EP0410974A1

EP0410974A1 - Nonionic x-ray contrast agents, compositions and methods

Info

Publication number: EP0410974A1
Application number: EP89903414A
Authority: EP
Inventors: David H. White; Youlin Lin
Original assignee: Mallinckrodt Inc
Current assignee: Mallinckrodt Inc
Priority date: 1988-03-01
Filing date: 1989-02-09
Publication date: 1991-02-06
Also published as: JPH0625094B2; AU612510B2; EP0410974A4; AU4072789A; JPH03504124A; WO1989008101A1

Abstract

Des composés tels que N, N'-bis(2,3-dihydroxypropyle)-5-[N-(2-méthoxyéthyle)glycolamido]-2,4,6-triiodoisophthalamide, et N, N'-bis (2,3-dihydroxypropyle)-5-[N-(2-hydroxyéthyle)méthoxyacétamido]-2,4,6-triiodoisophthalamide, sont utiles pour une utilisation comme agents de contraste de rayons X.Compounds such as N, N'-bis (2,3-dihydroxypropyl) -5- [N- (2-methoxyethyl) glycolamido] -2,4,6-triiodoisophthalamide, and N, N'-bis (2,3 -dihydroxypropyl) -5- [N- (2-hydroxyethyl) methoxyacetamido] -2,4,6-triiodoisophthalamide, are useful for use as X-ray contrast agents.

Description

NONIONIC X-RAY CONTRAST AGENTS, COMPOSITIONS AND METHODS

Background of the Invention

This invention relates to X-ray contrast agents and, more particularly, to novel nonionic X-ray contrast agents, radiological compositions containing such agents and methods for X-ray visualization utilizing such compositions .

Nonionic contrast agents for intravascular and central nervous system visualization are complex molecules. As is known, the iodine in the molecule provides opacification to the x-rays. The remainder of the molecule provides the framework for transport of the iodine atoms. However, the structural arrangement of the molecule is important in providing stability, solubility and biological safety in various organs. A stable carbon-iodine bond is achieved in most compounds by attaching it to an aromatic nucleus. An enhanced degree of solubiity as well as safety is conferred on the molecule by the addition of suitable solubilizing and detoxifying groups.

Several of the features that are desirable for intravascular and central nervous system nonionic contrast agents are often incompatible so that all such agents represent compromises. In searching for the best compromise, the controlling factors are pharmacological inertness; i.e., in vivo safety and high water solubility. Thus, the ideal intravascular or central nervous system nonionic agent represents a compromise in an attempt to obtain the following criteria: (1) maximum opacif ication to x-rays; (2) pharmacological inertness; (3) high water solubility; (4) stability; (5) selective excretion; (6) low viscosity; and (7) minimal osmotic effects. There is a continuing need for non-ionic contrast agents which meet all or substantially all the foregoing criteria.

Summary of the Invention

Among the several objects of the invention may be noted the provision of novel nonionic contrast agents, radiological compositions and methods for x-ray visualization; and the provision of such agents which are substantially non-toxic and meet the other criteria desired for nonionic contrast agents. Other objects and features will be in part apparent and in part pointed out hereinafter. Briefly, the present invention is directed to compounds of the formula:

wherein X is selected from the group consisting of hydroxymethyl and methoxymethyl and Y is selected from the group consisting of hydroxy and methoxy.

The invention is specifically directed to the compounds N,N'-bis(2,3-dihydroxypropyl)-5-(N-(2-methoxyethyl)glycolamido]-2,4,6-triiodoisophthalamide and N,N'-bis-(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)-methoxyacetamido]-2,4,6-triiodoisophthalamide. The invention is also directed to radiological compositions containing such compounds and methods for utilizing such compounds in x-ray visualization.

Description of the Preferred Embodiments

In accordance with the present invention, it has now been found that compounds of the formula set out above are suitable for use as nonionic x-ray contrast agents. More specifically in the practice of the invention, the compounds N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-methoxyethyl)glycolamidσ]-2,4,6-triiodoisophthalamide and N,N'-bis- (2,3-dihydroxypropyl)-5-{N-(2-hydroxyethyl)-methoxyacetamido]-2,4,6-triiodoisophthalamide may be used as nonionic x-ray contrast agents. These agents may be used in various radiographic procedures including those involving cardiography, coronary ar teriography, aortography, cerebral and peripheral angiography, orthography, intravenous pyelography and urography.

In further accordance with the present invention, radiological compositions may be prepared containing one of the aforementioned compounds as an x-ray contrast agent together with a pharmaceutically acceptable radiological vehicle.

Pharmaceutically acceptable radiological vehicles include those that are suitable for injection such as aqueous buffer solutions; e.g., tris(hydroxymethyl) amino methane (and its salts), phosphate, citrate, bicarbonate, etc., sterile water for injection, physiological saline, and balanced ionic solutions containing chloride and/or bicarbonate salts of normal blood plasma cations such as Ca, Na, K and Mg. Other buffer solutions are decribed in Remington's Practice of Pharmacy, Eleventh Edition, for example on page 170. The vehicles may contain a chelating amount, e.g., a small amount, of ethylenediamine tetracetic acid, the calcium disodium salt, or other pharmaceutically acceptable chelating agent.

The concentration of the x-ray contrast agents of the invention in the pharmaceutically acceptable vehicle, for example an aqueous medium, varies with the particular field of use. A sufficient amount is present to provide satisfactory x-ray visualization. For example, when using aqueous solutions for angiography, the concentration of iodine is generally 140-400 mg/ml and the dose is 25-300 ml. The radiological composition is administered so that the contrast agent remains in the living animal body for about 2 to 3 hours, although both shorter and longer residence periods are normally acceptable. Thus, N,N'-bis-(2,3-dihydroxypropyl)-5-[N-(2-methoxyethyl)glycolamido]-2,4,6triiodoisophthalamide and N,N'-bis(2,3-dihydroxypropyl) 5-[N-(2-hydroxyethyl)-methoxyacetamido]-2,4,6-triiodoisophthalamide may be formulated for vascular visualization conveniently in vials or ampoules containing 10 to 500 ml. of an aqueous solution. The radiological compositions of the invention may be used in the usual way in x-ray procedures. For example, in the case of selective coronary arteriography, a sufficient amount of the radiological composition to provide adequate visualization is injected into the coronary system and then the system is scanned with a suitable device such as a fluoroscope.

The compounds N,N'-bis(2,3-dihydroxypropyl)-5-[N-( 2-methoxyethyl)glycolamido]-2,4,6-triiodoisophthalamide and N,N'-bis(2,3-dihydroxyproρyl)-5-[N-(2-hydroxyethyl)- methoxyacetamido]-2,4,6-triiodoisophthalamide and the intermediates therefor may be prepared in accordance with the procedures set out below. All temperature designations are in degrees centigrade. The following examples illustrate the practice of the invention.

Example 1

N,N'-Bis(2,3-dihydroxypropyl)-5-[N-(2- methoxyethyl)glycolamido]-2,4,6- triiodoisophthalamide

Preparation of 5-Amino-N,N'-bis(2,3-diacetoxypropyl)- 2,4,6-triiodoisophthalamide(2)

To a slurry containing 22.5 gm (0.0319 moles) of compound 1 ( 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide) in 17 ml of N ,N '-dimethylacetamide (DMAC), 0.195 gm (0.0016 moles) of 4-dimethylaminopyr idine (DMAP) was added. Acetic anhydride (13.53 ml, 0.144 moles) was then added dropwise to this slurry with stirring and cooling (to maintain the temperature of the reaction mixture at 15°C). The slurry became gradually clear and the resulting solution was allowed to stir at room temperature for 20 hours. After this period, 12 ml of DMAC was removed by applying vacuum (30-35 mm) and heating the reaction solution at 100°. The reaction solution was then diluted with 70 ml of dichloromethane. A solution of 15.26 gm of sodium carbonate in 80 ml of water was added and the mixture was stirred for 15 minutes. The dichloromethane layer (brown bottom layer) was separated, washed with brine (2 X 30 ml) and dried over anhydrous Na₂SO₄. The solution was filtered and evaporated under reduced pressure at 60° to give 26.7 gm (96%) of compound 2 (5-amino-N,N'- bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide) as glassy product. LC purity: 98% (Lichrosorb RP-18, 10 m column, H₂O/CH₃CN: 1400/600).

B. Preparation of 5-Acetoxyacetamido-N,N'-bis(2,3- diacetoxypropyl)-2,4,6-triiodoisophthalamide (3)

Compound 2 (15.56 gm, 0.017 moles) and DMAC (6 ml) were combined. The stirred mixture was cooled to 5º. Acetoxyacetyl chloride (7.3 gm, 0.053 moles) was added slowly keeping the temperature at 5-10°. When the addition was complete, the reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. Water (15 ml) was added to the reaction mixture and the resulting mixture was extracted with dichloromethane (60 ml). The dichloromethane layer (bottom layer) was separated, washed with 10% NaHCO₃ solution (2 X 20 ml), water (30 ml), dried over Na₂SO₄ and evaporated under reduced pressure to give 14.7 gm of 3 (85%). LC purity: 99% (Lichrosorb RP-18, 10 m column, H₂O/CH₃CN:1400/600). Preparation of N,N'-Bis(2,3-diacetoxyρropyl)-5- [N-{2-methoxyethyl)acetoxyacetamido]-2,4,6- triiodoisophthalamide (4)

A mixture containing 27.6 gm (0.027 moles) of compound 3 and anhydrous potassium carbonate 7.7 gm (0.055 moles) in 27 ml of dimethylsulfoxide was stirred and kept in an oil bath at 40°. 2-Bromoethyl methyl ether (5.62 gm, 0.04 moles) was added all at once and the mixture was stirred and kept at 40° for 6 hours.

To the reaction mixture, 50 ml of dichloromethane and 50 ml of water were added and the resulting suspension was stirred for 30 minutes. Dichloromethane layer was separated, washed with brine (2 X 30 ml), dried over Na₂SO₄ and evaporated under reduced pressure to give

25.1 gm (86%) of compound 4. LC purity: 94% (Lichrosorb RP-18, 10 m column, H₂O/CH₃CN : 1400/600). This product was used as such in the next step.

Preparation of N,N'-Bis(2,3-dihydroxypropyl)-5- [N-(2-methoxyethyl)glycolamido]-2,4,6- triiodoisophthalamide (5)

Compound 4 (13 gms, 0.012 moles) and MeOH (65 ml) were combined and stirred until all solids dissolved. To this solution was added a solution of 30 mg (catalytic amount) of sodium in 1.5 ml MeOH and the contents were stirred and kept at 0-10° for 2 hours. Glacial acetic acid was added to adjust the pH at 6 and the solvent was removed under vacuo, when a glassy product was obtained. This material was purified using preparative liquid chromatography to give 9.6 gms (91%) of 5. Lc purity: 98.64% (uC₁₈, H₂O/MeOH:95/5). The cmr spectrum was consistent with the assigned structure. Cal. for

C₁₉H₂₆N₃O₉I₃H₂: C, 27 .19; H, 3.36; N, 5.01; I, 45.37. Found C, 27.45; H, 3.21; N, 5.02; I, 45.62.

Example 2

N,N'-Bis(2,3-dihydroxypropyl)-5-(N-(2-hydroxyethyl methoxyacetamido]-2,4,6-triiodoisophthaiamide

A. Preparation of 5-Amino-N,N'-bis^S-diacetoxypropyl)- 2,4,6-triiodoisophthalamide (2)

To a slurry containing 45.0 gm (0.0638 moles) of compound 1 in 35 ml of N,N'-dimethylacetamide (DMAC), 0.390 gm (0.0032 moles) of 4-dimethylaminopyridine (DMAP) was added. Acetic anhydride, 27 ml (0.288 moles), was then added dropwise to this slurry with stirring and cooling (to maintain the temperature of the reaction mixture at 15°). The slurry became gradually clear and the resulting solution was allowed to stir at room temperature for 20 hours.

After this period, 24 ml of DMAC was removed by applying vacuum (30-35 min) and heating the reaction solution at 100°. The reaction solution was then diluted with 150 ml of dichloromethane. A solution of 32 gms of sodium carbonate in 160 ml of water was added and the mixture was stirred for 15 minutes. Dichloromethane layer (brown bottom layer) was separated, washed with brine (2 X 60 ml) and dried over anhydrous Na₂SO₄. The solution was filtered and evaporated under reduced pressure at 60° to give 52.8 gms (95%) of 2 as glassy product. LC purity: 98% (Lichrosorb RP-18, 10 m column, H₂O/CH₃CN: 1400/600).

B. Preparation of 5-Methoxyacetamido-N,N'-bis(2,3- diacetoxypropyl)-2,4,6-triiodoisophthalamide (3)

Compound 2 (125 gms, 0.136 moles) and DMAC (300 ml) were combined. The stirred mixture was cooled to 5°. Methoxyacetyl chloride (30 gms, 0.276 moles) was added slowly keeping the temperature at 5-10°. When the addition was complete, the reaction mixture was allowed to warm to room temperature and was stirred for 24 hours. Water (150 ml) was added to the reaction mixture and the resulting mixture was extracted with dichloromethane (500 ml). The dichloromethane layer (bottom layer) was separated, washed with 10% NaHCO₃ solution (2 X 200 ml), water (300 ml), dried over Na₂SO₄ and evaporated under reduced pressure to give 131.0 gm of 3 (97%). LC purity: 97% (Lichrosorb RP-18, 10 m column, H₂O/CH₃CN: 1400/600), Tic (EtOAc: CHCl₃: gl-AcOH, 7:3:0.2; Analtech silica gel plate)-one spot. This product was used as such in the next step.

Preparation of N,N'-Bis(2,3-diacetσxypropyl)-5-[N-(2- acetoxyethyl)methoxyacetamido]-2,4,6-triiodoisophthalamide (4)

A mixture containing 65 gms (0.068 moles) of compound 3 and anhydrous potassium carbonate 21 gms ( 0. 15 moles) in 140 ml of dimethylsulfoxide was stirred and kept in an oil bath at 40°. 2-Bromoethyl acetate (18 gms, 0.1 mole) was added all at once and the mixture was stirred and kept at 40° for 4 hours and then left at room temperature overnight.

To the reaction mixture, 100 ml of dichloromethane and 100 ml of water were added and the resulting suspension was stirred for 30 minutes. Dichloromethane layer was separated, washed with brine (2 X 60 ml), dried over Na₂SO₄ and evaporated under reduced pressure to give 59.6 gm (84%) of compound 4. LC purity: 96% (Lichrosorb RP-18, 10 m column, H₂O/CH₃CH: 1400/600). This product was used as such in the next step. Preparation of N,N'-Bis(2,3-dihydroxypropyl)- 5-[N-(2-hydroxyethyl)methoxyacetamido]-2,4,6- triiodoisophthalamide (5)

Compound 4 (54 gms, 0.052 moles) and MeOH (200 ml) were combined and stirred until all solids dissolved. To this solution was added a solution of 100 mg (catalytic amount) of sodium in 5 ml MeOH and the contents were stirred and kept at 0-10° for 2 hours. Glacial acetic acid was added to adjust the pH at 6 and the solvent was removed under vacuo, when a glassy product was obtained. This material was purified by preparative liquid chromatography to give 40 gm (93%) of compound 5; m.p. 195-197°. LC purity: 98% (υC.g, H₂O/MeOH: 95/5). The cmr spectrum was consistent with the assigned structure. Tic

(CHCl₃:MeOH; gl-AcOH, 7:3:02 and n-BuOH : gl-AcOH: U20 , 10:3:5, Analtech silica gel plate)-one spot. Cal. for

C19H26N3°9I3: C, 27'79' H' 3.19; N, 5.11; I,

46.36. Found: C, 27.77; H, 3.25; N, 5.09; I, 46.32.

Example 3

The acute intravenous toxicities of the compounds of Examples 1 and 2 were determined as follows.

A solution of the compounds of Example 1 and 2 was injected into the lateral tail vein of young adult male and female mice (Sasco mice in the case of the compound of Example 1 and Charles River mice in the case of the compound of Example 2) at the rate of 1 ml/min. Following injections, the animals were observed for immediate reactions and then daily throughout a seven day observation period. The LD₅₀ values were calculated by the method of Litchfield and Wilcoxon (J. Pharmacol. Exp. Therap. 96:99-113, 1949) with the following results.

LD₅₀ (95% Confidence

Limits) Compound Concentration g I/Kg

1 32%I, w/v 17.3

2 37%I, w/v 16.4 In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As various changes could be made in the above compounds and methods without departing from the scope of the invention, it is intended that all matter contained in the above description or shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.

Claims

WHAT IS CLAIMED IS

A compound of the formula

2. A compound of claim 1 which is N,N'-bis(2,3-dihydroxypropyl)-5-(N-(2-methoxyethyl)glycolamido]-2,4,6-triiodoisophthaiamide.

3. A compound of claim 1 which is N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)methoxyacetamido]-2,4,6-triiodoisophthalamide.

4. A radiological composition containing a compound of the formula:

wherein X is selected from the group consisting of hydroxymethyl and methoxymethyl and Y is selected from the group consisting of hydroxy and methoxy, in a sufficient amount to provide satisfactory x-ray visualization together with a pharmaceutically acceptable radiological vehicle.

5. A radiological composition as set forth in claim 4 wherein said compound is N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-methoxyethyl)glycolamido]-2,4,6-triiodoisophthalamide.

6. A radiological composition as set forth in claim 4 wherein said compound is N,N'-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)methoxyacetamido]-2,4,6-triiodoisophthalamide.

7. In a method for x-ray visualization wherein a radiological composition containing an x-ray contrast agent in a pharmaceutically acceptable radiological vehicle is injected in a sufficient amount to provide adequate visualization and thereafter x-ray visualization is carried out, the improvement comprising utilizing as the radiological composition a composition containing a compound of the formula:

8. A method as set forth in claim 7 wherein said compound is N,N'-bis(2,3-dihydroxypropyl)-5-(N-(2-methoxyethyl) glycolamido]-2,4,6-triiodoisophthaiamide.

9. A method as set forth in claim 7 wherein said compound is N,N'-bis(2,3-dihydroxypropyl)-5-{N-(2-hydroxyethyl) methoxyacetamido]-2,4,6-triiodoisophthaiamide.