DE1643440B - 2,4,6-triiodo-3- (N-2-hydroxyethyl) carbamyl-5-acetaminobenzoic acid and its salts and processes for their preparation - Google Patents

Description

ι (I) The products obtained are in the form of their

CH ₃ CONH - * ^ / - COHNCHjjCHjOH ₁₀ Aqueous suspensions or solutions accumulated.

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 ⁰ C in 1470 ml of an ethanolic 1,5-N hydrochloric acid is known per se Way dissolved and the solution stirred at 50 ° C for 7 hours.

a) 5-nitro-isophthalic acid (II) with a lower then a solution of 350 g of sodium chloride in alkanol ^{semi-esterified 3 liters of water to} 'whereupon an oily liquid

b) on the resulting monoalkyl ester (III) Mono- ^{20 is} deposited, which crystallizes on cooling. The abäthanolamin lets act, ^tren " ^th ^ ^8t ?" E are neutralized with water

c) the obtained 3- (N-2-hydroxyethyl) -carb- ^was _u ^{chen un} . ^d dissolved ⁱⁿ 1.5 liters of a 9 ^O / _O Natnurnbiamyl-5-nitrobenzoic acid (IV) to the hydro carbonate solution suspended. After einstundigem chloride of the corresponding 5-amino acid (V) stirring the solution is filtered and the filtrate is acidified ^with dilute reduced ³ 5 hydrochloric acid to pH. 4 The here-

d) this iodized to the 2,4,6-triiodine compound (VI), ^falling , ^e ester (III) is watered after separation,

e) in the latter, the 5-amino group is acetylated ^sep ° ^'kn * Tl T umknstallisiert ethanol. yield

^J = 212 g (47 ° / _0), mp. = 162 ⁰ C, neutral equivalent 238th

and optionally a weakly alkaline hydro- The filtrate of the bicarbonate solution is the diethyl

analysis and salt formation. 30 esters of GI). that by boiling in 2N sodium hydroxide solution

and subsequent acidification to pH ¹ to the free

Acid (II) can be saponified. From the precipitation separated mother liquor is not yet the

The invention relates to 2,4,6-triiodo-3- (N-2-hydroxy-converted acid (II) available, a total of 190 g of (II), ethyl) -carbamyl-5-acetaminobenzoic acid (I) (cf. which can be fed back into the process.
Drawing) and its water-soluble carboxylic acid

Salts and their manufacture. These compounds are ^b > 3- (N-2-hydroxyethyl) -carbamyl-5-mtro-

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

Special in uro- and angiography, usable, 239 g (1 mol) of the ester (III) are 405 ml of a

According to the invention, the acid (I) according to the 40 30 ° / _o aqueous solution of ethanolamine (2 moles) is added in the drawing scheme shown in the manner of origin. After 3 hours heating at 70 ⁰ C., poured found that, in per se known manner, 250 ml of water in the solution is stirred for one

a) 5-nitro-isophthalic acid (II) with a lower half hour in the presence of charcoal and filtered. Half-esterified alkanol is mixed up with dilute sulfuric acid

b) acidified on the obtained monoalkyl ester (III) Mono- ⁴⁵ P ¹¹³ ″, the precipitate is allowed to act separately, washed and dried. Yield = 200 g (79 »/ _e ),

c) the obtained 3- (N-2-hydroxyethyl) -carbamyl- ^F P = ^{186 C} <neutral equivalent = 252.
5-nitrobenzoic acid (IV) _{reduced to the hydrochloride of c} ) 3- (N-2-hydroxyethyl) -carbamyl corresponding 5-amino acid (V),, 5-aminobenzoic acid hydrochloride (V)

d) this to 2,4,6-triiodo-compound (VI) jodierV ^{so on.,} "" / _{n x 1N} _, _o '

e) acetylated the 5-amino radical in the latter,. ¹ J ¹ g (°> ^{5 Mo1} ) of ^{the acid} < ^1V ) ^{sets raa} "* f ßf ^wöhn -

licher 1 temperature with stirring to 235 ml one

and optionally a weakly alkaline hydrolysis 40 ° / ₀ aqueous solution of ammonium sulfide to in such a way that, as well as performing the usual salt formation. the temperature does not exceed 40 ° C. After 3 hours

In process stage a) it is advantageous to work, after stirring, 1,5-N hydrochloric acid is added to the solution heated to 100 ° C. at about 50 ° C. within about 7 hours, ammonia and ammonium sulfide in excess. directs. The solution is then acidified to pH ¹

Process stage b) is advantageously carried out using concentrated hydrochloric acid. The sulfur is made from the in an aqueous medium at 50 to 90 ° C. 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 agents can also be used with the ^d) 2A6-Tnjod-HN-oxathyl) -carbamyl-

Hydroxyl radical of 3- (N-2-hydroxyethyl) -carbamyl- 65 5-ammobenzoic 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 added to the solution Carry out hydrolysis to the optionally 40 ° C 136 ml of a 70 percent by weight / percent by volume

Iodine-containing iodine chloride solution, which by Auf- „,,, - u ο ~ t

Solution of anhydrous iodine chloride in 60-year-old Sak pharmacology examination

acid was obtained, added. This is when the above solutions are compared when testing

while stirring 1 ¹ / · hours at 85 ° C, then at 95 ° C, some of the solutions with analogous solutions of the

over night. The excess iodine is removed by adding 5 iothalamin-

a sodium bisulfite solution in sodium iodide excess acid, which contains the 2,4,6-triiodo-3-N-methylcarbamyl-

leads. The centrifuged acid (VI) is washed with 5-acetylamino-benzoic acid and is thus

Water and dry. Yield 110 g (90 ° / ₀ ), mp. Of the acid (I) through the CH ₃ NHCO group in

= 246 ° C, death rate: found 70.9, calculated 71.2 ° / ". 3-position instead of the HOCH ₂ CH, NHCO group

ίο distinguishes,

e) acid (I) _L v _{Intravenous era} breichung (IV) in Mice:

60.2 g (0.1 mol) of the acid (VI) are in a The relevant Table II shows that the toxicity

Temperature below 45 ° C in a mixture of acid (I) and iothalamic acid are similar,

Suspend 75 ml acetic anhydride and 19 ml acetic acid

rtiert. The suspension is gradually added with ² x intracerebral administration to mice:

Maintaining a temperature below 45 ⁰ C solutions of the methylglucamine salts of the acid (1)

and while stirring with 18.5 ml of concentrated sulfuric and iothalamic acid were after the method

acid (d 1.83); ey after 1 VaStündigem stirring at 45 ⁰ C of a TJ H 1 and WG McCormick (Brit.

one cools down. 40 ml of ice water are then given in 20 J. Pharmacol., 12, 1957, pp. 12 to 15; see also J. K.

Assign that the temperature does not exceed ^{45 0 C;} Kodama et al., Exp. And Molecular

this is followed by 210 ml of a concentrated Ammo-Path. Suppl., 2, 1963, pp. 65 to 80) together

niac solution to adjust to pH equal to using 0.05 ml doses of the

about 7 and then acidify with 200 ml of a concentration corresponding to the dose administered

11 η-hydrochloric acid. After standing overnight, set it to 25 and add distilled water to dilute.

0 ° C, the gummy solid is spun off, used. The DL 50 for the salt was
washed with water, then in 84 ml of a 5N soda

dissolved alkali and the solution ER- 3 hours at 4O ⁰ C Jothalaminsäure 0.12 g of iodine, 0.25 g salt

^{warms to the acid which may} be formed in the 3-position 0 ° ^'12 8 ^iodine °' ²⁵ 8 ^salt

To saponify acetic acid ester residue. After cooling down 30

the solution is acidified with dilute hydrochloric acid, ³ - effect on arterial pressure

the precipitated acid (1) thrown off, watered ^{in dogs and} rabbits:

and recrystallized from ethanol, melting point = 345 ^° C. Various experiments were carried out with more or

100 g of the acid (1) are dissolved in 100 ml of the dilute injection rate of less than

Ammonia, adds 450 g of ammonium chloride to the solution, 35 12 ml / min) with doses of up to 3 g iodine / kg body weight

lets stand overnight and then flings 158 g through without any change in arterial pressure.

moist crystalline ammonium salt of acid (I). leads.

By dissolving the salt in water and injecting rats _{with 4 intracarotids:}
The acid (I) is obtained in pure form with dilute hydrochloric acid.

Yield 71 g (71%, calculated on the unpurified 40 According to H. Kutt and coworkers (Acta radio-acid quantity), melting point = 349 ° C, neutral equivalent = 640, logica, 5, 1966, p. 276) were rats which with about iodine content: found 58.8 calculated 59.16 ° / _0th 380 g of urethane were anesthetized, each 0.5 ml of a 48 ° / ₀

Iodine-containing solution of the sodium salts of the

Injected application forms acid (I) and iothalamic acid, whereby one

45 the injection every 5 minutes until death of the animal

For the application one uses the repeated ones mentioned above.

water-soluble salts of the acid (1) in the form of their Man observed contractions of the limbs and

aqueous solutions. It is therefore unnecessary to remove the salts from the throat, which differ according to the strength of the

Isolate the aqueous reaction mixture, enlarged in sections. On average, the

which by neutralizing the acid (I) with the 5 ° contractions only after the 4th injection of the I salt

stoichiometric amount of base are formed. solution, however already after the first or

Two or more different second injections of the iothalamic acid solution can also be used here

Bases are used simultaneously, creating mixtures of sodium. Any acid would cause death at the latest

Corresponding salts are formed, in some cases on the tenth injection. The general toxicity

are beneficial. The salt solution obtained is the same for both acids, but is local

if necessary, additions of preservatives ent- Tolerance in sows (1) better,
hold, for example, by about 10 minutes

long heating at 110 ° C and sterilized on a shadow-forming properties

pH adjusted to 7. _{1 <} Tjrography:

The salt solutions expediently contain 300 60

up to 1000 g / l of one of the salts or a mixture. Three rabbits weighing 2.5 to 3.5 kg while

of various salts and are preferably given in amounts 24 hours prior to the exam and were not fasted

injected from 5 to 100 ml. Had released water, the solution (E) or

Table I shows the corresponding manufacture (F) (see tables) with a speed of Various solutions used starting 65 injected 12 ml / min into the peripheral vein of the ear. X-ray materials, their mixtures with distilled water on grams were 5, 10, 20, 50 and 80 minutes after the 100 ml to be filled up. (Me: Eq. = N-methyl injection taken. From the first exposure

glucamide, Calc. Cem. = Disodium calcitetracemat.) The pelvis (bassinets) and ureters had shade

on. The calices became visible after 50 to minutes at the latest. A strong shadow formation in the bladder continued to advance.

2. Angiography:

Any vascular injection of the product gives excellent radiographs of the injected vessels and Vascular organs.

Although, as noted above, intravascular injection is the preferred mode of administration of the benzoic acid derivatives according to the invention. you can also use the latter on the oral, retrograde or ei Administer another route.

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

Table I.

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

Table II

solution

Acid%

Me-GIu g / 100 ml

Salts of

Na g / 100 ml approx
g / 100 ml

viscosity
37 ° cp

DX. 50 I.V. on mice

0.5 ml / min
Iodine / kg salt / kg

2 ml / min iodine / kg salt / kg

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

(G)

(I) jothalamine

(I) jothalamine

(D (I) (D jothalamine

(D (I)

28 28 38 38 38 38 48 48 48

38

61.6 59.5

0 51.4

52.4

66.4 63.3 25.7 63 83.6 80 83.6

26.2 (ethanolamine salt)

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

23.3

21.7

20.9

26.8

5.5 5.4 7.8 7.2 7.7 10 7.5 7.8 8.75

7.5

1 sheet of drawings

Claims (1)

τ, ^. -, acetylated hydroxyl group - without the 5-amino group claims: to divide up into acetylated hydroxyl groups. 1. 2,4,6 - triiodo - 3 - (N - 2 - hydroxyethyl) - carb- If salt formation is desired, the free amyl-6-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 Bases transferred. Sodium or calcium and methylglucamine or Ethanolamine salts.