DE1643440C - 2,4,6 Tnjod 3 (N 2 hydroxyathyl) carbamyl 5 acetaminobenzoic acid and salts thereof and processes for their preparation - Google Patents

Description

■ Example

a) 5-nitro-isophthalic acid monoethyl ester (III) and their water-soluble carboxylic acid salts. .... ,.

2. Process for the preparation of the compounds 15 422 g (2 mol) of 5-nitroisophthalic acid (II) are used in according to claim 1, characterized in that 50 ° C in 1470 ml of an ethanolic 1 5-n-baIzic acid is dissolved in a manner known per se and the solution is stirred for 7 hours.

a) 5-Nitro-i "> phthalic acid (II) with a lower one

^ Mono- SrSrJe ^ Ä ^ neSt

Let the ethanol lamb work in £ _d . _{5 Ljter a 9 "strength} Nairiumr-

c, the obtained 3- (N-2-hydroxyethyl) -carb- ™ _n ^e _a ⁿ _t . _Solution suspended. After one hour.v.

amyI-5-nrobenzoic acid (IV) to give the hydrochloric acid, filter the solution and acidify the acid

The chloride of the corresponding 5-amino acid (V) is filtered and the solution is filtered

^K 25 with dilute sabic acid up to pH 4. uer nieroei au-

reduced. falling bsi = '(III) becomes after separation water:

d this to the 2,4 6-tri-iodine compound (VI) iod.ert, £ _{knead and} * _a J _ethano , _U mcrystallized. Leverage c

e) in the latter the 5-amino radical is acetylated, ^ ' _{212 (4? e /} ^ _{pp = J6r c} neutral equivalent 23>.

and given ^r ills a weakly alkaline hydro- The filtrate of the bicarbonate solution is the dieth>.: -

analysis and salt formation. 30 ester of (II), which by boiling in 2N sodium bicarbonate! Au} v

and subsequent acidification to pH ¹ to the freu π

Acid (II) can be saponified. From the Niedc

blow separated mother liquor is still not the

The invention relates to 2,4,6-triiodo-3- (N-2-hydroxy-converted acid (II) available, a total of 190g (lh. äthyO-carbamyl-S-acetaminobenzoic acid (I) (cf. the 35 that can be returned to the process. Drawing) and diren water-soluble carboxylic acid, _, ... , «-." "

Salts and their manufacture. These compounds are b) 3- (N-2-lydroxyatbyl) -arbamyl-5-n, tro-

as a shadow creator in radiography, especially benzoic acid (Iv)

especially in uro- and angiography, usable. 239 g (1 mol) of the ester (HI) become 405 ml of one

According to the invention, the acid (I) is added to the 40 30% aqueous solution of ethanolamine (2 mol) in the scheme shown in the drawing in the manner shown. After 3 hours heating at 7O ⁰ C, poured found that, in per se known manner, 250 ml of water in the solution is stirred for one

^a) A'SoÄettT ^{(I!) with a lower one}

b) iüf the SSTMonoalkytaler (III) Mono- « *« »^ **" ** * " precipitate separated lets geethanolamine act, V *** ^ ΓΤΪ · l" t 9 ^ *

c) the obtained 3- (N-2-hydroxyethyl) -carbamyl- ^F P " ^{== 186 C} · Neutralaqu.valent = 252. 5-nitrobenzoic acid (IV) to the hydrochloride of _c ) 3- (N-2-hydroxyethyl) -carbamyl-corresponding 5-amino acid (V) reduced, 5-aminobenzoic acid hydrochloride (V)

Licher "temperature with stirring to 235 ml of a and optionally a weakly alkaline? hydrolysis 4O ° / o solution of ammonium sulfide in the way that as well as performing the usual salt formation. the temperature of 40 ⁰ C nichi Ub ⁰ Isteigt. After 3stündi-

In process step a) the work is to be in 55 like stirring into the heated to 100 ° C Löfung 1.5 N hydrochloric acid at about 5O ⁰ C within about 7 STUN ammonia and ammonium sulfide in excess eingeden orteilhaft. directs. The solution is then acidified to pH ¹

Process stage b) is advantageously carried out using concentrated hydrochloric acid. The sulfur is removed from the aqueous medium at 50 to ⁰ O ⁰ C by. spun off hot solution. The Hydrochloride (V)

For the iodination in stage d), preference is given to using 60 crystallized from the cooled solution, the ab-iodine chloride in acidic medium. centrifuged crystals are dried. yield

In the last stage e) all suitable acetyls are 90.3 g (78 ° / ₀ ), melting point = 205 ° C. funds applicable, z. B. acetyl chloride and vinegar- _ .. ,,,, .. ....,. . ,

Acid anhydride. Since these .Agent itself but also with the ^d> 2,4,6-Tr _l iodine-3- _(N-ox? Thyl) -carbamyl-

Hydroxyl radical of 3- (N-2-hydroxyJithyi) -carbamyl- 65 5-ain.nobenzoic acid (VI)

Group can implement, it is appropriate to 52.1 g (0.2 mol) of the Hydrochloride (V) are in

subsequent to the acetylation, a weakly alkaline 460 ml of an O, 5N hydrochloric acid dissolved and carried out to dissolve with hydrolysis to the optionally 40 ⁰ C 136 ml of a 70 weight percent / volume percent

Iodine-containing Jodchloridlösung, which was obtained by dissolving anhydrous iodine chloride in fiO ^o / "hydrochloric acid was added. This is followed by heating 1> / while stirring. ₂ hours at 85 ° C., then at 95 ^° C. overnight. The excess iodine is converted into sodium iodide by adding a sodium bisulfite solution. The centrifuged acid (VI) is washed with water and dried. Yield 1! Q «(W ⁰ /) mp = 246 ° C., iodine content: found 70.9. calculated 71.2%!

10

e) acid (!)

60.2 g (0.1 mol) of the acid (V!) Are suspended at a temperature below 45 ° C. in a mixture of 75 ml of acetic anhydride and 19 ml of acetic acid. The suspension is gradually added, while maintaining a temperature below 45 ° C. and with stirring, with 18.5 ml of concentrated sulfuric acid (d 1.83); after a 1½ hour stirrer, at 45 ° C., the mixture is cooled 40 ml of ice water are added in such a way that the temperature does not exceed 45 C; 210 ml of a concentrated ammonia solution are added to adjust the pH to about 7 and then acidified with 200 ml of a hydrochloric acid. After standing overnight at 0 Γ, the gummy solid is spun off, -. •• Washed with water, then dissolved in 84 ml of a 5N sodium hydroxide solution and the solution is shielded at 40 C for 3 hours in order to After cooling, the solution is acidified with dilute hydrochloric acid, the precipitated acid (I) is centrifuged, watered and recrystallized from ethanol, melting point 345 ° C. 100 g of the acid (I) Iu ₅ : man in 100 ml of diluted ammonia, the solution sets 450 g of ammonium chloride are added, the mixture is left to stand and then 158 g of moist crystalline ammonium salt of the acid (1) are spun off. ! By dissolving the salt in water and precipitating it with dilute hydrochloric acid, the acid (I) is obtained in pure form. Yield 71 g (71%, calculated on the unpurified amount of acid), melting point = 349.degree. Neutral equivalent 640. Iodine content: found 58.8, calculated 59.16%.

Uses Pharmacological testing

When testing the above-mentioned solutions, some of the solutions were compared with analogous solutions of the iothalamic acid, which has hitherto been recommended as a shadow-forming agent, which is 2,4,6-triiodo-3-N-methylcarba; ayl-5-acetylamino-benzoic acid and is thus from the acid (I) through the CH ₃ NHCO group in the 3-position instead of the HOCH _; CH ₂ NHCO group is different.

1. Intravenous administration (I.V.) to mice:

The related Table II shows that the toxicity acid (I) and iothalamic acid are similar.

2. Intracerebral administration to mice:

Solutions of the methylglucamine salts of the acid (I) and iothalamic acid were determined by the method of T. J. H a 1 e \ and W. G. M c C o r m i c k (Brit. J. Pharmacol., 12, 1957, pp. 12-15; see also J. K. Kο d a m a and coworkers, Exp. and Molecular Path. Suppl., 2, 1963. pp. 65 to 80) compared with one another, using 0.05 ml doses, the concentration corresponding to the dose administered and used distilled water to dilute. The D.L. 50 for the salt was

45 iothalamic acid
Acid (I)

0.12 g iodine 0.25 g salt 0.12 g iodine 0.25 g salt

The abovementioned water-soluble salts of acid (I) are used in the form of their aqueous solutions. It is therefore unnecessary to isolate the salts from the aqueous reaction mixtures in which they are formed by neutralization of the acid (I) with the stoichiometric amount of the base. Two or more different bases can also be used at the same time, resulting in mixtures of corresponding salts which are advantageous in some cases. The salt solutions obtained, which may contain additives of preservatives, are ^{sterilized, for example, by heating at 110 °} C. for about 10 minutes and adjusted to a pH of 7.

The salt solutions conveniently contain 300 up to 1000 g / l of one of the salts or a mixture of different salts and are preferably used in amounts injected from 5 to 100 ml.

Table I shows the starting materials used for the corresponding preparation of various solutions, whose mixtures are made up to HXImI with distilled water. (Me: CJIu. = N-methyl-glucamide. Calc. Cem. = Disodium calcite tetracemate.)

3. Effect on arterial pressure in dogs and rabbits:

Various attempts were made with a more or less high injection speed (up to / u 12 ml / min) with doses of up to 3 g iodine / kg body weight without any change in arterial pressure.

4. Intn> carotid injection in rats:

After H. K u 11 and collaborators: (Acta Radio-Iogica, 5, 1966, p. 276) were rats anesthetized with about 380 g urethane, each 0.5 ml of a 48% Iodine-containing solution of the sodium salts of acid (!) And Iothaiamic acid are injected, whereby one repeated the injection every 5 minutes until the animal died.

Contractions of the limbs and neck were observed, which varied according to the strength of the injections enlarged. On average, the contractions did not occur until after the 4th injection of I-saline on, however, already ntxh the first or second injection of sodium iothalamic acid solution. Any acid would cause death at the latest on the tenth injection. The general toxicity is the same for both acids, however the local toxicity is Tolerance in sows (I) better.

Shadow-forming properties 1. Urography:

Three rabbits who weighed 2.5 to 3.5 kg, had fasted for 24 hours prior to the test and had not given up any water, were given solution (E) or (F) (see tables) at a rate of 12 ml / min injected into the peripheral vein of the ear. Roentgenograms were taken 5, 10, 20, 50 and 80 minutes after the injection. From the first admission, the basinets and urinary organs were shown

on. The chalices (calices) were no later than after 50 to Minutes visible. The formation of strong shadows in the urinary bladder continued.

2. Angiographic:

Any vascular injection of the product gives excellent results X-ray diagrams of the injected vessels and vascular organs.

Although, as noted above, intravascular injection is the preferred mode of administration which is benzoic acid derivative according to the invention can the latter can also be administered by the oral, retrograde or other route.

Comparative information on the effect is given in »Neuroradiology«, Vol. I (1970), pp. 101 to 106 and "Acta Radiologica", Vol. 8 (1969), pp. 535 to 546, published.

Table 1

solution Acid 1 47.4 2N NaOH
solution 2N-Me-GIu-
solution Ca (OH) ₁ CaCl ₁ Calc-Cem. % ι g 64.2 ml ml 8th G G (A) 28 64.2 0 36.9 0 0 0.01 (B) 38 64.2 49.8 0 0 0 0.01 (C) 38 81.1 19.4 30.4 0 0 0.01 (D) 38 81.1 48.4 0 0.210 0 0.01 (E) 48 64.2 63 0 0 0 0.01 (F) 48 63 0 0 0.40 0.01 (G) 38 0 31.2 18.55 (2n ethanol 0.01 amine solution)

Table II

solution

Me-GIu g / 100 ml

Salts of

Na g / 100 ml Approx g / 100 ml

Viscosity 37 ° cp

D.L. 50 I.V. on mice

0.5 ml / min iodine / kg I salt / kg

2 ml / min iodine / kg salt / kg

(A) (Jl) (B) (J 2) (C) (D) (E) (J 3)

(I ⁷ ) (G)

(I) jothalamine

(D jothalamin

(D (D (D Jothalamin

(D (I)

28 28 38 38 38 38 48 48 48

38

61.6 59.5

0 51.4

52.4

0.40 (CaICl ₂ ) 26.2 (ethanolamine salt)

66.4 63.3 25.7 63 83.6 80 83.6 4.4 4.3 4.4 4.3 8.6 4.4 9.4 8.5 9.4

8.2

8.8 8.25

11.25

12th

11.5

13th

12th

12th

12.1

12.5

19.4

17.5

19.7

20th

23.3

21.7

20.9

20th

21

26.8

5.5 5.4 7.8 7.2 7.7 10 7.5 7.8 8.75

7.5

15.5

1 sheet of drawings

Claims (1)

1 2 acetylated hydroxyl group -without the 5-amino group Claims: to deacetylate - to restore. 1. 2,4,6-triiodo-3- (N-2-hydroxyethyl) -carb- If salt formation is desired, the free amyl-5-acetaminobenzoic acid of the formula acid (I) in the usual manner, preferably in alkali 5 or alkaline earth metal salts or in salts of organic COOH _bases unguided. Preference is given to the national I _n or calcium as well as the methylglucamine or I - ^N , - ι ethanolamine salts. . I i! (I) The products obtained are in the form of their CH ₃ CONH ^> J- COHNCH ₂ CH ₂ OH _lo aqueous suspensions or solutions accumulated.