A novel synthesis of the pyrazolo[1,5-a]quinoline ring system. New N1-C2 bridged DNA gyrase inhibitors via a novel tandem 1,4-conjugate addition-michael [3+2] annulation process

Tetrahedron

Volumn 52, Issue 25, 1996, Pages 8471-8488

  Barrett, David ^a   Sasaki, Hiroshi ^a   Kinoshita, Takayoshi ^a   Fujikawa, Akihiko ^a   Sakane, Kazuo ^a  

^a ASTELLAS PHARMA INC   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

DNA TOPOISOMERASE (ATP HYDROLYSING); PYRAZOLO[4,5 C]QUINOLIN 4 ONE DERIVATIVE;

ANTIBACTERIAL ACTIVITY; ARTICLE; DNA ADDUCT; DRUG SYNTHESIS; ENZYME INHIBITION; MICHAELIS CONSTANT; PRIORITY JOURNAL; TANDEM REPEAT;

EID: 0029884617     PISSN: 00404020     EISSN: None     Source Type: Journal    
DOI: 10.1016/0040-4020(96)00415-2     Document Type: Article

References (55)

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15. 3-Acylated compounds related to 4 (but lacking an N-alkyl group) have been obtained from the reaction of N-aminoquinolones with 1,3-diketones, but no report of their conversion to the final antibacterial agents has appeared. Additionally, adaptation of the route to our target compounds, notably 3, is not obvious. See: (a) Azev, Y.A.; Shorshnev, S.V.; Alexeev, S.G.; Charushin, V.N.; Chupakhin, O.N. Mendeleev Commun. 1993, 99.
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46. 2 at room temperature for 4 days led to a mixture rich in the minor isomer, indicating epimerisation at C3, along with a trace of 7, indicating that the retro-reaction ie 8a to 5 can occur to a certain degree.
47. 1H NMR spectroscopy, in particular the O-methyl resonances, indicated simple alkylation of the respective isomers of 8a without any C3 epimerization, further confirming the diastereisomeric nature of the components. Furthermore, exposure of the major isomer to DBU in dichloromethane at room temperature for 7 days resulted in smooth isomerisation to a mixture rich in the minor isomer, confirming their isomeric nature. equation presented
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52. 3) δ 13.08 (s, 1H), 8.05 (d, 1H, J = 2 Hz), 7.96 (ddd, 1H, J = 2.4, 7.6, 10.1 Hz), 6.88 (d, 1H, J = 2 Hz), 4.57 (q, 2H, J =7.1 Hz), 1.54 (t, 3H, J =7.1 Hz); MS m/z 310 (M+).
53. +).
54. 7c Compound 12b did not ring open in DMSO solution. equation presented
55. In vitro antibacterial activity of the new N1-C2 bridged tricyclic quinolones prepared in this work is shown below. Whilst activity is reasonable against P.vulgaris IAM 1025, overall potency is moderate. MIC (μg/ml) Bacteria 17b 17d 17f 18b Levofloxacin S.aureus 209P JC-1 6.25 25 3.13 25 0.39 E.coli NIHJ JC-2 0.78 6.25 >100 6.25 0.05 P.vulgaris IAM 1025 0.10 0.78 0.20 0.78 <0.025 P.aeruginosa IAM 1095 50 >100 >100 >100 1.56