JPS6364419B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula [In the formula, Z represents a direct bond or a lower alkylene group, X is a -COOH group,

[Formula] Group (where R ₁ represents a hydrogen atom and R ₂ represents a lower acyl group) or

[Formula] represents a group (where R ₃ and R ₄ each represent a hydrogen atom or a lower alkyl group which may be substituted with a hydroxy group), and Y
is a hydrogen atom, -COOH group or

[Formula] Group (where R ₃ and R ₄ each represent the above)
] and its physiologically acceptable salts, a method for producing the same, and an X-ray contrast agent containing the compound. The 2,4,6-triiodo-benzonitrile derivatives according to the invention are important radiographic contrast agents and are suitable as intermediate compounds for the production of radiographic contrast media. When using the new compound acid in its salt form,
All pharmaceutically acceptable cations are suitable as cations, such as sodium, calcium, magnesium, alkanolamines, such as ethanolamine, diethanolamine, N
- Methylglucamine, etc. acid amide group

Examples of the lower alkyl group for R ₃ or R ₄ in the formula include a methyl group, an ethyl group, a propyl group, and a butyl group. Examples of the lower alkyl group substituted with a hydroxy group include a 2-hydroxy-ethyl group-hydroxy-propyl group. The lower alkylene radical Z may be straight-chain or branched and preferably contain 1 to 4 carbon atoms. Examples of alkylene groups include methylene groups,
Ethylene group, propylene group, isopropylene group,
isobutylene group,

[Formula] List groups, etc. be able to. X is

[Formula] When R 2 represents a group, R ₂ represents an acyl group having 2 to 5 carbon atoms, such as an acetyl group, a propionyl group, a butyryl group, and a lactyl group. The novel 2,4,6-triiodo-benzonitrile derivatives are prepared by diazotization of amino compounds of the general formula and subsequent reaction with cyanide. Diazotization can be carried out by adding nitrite in a conventional manner. It is advantageous to carry out the diazotization under slightly acidic conditions, preferably in the PH range 2 to 4, with cooling, preferably at temperatures of 0 to +10°C. Nitrites suitable for the reaction are, for example, alkali metal nitrites, such as sodium nitrite and potassium nitrite. The resulting diazonium salt can be separated or the reaction can proceed immediately. It is advantageous to proceed with the reaction immediately, without isolating the diazonium salt from the solution or suspension, by adding a base to the reaction mixture to a pH of 4 to 7. Suitable bases are, for example, sodium hydroxide, potassium hydroxide, ammonia and the like. The introduction of the cyano group is carried out by a method known per se, for example by Sandmeyer reaction. in this case,
The diazonium compound is reacted in a customary manner with a cyanide complex, preferably a copper cyanide complex. Particularly suitable complex compounds include, for example, K ₂ [Cu
(CN) ₃ ], K ₃ [Cu(CN) ₄ ], and K ₂ [CuNH ₃ (CN) ₄ ]. The cyano groups can be introduced at room temperature and at elevated temperatures, temperatures between 20 and 40° C. being preferred. This reaction requires a polar solvent such as water, N,
N'-dimethylacetamide, N,N'-dimethylformamide, etc. and mixtures thereof are preferred, aqueous media being preferred. For the first time, by using the method of the present invention for producing a new compound of the general formula, by replacing the amino group in the triiodo-substituted aniline derivative with a nitrile group, the compound can be bonded to the triiodo-substituted aromatic nucleus via a C--C bond. We were able to successfully introduce the replacement component. By replacing the amino group in the compound of formula with a cyano group, new compounds are obtained, which are distinguished by good general tolerability, especially good neurological tolerability.

Table 1 shows, for the example of 5-cyano-2,4,6-triiodo-isophthalic acid, that the compounds according to the invention are as well tolerated by intravenous injection as the known comparison substances. show.

Table 2 shows that the compounds according to the invention are clearly less toxic than the known comparison substances 5-acetylamino-2,4,6-triiodo-isophthalic acid and amide triiodobenzoic acid. The compounds according to the invention are suitable for producing radiographic contrast agents for intravenous, intrathecal and oral applications, for example as urinary tract contrast agents, angiographic contrast agents, dorsal medullary contrast agents, cholangiographic contrast agents, etc. It is. Furthermore, the compounds of the invention are important intermediates for the production of X-ray contrast agents. For example, by reducing 5-cyano-3-acetylamino-2,4,6-triiodobenzoic acid, 5-aminomethyl-3-
acetylamino-2,4,6-triiodobenzoic acid, which was then acetylated to give 5-acetyl-aminomethyl-3-acetylamino-2,
It can be converted to 4,6-triiodobenzoic acid (iodoamide). Selective reduction of cyano groups can be carried out, for example, with hydrogen boride at elevated temperatures. Subsequently, the iodamide obtained by acetylation is available as a commercial preparation. The invention will now be explained in detail with reference to examples. Example 1 112 g of 5-amino-2,4,6-triiodo-isophthalic acid are suspended in 1100 ml of water, 10 g of sodium hydroxide is added and dissolved. Then, P.H.
2.5 is cooled to 0° C. and a solution of 20 g of sodium nitrite in 60 ml of water is added dropwise. Dilute sulfuric acid is then added to bring the pH value back to 2.0, and the reaction mixture is further stirred for 1 hour under constant ice cooling. The precipitated intramolecular diazonium salt is dissolved at pH 4.5 by slowly adding dilute sodium hydroxide solution dropwise. Meanwhile, 30 g of copper chloride () and 172 g of potassium cyanide in 800 ml of water
Prepare a solution at ℃ and add the diazonium salt solution all at once, stirring vigorously. After stirring for an additional 15 min at 30°C, the reaction solution was PH'd with dilute sulfuric acid.
3 to separate the copper salt. Further, dilute sulfuric acid was added to bring the filtrate to pH 0.5 to 1, and after stirring for several hours in an ice bath, the precipitate was suction filtered, washed with water,
Dry at 50℃. Water the reaction mixture for purification.
Suspend in 400 ml, add and dissolve sodium hydroxide solution, treat this solution with 10 g of activated carbon,
Stir for 30 minutes at room temperature and add excess mineral acid to the filtrate. After stirring for several hours in an ice bath, the precipitate is filtered off with suction, washed with water and dried at 50°C. 5-cyano- as a white powder with a decomposition point of 300℃ or higher
89 g (78% of theory) of 2,4,6-triiodo-isophthalic acid are obtained. Example 2 a 1.12 g of 5-cyano-2,4,6-triiodo-isophthalic acid is suspended in 15 ml of water, and dilute aqueous sodium hydroxide solution is added dropwise to dissolve at pH 2.5. A solution of 200 mg of sodium nitrite in 1 ml of water is added dropwise under ice cooling. Dilute sulfuric acid is then added to the reaction mixture to bring the pH back to 2.5, and the mixture is then stirred in an ice bath for 1 hour. The precipitated intramolecular diazonium salt was suction filtered, and first, with a small amount of ice-cold water,
It is then washed with methanol and carefully sucked dry under an argon atmosphere. A yellowish powder is obtained which turns gray under gas evolution at a melting point of 110°C in the tube, and shows iodine elimination above 300°C. b Dissolve 2.65 g of potassium cyanide in 2.5 ml of water, add 1.25 ml of concentrated aqueous ammonia solution, and
A solution of 3.9 g of copper sulfate pentahydrate in 250 ml of water is added. This solution is warmed to 30° C. and the diazonium salt solution prepared according to a) and brought to pH 5 with dilute sodium hydroxide solution is added. The yield is 5-cyano-2,4,6 recrystallized from ethanol.
-triiodo-isophthalic acid 82g (theoretical value 72
%). Example 3 20.6 g of 3-amino-2,4,6-triiodo-benzoic acid are suspended in 220 ml of water. After adding 24 ml of a 30% sodium nitrite aqueous solution dropwise at 0°C, the pH value is returned to 2 by adding dilute sulfuric acid. The reaction mixture is then after-stirred for a further 1 hour in an ice bath.
Slowly add dilute sodium hydroxide solution dropwise,
The reaction mixture is brought to pH 4.5 and the solution is left under ice cooling. During this time copper chloride () in 160ml of water
Prepare a warm solution of 20 g of potassium cyanide and 34 g of potassium cyanide at 30°C, and add the diazotization solution all at once, causing vigorous foaming. After stirring for a further 15 minutes at 30° C., the copper salts are then separated off by bringing the reaction solution to pH 3 with concentrated hydrochloric acid. Concentrated hydrochloric acid is further added to bring the filtrate to pH 0.5-1, and after stirring for several hours in an ice bath, the precipitate is suction filtered and washed with water. Suction-filtered, still damp material is suspended in 50 ml of water and dissolved by adding dilute sodium hydroxide solution.
This solution is treated by thorough stirring with activated carbon,
Filter clear. Add concentrated hydrochloric acid dropwise to this solution to adjust the pH
After stirring for several hours in an ice bath, the precipitate is filtered off with suction. After washing with acetone-containing water and drying at 50 °C, 3-cyano-2,4,6-triiodo-
16 g (76% of theory) of benzoic acid are obtained. Example 4 23.4 g of 5-amino-2,4,6-triiodo-isophthalic acid monomethylamide are suspended in 500 ml of water, dilute sodium hydroxide solution is added,
Dissolve. Add 8 g of sodium nitrite, cool the reaction mixture to 0°C, and slowly add dilute sulfuric acid dropwise until the pH reaches 2.0. The reaction mixture is then after-stirred for 3 hours in an ice bath and neutralized by slow addition of concentrated ammonia. During this time, water 320
Copper chloride () 20g and potassium cyanide 34g in ml
Prepare a warm solution of 30°C and add it to the diazotization mixture all at once. At this time, it foams violently. 30 more
The copper salts are separated off by after-stirring for a minute at 30° C. and then acidifying to PH4 with dilute hydrochloric acid. The filtrate is brought to pH 1 by the addition of concentrated hydrochloric acid and the reaction mixture is extracted with acetic acid ester. The acetate solution is washed with water, dried over sodium sulfate, treated with activated carbon under reflux and then evaporated to dryness. The residue is suspended in 100 ml of water and then dilute sodium hydroxide solution is added to ensure thorough dissolution. After treating the aqueous solution with activated carbon, the filtrate is acidified with excess concentrated hydrochloric acid and, after stirring for several hours in an ice bath, the precipitate is filtered off with suction, washed with water and dried at 50° C. 17 g of 5-cyano 2,4,6-triiodo-isophthalic acid monomethylamide as a white powder with a decomposition point of 300°C or higher (72% of theory)
is obtained. Example 5 25.8 g of 5-amino-2,4,6-triiodo-isophthalic acid-bis-(2-hydroxyethyl)-amide is heated to produce 100 g of dimethylacetamide.
Dissolve in ml. Cool in an ice bath and carefully add about the same volume of water to leave the material in the solvent.
Next, add a small amount of concentrated sulfuric acid to adjust the pH to 2, and add water to 12
A solution of 4 g of sodium nitrite in ml is added dropwise within 30 minutes with constant cooling on ice. After bringing the pH back to 2 with concentrated sulfuric acid, the reaction mixture is stirred in an ice bath for 3 hours. In the meantime, a warm solution of 20 g of copper(1) chloride and 35 g of potassium cyanide in 150 ml of water at 30 DEG C. is prepared and a diazonium salt solution neutralized with dilute sodium hydroxide solution is added in one portion. Post-stir for a further 15 min at 30°C until gas evolution has ceased, then cool to -10°C,
Extract the reaction mixture in small portions with 500 ml of acetic ester. The combined acetate ester extracts are washed several times with water, dried over sodium sulfate and concentrated to approximately 50 ml. The substance is precipitated by gradual addition of diisopropyl ether and, after stirring for several hours in an ice bath, is filtered with suction. Wash with diisopropyl ether,
After drying at 50℃, 5-cyano-2,4,6-triiodo-isophthalic acid with a decomposition point of 300℃ or higher
Bis-(2-hydroxyethyl)-amide 18g
(68% of the theoretical value) is obtained. Example 6 5.7 g of β-2,4,6-triiodo-3-amino-phenyl-α-ethyl-propionic acid are dissolved in 20 ml of concentrated sulfuric acid at room temperature with stirring. Then 0℃
2 g of finely powdered sodium nitrite was added in small portions to the solution cooled to
Keep at 5°C for an hour. Subsequently, 100 ml of water is added dropwise under constant cooling in an ice bath, and concentrated ammonia is added dropwise to bring the reaction mixture to pH 7, with an internal temperature of 5.
Do not exceed ℃. During this time, add 5 g of copper chloride (1) and 8.5 g of potassium cyanide in 100 ml of water at 30°C.
Prepare a warm solution of and then add the diazotization mixture. Warm for an additional 15 minutes at 30° C. until gas evolution ceases and decant from the precipitated reaction products. This is taken up in 50 ml of dilute sodium hydroxide solution and this solution is treated with activated carbon. The clear filtrate was decolorized by thorough stirring several times with activated carbon, then PH'd with concentrated hydrochloric acid.
Set it to 3.5. After several hours, stir and suction filter the precipitate.
Dry at 50℃. 3.9 g (68% of theory) of β-2,4,6-triiodo-3-cyanophenyl-α-ethyl-propionic acid are obtained as a white powder with a melting point of 218-220° C. (methanol). Example 7 30 g of 2,4,6-triiodo-5-amino-3-acetylaminobenzoic acid are suspended in 450 ml of water and concentrated sodium hydroxide solution is added to give a clear solution. Cool to 5°C in an ice bath, and add 2-fold diluted concentrated sulfuric acid dropwise to adjust the pH to 2.5. A solution of 8 g of sodium nitrite in 24 ml of water was added dropwise to the resulting fine suspension under ice-cooling, and the pH value was adjusted to PH2.5 with 2-fold diluted concentrated sulfuric acid.
Adjust to After stirring for 2 hours in an ice bath, dilute sodium hydroxide is added dropwise to a pH of 5 with constant cooling. Then poured into a warm solution of 20 g of copper chloride () and 33.4 g of potassium cyanide in 80 ml of water at 30°C,
The reaction mixture is kept at this temperature for a further 2 hours. Concentrated hydrochloric acid is then added to adjust the reaction mixture to pH 2, and the precipitate that separates is filtered with suction and washed with water. The crude product, which was dried at 50 °C and still contains copper salts, was then injected with 300 ml of methanol in each case.
The methanol solution is thoroughly concentrated. After adding 100 ml of water, add dilute sodium hydroxide solution to bring the batch to pH 11, treat this solution several times with activated carbon to decolorize it, add excess concentrated hydrochloric acid to precipitate the desired substance, and add water. Wash and dry at 50°C. Melting point 275-278℃
(decomposition) of 2,4,6-triiodo-5-cyano-3-acetylaminobenzoic acid (22.6 g of theoretical value)
75%). Example 8 3-amino-5-acetylaminomethyl-2,
28 g of 4,6-triiodobenzoic acid are suspended in 450 ml of water and a solution of 4.5 g of sodium nitrite in 24 ml of water is added to this suspension at 0 DEG to +5 DEG C. with cooling. After adjusting the pH to 2.5 by adding dilute sulfuric acid, the reaction mixture is after-stirred for 2 hours in an ice bath. Next, add 30 ml of 30% sodium hydroxide solution under cooling.
Add dropwise over time. Meanwhile, a hot solution of 45 g of copper sulfate pentahydrate and 11.7 g of common salt in 160 ml of water was mixed with a solution of 9.6 g of sodium binitrite and 6.3 g of sodium hydroxide in 80 ml of water, and after cooling, a new The precipitated copper chloride () is suction filtered. This is washed with water, suspended in 80 ml of water, and 30 g of potassium cyanide is added and dissolved. Add the diazotization mixture to this and stir at +30° C. until gas evolution has ceased. After adding 5 g of urea, glacial acetic acid is added to precipitate the copper salt, which is filtered with suction and concentrated hydrochloric acid is added dropwise to bring the pH to 1.8. After stirring for several hours in an ice bath, the crude product is filtered with suction, washed with water and dried. After recrystallization from 90% aqueous ethanol, 3-cyano-
20 g (70% of theory) of 5-acetylaminomethyl-2,4,6-triiodobenzoic acid are obtained. Example 9 48.2 g of 5-amino-2,4,6-triiodo-isophthalic acid-mono-N(2-hydroxyethyl)amide are suspended in 450 ml of water. Cool to 0° C. and add dropwise, with constant cooling, a solution of 7 g of sodium nitrite in 24 ml of water. Then, 2-fold diluted concentrated sulfuric acid is added at 0-5° C. to adjust the pH value to 2.5, and the mixture is stirred for 2 hours at this temperature. The reaction mixture is then neutralized by the dropwise addition of concentrated sodium hydroxide solution under cooling in an ice bath and 35.8 g of copper cyanide () in 320 ml of water are added.
and 66.8 g of potassium cyanide under vigorous stirring. After nitrogen generation has weakened, one more
After stirring at room temperature for an hour, add concentrated hydrochloric acid dropwise to PH value 3.5.
shall be. The precipitated copper salt is suction filtered, and the filtrate is acidified to a pH value of 0.2. After stirring for several hours in an ice bath, the precipitate is filtered off with suction, washed with water and dried at 60°C. 43.8 g (94.8% of theory) of 5-cyano-2,4,6-triiodo-isophthalic acid-mono-N(2-hydroxyethyl)amide having a decomposition point of 300° C. or higher is obtained. Example 10 Similarly to Example 9, 5-amino-2,4,6-
5-cyano-2,4,6- having a decomposition point of 300℃ or higher from triiodo-isophthalic acid monoamide
Triiodo-isophthalic acid-monoamide 37.4g
(82% of the theoretical value) is obtained.

Claims (1)

[Claims] 1. General formula [In the formula, Z represents a direct bond or a lower alkylene group, and X represents a -COOH group, a [formula] group (here, R ₁ represents a hydrogen atom, and R ₂ represents a lower acyl group) or a [formula] group (Here, R ₃ and R ₄ each represent a hydrogen atom or a lower alkyl group which may be substituted with a hydroxy group), and Y
is a hydrogen atom, -COOH group or [Formula] group (where R ₃ and R ₄ each represent the above)
and physiologically acceptable salts thereof. 2. The compound according to claim 1, which is 5-cyano-2,4,6-triiodo-isophthalic acid. 3. The compound according to claim 1, which is 5-cyano-2,4,6-triiodo-isophthalic acid-monomethyl-amide. 4. The compound according to claim 1, which is 5-cyano-2,4,6-triiodo-isophthalic acid-bis-(2-hydroxyethyl)-amide. 5. The compound according to claim 1, which is 5-cyano-2,4,6-triiodobenzoic acid. 6 β-2,4,6-triiodo-3-cyano-
The compound according to claim 1, which is phenyl-α-ethyl-propionic acid. 7 5-cyano-3-acetylamino-2,4,
The compound according to claim 1, which is 6-triiodo-benzoic acid. 8 3-cyano-5-acetylaminomethyl-
The compound according to claim 1, which is 2,4,6-triiodo-benzoic acid. 9 5-cyano-2,4,6-triiodo-isophthalic acid-mono-N-(2-hydroxyethyl)
- The compound according to claim 1, which is acetamide. 10 The compound according to claim 1, which is 5-cyano-2,4,6-triiodo-isophthalic acid monoamide. 11 General formula [In the formula, Z represents a direct bond or a lower alkylene group, and X represents a -COOH group, a [formula] group (here, R ₁ represents a hydrogen atom, and R ₂ represents a lower acyl group) or a [formula] group (Here, R ₃ and R ₄ each represent a hydrogen atom or a lower alkyl group which may be substituted with a hydroxy group), and Y
is a hydrogen atom, -COOH group or [Formula] group (where R ₃ and R ₄ each represent the above)
A method for producing a compound of the general formula [In the formula, Z, X and Y represent the above]
A method for producing a novel 2,4,6-triiodo-benzonitrile derivative, which is characterized by diazotizing the compound represented by and reacting it with cyanide. 12 General formula [In the formula, Z represents a direct bond or a lower alkylene group, and X represents a -COOH group, a [formula] group (here, R ₁ represents a hydrogen atom, and R ₂ represents a lower acyl group) or a [formula] group (Here, R ₃ and R ₄ each represent a hydrogen atom or a lower alkyl group which may be substituted with a hydroxy group), and Y
is a hydrogen atom, -COOH group or [Formula] group (where R ₃ and R ₄ each represent the above)
An X-ray contrast agent containing at least one compound or a physiologically acceptable salt thereof.