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2-substituted cephem compounds

a cephem compound and cephem technology, applied in the field of cephem compounds with substituents, can solve the problems of not disclosing a compound having a substituent, clinical problems, etc., and achieve the effects of high bioavailability, high blood concentration, and excellent kinetics in the body

Inactive Publication Date: 2015-10-22
GLAXO GROUP LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compounds in this patent are useful as pharmaceuticals with strong antimicrobial properties against a variety of bacteria, including Gram negative and Gram positive bacteria, beta-lactamase producing bacteria, and extended-spectrum beta-lactamase (ESBL) producing bacteria. They do not show cross-resistance with existing drugs and are effective at treating multidrug-resistant bacteria.

Problems solved by technology

Recently, clinical problem has been occurring due to the existence of Gram negative bacteria which have become highly resistant to a number of beta-lactam drugs including Cephems and Carbapenems by producing Class A (ESBL) and D types serine-beta-lactamases which have an extended substrate spectrum, and Class B type metallo-beta-lactamase which have an extended substrate spectrum.
However, these applications do not disclose a compound having a substituent at position 2 of the cephem skeleton.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

reference example 1

Synthesis of Compound X-1

[0301]

Step (1): Compound X-1a→Compound X-1b

[0302]Compound X-1a (26.47 g, 51.2 mmol) which was synthesized according to the synthesis in U.S. Pat. No. 4,463,172A1 was dissolved into dioxane (200 mL), and thereto was then added 4 mol / L hydrochloric acid solution in dioxane (25.6 ml, 102 mmol) at rt. The mixture was stirred at rt for 1 hour. The reaction mixture was concentrated under reduced pressure. The precipitated solid was then collected by filtration, and washed with diisopropyl ether / dichloromethane to yield compound X-1b (21.1 g, 75%).

[0303]1H-NMR (CDCl3) δ: 7.37-7.26 (11H, m), 7.03-6.99 (2H, m), 6.87 (1H, s), 6.36 (1H, d, J=8.7 Hz), 5.63-5.59 (1H, m), 5.23-5.20 (2H, m), 4.31 (1H, d, J=12.3 Hz), 4.09 (1H, d, J=12.3 Hz), 3.86 (2H, s), 1.99 (3H, s).

Step (2): Compound X-1b→Compound X-1c

[0304]Compound X-1b (5.53 g, 10 mmol) was dissolved into dichloromethane (60 mL), and thereto was then added dropwise a solution of m-chloroperoxybenzoic acid (3.45 g, 13 m...

reference example 2

Synthesis of Compound X-2

[0315]

Step (1): Compound X-1e+Compound X-2a→Compound X-2b

[0316]Compound X-1e (8.3 g, 15 mmol) and compound X-2a (10.4 g, 18 mmol) were used to synthesize the target compound in the same way as in step 4 and 5 of Reference Example 1.

[0317]Yielded amount: 10.4 g, (70%)

[0318]1H-NMR (CDCl3) δ: 8.27 (1H, d, J=8.1 Hz), 8.09 (1H, s), 7.43-7.29 (11H, m), 7.23 (2H, d, J=8.5 Hz), 6.94 (1H, s), 6.82 (2H, d, J=8.5 Hz), 5.92 (1H, dd, J=8.1, 4.9 Hz), 5.36 (1H, dd, J=8.4, 4.6 Hz), 5.23 (1H, d, J=4.9 Hz), 5.14 (1H, d, J=11.9 Hz), 5.05 (1H, d, J=11.9 Hz), 4.85 (1H, d, J=12.3 Hz), 4.23 (1H, d, J=12.3 Hz), 4.00 (1H, q, J=7.4 Hz), 3.76 (3H, s), 2.92 (1H, dd, J=16.4, 8.4 Hz), 2.83 (1H, dd, J=16.4, 4.6 Hz), 1.57 (3H, d, J=7.4 Hz), 1.54 (9H, s), 1.41 (9H, s).

Step (2): Compound X-2b→Compound X-2

[0319]Compound X-2b (10.4 g, 11 mmol) was used to synthesize the target compound in the same way as in step 6 of Reference Example 1.

[0320]Yielded amount: 10.7 g, (95%) 1H-NMR (CDCl3) δ: 8.3...

reference example 3

Synthesis of Compound X-3 and X-24

[0321]

Step (1): Compound X-3a→Compound X-3b→Compound X-3c

[0322]To a pre-cooled solution of compound X-3a (50 g, 97 mmol), which was synthesized according to the synthesis in Tetrahedron Letter, 37, 1971-1974 (1996), in dichloromethane (450 mL) at −10° C. was added peracetic acid (19.82 g, 102 mmol, 37% Wt). The mixture was stirred at −10 to −5° C. To the resulting mixture was added a solution of sodium bisulfite (12.1 g, 116 mmol) in water (200 mL). Water (150 mL) was added to the mixture, and then an organic layer was separated. The organic layer was washed with water (250 mL), 10% aqueous solution of sodium chloride (250 mL). The aqueous layers were successively extracted with dichloromethane (150 mL). The combined organic layers were dried over magnesium sulfate and filtered. To the filtrated was added dimethylformamide (200 mL) and then the solution was concentrated. The residue was placed in a reaction bottle with dimethylformamide (30 mL) and ...

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Abstract

The present invention relates to 2-substituted cephem compounds of Formula (I) having a quaternary ammonium group on the 3-side chain, preferably together with a cathechol group, or pharmaceutically acceptable salts thereof, which exhibit potent antimicrobial spectrum against a variety of bacteria including Gram negative bacteria and / or Gram positive bacteria, corresponding pharmaceutical compositions, methods of making, treatment methods for bacterial infections or uses thereof.

Description

TECHNICAL FIELD[0001]The compounds of the subject invention are related to 2-substituted cephem compounds, which have a wide antimicrobial spectrum, in particular exhibit potent antimicrobial activity against beta-lactamase producing Gram negative bacteria, and pharmaceutical compositions comprising the same.BACKGROUND[0002]To date, a variety of beta-lactam drugs have been developed and beta-lactam drugs have become clinically extremely important antimicrobial drugs. However, there are increasing number of bacterial types which have obtained resistance against beta-lactam drugs by producing beta-lactamase, which degrade beta-lactam drugs.[0003]According to the Ambler molecular classification, beta-lactamases are largely classified into four classes. Specifically, these are Class A (TEM type, SHV type, CTX-M type, KPC type and the like), Class B (IMP type, VIM type, L-1 type and the like), Class C (AmpC type) and Class D (OXA type and the like). Amongst these, Classes A, C and D type...

Claims

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Application Information

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IPC IPC(8): C07D501/48
CPCC07D501/48C07D501/50C07D505/24C07D519/06A61K9/0019Y02A50/30A61P1/00A61P1/02A61P1/16A61P11/00A61P13/02A61P13/12A61P17/02A61P27/16A61P31/04A61P9/00
Inventor AOKI, TOSHIAKIKUSANO, HIROKILIAO, XIANGMINPEARSON, NEIL DAVIDPENDRAK, ISRAILSATO, JUNTHALGI, REEMAYAMAWAKI, KENJIYOKOO, KATSUKI
Owner GLAXO GROUP LTD
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