Patent EA-005214-B1 (EA)
Title: Halo derivatives of 9-deoxo-9a-aza-9a-homerythromycin
Inventor: MARUSIC-ISTUK ZORICA
IPC: A61K31/70
Filed: 2000-05-02
Abstract: 1. Halo derivatives of 9a-N-(N'-arylcarbamoyl)-and 9a-N-(N'-arylthiocarbamoyl)-9-deoxo-9a-aza-9a-homoerythromycin A of the general formula (I) wherein R has the meaning of a substituted aryl group of the formula (II) wherein substituents a, b, c, d and e are the same or different and at least one of them has the meaning of halo, a (C1-C6) haloalkyl or a (C1-C6) haloalkoxy group whereas the remaining ones have the meaning of hydrogen, halo, a (C1-C6) alkyl or a (C1-C6) alkoxy group, and X has the meaning of oxygen or sulfur, and pharmaceutically acceptable addition salts thereof by inorganic or organic acids. 2. Compounds according to claim 1, characterized in that a has the meaning of halo, b, c, d and e are the same and have the meaning of hydrogen and X is oxygen or sulfur. 3. A compound according to claim 2, characterized in that a has the meaning of fluoro and X is oxygen. 4. A compound according to claim 2, characterized in that a has the meaning of fluoro and X is sulfur. 5. A compound according to claim 2, characterized in that a has the meaning of chloro and X is sulfur. 6. Compounds according to claim1, characterized in that a has the meaning of halo, b, c and d are the same and have the meaning of hydrogen, e has the meaning of a (C1-C4) alkyl group and X is oxygen or sulfur. 7. A compound according to claim 6, characterized in that a has the meaning of chloro, b, c and d are the same and have the meaning of hydrogen, e is methyl and X is oxygen. 8. Compounds according to claim 1, characterized in that a, c, d and e are the same and have the meaning of hydrogen, b is halo and X is oxygen or sulfur. 9. A compound according to claim 8, characterized in that b has the meaning of fluoro and X is oxygen. 10. A compound according to claim 8, characterized in that b has the meaning of chloro and X is oxygen. 11. A compound according to claim 8, characterized in that b has the meaning of bromo and X is oxygen. 12. A compound according to claim 8, characterized in that b has the meaning of fluoro and X is sulfur. 13. A compound according to claim 8, characterized in that b has the meaning of chloro and X is sulfur. 14. A compound according to claim 8, characterized in that b has the meaning of bromo and X is sulfur. 15. Compounds according to claim 1, characterized in that a, b, d and e are the same and have the meaning of hydrogen, c is halo and X is oxygen or sulfur. 16. A compound according to claim 15, characterized in that c has the meaning of chloro and X is oxygen. 17. A compound according to claim 15, characterized in that c has the meaning of bromo and X is oxygen. 18. A compound according to claim 15, characterized in that c has the meaning of chloro and X is sulfur. 19. A compound according to claim 15, characterized in that c has the meaning of bromo and X is sulfur. 20. Compounds according to claim 1, characterized in that a, d and e are the same and have the meaning of hydrogen, b has the meaning of a (C1-C6) haloalkyl group, c is halo and X is oxygen or sulfur. 21. A compound according to claim 20, characterized in that a, d and e are the same and have the meaning of hydrogen, b is a -CF3 group, c is chloro and X is oxygen. 22. Compounds according to claim 1, characterized in that b, d and e are the same and have the meaning of hydrogen, a and c are the same and have the meaning of halo and X is oxygen or sulfur. 23. A compound according to claim 22, characterized in that a and c are the same and have the meaning of chloro and X is oxygen. 24. A compound according to claim 22, characterized in that a and c are the same and have the meaning of chloro and X is sulfur. 25. Compounds according to claim1, characterized in that a, b, c, d and e are the same or different and have the meaning of hydrogen or of a (C1-C4) haloalkyl group and X is oxygen or sulfur. 26. A compound according to claim 25, characterized in that a is a -CF3 group, b, c, d and e are the same and have the meaning of hydrogen and X is oxygen. 27. A compound according to claim 25, characterized in that a, c, d and e are the same and have the meaning of hydrogen, b is a -CF3 group and X is oxygen. 28. A compound according to claim 25, characterized in that a, b, d and e are the same and have the meaning of hydrogen, c is a -CF3 group and X is oxygen. 29. A compound according to claim 25, characterized in that a, c, d and e are the same and have the meaning of hydrogen, b is a -CF3 group and X is sulfur. 30. Compounds according to claim1, characterized in that a, b, c, d and e are the same or different and have the meaning of hydrogen or of a (C1-C4) haloalkoxy group and X is oxygen or sulfur. 31. A compound according to claim 30, characterized in that b, c, d and e are the same and have the meaning of hydrogen, a is a -OCF3 group and X is oxygen. 32. A compound according to claim 30, characterized in that a, b, d and e are the same and have the meaning of hydrogen, c is a -OCF3 group and X is oxygen. 33. Process for the preparation of halo derivatives of 9a-N-(N'-arylcarbamoyl)-and 9a-N-(N'-arylthiocarbamoyl)-9-deoxo-9a-aza-9a-homoerythromycin(N'-arylthiocarbamoyl)-9-deoxo-9a-aza-9a-homoerythromycin A of the general formula (I) wherein R has the meaning of a substituted aryl group of the formula (II) wherein substituents a, b, c, d and e are the same or different; and at least one of them has the meaning of halo, a (C1-C6) haloalkyl or a (C1-C6) haloalkoxy group whereas the remaining ones have the meaning of hydrogen, halo, a (C1-C6) alkyl or a (C1-C6) alkoxy group, and X has the meaning of oxygen or sulfur, and pharmaceutically acceptable addition salts thereof with inorganic or organic acids, characterized in that 9-deoxo-9a-aza-9a-homoerythromycin A is subjected to a reaction with isocyanates orisothiocyanates of the general formula (III), R-N = C = X (III) wherein R and X have the abovemeanings, in an aprotic solvent, preferably toluene, at room temperature or at elevated temperature to 60 degree . 34. A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and an antibacterially effective amount of the compounds according to claim 1. 35. Use of compounds according to any of claims 1 to 32 for the treatment or prevention of bacterial infections.