DD238970A5 - METHOD FOR THE PRODUCTION OF IODIED TRIAMINOBENZEN COMPOUNDS - Google Patents

Abstract

The invention relates to a process for the preparation of iodinated triaminobenzene compounds of non-ionic type. The compounds obtained can be used in contrast media.

Description

(V)

and Vl

CONH,

CONH,

(VI)

obtained by a rearrangement reaction Hofmann type.

Field of application of the invention

The present invention relates to a process for the preparation of triaminobenzene compounds. The compounds according to the invention can be used in contrast media for radiography.

Characteristic of the known technical solutions

It has long been used as a contrast agent iodobenzene compounds having a plurality of iodine atoms in the benzene core, generally three iodine atoms per benzene nucleus in addition to various other substituents. These other substituents are pharmacologically acceptable groups that allow administration of the compounds in humans and animals. These

Substituents are generally selected in such a way that on the one hand they impart sufficient water solubility to the compounds with regard to their administration in aqueous solution and on the other hand that the compounds also ensure sufficient tolerance with regard to the human organism.

For this purpose, non-ionic structures have been proposed, that is, iodobenzene derivatives having non-ionic substituents.

Thus, patent FR-A-2053037 has proposed iodobenzene-carbamoyl compounds which contain in total at least one N-hydroxyalkyl group and at least two hydroxyl groups.

One compound that illustrates this class is the metrizamide, which, however, has proven to be of limited stability.

Object of the invention

The aim of the invention is to provide novel non-ionic compounds which are well tolerated by the human organism, are very stable in aqueous solution and can be conveniently obtained with low production costs.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

According to the invention, compounds of the formula I

(D

made in the

R ₁ , R'i and R "i are independently selected from a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, a polyhydroxyalkyl group having 1 to 6 carbon atoms, an alkoxy (C ₁ to C ₄ () hydroxyalkyl C ₁ DiS are C ₄₎ group and a hydroxy-alkoxy (C ₁ to C ₄₎ alkyl (C ₁ to C 4 group, and R _2, R _'2 and R' ₂ are independently selected under acyl groups of the formula

wherein R _{5 is} an alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, a polyhydroxyalkyl group having 1 to 6 carbon atoms, or an alkoxy (C ₁ to C ₄ ) alkyl (C, to ₄ ) group.

As examples of the groups Ri, R'i and R "i can be mentioned:

-H, -CH ₃ , -CH ₂ -CH ₂ -OH, -CH ₂ CHOH-CH ₂ OH, -CH ₂ -C (CH ₂ OH) ₃ , -CH ₂ -CHOH-CH ₂ OCH ₃ , -CH ₂ -CH ₂ -O-CH ₂ OH, -CH (CH ₂ OH) ₂ .

As an example of the groups R ₂ , R ' ₂ and R " ₂ can be mentioned:

-CO-CH ₃ . -CO-CH ₂ OCH _3, -CO-CHOH-CH _3, -CO-CH ₂ OH, -CO-CH ₂ -CHOH-CH ₂ OH, -CO-CHOH-CH ₂ OH, -CO-CH- ( CH ₂ OH) ₂ , gluconyl, -CO-C (CH ₂ OH) ₂ -CH ₃ .

As far as the issues of ease of synthesis of a preferred class of compounds of formula I are concerned, this is achieved by the compounds of formula Ia

(La)

E- I

formed and in particular by the symmetrical compounds of formula la '

U-R,

(La ·)

wherein R ₁ , R ' _1f R ₂ and R' _{2 have} the above given names. Another preferred class in terms of their properties is also that formed by the compounds of formula I in which at least one of the substituents of each nitrogen atom is a radical having at least one hydroxy or alkoxy group.

By and large, the compounds of formula I may be prepared by acylation with an acylating agent R ₅ -CO-Z (wherein Z is a chloride radical or a radical -O-CO-R ₅ ) of a compound chosen from the compounds of the Formula III

(III)

NR ".j R"

in which R ' _{1 #} R " _{1 (} R' ₂ and R" have the meanings given above or represent corresponding groups in which the hydroxy groups are protected, and the compounds of the formula IV

(IV)

is selected in which R ', and R' _{2 have} the meanings given above or represent corresponding groups in which the hydroxy groups are protected, wherein in each case compounds of the formula I b

HHR,

(Ib)

and the formula Ic

CLOCK,

CLOCK,

(Ic)

result.

Optionally, this reaction is followed by deprotection and / or alkylation using an alkylating agent RiZ '(wherein R _{1 is} as previously described except hydrogen and Z' is a labile group such as a halogen ), so that a compound of the formula I or Ia is obtained. The acylating agent used is an acid chloride or an acid anhydride, whereby the hydroxy groups possibly present on the group R ₂ are protected. The reaction is carried out in anhydrous medium, optionally in a polar solvent, preferably at a temperature of -10 ⁰ C to 100 ° C, depending on the type of reactants used.

As alkylating agent can be used chlorine, bromine or iodine derivatives. The alkylation reaction can be carried out in an aqueous or organic solvent, in the presence of a base such as in particular NaOH, KOH, K ₂ CO ₃ , NaH, MeONa. An optionally present polyhydroxyalkyl group R ₁ may be in the form of a precursor (oxirane or unsaturated hydrocarbon group, such as an alkyl group, which is then oxidized to the polyhydroxyalkyl group). The reaction can also be carried out by operating under the catalysis conditions of phase transfer.

These hydroxy groups can be protected in the form of the ester, acetal or ether group. In the case of protection, the protecting groups are cleaved off the hydroxy groups after the alkylation reaction.

It will be appreciated that the process of the present invention enables the use of low cost hydrophilic vectors, such as chloropropane-2,3-diol or epichlorohydrin. In addition, these vectors can be introduced in the cases of symmetrical compounds (compounds I a ') by trialkylation in the last stage of synthesis, which limits the problems associated with the purification of hydrophilic compound. The amino compounds of the formulas III and IV can each be prepared starting from the corresponding benzamides of the formulas V

COUH ₂

(V)

R ₂ R 'Π

and VI

COKH

(VI)

COHH ₂

obtained by a rearrangement reaction Hofmann type.

The preferred reactants for this reaction are the following: sodium hypobromite, sodium hypochlorite, sodium bromomethylate, lead tetraacetate. The steric bulk of the iodine atoms in the ortho and ortho position of the benzamide function limits the number of classically formed impurities in this reaction, in particular the unwanted side reactions of the halogenation of the ring and the dimerizations of the isocyanate groups, thereby allowing to obtain iodinated amines in very good yield (> 90%).

The benzamides of formulas V and VI can be obtained by classical reactions starting from the triiodinated aromatic acid chlorides, the non-iodinated benzoic or isophthalic acid esters, or the dinitrobenzoic or nitro-isophthalic acid.

In particular, the benzamides of formula V can be prepared starting from a compound of formula VII

(VII)

be obtained by alkylation, so that a compound of formula VIII is obtained:

-6- «8 D / U

COOH

(VIII)

-HR "., R"

Conversion of this compound into the acid chloride of the formula IX

COCI

KR "

Reaction of this compound in the benzamide of the formula X COHH

(12)

KR "

Acylation of this compound, so that a benzamide of the formula XI is obtained:

com

MR"

and alkylating this compound to obtain a benzamide of formula V.

The benzamides of the formula V, which have two identical substituents, namely the benzamides of the formula Va

COHH,

(Va)

can be prepared starting from a compound of formula XII

COHH,

(XII)

be obtained, by reduction to a compound of formula XIII

COUH,

(XIII)

MH,

then iodination of this compound of formula XIII to give a compound of formula XIV

CONH,

(XIV)

then acylation of this compound to obtain a compound of formula XV

com,

(XV)

HHR ¹

and optionally alkylating the compound of the formula XV to the compound of the formula Va. The benzamides of the formula VI can be prepared starting from 5-nitro-isophthalic acid by esterification to dimethyl ester, reaction of this ester to 5-aminoisophthalamide and iodination of the resulting compound, and acylation of obtained iodinated compound, so that a compound of formula XVI

CONH,

(XVI)

CONH,

is present, which is optionally subjected to the alkylation. The amino compounds of the formula IIIa

R ^f ₂ -HN "

(IIIa)

NH-R '

can be further starting from 3,5-diamino-1-nitrobenzene by acylation to give a compound of formula XVII

NO,

(XVII)

NHRV

and subsequent reduction to the corresponding amine of formula XVIII

-OE-

R ' ₂ HU

(XVIII)

YOUR ¹

and iodination of this compound.

The amino compounds of the formula IV can be prepared in the same way starting from 3,5-dinitroaniline by acylation to give a compound of the formula XIX

subsequent reduction to the diamine of formula XX

HH,

(XX)

Be obtained iodination and optionally alkylation.

The contrast agents comprise at least one compound of the formula I.

These contrast agents are used in humans and animals for radiological purposes.

The preferred pharmaceutical form of the contrast agents according to the invention consists in aqueous solutions of the compounds.

The aqueous solutions generally contain a total of 5 to 100 g of the compounds per 100 ml and the injectable amount of such solutions may generally vary between 1 and 1000 ml.

These compositions may be administered by any conventional route, as is conventional for nonionic iodinated contrast agents, and especially in the subarachnoid space and by the parenteral route (intravenous, intraarterial, etc.).

The following is an example of the compositions of the present invention.

composition

Compound of Example 3 50 g

Water for injection preparations ad 100 ml

embodiment

The following examples illustrate the preparation of the compounds of the invention.

In these examples, the compounds are characterized by thin layer chromatography performed on silica gel plates 6OF 254 Merck with the following eluents:

Eluant 1: methanol / dichloromethane (2/3)

Eluant 2: toluene / methyl ethyl ketone / formic acid (60/25/25) Eluant 3: chloroform / methanol / NH ₄ OH (6/4 / 0.1) Eluant 4: dioxane / water / NH ₄ OH (90/10/10 Eluant 5: ethyl acetate / isopropanol / NH ₄ OH (55/35/20) Eluant 6: dichloromethane / methanol (90/10) Eluant 7: dichloromethane / methanol (80/20) Eluant 8: butanol / water / acetic acid (50 / 25/11) In these examples, the ¹ H NMR spectra were recorded on a Varian apparatus at 60 MHz.

The chemical shifts expressed in ppm were measured relative to tetramethylsilane, which served as an internal reference.

example 1 Preparation of 2,4,6-triiodo-1,3,5-triacetamido-benzene (first method)

a) Preparation of methyl 3,5-dinitrobenzoate To a suspension of 214 g (1 mol) of 3,5-dinitrobenzoic acid in 930 cm ^{3 of} anhydrous methanol are added dropwise 9 ml of concentrated sulfuric acid. The reaction mixture is then maintained at a temperature of 70 ° C for 15 hours

kept, the crystallized methyl ester filtered off and then washed with a minimum of methanol (yield

Mp = 112 ⁰ C (literature 113 ° C)

CCM (Thin Layer Chromatography) Eluant 1 Rf = 0.87.

b) Preparation of 3,5-dinitrobenzamide

113 g (0.53 mol) of 3,5-dinitrobenzoic acid methyl ester are dissolved in 225 ml of chloroform to which 565 ml of ammonia (28%) are added. The biphasic system is stirred overnight at ambient temperature. The amide which precipitates from the reaction medium is filtered off and then washed with water (yield 82%) mp = 182 ⁰ C (literature 183 ° C) CCM Eluant 2 Rf = 0.6

c) Preparation of 3,5-diamino-2,4,6-triiodobenzamide

15 g (0.0284 mol) of 3,5-dinitrobenzamide and 0.1 g of palladium carbon (5% strength) are suspended in an autoclave in 125 cm ^{3 of} methanol in suspension. The suspension is hydrogenated at a pressure of 3.10 ⁵ Pa and a temperature of 70 ° C. The catalyst is separated by filtration and the resulting solution is introduced into a mixture of 125 cm ^{3 of} water and 18 cm ^{3 of} concentrated hydrochloric acid. Then 46 cm ^{3 of} iodine chloride (70% pure iodine) are added dropwise at a temperature of 60 ° C. After standing overnight at ambient temperature, the precipitate is filtered off, washed with water, with a bisulfite solution and again with water (yield 91%).

- purity of iodine: 100.4%

- melting point> 300 ° C (with decomposition)

CCM eluate tetrahydrofuran Rf = 0.92

- CCM Eluate 2 Rf = 0.48

- NMR spectrum ¹ H (DMSO-D6) 5.9, S (NH ₂ , 4H) 2 s 7.3-7.5 (2 H CONH ₂ ) disappear with D ₂ O.

d) Preparation of 3,5-di (N-acetylamino-2,4,6-triiodobenzamide

41 g (0.0775 mol) of 3,5-diamino-2,4,6-triiodobenzamide are introduced at a temperature of 80 ° C into a solution of 100 cm ^{3 of} acetic acid and 25 cm ^{3 of} acetic anhydride. Then 2.2 cm ^{3 of} concentrated sulfuric acid are added dropwise and the reaction mixture is kept at 11O ⁰ C. After 10 minutes of reaction, the suspension is cooled to ambient temperature and then taken up in 100 cm ^{3 of} water. The resulting precipitate is filtered off and then redissolved in a 2N sodium hydroxide solution. The solution is decolorized with carbon and acidified with dilute hydrochloric acid.

The 3,5-di (N-acetylamino) -2,4,6-triiodobenzamide precipitates immediately. After filtering off, the product is washed with water and dried at a temperature of 80 ^° C.

 Yield 84%.

- purity of iodine 96%

CCM eluant tetrahydrofuran Rf = 0.56

e) Preparation of 3,5-di (N-acetylamino) -2,4,6-triiodaniline

20 g (0.0326 mol) of 3,5-di (N-acetylamino) -2,4,6-triiodobenzamide are dissolved at a temperature of 0 ⁰ C in a Natriumhypobromit solution that was prepared during this operation (250cm ³ Water, 6.5 g sodium hydroxide and 1.9 cm ³ bromine).

The reaction mixture is stirred for 30 minutes at ambient temperature and then heated to a temperature of 70 ^° C. for 5 hours.

After standing overnight at ambient temperature, the precipitate formed is filtered off and then washed with water. Yield 90%

- purity of iodine 99%

CCM eluant tetrahydrofuran Rf = 0.77

- Infrared spectrum consistent.

f) Preparation of 2,4,6-triiodo-1,3,5-triacet-amido-benzene

3g (0.053 mol) of 3,5-di (N-acetylamino) -2,4,6-triiodoaniline are added at a temperature of 80 ⁰ C to a solution of 31 cm ³ of acetic acid and 10 cm ³ of acetic acid anhydride. After the dropwise addition of 2 cm ³ of concentrated sulfuric acid, the solution is a few minutes, maintained at a temperature of 105 ° C. The reaction mixture is then cooled to ambient temperature and then taken up in water. The resulting precipitate is filtered off, washed with water and dried

 Yield 97%.

- purity of iodine 98%

- Infrared spectrum and NMR spectrum coincident

- CCM Eluant 3Rf = 0.84

Example 2 Preparation of 2,4,6-triiodo-1,3,5-triacetamidobenzene

a) Preparation of methyl 5-nitro-isophthalate

1.5 mol (320 g) of 5-nitro-isophthalic acid are dissolved in 1.4 liters of methanol and 13 ml of concentrated sulfuric acid.

The reaction mixture is then refluxed for 10 hours. After progressive crystallization of the ester, the product is filtered off and then dried in a drying oven at a temperature of 70 ⁰ C.

- Fp = 123 ° C

- CCM Eluant 4 Rf = 0.9 Eluant 5 Rf = 0.9

b) Preparation of 5-nitro-isophthalamide

25 g of methyl 5-nitro-isophthalate (0.105 mol) in suspension of 250 ml of methanol and 80 ml of 10 N ammonia are heated to a temperature of 40 ° C. for 16 hours. The product obtained is centrifuged and washed with methanol. Yield 73%

- CCMEiuant4Rf = 0.8

- mp = 225 ⁰ C

c) Preparation of 2,4,6-triiodo-5-amino-isophthalamide

10 g of 5-nitroisophthalamide (0.048 mol) are suspended in 400 cm ^{3 of} water and 50 cm ^{3 of} 5N hydrochloric acid and then hydrogenated for 1 hour at ambient temperature in the presence of palladium carbon under a pressure of 3 10 ⁵ Pa. After filtering off the catalyst, the hydrogenation solution is iodinated directly by dropwise addition of 34.8 cm ³ iodine chloride (70% strength on I ₂ ) at a temperature of 70 ° C. The reaction medium is then left under stirring at the temperature of 7O ⁰ C for 48 hours. After cooling to ambient temperature, the triiodinated amine is centrifuged, washed with dilute bisulfite solution and with water and then dried in a drying oven at a temperature of 80 ⁰ C.

- Yield 85%

- CCMEIuant5Rf = 0.5 Eluant2Rf = 0.45

- purity of iodine 98%

- Infrared spectrum consistent

d) Preparation of 2,4,6-triiodo-5-acetamidoisophthalamide

16 cm ^{3 of} acetyl chloride (0.224 mol) are added dropwise to a suspension of 64 g of 2,4,6-triiodo-5-amino-isophthalamide and 120 cm ^{3 of} anhydrous dimethylacetamide.

In the course of the addition, the temperature rises to 35 ° C. After complete dissolution of the starting product, the acylated product precipitates gradually. The precipitate is centrifuged, washed with water and acetone and then dried for 16 hours in a drying oven at a temperature of 70 ⁰ C.

- Yield 89%

- purity of iodine 98.5%

- CCM Eluant 2 Rf = 0.3

Eluant CHCl3 / CH3OH (60/40) Rf = 0.65

- Infrared spectrum consistent

e) Preparation of 2,4,6-triiodo-5-acetamido-1,3-diaminobenzene

14g 2,4,6-triiodo-5-acetamido-isophthalamide (0.023 mol) are added at a temperature of 0 ⁰ C to a sodium hypobromite solution, which was prepared during this operation (addition of 2.36 cm ^{3 of} bromine to 460cm ³ l N sodium hydroxide solution).

The reaction mixture is stirred for 30 minutes at ambient temperature and then heated for 5 hours at a temperature of 70 ° C, the reaction product slowly precipitates. After cooling to ambient temperature, the product is centrifuged, washed with water and dried in a drying oven at a temperature of 70 ° C.

Yield 59.2%

A second portion of product is obtained by precipitation using hydrochloric acid.

Total yield 81%

- purity of iodine 99.7%

- Determination of acidity with sodium methylate: 100.1%

- CCM Eluant 2 Rf = 0.65

- Infrared spectrum consistent

f) Preparation of 2,4,6-triiodo-1,3,5-triacetamidobenzene

To a suspension of 7.1 g of 2,4,6-triiodo-5-acetamido-1,3-diaminobenzene in 14 cm ^{3 of} dimethylacetamide are added dropwise 3.8 cm ^{3 of} acetyl chloride.

After 16 hours reaction time at ambient temperature, the product which has precipitated from the reaction medium is washed with ether and then with water to remove the dimethylacetamide and the acetic acid formed.

- Yield 83%

- purity of iodine 97.6%

- CCM Eluant 2 Rf = 0.25 Eluant 3 Rf = 0.84

Example 3 Preparation of 2,4,6-triiodo-1,3,5-tris [N- (2,3-dihydroxypropyl) acetamido] benzene (first method)

10g2,4,6-triiodo-1,3,5-tri-acetamido-benzene (0.016 mol) were dissolved at a temperature of 40 ⁰ C in a solution of 100 cm ³ of water and 4g of sodium hydroxide (in lozenges). Then, 11 cm ^{3 of} chloro-propane-2,3-diol are added dropwise to the reaction medium. After 5 hours of reaction with stirring at a temperature of 70 ⁰ C, the suspension obtained is concentrated to dryness and then taken up in isopropyl alcohol. The precipitate separated by filtration is, after dissolution in water, purified by stepwise passage over ion exchange resins H ⁺ and OH ~ (Amberlite 77 and 78). Evaporation of the solution to dryness, after drying, allows to obtain a white product with a yield of 52%.

- purity of iodine 97%

CCM eluant 3 Rf = 0.56 and 0.38 (presence of two isomers)

- Mass Spectrometry (FAB) Bulk Pic 850 [MH ⁺ ]

NMR spectrum ¹ H (DMSO D6 + D ₂ O) 2S 1.90, 2.4 (COCH ₃ 9H)

m 3,5 (CH ₂ -CH-CH ₂ 15H)

¹³ CNMR (DMSO) (chemical shift in ppm relative to tetramethylsilane) 22.4 (CH ₃ -C); 52.66 (CH ₂ -N);

64.3 (CH ₂ -O); 69.7 (CH);

108.9-110.5-111.8 (C-I);

C-N (150.25); C = O (169.25) Example 4

Preparation of 2,4,6-triiodo-1,3,5-tris [N- (2,3-dihydroxy-propyl) acetamido] -benzene (second method with phase-transfer catalysis)

Dissolve 12g of 2,4,6-triiodo-1,3,5-triacetamidobenzen in a biphasic system composed of 400cm ³ of toluene and 72 cm ³ of water and 14 g sodium hydroxide containing (in lozenges).

Then 19,6gTetrabutylammonium hydrogen sulfate and 25 cm ³ of 2,2-dimethyl-4-bromomethyl-1,3-dioxolane is added under vigorous stirring. After 8 hours of reaction at a temperature of 80 ° C, the intermediate layer formed and the toluene are decanted, taken up in ethyl acetate and washed abundantly with water. After drying the organic phase over magnesium sulfate, evaporation to dryness and picking up in a mixture of isopropyl ether and petroleum ether to obtain 7.7 g of crystallized product.

Yield -41.5%

- purity of iodine 99%

CCM Eluant 6 Rf = 0.76-0.70-0.56

NMR spectrum ¹ H (CDCl ₃ ) d 1.1-1.4 (CH ₃ -C -CH ₃ 18H) 2S 1.9-9 (COCH ₃ 9H) Massive complex 3 to 4.8 (CH ₂ -CH-CH ₂ 15H)

This product is then deprotected by dissolution in 80 cm ^{3 of} ethanol in the presence of 5 g of resin H ⁺ Amberlite15.

After 3 days of reaction, the resin is filtered off and the solution is concentrated to dryness, after which the oily product is taken up in ether and filtered.

CCM Eluant 3 Rf = 0.56 and 0.38, 2 isomers

- Yield 75%

- purity of iodine 100.9%

Example 5 Preparation of 2,4,6-triiodo-1,3,5-tris [N- (1,3-dihydroxy-propyl) acetamido] -benzene

2g of 2,4,6-triiodo-1,3,5-triacetamido-benzene (3.2 mmol) are dissolved in 20 cm ³ of water and 3.5 cm ³ of 5N sodium hydroxide at a temperature of 60 ⁰ C. Then 1.4 cm ³ are chloropropane-1,3-diol was added dropwise and the temperature for further 6 Hour at 60 ⁰ C.

The reaction medium is partially evaporated and stored at 0 ^° C. for 4 days.

After filtration, the collected crude product is chromatographed over silanized silica (Merck 60) by stepwise elution with water and methanol.

- Yield 22%

Purity of iodine 98.8%

CMM Eluant 3, presence of 2 isomers Rf 0.55 and 0.38

Example 6 2,4,6-Triiodo-1,3,5-tris [N- (2- (2-hydroxyethoxy) -ethyl) -acetamido] -benzene

10g of 2,4,6-triiodo-1,3,5-triacetamido-benzene are added under anhydrous atmosphere to a suspension of 2.46 g sodium hydride in 200 cm ³ of dry DMAC.

After one hour of reaction, 30 g of 2- (2'-chloroethoxy) ethanol, protected in the form of the tetrahydropyranyl ether, are added dropwise. The reaction medium is retained for 12 hours at a temperature of 6O ⁰ C and then evaporated to dryness. The resulting oil is purified over a silica column (eluant CH ₂ Cl ₂ / Me0H 95/5). Rf = 0.62,0,70,0,77. The resulting oily product (19.6 g) is deprotected by catalysis over Amberlyst 15 resin in methanol. After evaporation to dryness, the product is chromatographed over silica (eluant CH ₂ Cl ₂ / MeOH 90/10).

- yield 40%

- purity of iodine 99%

- CCM eluant 6 3 isomers Rf = 0.25-0.35-0.4

NMR spectrum ¹ H (DMSO D6 + D ₂ O) 2 s, 1.8 and 2.2 (9HCOCH ₃ );

S, 3,4 (CH ₂ -O-CH ₂ , 12H); S, 3,7 (-N-CH ₂₁ -CH ₂ -0,12H)

Example 7 2,4,6-Triiodo-1,3,5-tris [N- (2-hydroxyethyl) -acetamido] -benzene

6.4 cm ³ of 2-chloroethanol were added dropwise to a solution, which is triacetamidobenzen 2,4,6-triiodo-1,3,5-composed of 10g (0.0159 mol) in 120 cm ³ of water and 20 cm ³ of 5N sodium hydroxide ,

After 24 hours reaction time at a temperature of 70 ° C, the precipitate formed is filtered off, washed with ice water and then dried overnight at a temperature of 60 ° C in a drying oven.

- Yield 60%

- purity of iodine 99%

- CCM Eluant 7 Rf = 0.49-0.52 Eluant2Rf = 0.12

NMR spectrum 1 H (DMSO D6 + D ₂ O) 2s, 1.9 and 2.4 (9HCOCH ₃ );

s, poorly resolved 3.7 (CH ₂ CH ₂ , 12 H)

Example 8

a) Preparation of 2,4,6-triiodo-3,5-bis [l \ J- (2,3-dihydroxy-propyl) -acetamido] -aniline

To a solution of 75 g of 2,4,6-triiodo-3,5-bis (acetamido) aniline in 910 cm ^{3 of} water and 300 cm ³ lON sodium hydroxide solution are added dropwise at a temperature of 70 ⁰ C 130 cm ^{3 of} chloropropane-2, Given 3-diol.

After 12 hours of reaction at a temperature of 70 ⁰ C, the reaction medium is cooled, neutralized by the addition of concentrated hydrochloric acid and then decolorized with charcoal. After evaporating the solution to dryness, taking up ethanol, filtering off the salts and concentrating to dryness, 223 g of an oil are obtained. This oil is purified by chromatography on silanized Silica Merck by elution with water and then with mixtures of water / methanol in the ratio of 9/1 to 5/5 eluted.

- yield 72%

-CCM Eluant 7 2 isomers Rf = 0.45 and 0.51

- purity of iodine 102.2%

b) Preparation of 2,4,6-triiodo-1- (methoxyacetamido) -3,5-bis [N- (2,3-dihydroxypropyl) -acetamido] -benzene

60 cm ^{3 of} methoxyacetyl chloride are added dropwise under anhydrous atmosphere to a solution of 40 g of the product described under a) in 350 cm ^{3 of} anhydrous DMAC. The reaction mixture is kept at a temperature of 60 ° C for 3 hours and then concentrated to dryness. The residue is taken up in dichloromethane, the organic phase is washed several times with water, then evaporated to dryness and finally the resulting oil is dissolved in 500 cm ^{3 of} methanol and 50 cm ^{3 of} 5N sodium hydroxide solution. The solution is then allowed to stand overnight at ambient temperature and then evaporated to dryness. The product obtained is purified by chromatography on silanized silica (Eluant H ₂ O) and ion exchange (demineralization) over H ⁺ and OH ~ resins.

- Yield 55%

- Acid determination with sodium methylate 105%

Purity of iodine 99.2%

- CCM Eluant 7 2.Isomer Rf = 0.59 and 0.42

- NMR spectrum ¹ H + D ₂ O 2s 1,75,2,3 (COCH _3, 9H);

m 3.2 to 3.6 (CH ₂ -CH-CH ₂ , 10H); S 3,5 (OCH ₃ , 3H); S 4 (CH ₂ -OCH ₃ , 2H)

Example 9 Preparation of 2,4,6-triiodo-1- (2-hydroxypropionyl-amino) -3,5-bis- [N- (2,3-dihydroxy-propyl) -acetamido] -benzene

100 g of O-acetyl-lactonic acid chloride are slowly added to a solution of 45 g of 2,4,6-triiodo-3,5-bis [N- (2,3-dihydroxy-propyl) -acetamido] -aniline in 400 cm ^{3 of} anhydrous Given DMAC. After 16 hours of reaction at a temperature of 50 ⁰ C, the solution is concentrated to dryness and then taken up in dichloromethane. The organic phase is washed three times with aqueous bicarbonate solution, dried over magnesium sulfate, decolorized with charcoal and concentrated to dryness.

The oily residue is taken up in 500 cm ^{3 of} methanol and 60 cm ^{3 of} 5N sodium hydroxide solution and left at ambient temperature for 12 hours.

Evaporation of this solution to dryness makes it possible to obtain an oil which is purified by chromatography on silica (gradient CH ₂ Cl ₂ / MeOH 8/2) and demineralized with H ⁺ and OH ~ resins.

- Yield 21%

- purity of iodine 100.2%

- CCM Eluant 7 2 isomers Rf = 0.31 and 0.20

NMR spectrum 1 H (DMSO D6 + D ₂ O)

d 1.4 (CH ₃ -C, 3H); 2s, 1.75, 2, 2 (COCH ₃ , 9H); m 3.3 (CH ₂ -CH-CH ₂ , 11H)

Example 10 Preparation of 2,4,6-triiodo-1,3,5-tris (methoxy-acetamido) -benzene

a) Preparation of 1-nitro-3,5-bis [methoxyacetamido] -benzene

A solution of 0.468 mol of methoxyacetyl chloride in 110 cm ^{3 of} anhydrous DMAC is added dropwise at a temperature of 0 ° C to a solution of 30 g (0.195 mol) of 3,5-diaminonitrobenzene (GH DENNY et al., J. Med. 1976, 19, [ 3] 426) dissolved in 80 cm ^{3 of} anhydrous DMAC and 35 cm ^{3 of} pyridine.

The reaction medium is kept at ambient temperature for 2 hours and then filtered. The precipitate is washed with water and then with ethanol. After drying at 40 ° C under vacuum to obtain 55 g of product.

- yield 95%

- CCMEIuant2Rf = 0.47

b) Preparation of 2,4,6-triiodo-3,5-bis [methoxy-acetamido] -aniline

20 g of the compound obtained under a) are reduced at a temperature of 80 ° C in 100 cm ^{3 of} acetic acid in the presence of palladium-carbon under a hydrogen pressure of 6 10 ⁵ Pa. After filtering off the catalyst, the acetic acid solution is diluted with 500 cm ^{3 of} water, to which 18 cm ^{3 of} concentrated hydrochloric acid and then 39.5 cm ³ iodine chloride (70% pure). The precipitate is centrifuged after 5 hours of reaction, washed with bisulfite-water and then dried in a drying oven under vacuum for 16 hours at a temperature of 70 ⁰ C.

- yield 80%

- CCMEIuant2Rf = 0.5 Eluant8Rf = 0.7

- purities iodine98.8%

c) Preparation of 2,4,6-triiodo-1,3,5-tris [methoxyacetamido] -benzene

0.054 mol methoxyacetyl chloride in solution of 100 cm ³ of dry DMAC are slowly added to a solution of 23g (0.036 mol) of 2,4,6-triiodo-3,5-bis- [methoxyacetamido] -aniline dissolved in 125 cm ³ of anhydrous DMAC added. The reaction time is 1 hour at a temperature of 0 ° C .; then the solution is treated by adding ice water. After centrifugation, washing with water and drying under vacuum in a drying oven at a temperature of 40 ° C, the product is collected.

- Yield 70%

- CCMEIuant2Rf = 0.35 Eluant8Rf = 0.70

Purity of iodine 98.8%

NMR spectrum 1 H (DMSO D6) S 3.5 (OCH ₃ , 9H)

S 4.05 (COCH ₂ -0.6H)

3S 8,45,9,3,10 (NHCO, 3H)

Disappear with D ₂ O

Example 11 Preparation of 2,4,6-triiodo-1,3,5-tris [N- (2,3-dihydroxy-propyl) methoxy-acetamido] -benzene

2 g (2.810 " ³ mol) of 2,4,6-triiodo-1,3,5-tris (methoxyamido) -benzene are dissolved in 24 cm ^{3 of} water and 1 g of sodium hydroxide at a temperature of 70 ° C. Then 0.01 mol chloropropane-2,3-diol was added slowly and the reaction maintained at a temperature of 7O ⁰ C 2V2 hours. the reaction medium is evaporated to dryness and then taken up in absolute ethanol. Then, the mineral salts are removed by filtration. After evaporation of the solution to dryness, the product is purified by chromatography on silanized silica (eluant: water / methanol).

- Yield 55%

- CCM Eluant 2 Rf = 0.67

Eluant 6 2 isomers Rf = 0.20 and 0.47

- purities iodine99%

Example 12 Preparation of 2,4,6-triiodo-1,3 _/ 5-tris [N- (2-hydroxy-ethyl) -methoxy-acetamido) -benzene

2g (2.810 ~ ³ mol) of 2,4,6-triiodo-1,3,5-tris [methoxy-acetamido] -benzene are dissolved in 24cm ³ of water and 1 g of sodium hydroxide. Then, 0.01 mol of 2-chloro-ethanol are added dropwise. After 2 hours heating to a temperature of 70 ⁰ C, the formation of a gum is determined, which is filtered and then taken up in absolute ethanol to remove the mineral salts. The product is then purified over silanized silica (eluant: water / methanol).

- Yield 50%

- purity of iodine 99.6%

CCm eluant 2 2 isomers Rf = 0.18, 0.25 eluant 6 4 isomers Rf = 0.25-0.27

0.36 to 0.40

NMR spectrum 1 H (DMSO D6) S 3.3 (OCH ₃ , 9H)

m 3.5 to 3.9

(-C-CH ₂ -O, CH ₂ -CH ₂ 18 H).

Example 13 Preparation of 2,4,6-triiodo-1-methoxyacetamido-3,5-bis (2-hydroxypropionamido) -benzene

a) Preparation of 1-nitro-3,5-bis- (2-acetoxy-propionamido) -benzene

A solution of 0.23 molo-acetyl-L-Lactonsäurechloridin 100 ml of anhydrous DMAC is added dropwise at a temperature of 0 ⁰ C to a solution containing 15.3 g (0.1 mol) of 3,5-Diaminonitrobenzen dissolved in 50 ml of DMAC and 30 ml of triethylamine. The temperature is held at about 10 ° C for four hours before allowing it to rise to ambient temperature. The triethylamine hydrochloride is filtered off and the solution poured into water. After centrifugation, the product is recrystallized in a mixture of ethyl acetate / petroleum ether (4/1), with an overall yield of 60%.

- CCM Eluant 2 Rf = 0.60

NMR (CDCl ₃ ) 1.5-1.6 (d 6H); 2.2 (S 6H); 5.1 (q 2H); 8.1 (m 2H;) 9 (m 1 H)

b) Preparation of 2,4,6-triiodo-3,5-bis (2-acetoxy-propionyl-amino) -aniline

7.69 reduced at ambient temperature in Anwesentheitvon palladium-carbon and under a pressure of 4 10 ⁵ Pa for 5 hours (2 × 10 ^-2 mol) of 1-nitro-3,5-bis (2-acetoxy-propionamido) -benzenwerdenin75ml methanol. After filtering off the catalyst, the reduction solution is diluted with 250 ml of water, acidified with 3 ml of hydrochloric acid and then heated to a temperature of 65 ° C. The iodination is carried out by adding 12 ml of a 70% iodine chloride solution. The iodinated derivative precipitates. After centrifuging and clarifying with water, 3 g of the compound are obtained.

- Yield 20%

- CCM element 2 Rf = 0.65

- determination of iodine purity 99.5%

NMR (DMSO) 1.4-1.5 (d 6H); 2.05 (S 6H); 4 (massively wide 2H); 5.2 (q 2H); 10 (m 2H).

c) Preparation of 2,4,6-triiodo-1- (methoxyacetylamino) -3,5-bis (2-acetoxy-propionamido) -benzene

To a solution of 0.005 mol methoxyacetyl chloride in 5 ml of a mixture of DMAC / dioxane (3/2) is added at a temperature of 2 to 5 ° C, 2.2 g (0.003 mol) of 2,4,6-triiodo-3,5 -bis- (2-acetoxy-propionamido) aniline.

After stirring at ambient temperature for 24 hours, the solution is evaporated and the oil is crystallized in ethyl ether and acetone.

- Yield 33%

- determination of iodine purity 99.5%

CCM (TH F 8O / CHCl 3 O) Rf = 0.85

NMR (DMSO + CDCl ₃ ) 1.6 (d, 6H); 2.2 (S 6H); 3.6 (s 3H); 4.1 (s 2H); 5.4 (m 2H);

9.3-9.8 (m 3H).

d) Preparation of 2,4,6-triiodo-1-methoxyacetamido-3,5-bis (2-hydroxy-propionamido) -benzene

19g 2 _/ 4,6-triiodo-1- (methoxyacetamido) -3,5-bis (2-acetoxy-prppionamido) -benzene are dissolved in 125 ml of methanol in the presence of 10 ml of 1N sodium hydroxide solution. After 3 hours at ambient temperature, the reaction is complete. The solution is filtered, evaporated and the product crystallized in dioxane after demineralization using ion exchange resins.

Yield 25%

- CCMEIuant2Rf = 0.30

- determination of iodine purity 96%

NMR 1 H (DMSO) 1.4-1.5 (d 6H);

3.5 (s, 3H); 4.1 (m, 4H); 5.5 (m, 2H); 9.7-10 (m, 3H)

Example 14 Preparation of 2,4,6-triiodo-1- (2-hydroxy-propionamido) -3,5-bis (methoxy-acetamide &) - benzene

a) Preparation of 2,4,6-triiodo-1- (2-acetoxy-propionamido) -3,5-bis (methoxy-acetamido) -benzene

A freshly prepared solution of 0.03 mol of O-acetyl-L-lactonic acid chloride in 10 cm ^{3 of} DMAC is added dropwise at a temperature of 0 ° C to a solution containing 6.5 g (0.01 mol) of 2,4, 6-Triiodo-3,5-bis- (methoxy-acetamido) -aniline dissolved in 10cm ³ DMAC. During the addition, a heat development is observed, followed by stirring for 12 hours and allowed to cool again to ambient temperature. After dilution of the reaction medium by adding one volume of acetone and three volumes of ether, the product crystallizes.

Yield 71% (5g)

- Determination of the iodine purity 95%

CCm eluant: tetrahydrofuran / CHClA (80/20) Rf = 0.70

NMR (DMSO) 1.5-1.6 (d, 3H); 2.2 (S, 3H);

3.5 (s, 6H); 4.1 (s, 4H); 5.3 (m 1 H); 10.1-10.3 (m, 3H).

b) Preparation of 2,4,6-triiodo-1- (2-hydroxy-propionamido) -3,5-bis (methoxy-acetamido) -benzene

5.5 g of 2,4,6-triiodo-1- (2-acetoxy-propionamido) -3,5-bis (methoxy-acetamido) -benzene are dissolved in the presence of 0.5 g of potassiumcarboantine 25 ml of methanol. After stirring for 3 hours at ambient temperature, the reaction medium is filtered and the filtrate is evaporated. The resulting oil is then crystallized in dioxane.

- Yield 29%

CCM (Eluant 2) Rf = 0.35

NMR (DMSO) 1.4-1.5 (d, 3H); 3.5 (s, 6H); 4 (m, 5H);

5.6 (m, 1H); 9.9 (m, 3H).

Example 15 Preparation of 2,4,6-triiodo-1-acetamido-3,5- [N- (2,3-dihydroxypropyl) -acetamido] -benzene

4.5 g of 2,4,6-triiodo-3,5-bis- [N- (2,3-dihydroxy-propyl) acetamido] aniline are at to a solution of acetic anhydride 5,85cm ³ and 50cm ³ of anhydrous acetic acid given a temperature of 8O ⁰ C. The reaction is catalyzed by addition of 0.5 cm ^{3 of} concentrated sulfuric acid; then the mixture is kept for another 2 1/2 hours at a temperature of 80 ° C. The reaction mixture is then cooled, hydrolyzed with 20 cm ^{3 of} water and then concentrated to dryness.

The ester formed is saponified directly by adding 40 cm ^{3 of} methanol and 5 cm ^{3 of} 1N sodium hydroxide solution. After concentration to dryness, the product is taken up in water and purified by chromatography on silanized silica (Eluant H ₂ O).

- Yield 67%

- CCM Eluant 7 Rf = 0.32

NMR ¹ H (DMSO D ₆ ) 3 s, 1.8-2.1-2.2 (9H, COCH ₃ );

m, 3.4-3.9 (1 OH, CH ₂ -CH); s 4.5 (4H, OH); s, 10.1 (1H, NH).

Disappear with D ₂ O

The η compounds according to the invention prove to be stable in the sterilization, such as the compounds obtained in Examples 3,8 and 9, which showed no changes during a treatment time of 10 minutes at a temperature of 121 ⁰ C.

In the following, test results are presented which illustrate the advantages of the compounds according to the invention.

1. Neurotoxicity

The acute toxicity of the compounds was determined on female mice (weight 20 g) of strain SWISS OFi by intracerebral administration in accordance with the method described by HOLEY and McCORMICK in BRIT. J. PHARMACOL. 12,2,1957 described technique.

There are five animals per determination used, the administered volume is 0.05 cm ³ -0,07cm ³ -0,10cm ³ per mouse, which are 2.5-3.5 and 5cm ³ per kg, at a slow rate of injection

Toxicity (DL ₅₀ ) is determined 7 days after administration.

2. osmolality

The osmolality expressed in mosmols per kg is determined by cryoscopy using a FISKE-OS type osmometer. The results are listed in the following table, where the solubility of the compounds was also reported.

Compounds Solubility in DL ₅₀ IC in osmolality

Examples mol / liter mmol per kg of mosmolprokg

3 1 4 630

8 0.94 3.3

9 1 3.5 690

Claims (2)

Invention claim: 1. A process for the preparation of a compound of the formula I. (D in the R ₁ , R ', and R "are independently selected from a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, a polyhydroxyalkyl group having 1 to 6 carbon atoms, an alkoxy (Ci to C ₄ ) - hydroxy-alkyl (C ₁ to C ₄₎ alkoxy -Gruppeund a hydroxy (C ₁ to C ₄₎ alkyl (C ₁ to C ₄₎ group; R ₂ , R ' ₂ and R "2 are independently selected from acyl groups of the formula , - 0 - Riding S wherein R _{5 is} an alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, a polyhydroxyalkyl group having 1 to 6 carbon atoms or an alkoxy (C _{1 to} C ₄ ) alkyl (C ₁ to C ₄ ) group is characterized in that the acylation is carried out with an acylating agent R ₅ -CO-Z (Z is a chloride radical or a ReSt-O-CO-R ₅ ) of a compound which is among the compounds of the formula III (III) R ' ₂ R'.N in which R ' _{1 (} R " _{1 (} R' ₂ and R" _{2 have} the meanings given above or represent corresponding groups in which the hydroxy groups are protected, and the compounds of the formula IV (IV) is selected in which R'-i and R ' _{2 have} the meanings given above or represent corresponding groups in which the hydroxy groups are protected, wherein in each case compounds of the formula I b and the formula IC HHR, NHR, NHR, (I (Ic) and, optionally, cleavage of the protective groups and / or alkylation with the aid of an alkylating agent R ₁ Z '(in which R 1 has the abovementioned meaning with the exception of hydrogen and Z' is a labile group) follow this reaction. 2. The method according to item 1, characterized in that the compounds of the formulas III and IV, starting from the corresponding benzamides of the formulas V CONH,