Halogenated quinazolinyl nitrofurans as antibacterial agents

• US 20060258693A1
• Filed: 08/06/2004
• Published: 11/16/2006
• Est. Priority Date: 08/08/2003
• Status: Active Grant

• Current Assignee: Ulysses Pharmaceutical Products, Inc.
• Original Assignee: Ulysses Pharmaceutical Products, Inc.
• Inventors: Malouin, Francois, Chamberland, Suzanne
• Granted Patent: US 7,410,974 B2
• Time in Patent Office: Days
• US Class Current: 514/266.240
• CPC Class Codes: A01N 43/54 1,3-Diazines; Hydrogenated 1,3-diazines
• CPC Class Codes: A61P 31/02 Local antiseptics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention includes novel compounds of the formula (I) wherein X is absent or trans or cis CHCH, R₁ is (C₁-C₁₀) alkyl unsubstituted or substituted by one to three hydroxy, (C₁-C₁₀) alkenyl unsubstituted or substituted by one to three hydroxy, (C₁-C₁₀) alkynyl unsubstituted or substituted by one to three hydroxy, or aryl unsubstituted or substituted by one to three hydroxy; R₂ is hydrogen, alkyl or aryl; R₃ and R₄ are, independently of each other, H, halogen, or a solubilizing group, with the provisio that at least one of R₃ and R₄ is halogen; and pharmaceutically acceptable salts thereof. The invention also includes pharmaceutically acceptable formulations of said compounds which exhibit antibiotic activity against a wide spectrum of microorganisms including organisms which are resistant to multiple antibiotic families and are useful as antibacterial agents for treatment or prophylaxis of bacterial infections, or their use as antiseptics, agents for sterilization or disinfection.

Claims

1. A compound of the formula

2. The compound according to claim 1, wherein R₁ is aryl unsubstituted or substituted by one to three hydroxy and R₂ is hydrogen.

4. The compound according to claim 1, wherein R₄ is a halogen.

6. The compound according to claim 1, wherein the solubilizing group of R₃ or R₄ is

7. The compound according to claim 6, wherein R₃ is a halogen and R₄ is partial formula (1.2) wherein Q is NH or NCH₃.

9. The compound according to claim 1, wherein R₃ is an amine containing heterocycle.

10. The compound according to claim 1, wherein R₃ is N-methylpiperazine.

11. The compound according to claim 1 wherein X is trans CHCH.

12. The compound according to claim 1, wherein R₁ is hydroxyethanol, hydroxyaniline, hydroxyphenyl, 2-hydroxyethanol, 4-hydroxyaniline, or 4-hydroxyphenyl.

18. The compound according to claim 1, wherein R₂ is phenyl, substituted phenyl, pyranyl, substituted pyridinyl, thiophenyl, substituted thiophenyl, furanyl, substituted furanyl, thiazole, oxazole or substituted or unsubstituted imidazole.

19. The compound according to claim 12, wherein R₂ is N-alkyl imidazole.

20. The compound according to claim 1 of the formula 6-fluoro-2-[2-(5-nitro-2-furyl)vinyl]-4-(p-hydroxyanilino)-quinazoline.

21. The compound according to claim 1 of the formula 7-(4-methylpiperazino)-6-fluoro-2-[2-(5-nitro-2-furyl)vinyl]-4-(p-hydroxyanilino)-quinazoline.

22. The compound according to claim 1 of the formula 6-fluoro-2-[2-(5-nitro-2-furyl)vinyl]-4-chloroquinazoline.

23. The compound according to claim 1 of the formula 7-(4-methyl piperazino)-6-fluoro-2-[2-(5-nitro-2-furyl)vinyl]-4-chloroquinazoline.

24. The compound according to claim 1 of the formula 6-fluoro-2-[2-(5-nitro-2-furyl)vinyl]-4-(3H)quinazolinone.

25. The compound according to claim 1 of the formula 7-(4-methylpiperazino)-6-fluoro-2-[2-(5-nitro-2-furyl)vinyl]-4-(3H) quinazolinone.

29. A method for preventing or treating a bacterial infection in a human or an animal, comprising administering to said human or said animal a prophylactically or therapeutically effective amount of a compound according to claim 1, effective in preventing or treating the bacterial infection.

31. A method for antisepsis of, or disinfecting or sterilizing the surface of an object, including a human, of bacteria, comprising:

contacting the object with the compound according to claim 1 in an amount and for a time sufficient to achieve a desired degree of antisepsis, disinfection or sterilization.

39. A process for the preparation of the compound according to claim 1,

comprising:

a) optionally reacting a compound of formula (1.3)

 

with hydrochloric acid, acetic anhydride and aqueous ammonia, to form a compound of formula (1.4)

b) optionally reacting the compound of formula 1.4 with 5-nitro-2-furancarboxaldehyde, to form a compound of formula (1.5)

c) optionally reacting the compound of formula 1.5 with phosphorus pentachloride and phosphorus oxychloride to form a compound of formula (1.6)

and

d) reacting the compound of formula 1.6 with a compound of the formula (1.7)

 

wherein X is H and R₁, R₂, R₃, and R₄ are as defined in claim 1.

3. (canceled)

5. (canceled)

8. (canceled)

13-17. -17. (canceled)

26-28. -28. (canceled)

30. (canceled)

32-38. -38. (canceled)

40-42. -42. (canceled)