine of the formula hey br with a diacid chloride of the formula Cl-00 (GHg) _n -COOl carried out _; 7. The method according to item 1 for the preparation of compounds of formula IHj characterized in that an amine of the formula 242 8 86 4 02/11/1983 AP C 07 C / 242 886/4 61 360/11 br N - COCH ₂ -IiH ₂ (CHZ) _n H with a chlorinated derivative of the formula Cl-CH ₂ COI implements. 8 "Process according to item 1 for the preparation of compounds of the formula IV, characterized in that the acylation of an amine of the formula 2 8 86 4 -69- 11.2 AP C 07 C / 242 886/4 61 360/11 -W-COR ₇ , where R "is a lower alkyl radical, lower hydroxyalkyl radical or lower alkoxy lower alkyl, and R _{g represents} hydrogen, lower alkyl radical or lower hydroxyalkyl radical; ₃
HZ ₁ ) _n1 H (CHZ ₂ ) _{n 2} H with an acid chloride of the formula Cl-CO-R LLt L · ö 8 6 4 -84- 11.2.1983 AP C 07 G / 242 886/4 61 360/11 whose hydroxy groups are preferably slit, followed, if appropriate, by cleavage of the protective groups » A process according to item 1 for the preparation of compounds of the formula V _1, characterized in that the hydrolysis of 2,4, 6-tribromo-5-cyanoisophthalamide is carried out, followed, if appropriate, after conversion of the amide into an acid chloride, the reaction with an amine the formula HNR ₄₈ R ₄ "connects",