FI67841C - SAOSOM ROENTGENKONSTRASTMELEL ANVAENDBARA IODBENSENDERIVAT - Google Patents

Description

1 67841 Iodobenzene derivatives for use as X - ray contrast agents

Separated by division of the application 75 1599 5

The invention relates to novel polyiodobenzene derivatives useful as X-ray contrast agents. In particular, the invention relates to novel compounds consisting of three triiodobenzene rings and one carboxyl group, which have low toxicity, which provide a good shadow effect and which can be prepared in industrially usable ways and which are therefore relatively inexpensive.

The formula of a compound having two triiodobenzene rings and one carboxyl group is already disclosed in U.S. Patent 2,708,678.

This formula is as follows:

COOH

20 JL / I I \ JL

XX XX

Ύ ^ NH-CO | NH 2

I I

25

However, all attempts to prepare this compound according to the method described in said patent failed under any working conditions.

The invention relates to compounds of formula (III) 2 67841 f2 5 cooh ch2-conh ^^^^ r3 1 j i / (111)

Rn T N-CO-CH "-N _.

1 1 2 \ i 2 10 1 R4 1 CH2-CONH R3 wherein radical is -CONHR8, wherein R4 is a (C1-C4) -alkyl radical or the radical ^ • R7 is -N, where R4 is {C1-C4- R 1) alkanoyl radical 3a R 9 R 8 is a (C 1 -C 4) alkyl radical, and R 2 and R 8 represent a radical -CONHR 8 having a (C 1 -C 4) hydroxyalkyl radical, R 4 represents a hydrogen atom or (O 4 -O 4) -alkyl-25 radical, as well as their salts with pharmaceutically acceptable bases.

As the salts of the acids of formula (III), mention may be made in particular of alkali metal (such as sodium and potassium) salts, ammonium salts, alkaline earth metal (such as calcium) salts and salts with organic bases (such as ethanolamine or methylglucamine salts).

Novel compounds of formula (III) may be prepared by reacting an amine of formula 3 67841

COOH

I. / k _ I

γΥ R £ ^^^^ N-CO-CH2-NH2 (IV) 5 I R4 to react with a compound of formula f2 10 * JL / 1 nT <vb>

Cl-CH2-CO-NH2 ^ Np X5R3 15 in which formulas R1, R2, R1 and R1 have the same meaning as above. This reaction may be followed, if necessary, by an N-alkylation, N-hydroxyalkylation, N-acylation or N-polyhydroxyacylation reaction, a deacylation reaction and also an esterification or salt-forming reaction in the usual manner.

Amines of formula (IV) (wherein R 4 = H and R 2 = H, -CONHCH 2 and NHCOCH 2) are described in U.S. Patent 3,210,412.

Amines of formula (IV) wherein R 4 is a hydrogen atom can be prepared by condensing an amine of formula

COOH

30 VV1, vi>

R1 Y NH2 I

4,67841 with a chlorine compound of the formula / co ~

Cl-CO-CH9-N () (VII) 5 * wherein R1 is as defined above, followed by the resulting condensation product of formula 10

COOH

1/1 15 R 1 NH-CO-CH 2 -N 2 (VIII) where R 1 means the same as or when R 1 contains a hydroxy group R 1 represents its acylation product with an acid chloride of formula VII, is hydrazinolysed.

The condensation reaction of the capped amine of formula (VI) with an acid chloride of formula (VII) is preferably carried out in a polar solvent such as dimethylacetamide or dimethylformamide at a temperature of 20-100 ° using an excess of acid chloride. The reaction time may vary from 2 hours to 4 days.

The hydrazinolysis reaction of a compound of formula (VIII) is carried out according to conventional methods using hydrazine in aqueous solution J.Am.Chem.Soc., 7, 1856 (1949), H.R.Ing. and R.F. Manske, J. Chem. Soc., 2348 (1926), Chem. Ber. 83 244 (1950)). Preferably a large excess of hydrazine (4-8 moles per mole of the compound of formula (VIII)) is used.

Amines of formula (IV) wherein R 1 is a lower alkyl radical of 5 67841 may also be prepared by reacting a compound of formula

COOH

5 'yV1

Y 1 R 2 / NSY 2 "V" nh-CO-CH 2 Cl 10 reacts with an alkylating agent to give a compound of formula

COOH

^ 1

XX

R 1 is NH-CO-CH 2 Cl 4 R 4 wherein R 1 is lower alkyl, after which the compound thus obtained is reacted with ammonia.

The reaction of a compound of formula (IV) with a compound of formula (Vb) is preferably carried out in an alkaline aqueous medium, for example using 1N sodium hydroxide in excess, at a temperature of 60-90 ° C. The reaction time may be 6 to 48 hours.

The following examples illustrate the invention.

The preparation of amines of formula (IV), derivatives of formula (Vb) and compounds of formula (III) is described in the following sections A, 3 and C, respectively.

In said examples, purity checks were performed: 6 67841 1. By thin layer chromatography (TLC) using a fluorescent silica gel plate (Merck F 254 in the following eluents: 1 - benzene / methyl ethyl ketone / formic acid (60:25:20) 2 - ethyl acetate / ammonia / isopropanol / isopropanol) 35:40) eluent 2 3 - ethyl acetate / isopropanol / ammonia (35:35:40) eluent 3 10 4 n-butanol / acetic acid / water (50:11:25) eluent 4

Note: with certain TLC eluents (especially eluent 4) it is possible to prove the existence of an N-methyl-N-acylaminobenzo group contained in different isomers of acids.

The pure mono-N-methyl compound of formula (III) gives 2 spots (slightly separated but clearly detectable) and in acid-varying proportions and the di-N-methyl compound gives 3 spots.

20 2. According to the following purity determination: 1 - halogen titration 2 - carboxylic acid titration back with sodium trihydroxide 3 - mobile hydrogen and carboxylic acid titration with sodium methoxide in anhydrous solution in the presence of azoviopropyl 4 - carboxylic acid titration in dimethylformamide solution in dimethylformamide tetrabutyl Titration of 5 - aliphatic amines using perchloric acid in acetic acid.

A. Preparation of amines of formula (IV) 7 67841

Example 1 Preparation of 2,4,6-triodo-3-N-methyl-carbamoyl-5-N-methyl-N-aminoacetylamino-benzoic acid (Compound 8) a) 2,4,6-triiodo-3-N-methyl- carbamoyl-5-N-methyl-chloroacetamidobenzoic acid:

Dimethyl sulfate (380 mL, 4 moles) is added dropwise at 5-10 ° C to 2,4,6-triiodo-3-N-methylcarbamoyl-5-chloroacetamido-benzoic acid (1300 g, 2 moles) (U.S. Patent 3,210,412) in a solution of 2N sodium hydroxide-10 (2 liters). After the addition is complete, the reaction mixture is allowed to warm to room temperature and stirring is continued for a further 20 hours. The reaction mixture is then filtered, a small amount of insoluble matter is removed and the substance is acidified to pH 1 with concentrated hydrochloric acid. The precipitate obtained is filtered off with suction, washed repeatedly with water and dried at 60 ° C. Purification is performed by dissolving the crude product in 900 ml of 2N sodium hydroxide and salting out with sodium chloride (1000 g). After stirring for 24 hours at room temperature, the precipitate is filtered off with suction and redissolved in water (2500 ml). It is then filtered and acidified to pH 1 with concentrated hydrochloric acid. It is then washed repeatedly with water, filtered off with suction, dried at 60 [deg.] C. to give 672 g of product (yield 51%).

Purity check: 1) TLC eluent 2 starting material Rf: 0.1 methyl compound Rf 0.2 and 0.25 (2 isomers) 2) purity: iodine titration: 97%, chlorine titration 104% b) 2,4,6-triiodo-3 -N-methyl-carbamoyl-5-N-30 methyl-N-aminoacetylamino-benzoic acid.

The acid prepared above (314 g, 0.49 mol) is dissolved in 3500 ml of concentrated ammonia and the solution is heated at 60 ° C for 20 hours. After evaporating the solution to dryness in vacuo, the substance is dissolved in 300 ml of water and acidified with sulfur dioxide. It is then left to crystallize in a refrigerator for 48 hours, filtered off with suction, washed repeatedly with water and dried in an oven at 80 ° C to give 160 g (yield: 51%) of product. Purity check: i) TLC eluent 3 Rf of the product obtained: 0.75 2) Purity: titration with sodium hydroxide, 102% purity with sodium methoxide: 98%.

Example 2 2,4,6-Triiodo-3-N-methyl-N-acetylamino-5-10 aminoacetamidobenzoic acid (Compound 13) a) 0.3 mol of 2,4,6-triiodo-3-N-methyl- N-acetylamino-5-benzoic acid (U.S. Patent 3,178,473) is dissolved in 300 ml of dimethylacetamide. 170 g (0.76 mol) of phthalylglycine are added dropwise while cooling in an ice bath. Stir overnight at room temperature and then dilute the reaction mixture with 1000 ml of water to form a precipitate. The product obtained is filtered off with suction, washed several times with 95% ethyl alcohol, filtered off with suction and dried in an oven to give a white solid.

b) 0.20 mol of the product obtained in a) is suspended in a mixture of 600 ml of water and 60 g of hydrazine hydrate and the suspension is heated at 80 ° C for 2 h, during which time dissolution occurs. During the reaction, crystallization occurs. After cooling and suction filtration, the crude hydrazinolysis product is purified by dissolving (267 g) in 550 ml of dilute sulfuric acid (1/10) at 80 ° C.

It is filtered hot and 25 g of phthalic hydrazide are removed 30

fycV

/ nh 35 9 67841

The sulfuric acid filtrate is treated with carbon and neutralized to pH 4-5 with ammonia. It is then crystallized, washed repeatedly with water, filtered off with suction and dried in an oven at 70 ° C and then at 105 ° C to give 211 g of a white substance.

3) 390 g of a white substance of the same quality as the above-mentioned 211 g are obtained by treating the hydrazinolysis liquid with hot sulfuric acid.

10 Table I

Amine Triiodo- Condensation Hydrazinolysis starting product amines obtained

Rf Life- Rf Life- Yield Rf Life- Rf Life- Yield! 15 ex 1 ex 1 ex 1 ex ex 2 '------- ^ -, 13. 0.65 0.4 90% 0.05 0.45 66% 0.53 ___ | 20

Table II

Amine 'Triiodic- Condensation product Amine 1 starting! substance 25 -----

Rf life- Rf life- Rf life yield Rf life- Rf life yield in former 2 teas 2 teas 1 former ex 1 1 -1 ------ 8 0.1 0.2 and 0.5 51% of life - 0.75 51% 30 0.25 tis 0.3

Table III summarizes the formulas of the prepared amines of general formula IV.

10

Table III 67841

COOH

I I

Χϊ 3 CH 3 NHCO 2 | / V '' 'NHCOCH 2 NH 2 10

COOH

I I / 1

jY

8 CH3NHCO2 ^ NCOCH2NH2

CHV

I J

20 25

COOH

I I I

XX

30 13 CH3CON ^ V'Y / V '' '' 'NHCOCH2NH2 CH3 τ 67841 B. Preparation of Formula Compounds

Example 3 Preparation of 2,4,6-triiodo-3,5-bis- (N-hydroxyethylcarbamoyl) chloroacetanilide 2,4,6-triiodo-3,5-bis- (N-hydroxyethylcarbamoyl) -aniline (645 g, 1 mol) (described in FR Patent 1,172,953) is dissolved in 2 liters of DMAC (dimethylacetamide) at room temperature. Chloroacetyl chloride (430 mL, 6 moles) is slowly added to the solution at the same temperature.

1C The completion of the reaction is checked by thin-layer chromatography on a silica gel plate in ethyl acetate / isopropanol / ammonia (55:35:20). Rf = 0.5. The reaction mixture is poured into water (6 liters) to give a very fine white precipitate which is preferably not filtered off with suction. After washing the precipitate with water, the resulting 2,4,6-triiodo-3,5-bis- (N-chloroacetoxyethylcarbamoyl) -chloroacetanilide is saponified by stirring with 2-n sodium hydroxide at room temperature for 2 hours and then at 40 ° C: within two hours.

Chromatography on a silica gel plate in the same eluent: Rf = 0.35.

The reaction mixture is cooled and neutralized with concentrated hydrochloric acid (100 ml), and stirring is continued overnight at room temperature, after which it is filtered off with suction, washed with water, filtered off with suction and dried overnight at 60 ° C to give 672 g of product (yield: 93 %).

Purity check: sodium methoxide titration: 105% iodine titration 99% chlorine titration 102.8% C. Preparation of compounds of formula (III)

Example 4 2,4,6-Triiodo-3-N-methylcarbamoyl-5- [N, N-bis- / 2,4,6-triiodo-3,5-bis- (N-hydroxyethylcarbamoyl) -35-phenylcarbamoylmethyl] aminoacetamido Preparation of benzoic acid (Compound 31) 12,67841 2,4,6-Triiodo-3-N-methylcarbamoyl-5-amino-acetamido-benzoic acid (126 g, 0/2 moles) (Compound 3 solution 1-n in sodium hydroxide (220 ml) is stirred with a solution of 2,4,6-triiodo-3,5-bis (N-hydroxyethylcarbamoyl) -chloroacetane-5-ylide (288 g) in 1N sodium hydroxide (400 ml) and heating is continued at 85 ° C. The solution is cooled to 20 [deg.] C. and acidified to pH 1. The resulting gum crystallizes on standing overnight at room temperature, the solid is filtered off with suction, washed with water and dried to give 280 g of crude acid. The crude acid is taken up in water, the pH is adjusted to 7 with ammonia, a small amount of insoluble matter is filtered off and the product is acidified to pH 1 with dilute (1/10) hydrochloric acid. water and dried to give 224 g of crude acid.

Titration with sodium hydroxide: 112%

Purification: 1. Ammonium salt: 224 g of acid are taken up in 150 ml of 20 ml of water. Ammonia is added until the solution is neutral.

Crystallization occurs. The substance is stirred for 24 hours at room temperature. The precipitate is filtered off with suction, washed with water and then taken up in 10N sodium hydroxide until complete dissolution. This is then precipitated with hydrochloric acid, filtered off with suction, washed with water and dried to give 155 g of acid.

Titration with sodium hydroxide: 107%.

2. Methylglucamine Salt: A methylglucamine salt solution containing 28% iodine is prepared from 155 g of the thus obtained. The insoluble matter is removed by centrifugation and filtration through a millipore filter.

The filtrate is acidified to pH 1 with hydrochloric acid. The precipitate is filtered off with suction and this treatment is repeated once to give 74 g of acid (total yield: 18.5).

35 Check the purity of the product as follows: 67841 TLC, silica gel plate, n-butanol / water / acetic acid (50:25:11) eluent:

Chlorine starting material Rf 0.75 Starting amine Rf 0.25 5 Condensation product Rf 0.25 - Titration with 0.1 N sodium hydroxide 103% - Titration with sodium methoxide 100% - Iodine titration 97% 32) 2,4,6-Triiodo-3-N-methylacetamido Preparation of -5-bis-10β / 2,4,6-triiodo-3,5-bis (N-hydroxyethylcarbamoyl) phenyl / carbamoylmethyl] aminoacetamido-benzoic acid (Compound 32) Using the procedure described for compound 31 using amine 13 amine 3 stations.

33) 2,4,6-triiodo-3-N-methylcarbamoyl-5-bis- [2,4,6-triiodo-3,5-bis- (N-hydroxyethylcarbamoyl) -phenyl] carbamoylmethyl] amino-N-methyl Preparation of acetamido-benzoic acid (Compound 33) The procedure described for compound 31 is used using amine 8 instead of amine 3.

Table V summarizes the characteristics associated with the preparation of the compounds of formula I and the compounds obtained. The formulas of the compounds are shown in Table VI.

Γ7 ^ I Τ Γ ^ Τ 67841 3 tn c ro H ui un m a) tn tl) -H • 'T (N into 3 to

-P - * »· rH * H

mc o oo ni-p OS 0) I (0 m -—-

3 W -n ID

h tn · —-

0) -H Τ- ΓΟ to LO

-μ r ~ τ- OJ

't i C ** »- to OS <D o o c -

dP

in dP

l "3 dP" O

Γ 'oo o σο (Ti 1— tfl dP -.

S df> m do o 0 o - τ- m 0) O 00 o S <- (Ti «- o ΓΜ U) _______ 3 o

(tj dP ID

p K · #> m -PO is' - «#>

-H f O O CO 00 -H

H JS r- σι o 4 *> ___ nj

•B

c o o o +> ε {<c g rO dP dP dP rtj K ro ro in co tn tn ro ^ ro -h

D 3 -H

t-t o -------

Cl tn cn to C

-H | «0 (0 ro D T3Q) E + K -P + Oi

JS C Ή <* O P O

C 3 φ <u a -p φ a p a a +> a w m z a h o _______tn

•B

1 (0 rö -—-

Cl tn -n vo -H

h tn tn m

Φ · ρ m i · η ro uo m O

-P (N 3 4-> '«T r-« - (N— C

m C ro * «m C *« · * · id (0 PS Φ tn o φ Φ oo o'— -p 3 ------ Xl o I o tn td -P -h

M C dP dP dP

rö rO id oo 'T ro (0 tO in co oo tn OS tn tn

B

______4J

C

I -H φ: 0 C 3

+ J -H m ro oo -H

Ä m <- W

: <σ ε

Cl tO -

CD

0)

P

tn • H <- (N ro ro ro ro X! S * 15 67841

Table VI

CONHCH _CH „0H

5 cooh jL3

I / v. I CH CONH CONHCH, CH-OH

31. VV / 2 'i / conhch2ch2oh CH3NHCO // XY ^ X NHCOCH2N t | χ

“\ 'XX

CH2CONH ^ CONHCH2CH2OH

15

CONHCH CH OH

20 1 J. 1

jX

COOH CH2CONH ^ CONHCH 2CH2 OH

"'' ö; 1 / '

CH3CON / ^ NHCOCH2N CONHCH2CH2OH

κ3έ \ I 1! \ ΊΠΓ

CH2CONH ^^ Y ^^ CONHCH 2CH 2 OH I

35 16 67841

CONHCH_CH_OH

I / £.

^ Ar 1

5 COOH CH2CONH CONHCH2CH2OH

I i .1 / 1 · Ä /

CHoNHCO ^^ Y ^^ NCOCH N CONHCH2CH2OH

3 I, 2 \

10 I ch3 \ I I I

\ XX

CH2CONH ^ CONHCH2CH2OH

15 D. Preparation of injection solutions

Pharmaceutical grade injection solutions are prepared in the form of methylglucamine or sodium salt containing 28, 38 or 48 g of iodine per 100 ml (solutions are said to contain 28%, 38% and 48% iodine).

Once the product is filled into ampoules under a nitrogen atmosphere, it is sterilized by heating at 120 ° C for 20 minutes.

The results of viscosity determinations of 28% methylglucamine salt solutions at 37 ° C are given in the following Table VII. From these results, it is apparent that, contrary to expectations, the compounds of formula (III) have relatively low solution viscosities.

Table VII

Compound Viscosity, cP 37 ° C

35 31 10.2 17 67841

The results of osmolality assays are given in Table VIII below.

Osmolality has been determined by extrapolation from the results of successive dilutions of 28% or 38% iodine-containing solutions. Osmolality readings have been made with a FISKE 230 / D / 330 D-type osmometer. This device gives this measurement in milliosmoles per kilogram of solution. Its operation is based on the principles of cryoscopy: Assays were performed with 28% iodine-containing solutions.

10

Table Vili

Compound Osmolality ____ mosm / kg 15 31 350 32 270 33 370 ax 1410 20 bx 1390 ex 950 xa, b and c are the following reference substances: 25 a: 2,4,6-triiodo-3-N-methylcarbamyl-5-acetamidobenzoic acid b: 2,4,6-triiodo-3-N-hydroxyethylcarbamyl-5-acetamido-benzoic acid c: 5,5'-adipoyldiimido-bis- (2,4,6-triiodo-N-methylisophthalam) -acid.

It is obvious that, as glucamine salts, the compounds of formula (III) have a significantly lower osmolality than the reference compounds.

35 The results of a comparative toxicological and pharmacological study are presented below.

18 678A1

Determination of acute toxicity ___

Intravenous toxicity in mice

An intravenous toxicity assay was performed on 5 LOPS mice of Swiss origin of Swiss origin.

Each dose level was injected into a group of 10 mice of 5 males and 5 females.

Splashes were administered manually into the tail vein at a rate of 2 ml / minute.

10 The number of deaths within 24 hours of injection was recorded.

Elimination of the compound by bile in cats This experiment was performed on adult male or female cats weighing 3-4 kg.

15 The test substance was injected intravenously at a dose of 0.10 g / kg at the vascular level. Elimination was eliminated by X-ray monitoring.

X-rays showing the gallbladder and bladder were taken at the following times: 30 minutes, 1 hour, 2 hours-20 tia, 3 hours, 4 hours, 5 hours, 6 hours.

Effect on relay artery flow rate This experiment was performed on mixed-breed dogs weighing 7-12 kg anesthetized with Nembutal.

Nembutal was administered at a dose of 30 mg / kg using Vetranquil 25 premedication (total intravenous injection 2.5 g) and breathing was spontaneous.

Flow velocity variations were recorded at the level of the right or left femoral artery with the Statham electromagnetic sensor system. The injections were administered to the lateral branch of the femoral artery from the sensor downstream of the sensor using a catheter placed to prevent blood flow from being disturbed.

The injections were administered in a constant volume of 1.5 ml over 3-5 seconds. The same volume of isotonic sodium chlorine-35 dilution was also injected. The results obtained are summarized in Table IX.

19 6784 1

Table IX

Compound J-content- Acute iryr- Peripheral Biliary-

No salt salinity cervical artery no in ti in a cat type intravenous flow rate intravenously g AND? sixt 0.10 g J / kg 31 28% 15 +0 __ 32 28% 15 +0 _Mgl___ 1Q 33 38% 17 ++ _Na _ a 28% 5.4 +++ 0 _Mgl _ b 30% 5.6 + ++ 0 _Mgl _ kc 28% _Mgl_6 ^ 2 _ ++ _ 0_ d 38% 5.7 +++ 0 mix.

Mgl. and Na salt e 28% 2 ++++ ++++ 20 .......- ----------- --- a = 2,4,6-triiodo-3- methylcarbanyl-5-acetamido-benzoic acid b = 2,4,6-triiodo-3N-hydroxyethylcarbamyl-5-acetamethyl-benzoic acid c = 5,5'-adipyl-imido-δ (2,4,6-triiodo-N -methyl-isophthalane) acid d = 2,4,6-triiodo-3,5-bis- (acetamido) -benzoic acid 25e = 3,3'-adipoyldiimino-bis (2,4,6-triiodiaminylbenzo) ) the number of acid + is proportional to the effect observed.

The results of a toxicological study of the neck injection of E. Melartin's method (Inbestigative Radiology 1970 5, 1,13-21) are also presented below.

20 67841

Compound Dose / rat Death rate 31 56 mg J 1/10 32 50 mg J 0/10 33 56 mg J 0/10 _ c 17 mg J 9/10 b

From the above data, it is apparent that the compounds of formula (XII) are useful X 1 X-ray contrast agents. The predominant uses for said compounds are urography, angiography, cholangiography and myelography.

Preferred pharmaceutical forms of X-ray contrast agents are aqueous solutions of the salts of the compounds of formula (III).

The aqueous solutions preferably contain 5 to 100 g of salt per 10 ml, and the amount of such solutions to be injected may vary from 5 ml to 100 ml.

Claims (2)

Iodobenzene derivatives of the formula (III) x ·> = .S - »» I ° X, mi ”M /. Ri> l'C0'CH2- \ I A · i K \ ΓοΤ CH2-CONH '^ ss ^ Avr3 Wherein R1 is -CONHR4, where R8 is a (C1-C4) - / R7 alkyl radical, or -N, where Rt is a (C1-C4) - / AO R8 alkanoyl radical and R8 is ( The C 1 -C 4 alkyl radical, R 2 and R 8 denote the radical -CONHR 8, in which R 8 is a (C 1 -C 4) hydroxyalkyl radical, R 4 is a hydrogen atom or a (C 1 -C 4) alkyl radical, and their salts with pharmaceutically acceptable bases.