Tricyclic quinolone derivative, preparation method and application thereof

A quinolone, quinolone technology, applied in the field of medicinal chemistry and chemotherapeutics, can solve problems such as adverse drug reactions

Active Publication Date: 2014-10-15
GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Although quinolone antibiotics have fewer side effects in clinical application, they are still withdrawn from the market due to serious adverse drug reactions

Method used

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  • Tricyclic quinolone derivative, preparation method and application thereof
  • Tricyclic quinolone derivative, preparation method and application thereof
  • Tricyclic quinolone derivative, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1: (S)-9-fluoro-10-(4-hydroxypiperidin-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4]oxa Preparation of oxazine[2,3,4-ij]quinoline-6-carboxylic acid L-arginine salt tetrahydrate (Q1)

[0071]

[0072] Step (a): Add boric acid (48.00g), acetic anhydride (220ml) and zinc chloride (0.88g) into a dry three-necked flask, stir at room temperature for 30min, then add ( S )-9,10-difluoro-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4]oxazine[2,3,4- ij ] Ethyl quinoline-6-carboxylate (1) (80.00g) was added to the above solution, reacted at 60°C for 16h, concentrated under reduced pressure, slowly added dichloromethane (2200ml) to the concentrate, and washed with saturated NaHCO 3 Solution washing (2×1400ml), liquid separation, organic layer was washed with NaCl solution, anhydrous NaCl 2 SO 4 Dry, filter, and concentrate the filtrate to obtain a solid, then add 900ml of anhydrous ether, stir for 30min, filter, and dry the solid in vacuum to obtain bis(acetyl- O )[(3 S ...

Embodiment 2

[0083] Example 2: (S)-9-fluoro-10-((S)-3-hydroxypyrrol-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1, 4] Preparation of oxazine[2,3,4-ij]quinoline-6-carboxylic acid 0.75 hydrate (Q2)

[0084]

[0085] Step (a) is the same as step (a) of Example 1.

[0086] Step (b): Add bis(acetyl- O )[(3 S )-9,10-difluoro-2,3-dihydro-3-methyl-7-dihydro-7 H -pyridin[1,2,3- de ][1,4]Benzoxazine-6-carboxylate- O 6 , O 7 ] Boron(2) (8.00g), ( S )-3-hydroxypyrrole hydrochloride (3.63g) and triethylamine (5.94g), then add acetonitrile 120ml, react at 75°C for 3h, concentrate to dryness under reduced pressure, slowly add dichloromethane (150ml) and water (150ml), separated, and the organic layer was washed with NaCl solution, anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate to obtain 9.29 g of a yellow solid. The yield of the crude product is quantitative, and it is directly put into step (c) for reaction.

[0087] Step (c): The solid (9.29g) obtained in the above step (b)...

Embodiment 3

[0094] Embodiment 3: ( S )-9-fluoro-10-(( S )-3-hydroxypyrrol-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4]oxazine[2,3,4- ij ] Preparation of methyl quinoline-6-carboxylate (Q3)

[0095]

[0096] Steps (a), (b) and (c) are the same as Steps (a), (b) and (c) of Example 2.

[0097] Step (d): add ( S )-9-fluoro-10-(( S )-3-hydroxypyrrol-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4]oxazine[2,3,4- ij ]quinoline-6-carboxylic acid (8.00g), K 2 CO 3 (6.36g) and DMF (46ml), stir well and add CH 3 I (4.90g), then heated to 50°C for 8h, cooled to room temperature, added ethyl acetate (100ml) and water (50ml), separated, the aqueous phase was extracted with ethyl acetate (100ml), separated, combined organic phase, the organic phase was washed with water (200ml), washed with saturated brine (200ml), Na 2 SO 4 After drying, filtering, and concentrating the filtrate to obtain a crude product, the crude product was recrystallized in ethanol to obtain 6.52 g of the product (Q3...

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Abstract

The invention discloses a tricyclic quinolone derivative or its salt and hydrate with a novel structure and a non-basic substituent substituted C10 peripheral group. Activity determination of the compound by various strains proves that the compound has antibacterial activity on a variety of sensitive strains and resistant strains, can be used for treatment of infection diseases caused by Gram negative and positive bacteria, and is especially suitable for treatment of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa infection.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and chemotherapeutics, in particular to a class of tricyclic quinolone compounds, their salts or their hydrates, their preparation methods and their application in medicines for treating bacterial infectious diseases. Background technique [0002] Quinolones are an important class of fully synthetic antibiotics, which are widely used in clinic because of their excellent pharmacodynamics, pharmacokinetic properties, excellent antibacterial properties and less side effects. However, with the widespread use of antibiotics, a large number of drug-resistant strains have emerged, including multidrug-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), penicillin-resistant Streptococcus pneumoniae (PRSP), vancomycin-resistant enterococcus (VRE) etc. (Mitscher, L. A. etc., Chem. Rev. 2005, 105, 559), so there is an urgen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/04C07C279/14C07C277/08A61K31/5383A61K31/55A61P31/04
CPCC07C279/14A61K31/55C07C277/08C07D498/04A61K31/5383A61P31/04C07D498/06
Inventor 黄小光陈矛朱少璇鲍颖霞张小娜
Owner GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY
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