SI7511368A8 - Process for obtaining 2,4,6-nitriiodo-5-(2,4,6-triiodo-5-amino-benzoyl)-amino-alkyl- carbonyl-amino-benzoic acids - Google Patents

Description

This step relates to the age of 2,4,6-triiodo-5- (2,4,6-tri iodo-5-amino-benzoyl) amino-alkyl-carbonyl-amino-benzoic acid of formula o ^{(1T )} coou

. j

C ° ri> tNH-CO (CHj) _n M <

YU 39658 and their pharmaceutically acceptable salts, in which the radicals have the meanings indicated in the description, used as contrast agents in radiography, characterized by reacting an amine of formula '

CO '\ x-XH-CO (CH) NH and in which R ,, R ₄ , ^R 2 ^{,, n} and' ⁿ 2 ' ^{a 1 b} have the meanings indicated above, with an acid chloride of the formula

^R 15 'is 16 u kojoj R _{2 <R} and R Eligible mentioned meanings, and the reasons why the reaction copies in polarnom solvent, at a temperature of from 20 to 60 ° C iu presence acceptor acid, and table acid of formula II with a pharmaceutically prihvatljivom bazom things pharmaceutically an acceptable are.

The invention relates to a compound of the formula

The subject matter of the invention is in the field of acyclic and carbocyclic compounds, in particular carboxylic acid amides in which the substituents are hydrocarbon or substituted hydrocarbon groups.

According to the International Patent Classification (IPC), the subject matter of the invention is classified, respectively classified and designated by the classification symbol C 07C 103/76 defining carboxylic acid amides in which hydrocarbon substituents or substituted hydrocarbon groups are substituted. A secondary classification symbol of the subject matter of the invention is A 61K 29/02 defining products for radiography, and in particular radiological contrast agents.

Technical problem

The technical problem to be solved by this application is the following: how to obtain compounds containing at least two ions of benzene kernels and only one carboxyl group, which are very little toxic, have good contrast and can be prepared by industrial processes and that according to tornadoes, are they relatively cheap?

The state of the art

U.S. Patent No. 2,708,678 describes

COOH

UH - NH ₂ . ^J. .

containing two triiodic benzene nuclei and one carboxyl group. However, all attempts to obtain this compound according to the process described in said patent have been unsuccessful regardless of the conditions under which it was operated. Takodje and compounds obtained by postupcima described in američkom panteritnom U.S. Pat 7,145,197 (jotalamična acid) francuskom Patent file F 6777 (joksitalamična acid) and američkira patetnim specification US 3,290,366 (jokarmična acid, US ^1,076,024 {diatrizoična acid) and US 2 776 241 (iodipamide) did not provide satisfactory results and benefits.

Description of technical problem management

The object of the invention is to provide a process for the preparation of 2,4,6-triiodo-5- (2,4,6-triiodo-5-amino-benzoyl) amino-alkyl-carbonyl-amino-benzoic acid of the formula

COOH '(C «2 ^ - ^C C (CH ₂ ) w ·

COF-S NH-Co (CH,) Nfl '2 * τνJ (II) h

N in which R ₁ represents a hydrogen atom, a radical of the formula -CD-NH-R 2 where hydrogen, methyl iii

- a C ₂ hydroxyalkyl group, or a radical of formula / ^R 7

N, where R 1 and R _{g are} independently hydrogen, acet ^R 8 or methyl, R 1 represents hydrogen, a radical of the formula -CO-NH-R _g where R _{g is} hydrogen, methyl or -CH ₂ CH ₂ OCOCH.j a group, iii a radical of the formula ' ^R 11 where R is hydrogen or an acetyl group, a

R _{q 2} is hydrogen or a methyl group, R is a radical of formula -CONHR ^ in which R * is a methyl group iii x ^R ii is a radical of formula -N where io r, acetyl, R 'xj ii' 12 ^R i?

methyl group, R is hydrogen * or methyl group, R is hydrogen or acetyl group, R is hydrogen atom, methyl or acetyl group, and is 0 or 1, n is an integer from 1 to 5, n ₂ is 0 or 1 , b is 0 or 1, and salts thereof with pharmaceutically acceptable bases, characterized in that the amine of formula \ X'1 [—v H. >

C0th.

, ...

> ·,> Jf 1

- ^ 'aii-coCcK ..) and Zn ...

wherein R ₁ , r ^R 4 ' ⁿ and' ⁿ 2 ' ^a and b have the foregoing meanings, reacts with an acid chloride of the condensation formula of which the formula

Cl-COA (Va) ^R l ·

COOH

I

- (CH ^ BH-CO (CH ₂ ) _n jf ⁼ ΊοΊ (Vin)

J.

Wherein R, R and ^R and 6 ^have the meanings given ⁱⁿ P and ^R in which the reaction is carried out in polar solvent at a temperature of from 20 to 60 C and in the presence of an acid acceptor, and which produces an acid of formula II with a pharmaceutically acceptable base a pharmaceutically acceptable salt.

For the salts of acids of formula II, particular reference may be made to alkali metal salts such as sodium and potassium, ammonium salts, alkaline earth metals such as calcium, and organic base salts such as ethanolamine or methylglucamine.

According to the invention, the compounds of formula II are prepared by the reaction of an amine of formula IVa in which R ₁ , R ₁ , n, n and b have the meanings indicated previously with an acid chlorine of formula Va in which R ₁ , R ₁ and R have the meanings given above.

The G V a reaction may optionally be followed by the reaction of N-alkylation, N-hydroxyalkylation, N-acylation or N-polyhydroxyacylation, deacetylation as well as esterification or village reactions according to conventional methods.

in which ain has the above meanings, and R ₁ 'has the same meaning as R ^, iii, in the case where R ^ carries one hydroxy group, R ₁ ' represents its acylation product with an acid chloride of formula VII.

The condensation of an amine of formula iv with an acid chloride of formula VII is carried out, preferably, in such a polar solvent as dimethylacetamide or dimethylformamide, at a temperature of 20 ° C of 100 C, wherein the acid chloride is used in excess. The duration of the reaction can vary from 2 hours to 4 days.

Hydrazinolysis of the products of formula VIII is carried out in the usual manner, by the action of hydrazine in an aqueous medium (see Journal of the American Chemical Society, 71 1856 (1949); H.R. Ing and R.F. Manske Journal of the Chemical Society, 2348 (1926);

Chemische Berichte, 83 244 (1950). A large excess of hydrazine is conveniently used (4 to 8 moles per mole of the product of formula VIII).

Amines of formula IV wherein N = 1, a = 0 and aR is a lower alkyl radical can also be prepared by reacting a compound of formula

Amines of the formula

COOH

J J

To and

1 ^ - ^ (CH ₂ ) _a -H-C0 (CH ₂ ) -SH ₂

J 'J r // ^ Ahh-co CH ₂ Cl (n) (IV) with an alkylating agent of the compound of the formula to obtain when j has A = O, n = 1, R ^ = H, and R _] = H, -CONHCH _q, and -NHCOCH _{q are} described in U.S. Patent No. '210 4) 2.

The amines of formula IV in which R1 is hydrogen can be obtained by condensation of an amine of formula

COOH

with the acid chloride of the formula

ClCO <CH ₂ ) _n l <^ _o ^ C?) _(Yll) wherein R ₁ , ain have the meanings given above and then hydro-zir.clizom obtained.cg of the product

in which R _{4 is a} lower alkyl radical, after which the compound thus obtained is treated with ammonia.

The condensation of compounds IVa and Va is carried out in such a polar solvent as dimethylacetamide or dimethyl sulfoxide at a temperature of 20 ° C to 60 ° C and in the presence of excess acid acceptors such as triethylamine or sodium carbonate. The duration of the reactions may vary from 2 hours to approximately 4 days.

In order to obtain a compound of formula II wherein R1 is alkyl or hydroxyalkyl, a compound of formula II wherein R4 is hydrogen is reacted in a conventional manner with an alkylating agent or hydroxyalkyl.

In order to obtain the compound of formula II in which

R is a lower alkanoyl radical or a polyhydroxy lower alkanoyl radical, a compound of formula II, in which c1- R1c ^are hydrogen atoms. reacts with acylating agent or polyhydroxyacylation. Conversely, compounds of formula II in which R1, R8, and R are hydrogen atoms can be obtained by saponification, or deacylation of compounds of formula II whose nitrogen is acylated. A compound of formula II in which b = 2 can be obtained when a compound of formula II is used as the amine of formula VI wherein R ₁ and R 4 are hydrogen atoms.

The following examples illustrate methods of carrying out the invention.

Sections A, B and C show the corresponding amine preparations of formula IV, derivatives of formula V and compounds of formula II.

In these examples, purity controls were performed as follows:

1. Thin layer chromatography (HTS), on fluorescent silica gel plates (Merk F 254 quality) in the following elements:

- benzene / methyl-ethyl-ketone / formic acid (60:25:20) eluent 1,

- ethyl acetate / isopropanol / ammonia (55:35:40) eluent 2,

- ethyl acetate / isopropanol / ammonia (35:35:40) eluent 3,

- n-butanol / acetic acid / water (50:11:25) eluent 4.

Note: Some HTS eluents, in particular eluent 4, allow the observation of various acid isomers containing N-methyl-N-acyl-amino benzoic acid function.

Such a pure compound of formula II which is mono-N-methylated can give 2 spots (poorly separated, but at the same time differ well in amounts that are different depending on acid), while di-N-methylated compound gives 3 spots.

2. Determining the purity of the business:

- addition of halogens,

- the addition of carboxylic acid to the aid of sodium hydroxide by recirculation,

- the addition of mobile hydrogen and carboxylic acid, with the aid of sodium methylate, in the said environment and in the presence of an azole color,

- adding a solution of carboxylic acid in dimethylformamide, tetrabutylammonium hydroxide dissolved in isopropanol,

- the addition of aliphatic amines to the aid of perchloric acid in acetic acid.

A. Preparation of an Amine of Formula XV

Example I

Preparation of triiodo-2,4,6-N-hydroxyethyl-carbamoyl-3-aminoacetyl-amino-5-benzoic acid (Compound I)

a) Preparation of triiodo-2,4,6-N-phthalimido-acetoxyethyl-carbamoyl-3-phthalimidoacetylamino-5-benzoic acid

COOE

/.+ ^{0 J} To></ | t 'i «CH-COOCH.CHjiraCO / KHCOCHjS Q

Dissolve 180 g (0.3 mol) of triiodo-2,4,6-N-hydroxyethyl-carbamoyl-3-amino-5-benzoic acid in 300 ml of dimethylacetamide. 170 g (Ο, Ι′β mole) of phthaliglycine chloride were added in portions with cooling in an ice bath. After stirring at room temperature overnight, dilute with 1000 ml of water and create a precipitate. After straining, washing with water, straining and drying in a furnace, 275 g of white product are obtained, which gives a 95% yield.

Cleanliness control:

Rf of starting acid triad 0.4

Rf of starting phthalylglycine 0.77

Rf of the condensation product 0.68

b) Preparation of triiodo-2,4,6-N-hydroxyethyl-carbamoyl-3-amino-acetamino-5-benzoic acid

J

HOCH ₂ CH ₂ NhCO

COOH <J (COCHgC ^

J

It condenses 19 ^ g (0.20 mol) of the previous product in 600 m of water and 60 g of hydrazinhydrate (1.20 m) and is heated to 80 C with stirring for 2 hours, dissolving. Crystallization occurs during the reaction. After cooling, straining, rinsing and drying in the oven, 125 g of product is isolated, yielding a 95% yield.

Cleanliness control:

1. HTS eluent 1

Starting Product Rf 0.68 Product Starting Rf 0.05

When challenged with ninhydrin, a yellow-orange stain appears.

2. Product purity after iodine addition: 97,7% Product purity after sodium hydroxide addition: 100%

Example II

Preparation of triiodo-2,4,6-N-methylcarbamoyl-3-gamma-amino-butyryl-amino-5-benzoic acid (compound II)

The procedure is the same as for Compound I, except that triodo-2,4,6-N-methyl-carbaraoyl-3-amino-5-benzoic acid is used as the starting product containing iodine and acid chloride-gamma- phthalimid-butyric acids.

Example III

Preparation of triiodo-2,4,6-N-methyl-carbamoyl-3-amino-acetylamino-5-benzoic acid (compound III)

The procedure is the same as for compound I, except that triodo-2,4,6-N-methyl-carbamyl- ^O- amino-5-benzoic acid was used as the starting product.

In addition, another purification of the raw product is performed. It is regenerated using ethanol at 95 C (about 3000 g / 5 liters). After refluxing, it is filtered warm. The total yield from condensation ⁰ and purification is 62.5%.

Example IV

Preparation of triiodo-2,4,6-acetamido-3-amino-acetamido-methyl-5-benzoic acid

The procedure is the same as for Compound I, except that the starting material is triiodo-2,4,6-acetamido- ^q -aminomethyl-5-benzoic acid, which is obtained under the following conditions:

dissolve 111 g (0.177 mol) of triiodo-2,4,6-acetamido-3-acetamidomethyl 1-5-benzoic acid (according to Swiss Patent File CH 1 + .788 / 62) in 220 ml of ION sodium hydroxide and hold for 2 hours at 70 ° C. After cooling to 0 C, adjust to pH 7 with concentrated hydrochloric acid. Allow to crystallize overnight in the refrigerator. After straining, rinsing with water, straining and drying in the oven, 100 g of product are obtained, yielding 96%.

Cleanliness control:

1. HTS eluent 2

Rf of starting product 0,30 Rf of starting product 0,25

2. Purity of product after iodine addition 99.5% Condensation of 2,4,6-triiodo-acetamido-3-aminomethyl-5-benzoic acid and phthalylglycine chloride. Dissolve 100 g (0.17 mol) of triiodic acid in 200 ml of dimethylacetamide and add 55 g of phthalylglycine chloride (0.25 mol). The solution was allowed to react at room temperature overnight. After 24 hours, another 20 g of phthalylglycine chloride was added, and after 24 hours a third time, 45 g of phthalylglycine chloride was added.

the product is precipitated, washed, strained, dried, and then hydrazinolized as in compound I.

Example V

Preparation of triiodo-2,4,6-eta-arainocapylamino-3-benzoic acid (compound V)

The procedure is the same as for compound 1 except that triodo-2,4,6-amino-l'-benzoic acid and chloride-eta-phthalylidocaproic acid are used as starting products.

Example VI

Preparation of triiodo-2,4,6-amino-acetamido-3-benzoic acid (compound VI)

The procedure is the same as for Compound I, except that triodo-2,4,6-amino-3-benzoic acid is used as the starting product containing iodine.

Example VII

Preparation of triiodo-2,4,6-acetamido-3-aminoacetamido-5-benzoic acid (compound VII)

The procedure is the same as for Compound I, except that triodo-2,4,6-acetamido-3-amino-5-benzoic acid is used as the starting product containing iodine

Example VIII

Preparation of triiodo-2,4,6-N-methyl-carbamiol-3-N-methyl-N-aminoacetylamino-5-benzoic acid (Compound VIII)

a) Triiodo-2,4 is-N-methyl-carbamoyl - N - N-methyl-chloroacetamido-5-benzoic acid:

.380 ml of dimethylsulfate is added dropwise at a temperature of between 5 C and 10 C to a solution of 1300 g (2 mol) of triiodo-2,4,6-N-methyl-carbamyl-3-chloroacetamido-5-benzoic acid. (according to U.S. Patent No. 3,210,412) in a solution of 2N sodium carbonate (3 liters). When the addition is complete, allow to cool to room temperature and continue stirring for 20 hours. It is filtered to remove insoluble matter and then acidified to pH 1 with concentrated hydrochloric acid. The precipitate was filtered, washed several times with water and dried at 60 C. Purification was performed by dissolving the product in 900 ml of 2N sodium carbonate and extracting with the aid of 1000 g of sodium sulfate. After stirring for 24 hours at room temperature, the precipitate was filtered off and then redissolved in 2500 ml of water. It is filtered, then acidified to pH 1 with concentrated hydrochloric acid. After washing with water, straining, drying at 60 C, 672 g (51% yield) of the product is obtained.

Cleanliness control:

1. HTS eluent 2

Starting Product Rf 0.1

Rf of methylated product 0.2 and 0.25 (2 isomers)

2. Purity: 97% addition of iodine

Purity: addition of chlorine 104%

b) Triiodo-2,4,6-N-methyl-carbamoyl-3-N-methyl-N-aminoacetylamino-5-benzoic acid:

314 g (0.49 mol) of the acid obtained previously was dissolved in 3500 ml of concentrated ammonia and heated for 20 hours at 60 C. After evaporation to dryness in vacuo, 300 ml of water was acidified with sulfuric acid anhydride. It is left in the refrigerator for 48 hours to crystallize and then it is quenched, washed repeatedly with water and dried in an oven at 80 C. This gives 160 g (51% yield) of the product.

Cleanliness control:

1. HTS eluent 3

Rf of the obtained product 0.75

2. Purity: Addition to Sodium Carbonate 102% Purity: Addition to Sodium Methylate 98%

Example IX

Preparation of Triodo-2,4,6-N-Methylcarbamoyl-3- (triiodo-2,4,6-N-methyl-N-acetylamino-3-amino-acetylamino-5-benzoyl) -glycylamino-5-benzoic acid ( compound IX)

The procedure is the same as for Compound I, except that triiodo-2,4,6-N-methyl-carbamoyl-3- (triiodo-2,4,6-N-methyl-N is used as the starting product containing iodine -acetylamino-3-amino-5-benzoyl) glycylamino-5-benzoic acid (compound 15 described later), the reaction being longer (4 days at room temperature).

Example X

Preparation of triiodo-2,4,6-N-methyl-N-amino-acetylamino-3-benzoic acid (compound X)

a) Preparation of triiodo-2,4,6-chloroacetamido-3-benzoic acid. It is performed according to U.S. Patent No. 3 210 412.

Cleanliness control:

1. HTS eluent 2

The product's Rf starting from 0.3 Rf of the resulting product is 0.25

2. Purity after addition to sodium carbonate 99,8%

b) Triiodo-2, 4, 6-N-methyl-N-chloroacetylamino-3-benzoic acid:

Dissolve 591.5 g (1 mol) of the previously obtained product in 2.3 moles of 5N sodium carbonate and 100 ml of acetone.

1.3 moles of methyl iodide were added dropwise while maintaining the temperature at 10 ° C using a water bath. After stirring for 16 hours at room temperature, the reaction mixture was poured into 2 liters of 1/10 diluted hydrochloric acid, cooled in an ice bath. The precipitated product is drained and washed with water several times. After drying in an oven at 50 ° C, 591 g is obtained, which yields an 85% yield.

Cleanliness control:

1. HTS eluent 2

Starting product Rf 0.25

Rf of methylated product (separation of 2 isomers) 0.35 and 0.45

2. Purity after chlorine addition 92%

Purity after adding iodine 100%

Purity after addition of sodium methylate 92%

c) Triiodo-2, 4, 6-N-methyl-N-aminoacetylamyr.-1-benzoic acid:

Dissolve 590 g (0.90 mol) of precursor acid obtained in 9 liters of concentrated ammonia. The dissolution is complete, with only filtration to remove 3 g of the insoluble matter formed by the starting acid methyl ester.

The resulting solution (light yellow color) was heated at 60 C for 20 hours and then concentrated to 2 liters in vacuo to give ammonium salt crystallization. It is then filtered, dissolved in 500 ml of water and a minimum volume of sodium carbonate, and re-precipitated with acetic acid at pH 4. After straining, washing with water, straining and drying, g6 g of white product is obtained, yielding 52 %.

Cleanliness control:

1. HTS eluent 1

Starting Product Rf 0.9

Rf of the obtained product 0.25, with ninhydrin a yellow stain is obtained

2. Purity after addition to sodium carbonate

98.5%

Purity after addition to sodium methylate

100%

Example XX

Preparation of trido-2,4,6-N-gamma-aminobutyryl-amino-3-benzoic acid (compound XI)

The same procedure as for Compound II applies, except that triodo-2,4,6-amino-3-benzoic acid is used as the starting product containing iodine

In this case, it is necessary to purify the crude product obtained by dissolving '50 g in 4 liters of satin and 280 ml of concentrated sulfuric acid. The undissolved impurities are filtered and the solution neutralized. The amine is then re-precipitated with acetic acid at pH 4. 309 g of the purified product are obtained.

Example XII

Preparation of triiodo-2,4,6-beta-amino-propionyl-amino-3-benzoic acid (compound XII)

The procedure is the same as for Compound I, except that triodec-2,4,6-amino-3-benzoic acid and beta-phthalimidopropionic acid chloride are used as the starting product containing iodine.

Example XIII

Preparation of triiodo-2,4,6-N-methyl-N-acetylamino-3-aminecacetamido-5-benzoic acid (compound XIII)

The procedure is the same as for compound I, except that triodo-2,4-6-N-methyl-N-acetyl-amino-3-amino-5-benzoic acid (according to U.S. Pat. US 3 178 4- ¹ ) with the following characteristics:

1. The condensation product with phthalylglycine is washed off (washing 1554 g in 2 liters of ethyl alkaline at 95 ° C) and isolating 1200 g of the purified product.

2. The resultant crude product was purified by dissolving hidrazinciizom 26 ^-1 gu 550 ml razredjene sulfuric acid of 1/10 at 80 ° C.

g of phthalylhydrazide of formula

it is filtered warm and removed.

The sulfur filtrate is filtered through charcoal filtration and neutralized with ammonia to pH 4 to 5. After crystallization, washing with water, straining and drying at 70 C and then at 105 C, 211 g of white product are obtained.

3. By treating the hydrazinolysis fluid with sulfuric acid, 390 g of a white product of the same quality as 211 g previously deboned are isolated in warm.

Example xiv

Combination of tridio-2,4,6-N-hydroxyethyl-carbamoyl-3-aminobutyryl-amino-5-benzoic acid (compound XIV)

The procedure is the same as for compound II, except that triodo-2,4,6-K-hydroxyethyl-carbamyl-3-amino-5-benzoic acid is used as the starting product.

Example XV

Preparation of triiodo-2,4,6-N-methyl-carbamoyl-3 (triiodo-2,4,6-N-methyl-carbamoyl-3-aminoacetamido-5-benzoyl) glycyl-N-methylamino-5-benzoic acid Procedure is the same as for Compound I, except Compound 14a is used as starting material, which will be described later.

Example XVI

Preparation of triiodo-2,4,6- (triiodo-2,4,6-N-methyl-carbamoyl-3-aminoacetamido-5-benzoyl) glycylamino-5-benzoic acid (compound XVI)

The procedure is the same as for Compound I, except that as the starting material containing iodine, it uses Compound 34, which will be described later.

Example XVII

Preparation of triiod-2,4,6-N-hydroxyethyl-carbamoyl -? - (triiodo-2,4,6-N-methyl-carbamoyl-3-aminoacetamido-5-benzoyl) glycyl-amino-5-benzoic acid (compound XVII)

The procedure is the same as for compound I, except that the starting material is the compound used, which will be described later.

Example XVIII

Preparation of triiodo-2,4,6-N-methyl-carbamoyl-3-amino-propionyl-amino-5-benzoic acid (compound XVIII)

Process j <= same kac for compound I, except that triodo-2,4, N-methylcarbamoyl-N-amino-S-benzoic acid is used as the starting product.

Example XXVIII

Treatment of triiodic-2,4,6-carbamoyl-3-amino-acetamido-5-benzoic acid (compound XXVIII) The procedure is the same as for compound I except that triodo-2 is used as a starting material for condensation with phthalyl-allin chloride , 4,6-Carbamoyl -? - amino-5-benzoic acid.

Hydrazinolysis is performed as follows:

4.85 moles of the previously obtained product were dissolved in 4,850 l of water and 940 ml of hydrazine hydrate. After stirring for 24 hours at ambient temperature, the resulting precipitate was filtered off and dried. 2. ¹ kg of dry product containing phthalylhydrazide is obtained. 1.88 kg of this product is washed twice under reflux in 3.8 liters of ethanol, sizzling warm

TABLE and clear with warm ethanol. After drying, 1.566 kg of dry product is obtained which makes a total yield of 52%.

Cleanliness control:

1. HTS eluent 1

Rf of starting product 0.65 Rf of starting product 0.00

2. Product purity after iodine addition 91.5%. Table I shows the data relating to the preparation of amines of formula IV by condensation and hydrazinolysis, as well as data for the amines thus obtained; while Table II shows the data related to the preparation of amines of formula iv starting from chlorinated derivatives of formula IX, as well as data for the amines thus obtained.

I

Amin Starting triiod product Product con denzaci.ie Amines obtained by hydrazinols. zone Rf u eluent 1 Rf in elu- Yield Ent 1 Rf in ent elu- Rf to elu- Yield 1 entu 1 I 0.4 0.68 95% · 0.05 0.5 95% II 0.7 0.5 100% 0.05 0.15 eluent 4 95% III 0.65 0.4 100% 0.05 0.1 0.45 62% IV .0,1 0.45 89% 0.05 0.5 85% V 0.9 0.75 100% 0.15 87% VI 0.7 0.55 ^F} neizo- lovan 0.5 0.1 eluent 3 71% total VII 0.5 ........ 0.4 85% 0.05 0.44 .73% IX  0.4 0.3 83% 0.05 0.55 / 0.60 83% XI 0.9 0.80 100% 0.2 0,05 ' 81% XII 0.9 0.85 100% 0.2 0.2 eluent 4 75% XIII 0.65 0.4 90% 0.05 0.45 0.53 66% XIV 0.4 0.6 uninsulated 0.0 0.1 58% total XV 0.4 0.35 7.2%. 0.0 0.25 50% XVI 0.4 0.3 92% 0.05 0.1 eluent 3 41% XVII 0.15 0.3 97% 0.0 0.5 50% ¹ . XVIII OJ .0,12 85% 0.05 0.02 . 53%

total

1) Pgsle iaping warm in dimethyl oimamide.

2) 0 eluent benzene / methyl-ethyl-ketone / carboxylic acid (8o / 20 / l0)

TABLE II

Starting Tri- Chlorinated Condensing Amine,, _and Iodo Product _ Product_ _

Rf in eluent Rf a elu-Rf in elu- Yield Rf in elu- kf in _p , entu 2 entu 1 entu 1 eluen- ^{373: 1110} tu 2

VIII 0.1 0.2 and 0.25 0.5 51% 0.3 in eluent 4 0.75 51% X 0.25 D, 3 i 0.45 0.9 97% L, 25 D, 15 and • 0.25 54%

Table III shows the information of the amines of general formula IV obtained.

TABLE III

COOH

J / J 'O!

H OC H ₂ CH ₂ NHC (> - \ ^ ^A TiH C OC H ₂ NH ₂ J

II

COOH

1 ⁰ 1.

CHjiraco _ / ^a hhco (ch ₂ ) ₃ nh ₂

III

j

NHC0CH ₂ NH ₂

J

CH ₂ NHCOCH ₂ NH ₂

VI

VII

VIII

IX

COOH

HC0CH ₂ KHC0

CH ₅ -S-COCH ₅

NHCOCHjNHj

XI

COOH

J

Oh

-NHCO (CH ₂ ) ₃ NH ₂

XII

COOH

J 'K' J

NHCO (CH ₂ ) ₂ NH ₂

COOH CONHCHj

J J jONHCH

COOH mi ^J ΥθΥ

HOCE ₂ CB ₂ NHCO ' ^J - \ ./''- nhcoch ₂ hhc

J ^J

COOH

XVIII jH ^ HCO

J

NHCO (CH ₂ ) ₂ ira ₂

COOH ^J Yv ^J

XXVIII C hh ₂ co aAnhcoch ₂ nh ₂

S. Preparation of Derivatives of Formula V

Example XIX

Preparation of triiodo-2,4,6-N-methyl-crabamoyl -> - N-acetyl-N-methyl-amino-5-benzoic acid chloride (compound XIX)

Suspend 50 g of triiodo-2,4,6-methylcarbamoyl-3-N-acetyl-N-methylamino-5-benzoic acid (described in French patent F 2 085 6? 6) in 90 ml of thionyl chloride and stir with stirring at 65 C for 5 hours. The resulting solution was allowed to cool. After straining and washing the acid chloride with diisopropylether. The product is dried in vacuo.

37 37 g of product is boiled, which gives a yield of 73%.

Cleanliness control-.

HTS after reaction with propylamine, in excess dimethylacetamide: eluent 1 Rf starting product 0.5

Condensation product rf with propylamine 0.85

Example XX □ Trihydro-2,4,6-methylcarbamoyl-3-amino-5-benzoic acid (Compound XX)

The procedure is the same as for compound XIX except that three iodo-2,4,6-N-methylcarbamoyl-3-amino-5-benzoic acid is used as the starting product. The yield is 85%.

Cleanliness control:

1. HTS: same procedure as for the previous product but after condensation with ethanolamine Rf starting acid 0.8

Condensation product Rf 0.4

2. HTS in eluent acetone / chloroform / acetic acid (50:40:10)

Acid Rf 0.55 Rf Acid Chloride 0.95

Example XXI

Preparation of triiodo-2,4,6-N-methyl-N-acetyl-amino-5-benzoic acid chloride (Compound XXI) The procedure is the same as for Compound XIX, except that triodo-2 is used as the starting product. 4,6-N-Methyl-N-acetylamino-3-benzoic acid. The yield is 85%.

Example XXII

Preparation of triiodo-2,4,6-N-methyl-carbamoyl-N- diacetyl-amino-5-benzoic acid chloride (compound XXII)

a) Diacetylation of triiodo-2,4,6-N-methylcarbamoyl-3-amino-5-benzoic acid (described in U.S. Patent No. 3,145,197)

800 g of three iodic acid (1.4 mol) in 1.6 liters of acetic anhydride are heated to 120 C overnight. After cooling, the undissolved portion of 123 g, which is the starting product, is filtered. The reaction liquid is gently poured over 3 liters of water with 1 kg of ice. On this occasion two phases are decanted. The lower phase is regenerated with 2.4 liters of water to give a resin which is redissolved in 800 ml of acetic acid. This solution precipitates by adding 5.4 liters of water with 1 kg of ice. After straining and rinsing with water, 500 g of a wet product is obtained which is used as such.

b) Preparation of acid chloride.

500 g of crude product is gradually added. in 830 ml of thionyl chloride, resulting in a decrease in temperature. After 30 minutes, another 300 ml of thionyl chloride was added, followed by another 400 ml of thionyl chloride after a further 30 minutes. The reaction was terminated after heating for 2 hours at 70 ° C. The thionyl chloride is evaporated in vacuo, regenerated in benzene and then evaporated in vacuo to dryness. Regeneration with benzene and evaporation is done twice.

In This way to afford 305 g of product buoy Natural wool hundred ranks Total yield of ^8% in relation to the triiodo-2,4,6-N-methyl-carbamoyl-3-amino-5-benzoevu kiselinu of Koje is run out Since.

Cleanliness control:

The procedure is the same as for compound XIX after condensation with propylamine.

). HTS eluent acetone / chloroform / acetic acid (5: 4: 1) Rf = 0,8 '

2. Purity after iodine addition: 97%

Purity after addition in methylate: 101%

Example XXIII

Preparation of Triiodo-2,4,6-N-Acetoxyethylcarbamoyl-1-N-diacetylamino-5-benzoic acid chloride (Compound XXIII)

a) Triacetylation of triodo-2,4,6-N-hydroxyethyl-carbamoyl-3-amino-5-benzoic acid.

60.2 g (0.1 mol) of triiodo-2,4,6-N-hydroxyethyl-carbamoyl-1-amino-5-benzoic acid were dissolved in 150 ml of acetic anhydride and heated to 160 C for 48 hours. After cooling, the solution is poured into 250 ml of water. A resin is created which is regenerated 3 times with 150 ml of chloroform each. The chloroform was washed twice with 100 ml of water each and then dried over calcium chloride. After filtration, it was evaporated in vacuo to give 60 g of an oil product, yielding an 82% yield.

Cleanliness control:

1. HTS eluent 1

Rf t.riacetilovar.cg product 0.75

2. Addition: The product is not insulated

b) Preparation of acid chloride g (0.082 mol) of triiodo-2,4,6-N-acetoxyethyl-carboxyloyl-? - diacetylamino-5-benzoic acid was dissolved in 150 ml of thionyl chloride.

The solution was maintained at 80 ° C for 4 hours. After evaporation in vacuo, the residue was recovered with 100 ml of chloroform. The insoluble residue is removed and the acid chloride is precipitated by light and long-term addition to ethyl ether. After straining and drying, 45 g are obtained, which gives a yield of 73% calculated on the triacetylated product.

Cleanliness control:

1. HTS eluent 1

Acid chlorine Rf 0.9

2. Addition: The product is not an isolated product, which makes a yield of 6 ”%.

Cleanliness control:

1. HTS eluent 1

Rf of starting product 0.45 Rf of starting product 0.8

2. Purity after adding iodine: 100%

Example XXIX

Preparation of triiodo-2,4,6-carbamoyl-3-amino-5-benzoic acid chloride (compound XXIX)

1,024 kg of triiodo-2,4,6-carbamoyl-3-amino-5-benzoic acid was added to 1.2 liters of thionyl chloride and the solution was stirred at 80 ° C with stirring for 7 hours. It is then maintained at room temperature overnight and finally strained and clear twice with 250 ml of thionyl chloride each. It is then washed with 3 liters of isopropyl ether and air-dried.

920 g of product are obtained, yielding an 87% yield.

Cleanliness control:

1. HTS

The procedure is the same as for product XIX Eluent: acetone / chloroform / acetic acid (50:40)

Acid Rf 0.3

The condensation product Rf is 0.85

2. Purity after iodine addition: 91%

Purity after chlorine addition: 90%

Table IV shows the formulas of the acid chlorides obtained, as well as other already known acid chlorides used to prepare the compounds of general formula II.

TABLE IV

Example XXIV

Preparation of Triiodo-2,4,6-N-Acetoxyethylcarbamoyl-5-N-methyl-N-acetylamino-5-benzoic acid chloride (Compound XXIV)

a) Acetylation of triodo-2,4,6-N-hydroxyethyl-carbamoyl-3-N-methyl-N-acetylamino-5-benzoic acid

157 g (2 mol) of acetyl chloride was added to a suspension of 658 g (1 mol) of triiodo-2,4,6-N-hydroxyethyl-carbamoyl-3-N-methyl-N-acetamido-5-benzoic acid (described in French F 2 074 734) in 2 liters of dioxane.

The suspension was heated to 80 C for 20 hours, dissolving. Evaporation of the dioxane under vacuum afforded 700 g of acid, yielding 100%.

Cleanliness control:

1. HTS eluent 1

Rf of starting product 0.25 Rf of starting product 0.45

2. Purity after addition: the product is not insulated

b) Preparation of acid chloride.

790 g (1 mol) of the resulting acid was dissolved in 1200 ml of thionyl chloride and heated for 2 hours at 50 ° C.

On this occasion an arsenic solution is obtained from which, after 48 hours of standing in the refrigerator, a crystalline product is separated, by straining. After washing with isopropyl ether and drying, 485 g are obtained

XIX

XX

XXI

XXII

C0C1

COC1

COCHj coch ₃

XXIII

C0C1

CH ₅ COOCH ₂ CH ₂ NHOO ' ¹

COCH ₅

COCHj

XXIV

COC1

J

CH, COOCH ₉ CH.NHCO / NC0CH,? ί ί Ύ, 5

J CH ₃

COC1

XXV

NH <J \ cOCH,

J CH,

J

C. Preparation of Compound of Formula II

Example 1.

Preparation of triiodo-2,4,6-N-hydroxyethylcarbamoyl-3-triido-2,4,6-N-methylcarbamoyl-1 ^! -N-methyl- N -acetylaryano-5-benzoyl-glycylamino-5-benzoic acid (compound 1)

a) Condensation

165 g (0.25 mol) of triiodo-2,4,6-N-hydroxyethylcarbamoyl-3-amino-acetamido-5-benzoic acid (compound I) was suspended in a mixture of dimethylacetamide (250 ml) and triethylamine (58.50 g ). To this suspension was added 163 g of the triiodo-2,4,6-N-methyl-carbamoyl-3-N-methyl-N-acetylamino-5-benzoic acid chloride (compound XIX) (0.25 mol). The mixture was stirred vigorously at 50 C for 6 hours. Thin layer chromatography (HTS) has proven that it remains the '' starting material ''.

The solution is poured into 1240 ml of water. an insignificant precipitate is created which becomes clear. Hydrochloric acid was added to the filtrate to a very acidic pH, then the mixture was washed with water and dried in an oven at 80 C. 186 g of crude product were obtained, yielding 61%.

Cleanliness control:

1. HTS eluent 1

R 1 of starting amine 0.05 Rf acid chloride 0.80 Rf condensation product 0.15

2. Product purity after addition of sodium carbonate 95% purity of the product after addition of methylate 98,5%

Product purity after iodine addition of 97%

b) Purification

It is achieved by crystallization by warming in ethanol at 95 C. 186 g is suspended in 400 ml of ethanol at 95 C and kept under reflux. After 6 hours complete dissolution occurs and then the product crystallizes. Total warm-up takes 36 hours. It is then allowed to cool.

After straining, the wet product is dissolved in 400 ml of water and sodium hydroxide. The pH was adjusted to 4 - 5 with acetic acid and passed through charcoal twice. It is filtered and then acidified to a strongly acidic pH with concentrated hydrochloric acid.

After filtration, washing with water, straining and drying, 115 g of pure product are obtained, yielding 62%.

Cleanliness control:

1. HTS as in concentration

2. Product purity after addition of sodium carbonate 101%

Product purity after addition to methylate 98,5%

Purity after iodine addition 100.5%

Example 2

Preparation of triiodo-2,4,6-N-methylcarbamoyl-3- (triiodo-2,4,6 ~ N-methylcarbamoyl-3-N-methyl-acetamido-5-benzoyl)-gamma-arainobutyryl-amino-5-benzoyl acids (compound 2)

This is for compound 1 starting from amine II and acid chloride XIX.

Example 3.

Preparation of triodo-2,4,6-N-hydroxyethyl-carbamoyl-3- (triiodo-2,4,6-N-methyl-carbamoyl-3-acetamido-5-benzoyl) -glycylamino-5-benzoic acid (compound 3 )

It is assisted by two procedures:

a) starting from triiodo-2,4,6-N-hydroxyethyl-carbamoyl-3- (triiodo-2,4,6-methyl-carbamoyl-3-amino-5-benzoyl) -glycylamino-5-benzoic acid (compound '' A). First, compound 3a was prepared as in compound 1, starting with amine I and acid chloride XX. Compound 3 is obtained by acetylation of compound 3a.

b) Starting from triiodo-2,4,6-N-hydroxyethyl-carbamoyl-3- (triiodo-2,4,6-N-methylcarbamoyl-3-diacetylamino-5-benzoyl) -glycylamino-5-benzoic acid (compound 3b). First, compound 3b is prepared as in compound 1, starting from amine I and acid chloride XXII. Compound 3 is obtained by saponification of compound 3b.

Example 4

Preparation of triiodo-2,4,6-N-methyl-carbamoyl-3- (triiodo-2,4,6-N-hydroxyethyl-carbamoyl-3-N-acetylamino-5-benzoyl)-gamma-aminobutyrylamino-5-benzoyl acids (compound 4)

a) First, triiodo-2,4,6-N-methylcarbamoyl-3- (triiodo-2,4,6-N-acetoxyethylcarbamoyl-3-N12) is obtained

-diacetylamino-5-benzoyl)-gamma-amino-butyrylamino-5-benzoic acid (compound 4a)

It works as with compound 1 but starting with amine II and acid chloride XXIII. b) Compound 4 is obtained by saponification of compound 4a.

Example 5

Preparation of triiodo-2,4,6-acetamido-3- (triiodo-2,

4.6- N-methylcarbamoyl-3-N-methylacetamido-5-benzoyl) -glycylmethylamino-5-benzoic acid (compound 5)

It works as with compound 1 but starting with amine IV and acid chloride XIX

Example 6

Preparation of Triodo-2,4,6-N-Hydroxyethyl-carbamoyl-3- (triiodo-2,4,6-acetamido-3-N-methyl-acetamido-5-benzoyl) -glycylamino-5-benzoic acid (compound 6)

a) Triiodo-2,4,6-N-hydroxyethyl-carbamoyl-3- (triiodo-2,4, 6-amino-3-N-methyl-acetamido-5-benzoyl) -glycylamino-5-benzoic acid (compound 6a)

It works as with compound 1 but starting with amine I and acid chloride XXV.

b) Compound 6 is obtained by acetylation of compound 6a

Example ⁿ

Preparation of triiodo-2,4,6-N-methyl-carbamoyl-3- (triiodo-2,4,6-N-hydroxyethyl-carbamoyl-3-N-methyl-acetamido-5-benzoyl)-gamma-amino-butyrylamino -5-benzoic acids (compound 7)

a) Triiodo-2,4,6-N-methyl-carbamoyl-3- (triiodo-2,

4.6- N-Acetoxyethyl-carbamoyl-3-N-methylacetamido-5-benzoyl) -aminobutyryl-amino-5-benzoic acid (compound 7a)

It works as with compound 1 but starting from amine II and acid chloride XXIV

b) Compound 7 is obtained by saponification of compound 7a

Example 8

Preparation of triiodo-2,4,6-N-methylcarbamoyl-3- (tridido-2,4,6-N-hydroxyethylcarbamoyl-3-N-methyl-acetamido-5-benzoyl) -glycylamino-5-benzoic acid (compound 8 )

a) Triiodo-2,4,6-N-methyl-carbamoyl-3- (triiodo-2,

4.6- N-Acetoxyethyl-carbamoyl-3-N-methyl-acetamido-5-benzoyl) -glycylamino-5-benzoic acid (compound 8a)

It works as with compound 1 but starting with amine III and acid chloride XXIV

b) Compound 8 is obtained by saponification of compound 8a

Example 9

Preparation of triiodo-2,4,6-N-methyl-carbamoyl-3- (triiodo-2,4,6-N-methyl-carbamoyl-3-N-methyl-acetamido-5-benzoyl) -glycylamino-5-benzoyl acids (compound 9)

It works as with compound 1 but starting from amine III and acid chloride XIX.

Example 10

Preparation of triiodo-2,4,6, - (triiodo-2,4,6-N-methylcarbamoyl-3-N-methyl-acetamido-5-benzoyl) -eta-amino-caproylamino-5-benzoic acid (compound 10)

It works as with compound 1 but starting from amine V and acid chloride XIX.

Example 11

Preparation of triodo-2,4,6-N-methyl-carbamoyl-3- (trido-2,4,6-N-methylacetamido-3-benzoyl)-gamma-amino-butyrylamino-5-benzoic acid (compound 11)

It works as with compound 1 but starting from amine II and acid chloride XXI.

Example 12

Preparation of triiodo-2,4,6- (triiodo-2,4,6-acetamido-3-benzoyl) -glycylamino-3-benzoic acid (compound 12)

a) Triiodo-2,4,6- (triiodo-2,4,4,6-amino-3-benzoyl) -glycylamino-3-benzoic acid (compound 12a)

It works as with compound 1 but starting from amine VI and acid chloride XXVI.

b) Compound 12 is obtained by acetylation of compound 12a

Example 13

Preparation of triiodo-2,4-6- (triiodo-2,4,6-N-methyl-acetamido-3-benzoyl) -glycyl-N-methylamino-3-benzoic acid (compound 13)

It works as with compound 1 but starting from amine X and acid chloride XXI.

Example 14

Preparation of tridoc-2,4,6-N-methyl-carbamoyl-3- (trido-2,4,6-N-methylcarbamoyl -? - acetamido-5-benzoyl) -glycyl-N-methylamino-5-benzoic acid ( compound 14)

a) Triiodo-2,4,6-N-methyl-carbamoyl-3- (triiodo-2,

4.6- N-Methyl-carbamoyl-3-amino-5-benzoyl) -glycyl-N-methylamino-5-benzoic acid (compound 14a)

It works as with compound 1 but starting from amine VIII and acid chloride XX.

b) Compound 14 is obtained by acetylation of compound 14a

Example 15

Preparation of triiodo-2,4,6-N-methyl-carbamoyl-3- (triiodo-2,4,4,6-N-methyl-acetamido-3-amino-5-benzoyl) -glycylamino-5-benzoic acid (compound 15 )

It works as with compound 1 but starting with amine III and acid chloride XXV

Example 16

Preparation of triodo-2,4,6-N-methylacarbamoyl-3- (triiodo-2,4,6-N-methyl-acetamido-3- (triiodo-2,4,6N-methylcarbamoyl-3-acetamido-5-benzoyl) ) -glycylamino-5-benzoyl glycyl-5-benzoic acid (compound 16)

a) triiodo-2,4,6-N-methyl-carbamoyl-3- [triiodo-2,

4.6-N-methyl-acetamido-3- (triiodo-2,4,6-N-methylcarbamoyl-3-amino-5-benzoyl) -glycylamino-5-benzoyl glycyl-amino-5-benzoic acid (compound 16a).

It works as with compound 1 but starting with amine IX and acid chloride XX.

b) Compound 16 is obtained by acetylation of compound 16a.

Example 1

Preparation of triiodo-2,4,6-methyl-carbamoyl-3- [triiodo-2,4,6-N-methylacetamido-3- (triiodo-2,4,6-N-methyl-carbamoyl-3-N-methyl -acetamido-5-benzoyl) -glycylamino-5-benzoyl3-glycylamino-5-benzoic acid (compound 17)

It works as with compound 1 but starting from amine IX and acid chloride XIX.

Example 18

Preparation of triodo-2,4 &apos; -N-methylcarbamoyl- ^9- (trido-2, 4, 6-N-methyl-acetamido-3-benzoylglycyl) amino-5-benzoic acid (compound 18)

It works as with compound 1 but starting from amine III and acid chloride XXI.

Example 19

Preparation of triiodo-2,4,6- (triiodo-2,4,6-N-methyl-carbamoyl-3-N-methylacetamido-5-benzoyl) glycylamino-5-benzoic acid (compound 19)

It works as with compound 1 but starting from amine VI and acid chloride XIX.

Example 20

Preparation of triiodo-2,4,6-acetamido-3- (three iodo-2,

4,6-N-Methyl-acetamido-3-acetamido-5-benzoyl) -glycylamino-5-benzoic acid (compound 20)

a) Triiodo-2,4,4-acetamido-3- (triiodo-2,4,4-N-methyl-acetamido-3-amino-5-benzoyl) -glycyl-amino-5-benzoic acid (compound 20a)

It works as with compound 1 but starting from amine VII and acid chloride XXV.

b) Compound 20 is obtained by acetylation of compound 20a

Example 21

Preparation of triiodo-2,4,6- (triiodo-2,4,6-N ~ methyl-carbamoyl-3-acetamido-5-benzoyl) -glycyl-N-methylamino-3-benzoic acid (Compound 21)

a) Triiodo-2,4,6- (triiodo-2,4,6-N-methyl-carbamoyl-3-amino-5-benzoyl) -glycyl-N-methylamino-3-benzoic acid (compound 21a).

It works as with compound 1 but starting from amine X and acid chloride XX.

b) Compound 21 is obtained by acetylation of compound 21a.

Example 22

Get the ar. is tri-iodo-2,4,6- (triiodo-2,4,6-N-methylcarbamoyl-3 ~ N-methyl-acetamido-5-benzoyl) -aminobutyryl-amino-3-benzoic acid gamma (compound 22)

It works as with compound 1 but starting from amine XI and acid chloride XIX.

Example 23

Preparation of triiodo-2,4,6- (tridido-2,4,6-N-methylcarbamoyl-3-N-methylacetamido-S-benzoyl) - gamma aminopropionyl-amino-3-benzoic acid (compound 23)

It works as with compound 1 but starting from amine XII and acid chloride XIX.

Example 24

Preparation of triodo-2,4,6-N-hydroxyethyl-carbamoyl-3- (trido-2,4,6-N-methylcarbamoyl-3-N-methyl acetamido-5-benzoyl)-gamma-aminobutyrylamino-5 benzoic acid ( compound 24)

It works as with compound 1 but starting from amine XIV and acid chloride XIX.

Example 25

Preparation of triiodo-2,4,6-acetamido-3- (triiodo-2,

4.6- N-Methyl-carbamoyl-3-N-methyl-acetamido-5-benzoyl) -glycylamino-5-benzoic acid (compound 25)

It works as with compound 1 but starting from amine VII and acid chloride XIX.

Example 26

Preparation of triodo-2,4,6-N-methyl-acetamido-3- (trido-2, 4,6-N-methyl-carbamoyl-3-acetamido-5-benzoyl) -glycylamino-5-benzoic acid (compound 26 ).

a) Triiodo-2,4,6-N-methyl-acetamido-3- (triiodo-2,4, 6-N-methyl-carbamoyl-3-amino-5-benzoyl) -glycylamin-5-benzoic acid (compound 26a)

It works as with compound 1 but starting from amine XIII and acid chloride XX.

b) Compound 26 is obtained by acetylation of compound 26a.

Example 27

Preparation of triiodo-2,4,6-N-methyl-carbamoyl-3- (tridido-2,4,6-N-methyl-carbamoyl-3-amino-5-benzoyl) -glycylamino-5-benzoic acid (compound 27 )

It works as with compound 1 but starting with amine III and acid chloride XX.

Example 28

Preparation of triiodo-2,4,6-N-methyl-carbamoyl-3- [triiodo-2, 4,6-N-methylcarbamoyl-3- (triiodo-2,4,6-N-methylcarbamoyl-3-acetamido-5 -benzoyl) -glycylamino-5-benzoyl] glycyl-N-methylamino-5-benzoic acid (compound 28)

a) Triiodo-2,4,6-N-methyl-carbamoyl-3-fluorodo-2,

4.6- N-Methylcarbamoyl -? - (triiodo-2,4,6-N-methylcarbamoyl-3-amino-5-benzoyl) -glycylamino-5-benzoyl glycyl-N-methylamino-5-benzoic acid (compound 28a) .

It works as with compound 1 but starting from amine XV and acid chloride XX.

b) Compound 28 is obtained by acetylation of compound 28a.

Example 29

Preparation of three iodo-2,4,6, [[three iodo-2,4,6-N-methylcarbamoyl-3- (triiodo-2,4,6-N-methylcarbamoyl-3-N-methyl] acetamido-5- benzoyl) g licamylamino-5-benzoyl 'glycylamino-3-benzoic acid (compound 29) Worked as for compound 1 but starting from amine XVI and acid chloride XIX.

Example 30

Preparation of triiodo-2,4, -6-N-hydroxyethyl-carbamoyl-3- [triiodo-2,4,6-N-methyl-carbamoyl-3 (triiodo-2,4,6-N-methyl-carbamoyl-3 -N-methylacetamido-5 benzoyl [glycillainino-5-benzoic acid (compound 30)

It works as with compound 1 but starting from amine XVII and acid chloride XIX.

Example 34

Preparation of triiodo-2,4,6- (triiodo-2,4,6-N-methylcarbamoyl-3-amino-5-benzoyl) glycylamino-3-benzoic acid (compound 34)

It works as with compound 1 but starting from amine VI and acid chloride XX.

Example 35

Preparation of triiodo-2,4,6-N-methyl-carbamoyl-3- (triiodo-2,4,6-N-methyl-carbamoyl-3-gluconylamino-5-benzoyl) -glycylamino-5-benzoic acid (compound 35 )

a) Condensation

Suspended 53.5 g (0.045 mol) of compound 2? in 100 ml of dimethylacetamide. To this was added 39 g of pentaacetylgluconic acid chloride (0.091 mol) obtained according to C.E. Brown and C.D.COOK: Organic Synthese, Vol. 41, p. 79-82. The suspension was stirred for 24 hours at room temperature. The reaction solution is then poured into 500 ml of water. On this occasion, a resin is formed which crystallizes after 48 hours of standing in the refrigerator.

Drain and rinse several times with water.

HTS in eluent 1

Starting product Rf 0.5

Condensation product Rf 0.35

b) The crude product obtained is dissolved in 300 ml of ammonia. It is stirred overnight at room temperature. It was then evaporated to dryness under vacuum and regenerated in 125 ml of water.

Acidify with hydrochloric acid by half.

After standing in the refrigerator for 48 hours, the precipitate is drained and washed with water several times. After drying, 35 g of the product are washed, which is washed with 350 ml of ethanol. After straining and drying, 30 g of acid are obtained, accounting for a total yield of 49%. Cleanliness control:

HTS eluent 1: Rf 0.0 eluent 3: Rf 0.25 eluent 4: Rf 0.15

Addition to Sodium Carbonate: 98% Addition to Iodine: 100%

Example 36

Preparation of triiodo-2,4,6-hydroxyethyl-carbamoyl -3- (triiodo-2,4,6-N-methyl-carbamoyl-3-gluconyl amino-5-benzoyl) -glycylamino-5-benzoic acid (compound 36)

It is obtained as compound 35, but starting from compound 3a.

eluent. 1: Rf 0.0 eluent 7. Rf 0.15 eluent 4: Rf 0.1

Example 37

Preparation of triiodo-2,4,6- (triiodo-2,4,6-N-methyl-acetamido-3-benzoyl) -glycyl-N-methylamino-benzoic acid (compound 13, second method)

146 g (0.13 mol) of compound 12 was dissolved in 0.468 mol 4n sodium carbonate.

To this was added, with cooling, 0.338 moles of methyl iodide. After 16 hours of stirring at room temperature, another 10% of the methylcarbonate is introduced into 4N sodium carbonate as well. After being allowed to react for 48 hours, precipitation in an acidic medium occurs. After straining, rinsing and drying, 118.5 g of product are obtained. (Methylation yield is 72%).

Cleanliness control:

1. HTS eluent 1

Rf of methylated product 0, ^ 5 Rf of methylated product 0, ^ 8 and 0,8 HTS eluent 2

Rf of unmethylated product 0,4

Rf of methylated product 0.4 and 0.5 HTS eluent 4

Rf of methylated product 0,7 Rf of methylated product 0, ^-1 and 0,75

Purification:

This is achieved by extracting the ammonium salt. The yield is 80%.

Adding to methylate 101%

Adding to sodium carbonate 97%

Example 38

Preparation of triodo-2,4,6-N-methyl-carbamoyl-3- (triiodo-2,4,6-N-methyl-carbamoyl-3-acetamido-5-benzoyl) -glycyl-N-methylamino-5-benzo acids (compound 14, second mode)

a) Preparation of compound 14a otherwise. Dissolve 11.8 g (0.01 mol) of product 27 in 15 ml of 2N sodium carbonate (0.0 ¹ mol) and 4 ml of acetone. Added to that, drop by drop. 2.8 ml of methyl iodide (0.04 mol). After stirring for 48 hours at room temperature, it was acidified to pH 1, resulting in precipitation. After straining, rinsing with water, the product is redissolved. The pH was then adjusted to '-4 and passed through charcoal. It's filtered, taichi, strained. After germination, 9 g of product is isolated. The yield is 75%. Cleanliness control:

HTS eluent 1

Rf of starting product 0.5 Rf of methylated product 0.6 Adding to methylate 98%

b) Compound 14 is obtained by acylating compound 14a.

It is carried out in the usual manner with the aid of CH 2 COCl dissolved in DMAC. The yield is 40%.

Example 39

Preparation of triiodo-2,4,6-N-methyl-carbamoyl- ^1- (tri-odo-2,4,6-N-methylcarbamoyl) -1-3-N-methyl-tamido-5-benzoyl-gamma-aminobutyryl- N-methylamino-5-benzoic acid (compound 37)

Dissolve 2 ¹ g (0.082 mol) of compound 2 in 8.3 ml of 5N sodium carbonate (0.0418 mol) and 12 ml of water. 5.9 g of methyl iodide (0.0418 moles) was added dropwise thereto. After stirring at room temperature for 24 hours, it was acidified to pH 1. It was drained, washed with water and the residue dried. 20 g of crude acid are obtained.

Purification

It was obtained by crystallization in warm, ethanol (20 g / 40 ml) and refluxed for 3 hours. After straining, the product is regenerated in an alkaline medium and passed over charcoal. After precipitation with acid, it is drained, washed with water and dried. A total of 4.5 g of product is isolated. The yield is 20%.

Cleanliness control:

HTS eluent 1

Rf of non-methylated product 0,25 Rf of methylated product 0,55

HTS eluent 4

Rf of non-methylated product 0,3 and 0,4 Rf of methylated product 0,35, 0,30 and 0,25 Addition to sodium carbonate: 98% Addition to methylate: 98%

Example 40

Preparation of triodo-2,4,6-N-hydroxyethyl-carbamoyl-3 (triiodo-2,4,6-U-methyl-carbamoyl-3-acetami 15 do-benzoyl) glycyl-N-methylamino-5-benzoic acid ( compound 38)

a) Preparation of trifluoro-2,4,6-N-hydroxyethyl-carbamoyl-3- (triiodo-2,4,6-N-methylcarbamoyl-3-amino-5-benzoyl) glycyl-N-methylamino-5-benzoic acid (compound 38a).

It is obtained as with compound 14a but starting from compound 3a by methylation.

b) Compound 38 is obtained by acetylation of compound 38a in the usual manner. The yield is 53%. Rf of compounds 38 and 38a

Eluent 1 Eluent 4

0.15 0.25 and 0.30 (2 isomers)

38a 0.25 0.32 and 0.40 (2 isomers)

Example 41

Debut of triiodo-2,4,6-N-methylcarbamoyl -? - (trido-2,4,6-N-methyl-carbamoyl-3-N-methylacetamido-5-benzoyl) -beta-aminopropionyl-amino-5-benzoyl acids (compound 39)

It is obtained as well as compound 1, but starting from amine XVIII and acid chloride xix, where the heating time is at a temperature of 50 C for 3 hours. Gross yield is 48%.

Example 42

Preparation of triiodo-2,4,6-N-methyl-carbamoyl-3- (triiodo-2,4,6-N-methyl-carbamoyl-3-N-methylacetamyl-5-benzoyl) -beta-aminopropionyl-N- methylamino -5-benzoic acid (compound 40)

Obtained by methylation of compound 39.

Example 43

Yo is three iodo-2,4,6-carbamoyl- ¹ - (three iodo-2,

4.6-Carbamoyl-3-amino-5-benzoyl) -glycyl-amino-5-benzoic acid (compound 41)

It works as with compound 1 but starting from amine XXVIII and acid chloride XXIX.

Example 44

Preparation of tridio-2,4,6-carbamoyl-3- (trid-2,

4.6- N-Methyl-carbamoyl-3-amino-5-benzoyl) -glycylamino-5-benzoic acid (compound 42)

It works as with compound 1 but starting with amine XXVIII and acid chloride XX.

Example 45

Preparation of triiodo-2,4,6-carbamoyl-3- (triiodo-2,

4.6- N-Methyl-carbamoyl ~ 3-acetamido-5-benzoyl) -glycyl-amino-5-benzoic acid (compound 43) Compound 43 is obtained by acetylation of compound 42.

Example 46

Preparation of triodo-2,4,6-N-methylcarbamoyl-3- (trido-2,4,6-carbamoyl-3-acetamido-5-benzoyl) -glycyl-N-methylamino-5-benzoic acid (compound

44)

a) Preparation of triiodo-2,4,6-N-methylcarbamoyl-3- (triiodo-2,4,6-carbamoyl-3-amino-5-benzoyl) -glycyl-N-methylamino-5-benzoic acid (compound 44a ).

It works as with Compound 1, but starting from amine VIII and acid chloride XXIX.

b) The compound. 44 is obtained by acetylation of compound 44a

Example 47

Preparation of triiodo-2,4,6-N-methylcarbamoyl -? - (triiodo-2,4,6-N-methylacetainido-3-acetamido-5-benzoyl) -glycylamino-5-benzoic acid (compound

45)

a) Preparation of triiodo-2,4,6-N-methylcarbamoyl -? - (triido-2,4,6-N-methylacetamido-3-amino-5-benzoyl) -glycyl-N-methylamino-5-benzoyl acids (compound 45a).

It works as with compound 1 but starting from amine VIII and acid chloride XXV.

b) Compound 45 is debuted by acetylation of compound 45a.

Example 48

Preparation of triiodo-2,4,6-N-methylcarbamoyl -? - (triiodo-2, 4, 6-N-hydroxyethyl ylcarbamoyl-3-acetamido5-ber, zoyl) -glycyl-N-methyl-amino-5-benzoic acid (compound 46)

a) Preparation of triiodo-2,4,6-N-methylcarbamoyl -? (triiodo-2,4,6-N-acetoxyethylcarbamoyl-3-diacetylamino-5-benzoyl) -glycyl-N-methyl-amino-5-benzoic acid (compound 46a).

It works as with Compound 1 but starting with amine VIII and acid chloride XXIII:

b) Compound 46 is obtained by saponification of compound 46a.

Example 49

Beekeeping of triiodo-2,4,6-N-methylcarbamoyl-3-trifluoro-2,4,6-M-methylcarbamoyl-3- (bis-hydroxymethyl-propionylamino) -5-benzoyl-glycyl-N-methylamino-5-benzoyl acids (compound 47)

It works as with Compound 35, but starting or using Compound 14a and bis-acetylmethyl-propic acid chloride obtained in the same way as pentaacetylgluconic acid chloride.

Example 50

Preparation of triodo-2,4,6-N-methylcarbamoyl-3- (triddo-2, 4,6, -N-methylcarbamoyl-3-gluconylamino-5benzoyl) -glycyl-N-methylamino-5-benzoic acid (compound 48)

It works as with compound 35 but starting from compound 14a.

Example 51

Preparation of triiodo-2,4,6-acetamido-3- (triiodo-2,

4,6-N-Methylcarbamoyl-3-acetamido-5-benzoyl) -glycyl-N-methylamino-5-benzoic acid (Compound 49)

a) Preparation of triiodo-2,4,6-acetamido-3- (triiodo-2,4,6-N-methylcarbamoyl-3-amino-5-benzoyl) -glycyl-amino-5-benzoic acid (compound 49a). It works as with Compound 1 but starting from triiodo-2,4,6-acetamido-3-aminoacetylamino-5-benzoic acid VII and acid chloride XX.

b) Preparation of triiodo-2,4,6-acetamido-3- (triiodo-2,4,6-N-methylcarbamoyl-3-amino-5-benzoyl) -glycyl-N-methylamino-5-benzoic acid ( compound 49b).

The compound obtained under a) is methylated to methyl iodide.

c) Preparation of triiodo-2,4,6-acetamido-3- (triiodo-2,4,4-N-methylcarbamoyl -? - acetamido-5-benzoyl) -glycyl-N-methylamino-5-benzoic acid (To be achieved by acetylating the compound under b).

Eluent 1 Eluent 4 Rf a) 0.55 Rf b) 0.5 Rf C) 0, ¹ Rf c) 0.35 and 0.4

Table V shows data relating to the preparation of compounds of formula II and the compounds obtained, while the formulas of the compounds obtained are shown in Table Vi.

Table V

Juii.-JoRje; olaccl antn

rroko I I pioka I __2i_ profcu JI ia

Iv_iv.

prsLo I

G c olacni Ciutc nr a ela- Γτίηοβ - «cetil *. ft / _u eluants 1 felortd prince aata 1 out »♦ uepoaLfl. poei * oaveGiilMaSiUfi_Metla _ \ fc »on» _ __5_ <, ____ 5_6_ _ t _Π £ _H * o · »_ <U_Q.?S ____

XX 52% 0.2 54> o.l _ & __: _

XXiI Kile U 0.2 70 / -aalc conde «0.1

- ____ clovas _ fcaoile _. "

ΧλΙΙΙ Nilc 1 * -0.2 $ -ljc laclovfcA 0 * 15 _ £ i2 »£ D ____ '_

Λίχ_e; «c.20_ i_ m Tti o, 2t 76; i 0,1?

r ^ čtLč-vaiija - oiizt.cj · u clacntB

-lp Irlnoc B, QB 'o; -a J _a__d_io n i2 »lil;! _ C2 '/ ICC» le · »110¾ ¢ .1¾

Λ __._ Ό * _leo "9.¾? 9.c ·" 0.25_ x; ₄ 'ivj. ioiy 5; »53.5» oi

7 (5 ϊόΰ ί (· Λ & <w <ζϊ

Evdl 17 »Wf 97» 9 £ Jt oTS

Ul.gpaA

ΝΒ, Ι__44 «ion« W /._ 0.1 m: ₄ 521 1021 95.5? 99.8 "o,": · ί α «l» »Ota 4

Unfortunately L M ^ iiC.4

L, 1 «« Ji «ata 2 o, l O« tl cr.ta 2

0.15 1 0Λ

7 proko ? a II XXIV Streets and> οίστχα 0.20 filla laoloraa 1 C.1 os / 54 « oVoner 97 « 97 « 9S » o.io β proto ·· a III XXIV Kida U- $ 0.2 Oil gIgY »J ieolovsa KUo i »olor« n Π, '43 · / Utcjmjl 95 » 99 » with » 0 * 25 0.3 1 0.35 S IH XIX - hour _ Tren.ua 63 » 'jU5i · lot » 9 J. 5 « 0.2 C.4 1 0 * 5 10 Y XIX 68,5 / 0.4 1 0.5 in elatn- OJ 44) 17 « 100% 96 » 58,5 « 0.4 0.4 1 0.75 -11 II XXI §8 < £ xi «H? · / 5» hunting * 50.5 «98.5» 0.5 0.25'a il.O 12 pi n · VI XXVI 91 » 0.7 1 0.75 a cluoate 4 i 0.75 Nile prsfciičea 0.75 13 X XXI 95 » o, 7 1 0.75 β «luSAIsU i U> 10L » ΚΌ » 100 * 0.7 0.7 1 0.75 14 prana l4a VIII XV 57 » 0.5 ¢ 5.- i 0.5 Here is «51» 10b% 95 « 0.3 B OU 2 0.J5 1 8Λ 15 III XXV 03% 0.4 • Nllc r »e * l« don 0.40 Ιέ ».roko ifa IX XX 0.3 1 J2U 5 «' 1 0.08 (5) 45 » : oi « 99,9 » 93 « 0.3 1 0.35 17 IT XIX 60% ..... ». IR - 13 III XXI □ 6% S * 35 ttOH 29 33 » 102 « 101 » 99% 0.35 0.3 * el <2 19 n XIX 94 » 0.7 «alnen * W 4 1 · - .-_ L. EtUH 2z 41Χ icz; 101% 9B * O <52 0.7 * 0.45 in oleaet » ..?. 20 over ? 0a vii nv M 0.25 1 0.3 96 » 1 0.12 1 0.15 «T / 35» 103 » 97,5 » 0.10 and eluent 2 21 over 21 » X XX QQf. 0.7 94 » i 0.5 EtCM 33 » 100 » 102 «. 97 » 0.5 C, 3 e «tuanta t 22 XI XIX 73% 0.45 —I EtOH 2 * 19% 99> 99% 99 « 0.65 25 ΧΠ XIX 90% ω , i EtCSl «6% 98 « 96% 99.3 « 0.4 24 XIV XIX 79% 0.15 a »luent 4 1, ·. 1 ItCJ '47 »sk ₄ 97 » 97% 99% 0.1 $ «eluent 4 25 no III 50 » 0.20 l · 1 E tov '39% «V ...... 90 » 89% 97 » 1,20 26 over 26 « XIII XX «9» 0.40 40% t 0.20 WK ₄ 46 » 98.5% 98.5 »95» 0.20 27. III XX 73 » 0.5? O »le AlulcoallsVMd · Bij * Ibo- lJVBB 0.7 « (7) 49 » ukttnaa -98 » 100 « 0.25 0.15 29 over 20 « XV XI 97.2JC ° »30 83 » i 0.15 There »16» 93 » 97,9 * 38 » 0.15 XVI XIX 07% 0.35 .. <« ₄ * 32» IS4 £ - 22Ž- - ° .I5 Λ Z. 30 λΠΣ XIX 61 » 1.5 a elaonta 2 0.5 o clB-0; Uorletl aa alrurl 99.5% 0.40 90% 0.40 ^v (7) 45 «Bin. 99.7 »931 1CO% 0.15 ϋ 2J XX 52% ObZ _ ί · 55 ' ^b ~ ITI 40% 0,7540.350,65 >? ---- c— ..... 40 · - ·. TTTT 72% 0.3 .43 .... A / .TJA * mind: XX ------ XX n. ^ EtOl 85 » 1O1> »45» »/ *> 73% 0.3 50% ecetUorenJ · 1— Ο. » 17,25 > 3 X 0 ^ .4 44; »it we XXIV 77 » 0.4 92 » 0.35 Vide prodisčcrao 0.35 0.4 1 0.45 44 * $ 4 over we XXV 88 » 0.6 S5> rosic smoaua · —utic p ^ eciecavan fcMlj «0.2 ύ.Χ In «33 and 0.4 j .....— US_ 46 over 46 « VIII μπ 76 » $ 0.6 li) 0% J k «Ala« aponi.Il «elite 0.2 Uide> rač4čaVan a 0.2 0.3 $ 1 0.4

beer Willie Xx 144

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... ------- i-— jobs «apor.iri_ Molla O__

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(4) Γχ-οίχίοηο taloierde raatvoio 1 dloutilfonamldu pcooiu water.

(5) Melting of solution 1 nettnoi foam of ltopropll-alcohol, (7) leprosy m etsnoloa.

TABLE ΥΙ

COOH hoch ₂ ch ₂ nhci

J s / J

HHC0CH ₂ NHC0

CONHCH,

J

NCOCH, i i

J ^CH 3

3b

COOH

J> 'In J

CONHCH, ^ 2 3

H0CH ₂ CH ₂ HNCi

ONHCH,

NHCOCHgNHCO ^ · ^ NHCOCHj

COOH ^J ToT

HOCH ₂ CH ₂ HNCO - * \ _z x ^> 'NHCOCHpNHCO

COOH

Tof

CONHCH,

COCH,

J · J / OOCH ^

HOCHgCHgHNCO ^^ / ^ HHCOCHgNHCO 'ch ₃ nhco

COOH CONHCHjCHgOH

J '<J J / V o i! oT

NHCO (CH ₂ ) ₃ ΝΗΟΟ '^ χ / ⁴ ' NHO CCHj

cooh conhch ₂ ch ₂ oocch ₃

J> / \ z J J J “I ° I 1 ° ϊ

CH ₃ NHC0 ^zK x _y X ^ NHC0 (CH ₂ ) ₃ irHC0 NCOCH ₃

CC J CCCHj

H0CH ₂ CH ₂ NHC

hcoch ₂ nhco

H0CH ₂ CH ₂ NHC

CHjNHC

COOH

CHjNHCO

NHCOCH,

NCOCH, sbccch ₂ nhco

NCOCH,

COKHCH ₂ CH ₂ OH

NHCO (CH ₂ ) ₃ NHCO

CONHCH ₂ CH ₂ OOCCH ₅

NHCO (CH ₂ ) ₃ NHCO NCOCHj

J CH,

NHCO (CH ₂ ) ₅ -HHCO

COOH

COOH

14 »

CH ^ NHCO

NHC0CH ₂ NHC0

-NH,

COOH

1 * ΎοΥ! o

CH ^ NHCO> \ .XnHCOCH ₂ NHCO

CHjNCOCH,

NHCOCHjNHCO '

CONHCH, 1 r '·.

-'J

Xhcoch,

1ЧБ

COOH j γ'ο'Ύ ^J

CH ₃ NCOCH ₃

CONHCH,

CH.NHCCT ^ / ^ NHCOCH, NHCO

CHjNHCO

NECOCH ₂ NHCO

NHC0CH ₂ NHC0

CH, NCOCH, J 1 J

NHCOCHgNHCO ·

NH,

CONHCH,

Y ^J

I

Ajcoch,

I i

C H, la

COOH

CH, C0H (X \. NHCOCH-NHCO ^ x ^ XNC0CH, 3 r 2 II ⁵

J J CHj

COOH ' ^L

RH, t 2

20a

CH ^ COHNHHcocH ₂ : raco A ^ .- ^ ncocHj

COOH

CONHCH,

SiCOCHjNHCO J ch ₃

J 'KCOCH,

COOH

λ.

CONHCH

21a * T r ~ \ f o

RC0CH ₂ NHC0 - _x NH, CH,

COOH hoch ₂ ch ₂ nhco

co (ch ₂ ) ₃ nh »

CONHCH

CONHCH,

COOH ¹ 'θ X

CH ₃ CONH - ^ \ / BHCOCH ₂ NHCO 'NCOCH, I and 3

J CK,

COOH! C i i

CONHCH,

26a ch, co;

> ^C ° k

NHCOCH ₂ NHCO NHCOCHj

CH, CON ⁵ CH.

ONHCH nhcoch ₂ nhco

OOH

CHjNHCO 'nhcoch ₂ nhco

CONHCH,

COOH

CONHCH,

CONHCH,

'NHCOCHjNHCO

CH, NHCC ^ \ / ^ NCOCH-NHCO 3 ri ^z

J CH,

HCOCH,

CONHCH,

CONHCH,

COOH

NCOCH., NHCO I 2 ch ₃ nhcoch ₂ nhco NH ₂

NHCOCHjNHCOCONHCH,

CONHCH, 'NHCOSH ₂ NHCC

COCH,

J ^CH 3

COOH

J x J 'n pONHCEj J X / J

C ONHCH ₃

J '.

: r-.

nhcoch ₂ nhco • - 'NCOCHj

J CH ₃

COOH

J Χ-Χ

CONHCH,

CH, tiHCO ^z '. . ^x NHCCCH NHCO X. · ΉΗΟθ (0ΗΟΗ) ςΗ

J t

COOH

H0CH ₂ CH ₂ HNC0 '

Λ χΧχ · 'J

Ί O;

nhcoch ₂ nhco

CONHCH,

X · c NHCO (CHOH) ₅ H

CONHCH,

COOH

J. 'J

CHjNHCO

NCO (CH ₂ ) jNHCI CH, or ^J

COCH,

J ^CH 3

HOCH ₂ CH ₂ HNCO

HOCH ₂ CH ₂ HNCO

NC0CH ₂ NHC0

JONHCH,

ncoch ₂ nhco 'ΧγΧ'ra ₂ J CH ₃ j

COOH

CHjNHCO

CHjNHCO-

CONHCH ·

nhgo (ch ₂ ) ₂ nhco

CONHCH, <χ. ·>

and o 1

NHCO (CH ₂ ) ₂ NHCO XXX N-COCH ₃ CHj J CHj

COOH

CCNHCH, nh ₂ co - \ ^. ^ Nhcoch ₂ nhcc

'rof a ₂ CO' ^^ SHCOCHjSHCO - ^ / TiHCOCBj

COOH jAj

CCNH,

CH ^ ilHCO ^z \ / ^ N-COCH ₂ NHCO ^/ \ z 'NHj J CH, \ (44a)

CH

COOH

CONH, · .'J (44) ^ NHCO / fl N-COCHgNHCO ^ζ γ HHCOCHj

J CH,

CHjNHCO

COOH J / P J io:

CH, -N-COCH, J / \ / J (45 »)

N-COCHgNHCO J * ^H 3

NH,

COOH

Jv '^ J iO ch ₅ -n-coch ₃

J pYj

O;

(45)

CHjNHC '

N-COCH, NHCO I 4

CH,

NHCOCH,

COOH CONHCH, CH „OCOCH, i i 2 2 3 j / \ / J

N-COCH, NHCO Λ. 'CH,'. COCH,

CHjNHC

N-COCH, NHCO and ²

2ONHCH ₂ CH ₂ OH (46 «(46)

COOH

Jx / vJ! Rv

CONHCH,

J / v J

Oh

CH, NHCO'V ¹ N-COCH, NHCO ^Λ · - / NH, (14 «)

T ¹ and ^J CH,

COOH

J

CONHCH,

J \ / 'with J

CHjNHCO /

CH.OH

Pi ¹

N-COCHgNHCO A / NHCO-CH-CH2

CH,

CH ₂ OH (47)

COOH CONHCH, j / \ - J J _Z J · 'N-CCCH ₂ NHCO>., _Z / 'NHC0 (CH0H) ₅ H J CH ₃ j

(48)

D. Solution of injection solutions

Pharmaceutical grade injectable solutions are made in the form of methylglucamine or sodium salts and contain 28, 38 or 48g of iodine per 100 ml (so-called 28, 38 and 48% iodine solutions).

After being charged to ampoules under a nitrogen atmosphere, the product is sterilized by 2 heating at 120 C for 20 minutes.

Table VII presents the data, that is, the results of measuring the viscosity of a solution of methylgucamine salts of 2% at 3 C. These results show that the compounds of formula II, in contrast to cd of what can be expected, have, when dissolved, relatively low viscosity.

Table VII

The compound o

Viscosity at C in centipoises

5.4

6.56

5, ^ 2

5.2

5.5

5.8

5.2

The results of osmolarity measurements are given in Table VIII.

Osmolarity measurement

The magnitude of the osmolarity is obtained by extrapolating the figures obtained by successively diluting the solution with 28% and 38% iodine.

Osmolarity is determined using the FISKE osmometer model 230 / D / 330 D.

This apparatus gives these sizes in myosmol per kilogram of solution. The device works on the principle of cryoscopy.

Measurements are made in solutions of 28% iodine.

Table VIII

Foods- her Osmolarity mosmo / kg The compound Osmolarity mosmo / kg 1 510 17 200 2 475 18 390 3 550 19 500 3a 395 20 5 490 3? ^ 30 6 480 21 580 7 525 2 3 535 8 535 36 635 9 440 24 575 10 420 25 925

11 390 26 500 14 600 16 250

a * 1410 * a, b and c are the following products to which b * 1390 c * 950

a. Triiodo-2,4,6-N-methylcarbamoyl-3-acetamido-5-benzoic acid b: Triiodo-2,4,6-N-hydroxyethyl-carbamoyl-3 acetamido-5-benzoic acid c: Adipoildiimido-5,5 ^1- bis- (triiodo-2,4,6-N methylisophthalamine)

The compounds of formula II are obviously, when in the form of methylglucamine salts, have an osmolarity that is less than the osmolarity of the product referred to.

The results of advanced toxicological and pharmacological studies follow.

Determination of acute toxicity

Toxicity to mice by intravenous administration This determination by vein delivery is performed on IOPS mice, an OFI strain, of a Swiss breed.

Each dose is injected into a group of 10 mice, of which 5 are males and 5 females.

Injections are given manually, in the neck vein, at a rate of 2 ml / min.

Mortality is determined 24 hours after the injection.

Tests for elimination via the bile or the biliary tract in cats

The test is performed on adult cats, males or females weighing cd 3 to 4 kg.

The product is administered intravenously at a dose of 0.10 g / kg iodine, into the internal vein of the leg. Elimination of the product is monitored by radiological control.

Shots showing gallbladder and bladder are taken at the following intervals:

minutes, 3 hours, 2 hours, 3 hours, 4 hours, 5 hours and 6 hours.

The effect on the enlargement of the femoral artery

The test is performed on dogs of impure race, males or females, 7 to 12 kg body weight, anesthetized with Nembutal.

Nembutal is used in an amount of 30 mg / kg with the prior administration of Vetranouil (a 2.5 mg intravenous injection); respiration is spontaneous.

Tests for the variation of artery expansion are performed at the level of the right and left femoral arteries using an electromagnetic sensor.

Injections are given collaterally from the femoral artery, dissenting from the sensor, using a catheter that is placed retrograde to prevent blood leakage.

The injections are of a constant volume of 1.5 ml and are administered over a period of 3 to 5 s.

The same volume of isotonic sodium chloride solution is also given.

The results obtained are shown in Table IX.

Table IX

Foods- Content Acute flow- Peripheral Eliminate- her *? injeke- sichnost u vasodila- a dream is and is- mice code tation billiard- that salt intravensk- femur nim tra- of giving of the artery who u g iodine / kg cats, intra- venous

0, 10 g / kg J

1 38% Mgl 11.5 + + 2 28% Mgl 9.5 + 0 3 28% Mgl 9-10 + 3a 7 + 5 6,8 ++++ + 6 28% Mgl 10 + 0 7 28% Mgl ++ 0 8 ah 12 ++ + 9 38% Mgl 11.5 + ++ 10 28% Mgl 1.5 ++++ ++++ 11 28% Mgl 2.3 ++++ +++ 14 28% Mgl 12 + + 16 28% Mgl + 0 1? 28% On ++ 0 18 28% Mgl ++++ ++++ 19 28% Mgl ' 4 ++++ ++++

28% and 38%

On

7.5

21 20% Mgl 4 to 5 4- + + + + + + 23 28% Mgl 3.5 +++ ++ + + 24 28% Mgl 8.5 + 0 25 34% On 9 + + 0 26 38% On 1? ++ 0 35 23% Mgl 8 + + 0 36 28% Mgl 8 ++ 0 V 28% Mgl 6 + +++ ++ 58a 4 + + + a 28% Mgl 5.4 ++ + 0 b 30% Mgl 5,6 + + + 0 c 28% Mgl 6.2 + + 0 d 38% with Mgl i The mixture 5, ¹ ++ + 0 P 28% Mgl 2 + + + + ++++ a: Trijodo-2,4, -5-benzoic , 6-methylcarbamoyl-3 acid -acetamido-

b: Triiodo-2,4,6-N-hydroxyethyl-carbamoyl-3-acetamido-5-benzoic acid

C; Adipyldiimino-5,5'bis (triiodo-2,4,6-N-methylisophthalic) acid d; Triiodo-2, 4, 6-bis (acetamido) -3,5-benzoic acid is: Adipoildiimino-3,3'-bis (triiodo-2,4,6-amino-benzoic acid)

According to the invention, the compounds of formula II can be used as contrast agents for radiological purposes.

The main purpose of these compounds is in urography, angiography, cholangiography and myelography.

The pharmaceutical formulations of contrast agents, for example, are aqueous solutions of salts of the compounds of formula II.

Aqueous solutions preferably contain from 5 to 100 g of salt per 100 ml, and the amount of these injectable solutions can vary from 5 to 1000 ml.

οΐξΐκ ^ ⁵ ! -CO (0Hj) NH

As the best way to commercially use the claimed invention, the applicant states the following;

Preparation of triiodo-2,4,6-N-hydroxyethylcarbamoyl-3-triido-2,4,6-N-methylcarbamoyl -? - N-methyl-N acetylamir.-5-benzoyl-glycylamino-5-benzoic acid

a) Condensation:

165 g (0.25 mol) of triiodo-2,4,6-N-hydroxy ^, tilcarbamoyl-3-amin-acetamido-5-benzoic acid was suspended in a mixture of dimethylacetamide (250 ml) and triethylamine (58.50 g ). To this suspension was added 16 ¹ g of triiodic-2,4,6-N-methyl-carbamoyl-3-N-methyl-N-acetylamino-5-benzoic acid o (0.25 mol) chloride. The mixture was stirred vigorously at 50 C for 6 hours. Thin-layer microscopy (HTS) has shown that less than>% of the starting product remains.

The solution is poured into 1240 ml of water. An insignificant precipitate is created, which becomes clear. Hydrochloric acid is added to the filtrate to a very acidic pH, then it is washed and washed with water and dried at 80 C. The 186 g of crude product is debuted, making a cd yield of 61%.

Cleanliness control:

HTS elu <= nt 1

1. Rf of starting amine 0.05 R1 'acid chloride 0.80

The condensation product Rf is 0.15

2. Purity of product after addition of sodium carbonate 95%

Product purity after the addition of methylate 98.5%

Product purity after iodine addition 9 ^Ί %

b) purification:

It is obtained by crystallisation by warming in ethanol at 95 _q C. 186 g is suspended in 400 ml of ethanol at 95 C and kept under reflux, after 5 hours, a five-hour dissolution occurs, and then the product crystallizes. Total warm-up takes 36 hours. It is then allowed to cool.

After straining, the wet product is dissolved in 400 ml of water and sodium carbonate. pH se. adjust to 4-5 with acetic acid and pass through twice through charcoal. it is filtered and then acidified to a strongly acidic pH with concentrated hydrochloric acid.

Filtration, washing with water, straining and drying gave 115 g of pure product, yielding 62%.

Cleanliness control:

1. HTS as in concentration

2. Product purity after addition of sodium carbonate 101%

Product purity after addition to methylate 98,5%

Product purity after iodine addition 100,5%

Claims (2)

PATENT APPLICATION A process for the preparation of 2,4,6-triiodo-5- (2,4,6-triiodo-5-amino-benzoyl) amino-alkyl-carbonyl-amino-benzoic acid of the formula "OH" (ioti in which R represents an atom hydrogen, a radical of the formula -CO-NH-R wherein R is hydrogen, methyl iii - a C ₂ hydroxyalkyl group, or a radical of the formula - ^R 7 N. where R and R are independently, hydrogen, acet '8 ^K 8 or iii methyl group, R represents hydrogen, a radical of formula -CO-NH-R where R _{g is} hydrogen, methyl iii -CHCH OCOCH group, or a radical of formula ^R n ./ 11 -N where hydrogen or an acetyl group, ar ^ is hydrogen or a methyl group, R is a radical of the formula -CONHR _g in which R _g 'is a methyl group iii x ^R 11 is a radical of the formula -N where R ^, acetyl, ^R ^ ₂ 'methyl group, R is hydrogen or methyl group, R ^^ is hydrogen or acetyl group, R ^^ is hydrogen atom, methyl or acetyl group, and is 0 or 1, n, is an integer from 1 to 5, n ₂ is 0 or 1, b is 0 or 1, and salts thereof with pharmaceutically acceptable bases having the amine of the formula _; 5 'ToT''ί ΎοΓ i SO ^^^ KK-OOCCH ^) Mii -K ^s ύ * ii. ² ; b <> v ») in which R ^, R ₂ ', R ₄ , n ,, n ₂ , aib have the meanings given above, reacts with an acid chloride of the formula.-coALAir; '\ n. (Vo) in which R ₂ , R ₁ and R ₂ have the foregoing meanings, wherein the reaction is carried out in polar solvent at a temperature of from 20 to 60 C and in the presence of an acid acceptor, and that the acid of formula II with a pharmaceutically acceptable base produces a pharmaceutically acceptable are. 2. The process of claim 1 wherein the polar solvent is dimethylacetamide and the acid acceptor is triethylamine. Published and printed by: Federal Patent Office, Belgrade, Uzun Mirkova 1