Synthesis and Structure−Activity Relationships of 5-Amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolonecarboxylic Acid Antibacterials Having Fluorinated 7-[(3R)-3-(1-Aminocyclopropan-1-yl)pyrrolidin-1-yl] Substituents

Abstract

A series of novel 5-amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolones bearing fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl substituents at the C-7 position (2-4) was synthesized to obtain potent drugs for infections caused by Gram-positive pathogens, which include resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant enterococci (VRE). These fluorinated compounds 2-4 exhibited potent antibacterial activity comparable with that of a compound bearing a non-fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidine moiety at the C-7 position (1) and had at least 4 times more potent activity against representative Gram-positive bacteria than ciprofloxacin (CPFX), gatifloxacin (GFLX), or moxifloxacin (MFLX). Among them, the 7-[(3S,4R)-4-(1-aminocyclopropan-1-yl)-3-fluoropyrrolidin-1-yl] derivative 3 (=DQ-113), which showed favorable profiles in preliminary toxicological and nonclinical pharmcokinetic studies, exhibited potent antibacterial activity against clinically isolated resistant Gram-positive pathogens.

Fluorinated Five‐Membered Nitrogen‐Containing Heterocycles

“…24 To distinguish between hydrogen bonding effects and inductive effects, peptides were prepared that contained (2S,4R)-fluoroproline (4R-FPro) instead of Pro or Hyp and a comparison of triple helices formed from three peptides was made. The presence of 4R-FPro dramatically increased the stability in the series: (Pro-Pro-Gly) 10 < (Pro-Hyp-Gly) 10 < (Pro-4R-FPro-Gly) 10 . This dramatic increase in stability is not consistent with hydrogen bonding associated with Hyp but indicates the importance of inductive effects.…”

“…6 These fluoropyrrolidines included tetrafluoropyrrolidine (10) as well as trans-(9) and cis-3,4-difluoropyrrolidine (11). Tetrafluoropyrrolidine (10) was prepared by cyclization of tetrafluorobutane diol, as shown in Fig. 3.6.…”

“…An example of preparation of fluoropyrrolidine derivatives through electrophilic fluorination is found in the synthesis of a new fluoroquinolone antibiotic 12. 10 The intermediate lactam 13 was fluorinated with N-fluorobenzenesulfonimide (NFSi) to give a single diastereomer, the monofluoropyrrolidinone 14. Treatment of 14 with base followed by quenching with 2,6-di-tert-butylphenol produced the other diastereomer 15.…”

Catalytic Enantioselective .ALPHA.-Fluorination of Carbonyl Compounds Using Chiral Transition Metal Complexes

“…Otherwise, the reaction did not proceed to completion. The catalyst amount could be reduced to 5 mol % without problem, although a drop in the selectivity was finally observed when 2.5 mol % of 32b was used (entries [6][7][8]. It is interesting that no formation of a difluorinated compound and no racemization of the monofluorinated product were observed under these reaction conditions.…”

“…4 The efficacy of the fluorine-substitution at chiral sp3 carbon centers has been demonstrated by the development of medicinally important compounds 1-4 (Chart 2). 5,6,7,8 In addition to the development of chiral electrophilic fluorinating reagents,9 catalytic enantioselective fluorination reactions have been attracting increasing attention.4 Before our work, there had been only two reported examples using a chiral Ti complex and a chiral phase transfer catalyst, where pioneering, but limited success was achieved in respect to both substrate-generality and enantioselectivity.1° In the past fivc years, great pi ogress has been made in this field with the development of novel metal catalysts" and organocatalysts,12 and not only active methine compounds but also primary …”