JPH0625094B2 - Nonionic X-ray contrast agents, compositions and methods - Google Patents

Description

Description: BACKGROUND OF THE INVENTION The present invention relates to X-ray contrast agents, and more particularly to novel nonionic X-ray contrast agents, radiological compositions containing such agents and X using such compositions. Regarding line visualization method.

Nonionic contrast agents for intravascular and central nervous system visualization are complex molecules. As is known, the iodine in the molecule becomes opaque to X-rays. The rest of the molecule is the framework for carrying the iodine atom. However, the structural arrangement of the molecule is important in conferring stability, solubility and biological stability in various organs. A stable carbon-iodine bond is achieved in most compounds by attaching it to an aromatic nucleus. High solubility and stability are imparted to the molecule by the addition of suitable solubilizing and detoxifying groups.

Often some of the desirable characteristics of intravascular and central nervous system nonionic contrast agents are incompatible, so all such agents represent an eclectic compromise. The controlling factors in investigating the best compromise are pharmacological inactivity, ie in vivo safety and high water solubility. Thus, the ideal intravascular region represents a compromise between central nervous system nonionics seeking the following criteria: (1) maximum opacity to X-rays; (2) pharmacological inactivity; (3) High water solubility; (4) Stability;
(5) Selective drainage; (6) Low viscosity; (7) Minimal osmotic effect.

There is a continuing need for nonionic contrast agents that meet all or substantially all of the criteria set forth above.

SUMMARY OF THE INVENTION Among the several objects of the invention, novel nonionic contrast agents, radiological compositions, X-ray visualization methods, and substantially nontoxic and desired nonionic contrast agents are desired. Mention may be made of the provision of such agents which meet other criteria. 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: Here, 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 particularly directed to the following compounds: N, N'-bis (2,3-dihydroxypropyl) -5- [N- (2-
Methoxyethyl) glycolamide] -2,4,6-triiodoisophthalamide and N, N'-bis (2,3
-Dihydroxypropyl) -5- [N- (2-hydroxyethyl) -methoxyacetamide] -2,4,6-triiodoisophthalamide. The invention is also directed to radiological compositions containing such compounds and methods of using such compounds in X-ray visualization.

DESCRIPTION OF THE PREFERRED EMBODIMENTS According to the present invention, compounds of the above formula are now nonionic X
It has been found to be suitable for use as a line contrast agent. More particularly in the practice of the invention, the compound N,
N'-bis (2,3-dihydroxypropyl) -5-
[N- (2-methoxyethyl) glycolamide]-
2,4,6-triiodoisophthalamide and N, N '
-Bis (2,3-dihydroxypropyl) -5- [N-
(2-Hydroxyethyl) -methoxyacetamide]-
2,4,6-Triiodoisophthalamide can be used as a nonionic X-ray contrast agent. These agents can be used in a variety of radiographic methods, including those including heart rate recordings, coronary angiography, aortography, cerebral and peripheral angiography, orthography, transvenous nephroureterography and urography.

Further in accordance with the present invention, a radiological composition can be prepared containing one of the compounds described above as an X-ray contrast agent, together with a pharmaceutically acceptable radiological vehicle.

Pharmaceutically acceptable radiological vehicles include those suitable for injection such as: buffered aqueous solutions such as tris (hydroxymethyl) aminomethane (and salts thereof), phosphates, citrates, bicarbonates,
Etc. Sterile water for injection, physiological saline, chloride and / or C
Balanced ionic solution containing bicarbonate salts of common plasma cations such as a, Na, K, Mg. Other buffers are Remington's Practice of Pharmac
y, 11th edition, for example page 170. The vehicle may contain a chelating amount, eg, a small amount, of ethylenediaminetetraacetic acid, calcium disodium salt, or other pharmaceutically acceptable chelating agent.

The concentration of the inventive X-ray contrast agent in a pharmaceutically acceptable vehicle, such as an aqueous medium, will vary with the particular field of use. Sufficient amount is present to provide satisfactory X-ray visualization. For example, when an aqueous solution for angiography is used, the iodine concentration is usually 140 to 400 mg / m 2.
1 and the dose is 25-300 ml.

The radiological composition is administered such that the contrast agent remains in the living animal body for about 2-3 hours, although both shorter and longer residence times are usually acceptable. Thus, N, N'-bis (2,3-dihydroxypropyl) -5- [N- (2-methoxyethyl) glycolamide] -2,4,6-triiodoisophthalamide and N, N'-bis ( 2,3-dihydroxypropyl) 5-
[N- (2-hydroxyethyl) -methoxyacetamide] -2,4,6-triiodoisophthalamide can be conveniently formulated in a vial or ampoule containing 10-500 ml of an aqueous solution for vascular visualization.

The radiological composition of the invention can be usefully used in X-ray methods. For example, in the case of selective coronary angiography, a sufficient amount of radiological composition to provide adequate visualization is injected into the coronary system, and the system is then fluoroscopy.
Scan with a suitable device such as scope).

Compound N, N'-bis (2,3-hydroxypropyl)
-5- [N- (2-methoxyethyl) glycolamide] -2,4,6-triiodoisophthalamide and N, N'-bis (2,3-hydroxypropyl) -5-
[N- (2-hydroxyethyl) methoxyacetamide] -2,4,6-triiodoisophthalamide and intermediates thereof can be prepared according to the procedures described below. All temperature indications are in ° C.

The following example illustrates the practice of the invention.

Example 1 N, N'-bis (2,3-dihydroxypropyl) -5
-[N- (2-methoxyethyl) glycolamide]-
2,4,6-triiodoisophthalamide A. Preparation of 5-amino-N, N'-bis (2,3-diacetoxypropyl) -2,4,6-triiodoisophthalamide (2) Compound 1 (5-amino-N, N'-bis (2,3-dihydroxypropyl) -2,4,6-triiodoisophthalamide) (22.5 g, 0.0319 mol) was added to N, N '.
-To the slurry contained in 17 ml of dimethylacetamide (DMAC), 4-dimethylaminopyridine (DMA
P) 0.195 g (0.0016 mol) was added. Acetic anhydride (13.53 ml, 0.144 mol) was then added dropwise to this slurry with stirring and cooling (keeping the temperature of the reaction mixture at 15 ° C). The slurry gradually became clear and the resulting solution was allowed to stir at room temperature for 20 hours.

After this period, a vacuum (30-35 mm) was applied and the reaction solution was heated at 100 ° to remove 12 ml of DMAC. Then the reaction solution was diluted with 70 ml of chloromethane. A solution of 15.26 g sodium carbonate in 80 ml water was added and the mixture was stirred for 15 minutes. The dichloromethane layer (brown lower layer) was separated and washed with a plain (2
(30 ml), dried over anhydrous Na ₂ SO ₄ . The solution was filtered and evaporated under reduced pressure at 60 ° C to give compound 2 (5-amino-N, N'-bis (2,3-diacetoxypropyl).
-2,4,6-triiodoisophthalamide) 26.7
g (96%) was produced as a glassy product. LC purity: 98% (Lichrosorb RP-18, 10 m column,
_{H 2 O / CH 3 CN:} 1400/600).

B. Preparation of 5-acetoxyacetamide-N, N'-bis (2,3-diacetoxypropyl) -2,4,6-triiodoisophthalamide (3) Compound 2 (15.56 g, 0.017 mol) and DMA
C (6 ml) were combined. The stirred mixture was cooled to 5 °. Acetoxyacetyl chloride (7.3 g,
0.053 mol) while maintaining the temperature at 5 to 10 ° C,
I added it slowly. When the addition was complete, the reaction mixture was allowed to warm to room temperature and stir for 16 hours. Water (15m
1) was added to the reaction mixture and the resulting mixture was extracted with dichloromethane (60 ml). The dichloromethane layer (lower layer) was separated and 10% NaHCO ₃ solution (2 × 20 m
1), washed with water (30 ml), dried over Na ₂ SO ₄ and evaporated under reduced pressure to give 14.7 g (85%) of 3. LC purity: 99% (Lichrosorb RP-18, 10 m
_{Column, H 2 O / CH 3 CN} : 1400/600).

C. N, N'-bis (2,3-diacetoxypropyl)
-5- [N- (2-methoxyethyl) acetoxyacetamide] -2,4,6-triiodoisophthalamide
Preparation of (4) A mixture containing 27.6 g (0.027 mol) of compound 3 and 7.7 g (0.055 mol) of anhydrous potassium carbonate in 27 ml of dimethylsulfoxide was stirred and 40 ° C.
Kept in an oil bath. 2-Bromoethyl methyl ether (5.62 g, 0.04 mol) was added all at once and the mixture was stirred and kept at 40 ° C. for 6 hours.

To the reaction mixture, 50 ml of dichloromethane and 50 ml of water
Was added and the resulting suspension was stirred for 30 minutes. The dichloromethane layer was separated and washed with brine (2 x 30 m
1), dried over Na ₂ SO ₄ and evaporated under reduced pressure to yield 25.1 g (86%) of compound 4. LC purity: 94
% (Lichrosorb RP-18, 10 m column, H ₂ O /
CH ₃ CN: 1400/600). This product was used as such in the next step.

D. N, N'-bis (2,3-dihydroxypropyl)
Preparation of -5- [N- (2-methoxyethyl) glycolamide] -2,4,6-triiodoisophthalamide (5) Compound 4 (13 g, 0.012 mol) and MeOH (6
5 ml) were combined and stirred until all solids were dissolved. To this solution was added 30 mg (catalytic amount) of sodium in Me
A solution dissolved in 1.5 ml OH was added, the contents were stirred and kept at 0-10 ° for 2 hours. Glacial acetic acid was added to adjust the pH to 6
The solvent was removed under reduced pressure, whereupon a glassy product was obtained. This material was purified using preparative liquid chromatography to yield 9.6 g (91%) of 5. LC purity: 98.64% (UC ₁₈ , H ₂ O / Me
OH; 95/5). The cmr spectrum was consistent with the listed structure. _{C 19 H 26 N 3 O 9} I 3 H 2 calculated for:
C, 27.19; H, 3.36; N, 5.01; I, 4
5.37. 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) methoxyacetamide] -2,4,6-triiodoisophthalamide A. Preparation of 5-amino-N, N'-bis (2,3-diacetoxypropyl) -2,4,6-triiodoisophthalamide (2) Compound 1 (45.0 g, 0.0638 mol) was added to N, N '
-To a slurry contained in 35 ml of dimethylacetamide (DMAC), 4-dimethylaminopyridine (DMA
P) 0.390 g (0.0032 mol) was added. Then 27 ml (0.288 mol) of acetic anhydride were added dropwise to this slurry with stirring and cooling (keeping the temperature of the reaction mixture at 15 °). The slurry gradually became clear and the resulting solution was allowed to stir at room temperature for 20 hours.

After this period, a vacuum (30-35 mm) was applied and the reaction solution was heated at 100 ° to remove 24 ml of DMAC. Then the reaction solution was diluted with 150 ml of dichloromethane. A solution of 32 g of sodium carbonate in 160 ml of water was added and the mixture was stirred for 15 minutes. The dichloromethane layer (brown lower layer) was separated and washed with brine (2
X 60 ml) and dried over anhydrous Na ₂ SO ₄ . The solution was filtered and evaporated under reduced pressure at 60 ° C. to give 252.8 g (9
5%) as a glassy product. LC purity: 98
% (Lichrosorb RP-18, 10 m column, H ₂ O /
CH _3: 1400/600).

B. 5-methoxyacetamide-N, N'-bis (2,2
Preparation of 3-diacetoxypropyl) -2,4,6-triiodoisophthalamide (3) Compound 2 (125 g, 0.136 mol) and DMAC
(300 ml) together. The stirred mixture was cooled to 5 °. Methoxyacetyl chloride (30 g,
0.276 mol) while maintaining the temperature at 5 to 10 ° C.
I added it slowly. When the addition was complete, the reaction mixture was allowed to warm to room temperature and stir 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 (lower layer) was separated and 10% NaHCO ₃ solution (2 × 20) was added.
0 ml), washed with water (300 ml), dried over Na ₂ SO ₄ and evaporated under reduced pressure to give 131.0 g of 3 (97 ml).
%)occured. LC purity: 97% (Lichrosorb RP-1
8, 10 m column, H ₂ O / CH ₃ CN: 1400/6
00). _{T / C (EtOAc: CHCl 3} : gl-Ac
OH, 7: 3: 0.2, Analtech silica gel plate)
-1 spot. This product was used as such in the next step.

C. N, N'-bis (2,3-diacetoxypropyl)
-5- [N- (2-acetoxyethyl) methoxyacetamide] -2,4,6-triiodoisophthalamide
Preparation of (4) Compound 3 65 g (0.068 mol) and anhydrous potassium carbonate 21 g (0.15 mol) were added to dimethyl sulfoxide 1
The mixture contained in 40 ml was stirred and kept in a 40 ° C. oil bath. 2-bromoethyl acetate (18 g,
0.1 mol) all at once and the mixture is stirred and 4
It was kept at 0 ° C. for 4 hours and then left at room temperature overnight.

To the reaction mixture, 100 ml dichloromethane and 100 water.
ml was added and the resulting suspension was stirred for 30 minutes. Separate the dichloromethane layer and wash with brine (2 x 60 m
1), dried over Na ₂ SO ₄ and evaporated under reduced pressure to yield 59.6 g (84%) of compound 4. LC purity: 96
% (Lichrosorb RP-18, 10 m column, H ₂ O /
CH ₃ CN: 1400/600). This product was used as such in the next step.

D. N, N'-bis (2,3-dihydroxypropyl)
-5- [N- (2-hydroxyethyl) methoxyacetamide] -2,4,6-triiodoisophthalamide
Preparation of (5) Compound 4 (54 g, 0.052 mol) and MeOH (2
00 ml) were combined and stirred until all solids were dissolved. To this solution was added a solution of 100 mg (catalytic amount) of sodium in 5 ml of MeOH, the contents were stirred and kept at 0-10 ° for 2 hours. Glacial acetic acid was added to adjust the pH to 6
The solvent was removed under reduced pressure, whereupon a glassy product was obtained. This material was purified by preparative liquid chromatography to give compound 5; mp 195-197.
Yielded 40 g (93%). LC purity: 98% (UC
_{18, H 2 O / MeOH:} 95/5). The cmr spectrum was consistent with the listed structure. T / C (CHCl ₃ : Me
OH: gl-AcOH, 7: 3: 02 and n-BuO
_{H: gl-AcOH: H 2} O, 10: 3: 5, Analtech
Silica gel plate) -1 spot. C ₁₉ H ₂₆ N ₃
Calculated for O ₉ I ₃ : C, 27.79; H, 3.1.
9; N, 5.11; I, 46.36. Actual measurement: C, 27.
77; H, 3.25; N, 5.09; I, 46.32.

Example 3 The acute intravenous toxicity of the compounds of Examples 1 and 2 was determined as follows.

A solution of the compounds of Examples 1 and 2 was applied to the lateral tail vein of young male and female adult mice (Sasco mouse for the compound of Example 1 and Charles River mouse for the compound of Example 2) at a rate of 1
Injected at ml / min. After injection, animals were observed for immediate response, then daily throughout the 7 day observation period. The LD ₅₀ value was determined by the method of Litchfield and Wilcoxon (J.
Pharmacol. Exp. Therap. 96: 99-113, 194.
9), and the following results were obtained.

From the foregoing, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

Since various modifications can be made in the above compounds and methods without departing from the scope of the invention, all matters contained in the above description or shown in the accompanying drawings are to be understood as exemplifications and are intended to be construed in a limiting sense. Intended not to be.

Claims (6)

[Claims] 1. N, N'-bis (2,3-dihydroxypropyl) -5- [N- (2-methoxyethyl) glycolamide] -2,4,6-triiodoisophthalamide. 2. N, N'-bis (2,3-dihydroxypropyl) -5- [N- (2-hydroxyethyl) methoxyacetamide] -2,4,6-triiodoisophthalamide. 3. N, N'-Bis (2,3-dihydroxypropyl) -5 in an amount sufficient to provide satisfactory X-ray visualization.
-[N- (2-methoxyethyl) glycolamide]-
A radiological composition containing 2,4,6-triiodoisophthalamide together with a pharmaceutically acceptable radiological vehicle. 4. N, N'-Bis (2,3-dihydroxypropyl) -5 in an amount sufficient to provide satisfactory X-ray visualization.
A radiological composition comprising [-N- (2-hydroxyethyl) methoxyacetamide] -2,4,6-triiodoisophthalamide together with a pharmaceutically acceptable radiological vehicle. 5. An X-ray in which the radiological composition containing the X-ray contrast agent in a pharmaceutically acceptable radiological vehicle is injected in an amount sufficient to provide suitable visualization, followed by X-ray visualization. In the visualization method, N, N′-bis (2,3-dihydroxypropyl) -5- [N- (2-
Methoxyethyl) glycolamide] -2,4,6-triiodoisophthalamide is used as a radiological composition. 6. An X-ray which comprises injecting a radiological composition containing an X-ray contrast agent in a pharmaceutically acceptable radiological vehicle in an amount sufficient to provide suitable visualization, followed by X-ray visualization. In the visualization method, N, N′-bis (2,3-dihydroxypropyl) -5- [N- (2-
Hydroxyethyl) methoxyacetamide] -2,4
Use of a composition containing 6-triiodoisophthalamide as a radiological composition.