Antibacterial compounds and biological applications thereof

• US 9,975,911 B2
• Filed: 10/28/2013
• Issued: 05/22/2018
• Est. Priority Date: 10/29/2012
• Status: Active Grant

• Current Assignee: Mutabilis
• Original Assignee: Mutabilis
• Inventors: Atamanyuk, Dmytro, Gerusz, Vincent, Moreau, Francois, Henryon, Vivien, Monbrun, Jerome, Airiau, Etienne
• Primary Examiner(s): Brooks, Clinton A
• Application Number:
  US14/438,929
• Publication Number:
  US 20150291636A1
• Time in Patent Office: 1,667 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/661 Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 9/09 Esters of phosphoric acids
• CPC Class Codes: C07F 9/091 with hydroxyalkyl compounds with further substituents on alkyl
• CPC Class Codes: C07F 9/38 Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to compounds of formulae (Ia), (Ib) or (Ic) wherein, A₁ and A₂, identical or different, are H, (C₁-C₆) alkyl, (C₁-C₆) fluoroalkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C₁-C₆) alkyl-OR_a, (C₁-C₆) alkyl-SR_a, (C₁-C₆) alkyl-NR_aR_b, OR_a, SR_a, NR_aR_b, or COR_a; A₃ is H, OH or form a carbonyl with A₄; A₄ is H, OH or form a carbonyl with A₃; A₅ is H, CR_aR_bOH, F, OH or forms a double bond with X in the case where X is CH; A₆ is H or F; X is CH₂, CHF, CF₂, CHOH, O, S, NR_a or a simple bond, or X is CH in the case where A₅ forms with X a double bond; Y is P(O)(OR_a)(OR_b) or P(O)(OR_a)(NR_aR_b); V is O or S; A₇ is H, (C₁-C₆) alkyl, (C₁-C₆) fluoroalkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl or (C₁-C₆) alkyl-OR_a; A₈ is OH or H, R_a and R_b, identical or different, are H, (C₁-C₆) alkyl, (C₁-C₆) fluoroalkyl, (C₁-C₆) alkyl-OH or (C₁-C₆) alkyl-O—(C₁-C₆) alkyl; and their addition salts thereof with acids and bases, their preparation and their use in the antibacterial prevention and therapy, used alone or in association with antibacterials, antivirulence agents or drugs reinforcing the host innate immunity.

Claims

1. The compounds having the general formula (I)

2. The compounds of formula (I) and their addition salts thereof with acids and bases, according to claim 1, wherein Y is P(O)(OH)₂.

3. The compounds of general formula (I) and pharmaceutically acceptable addition salts thereof with acids and bases as defined in claim 2, for use as drugs.

4. The compounds of formula (I) and their addition salts thereof with acids and bases, according to claim 1, wherein X is CH₂, CHF, CF₂, CHOH or O.

5. The compounds of formula (I) and their addition salts thereof with acids and bases, according to claim 1, wherein A₁ and A₂ are H or one of them is H and the other is (C₁-C₆)alkyl or one of them is H and the other is fluoro(C₁-C₆)alkyl or one of them is H and the other is (C₁-C₆)alkyl-OR_a or one of them is H and the other is (C₁-C₆)alkyl-SR_a or one of them is H and the other is COR_a, R_a being as defined in claim 1, or one of them is H and the other is OH.

6. The compounds of formula (I) and their addition salts thereof with acids and bases, according to claim 1, wherein when A₃ forms a carbonyl with A₄, As is OH or CR_aR_bOH, R_a and R_b being as defined in claim 1, and when A₃ doesn'"'"'t form a carbonyl with A₄, As is H or F.

7. The compounds of formula (I) and their addition salts thereof with acids and bases, according to claim 1, wherein A₇ is H or (C₁-C₆)alkyl.

8. The compounds of formula (I) according to claim 1 which names follow:

N-hydroxy-N-formylamino-1-deoxy-D-ribitol-5-phosphate, [6-(Formyl-hydroxy-amino)-(3R,4R,5S)-3,4,5-trihydroxy-hexyl]-phosphonic acid, [[6-(Formyl-hydroxy-amino)-(3R,4R,5S)-1,3,4,5-tetra-hydroxy-hexyl]-phosphonic acid, [(2S,3S,4S)-5-(Formyl-hydroxy-amino)-2,3,4-trihydroxy-pentyl]-phosphonic acid (1-(N-benzyloxy-N-formylamino)-1,5-dideoxy-D-ribitol] 5-phosphonic acid), 1-(N-benzyloxy-N-formylamino)-1-deoxy-5,6-dihydroxy-D-ribo-hexitol)]-6-phosphonic acid, [(3R,4R,5S)-6-(Formyl-hydroxy-amino)-3,4,5,7-tetrahydroxy-heptyl]-phosphonic acid (diastereoisomers DIA1 and DIA2), [1-Fluoro-6-(formyl-hydroxy-amino)-(3R,4R,5S)-3,4,5-trihydroxy-hexyl]-phosphonic acid, (3R,4S,5R)-3,4,5-trihydroxy-6-(N-hydroxyformamido) hexyl)phosphonic acid, (3R,4R,5R)-3,4,5-trihydroxy-6-(N-hydroxyformamido)-hexylphosphonic acid, [1,1-Difluoro-6-(formyl-hydroxy-amino)-(3R,4R,5S)-3,4,5-trihydroxy-hexyl]-phosphonic acid, [1-(N-hydroxy-N-formylamino)-1,6-dideoxy-D-allo/L-talo-hexitol)] 6-phosphonic acid, 1-(N-benzyloxy-N-formylamino)-1-deoxy-D-ribo-5-(E)-hexenitol 6-phosphonic acid and their addition salts thereof with acids and bases, in particular their sodium salts.

9. The compounds of general formula (I) and pharmaceutically acceptable addition salts thereof with acids and bases, as defined in claim 8, for use as drugs.

10. The compounds of general formula (I) and pharmaceutically acceptable addition salts thereof with acids and bases as defined in claim 1, for use as drugs.

11. The compounds of general formula (I) and pharmaceutically acceptable addition salts thereof with acids and bases as defined in claim 1 for use as drugs for the therapeutical treatment of infections due to Gram-negative bacteria in human or animals.

12. The compounds of general formula (I) and pharmaceutically acceptable addition salts thereof with acids and bases, as defined in claim 1, for use as drugs in combination with an antibacterial, an antivirulence agent, a drug reinforcing the host innate immunity or a combination of any of them.

13. The compounds of general formula (I) and pharmaceutically acceptable addition salts thereof with acids and bases, as defined in claim 1, for use as drugs in combination with macrolides, streptogramins, pleuromutilins, FabI inhibitors, rifamycins, lipopeptides, GM-CSF or a combination of any of them.

14. Pharmaceutical compositions containing as active principle a compound of general formula (I) or a pharmaceutically acceptable addition salt thereof with an acid or a base, as defined in claim 1.

15. Mixture or pharmaceutical association comprising as active principles a compound of formula (I) or a pharmaceutically acceptable addition salt thereof with an acid or a base, as defined in claim 1, and an antibacterial, an antivirulence agent, a drug reinforcing the host innate immunity or a combination of any of them.

16. Mixture or pharmaceutical association comprising as active principles a compound of formula (I) or a pharmaceutically acceptable addition salt thereof with an acid or a base, as defined in claim 1, and a macrolide, a streptogramin, a pleuromutilin, a FabI inhibitor, a rifamycin, a lipopeptide, a GM-CSF or a combination of any of them.