Dicarboxylic acid-bis(3,5-dicarbamoyl-2,4,6-triiodoanilides) and x-ray contrast media containing them

• US 5,073,362 A
• Filed: 07/16/1990
• Issued: 12/17/1991
• Est. Priority Date: 09/17/1987
• Status: Expired due to Fees

• Current Assignee: Schering Ag (Merck & Co., Inc.)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Speck, Ulrich, Blaszkiewicz, Peter
• Primary Examiner(s): Dees, Jose G.
• Assistant Examiner(s): CLARKE, VERA
• Application Number:
  US07/554,948
• Time in Patent Office: 519 Days
• Field of Search: 564/153, 424/5
• US Class Current: 424/9.452
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• CPC Class Codes: A61K 49/04 X-ray contrast preparations
• CPC Class Codes: C07C 233/00 Carboxylic acid amides
• CPC Class Codes: C07C 233/12 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups

Abstract

Dicarboxylic acid bis-(3,5-dicarbomoyl-2,4,6-triiodoanilides) of general formula I ##STR1## wherein the amide radicals --CONR¹ R² and --CONR³ R⁴ are different from one another and

R¹ is a hydrogen, a lower alkyl radical or R²,

R² is a straight-chain or branched-chain monohydroxy or polyhydroxy alkyl radical,

R³ is hydrogen, a lower alkyl radical or R⁴,

R⁴ is a straight-chain or branched-chain monohydroxy or polyhydroxy alkyl radical,

R⁵ is hydrogen, a lower alkyl radical or a monohydroxy or polyhydroxy alkyl radical,

X is a straight-chain or branched-chain alkylene with 1 to 6 carbon atoms, which optionally can be substituted by 1 to 6 hydroxy or alkoxy groups or interrupted by one or more oxygen atoms,

possess good pharmacological and physicochemical properties rendering them outstandingly suitable as radiopaque substances in X-ray contrast media for use in all fields of application for X-ray contrast media.

Claims

1. A dicarboxylic acid bis-(3,5-dicarbamoyl-2,4,6-triiodoanilide) of the formula ##STR8## wherein the amide radicals --CONR¹ R² and --CONR³ R⁴ are different from one another and

R¹ is hydrogen, C_1-4 -alkyl or R², wherein R¹ and R² may be the same or different,

R² is monohydroxy- or polyhydroxy-C_2-8 alkyl,

R³ is hydrogen, C_1-4 -alkyl or R⁴, wherein R³ and R⁴ may be the same or different,

R⁴ is monohydroxy- or polyhydroxy-C_2-8 -alkyl,

R⁵ is hydrogen, C_1-4 -alkyl or monohydroxy- or polyhydroxy-C_1-4 -alkyl, and

X is C_1-6 -alkylene, optionally substituted by 1 to 6 hydroxy, C_1-7 -alkoxy, benzyloxy, hydroxybenzyloxy or hydroxy-C_1-7 -alkoxy groups and/or interrupted by 1-3 oxygen atoms.

2. A compound of claim 1, wherein X is --CH₂ --.

3. A compound of claim 1, wherein X is ##STR9##

4. A compound of claim 1, wherein X is straightchained.

5. A compound of claim 1, wherein R¹ is H or CH₃.

6. A compound of claim 1, wherein R² is ##STR10##

7. A compound of claim 1, wherein R₃ is H or --CH₂ CH₂ OH.

8. A compound of claim 1, wherein R₄ is ##STR11##

9. A compound of claim 1, wherein R₅ is --CH₃, --CH₂ CH₂ --OH or ##STR12##

11. 3-dihydroxy succinic acid bis-[3-(2,3-dihydroxy-propylcarbamoyl)-5-(2-hydroxy-ethylcarbamoyl)-2,4,6-triiodo-N-(2-hydroxyethyl) anilide] or

Hydroxymalonic acid bis-{3-(2,3-dihydroxy-N-methyl-propylcarbamoyl)-5-(2,3-dihydroxy-propylcarbamoyl)-2,4,6-triiodo-N-methyl anilide}, each a compound of claim 1.

12. A compound according to claim 1, wherein --CONR³ R⁴ is 2,3-dihydroxypropyl-carbamoyl.

13. A compound according to claim 1, wherein --CONR¹ R² is 2,3-dihydroxy-1-hydroxymethylpropyl-carbamoyl.

14. A compound according to claim 11, wherein --CONR¹ R² is 2,3-dihydroxy-1-hydroxymethylpropyl-carbamoyl.

15. A compound according to claim 11, wherein X is --CH₂ --.

16. A compound according to claim 12, wherein X is --CH₂ --.

17. Malonic acid bis-[3-(2,3-dihydroxypropyl-carbamoyl)-5-[(1RS,2SR)-2,3-dihydroxy-1-hydroxymethylpropyl-carbamoyl]-2,4,6-triiodo-N-methyl anilide], a compound of claim 1.

18. An X-ray contrast pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.

20. A method of performing X-ray imaging of a patient comprising administering to such patient an effective amount of a compound of claim 1.

10. Malonic acid bis-[3-(2,3-dihydroxy-N-methyl-propylcarbamoyl)-5-(2,3-dihydroxy-propylcarbamoyl)-2,4,6-triiodo-N-methyl anilide],

Malonic acid bis-{3-(2,3-dihydroxy-propylcarbamoyl)-5-[bis-(2-hydroxyethyl)-carbamoyl]-2,4,6-triiodo-N-methyl anilide},

Malonic acid bis-{3-(2,3-dihydroxy-propylcarbamoyl)-5-[(1RS,2SR)-2,3-dihydroxy-1-hydroxymethylpropyl-carbamoyl]-2,4,6-triiodo-N-methyl anilide},

Malonic acid bis-[3-(2-hydroxy-N-methyl-ethyl-carbamoyl)-5-(2,3-dihydroxy-propylcarbamoyl)-2,4,6-triiodo-N-(2-hydroxy-ethyl) anilide],

Malonic acid bis-[3-(2,3-dihydroxy-N-methyl-propyl-carbamoyl)-5-(2-hydroxy-ethyl-carbamoyl)-2,4,6-triiodo-N-methyl anilide],

Malonic acid bis-{3-(2,3-dihydroxy-propylcarbamoyl)-5-(2-hydroxyethyl-carbamoyl)-2,4,6-triiodo-N-(2,3-dihydroxy-propyl) anilide},

Hydroxymalonic acid bis-[3-(2,3-dihydroxy-propylcarbamoyl)-5-(2-hydroxy-ethyl-carbamoyl)-2,4,6-triiodo-N-(2,3-dihydroxy-propyl) anilide],

Hydroxymalonic acid bis-[3-(2-hydroxy-1-hydroxymethylethyl-carbamoyl)-5-(2,3-hydroxy-propyl-carbamoyl)-2,4,6-triiodo-N-methyl anilide],

Methoxymalonic acid bis-[3-(2-hydroxy-1-hydroxymethylethyl-carbamoyl)-5-(2,3-dihydroxy-propyl-carbamoyl)-2,4,6-triiodo-N-methyl anilide],

19. An X-ray contrast pharmaceutical composition comprising an effective amount of a compound of claim 10 and a pharmaceutically acceptable excipient.

21. A method of performing X-ray imaging of a patient comprising administering to such patient an effective amount of a compound of claim 10.