Cyclic gyrase and topoisomerase IV inhibitor

A technology of stereoisomers and heterocyclic groups, applied in anti-inflammatory agents, non-central analgesics, medical preparations containing active ingredients, etc., can solve the problem of poor bacterial outer membrane penetration, poor solubility, and clinical Application and other issues

Active Publication Date: 2016-08-24
BEIJING SIHUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Quinolones mainly act on the GyrA subunit for the DNA gyrase target, and mainly act on the ParC subunit for the topoisomerase. However, there are few reports about the mutations of GyrB subunit and PaerE subunit, so the clinical application of quinolone antibiotics is limited to a certain extent.
Coumarin compounds, such as novobiocin, chlorobiocin and coumarin, mainly target DNA gyrase. Such compounds have problems such as poor solubility and poor penetration of bacterial outer membranes, so they are not Not widely used clinically

Method used

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  • Cyclic gyrase and topoisomerase IV inhibitor
  • Cyclic gyrase and topoisomerase IV inhibitor
  • Cyclic gyrase and topoisomerase IV inhibitor

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preparation example Construction

[0103] The present invention also provides the preparation method of above-mentioned compound:

[0104]

[0105] Reaction steps:

[0106] Step 1: Preparation of Intermediate 1

[0107] Dissolve raw material 1 and raw material 2 in an organic solvent (such as 1,4-dioxane, tetrahydrofuran), add potassium acetate, and add tricyclohexylphosphine and palladium catalyst (such as tris(dibenzylideneacetone) Dipalladium), heated to completion of the reaction. The reaction solution was directly used in the next reaction.

[0108] Step 2: Preparation of Intermediate 2

[0109] Add raw material 3, alkaline aqueous solution (such as sodium bicarbonate) and palladium catalyst (such as [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex ), heated under nitrogen until the end of the reaction. Cool, filter with suction, concentrate and purify to obtain intermediate 2.

[0110] Step 3: Preparation of intermediate 3

[0111] Add intermediate 2 into a mixe...

Embodiment 1

[0152] Example 1 1-ethyl-3-(6-fluoro-5-(7-hydroxyl-6,7-dihydro-5H-cyclopentyl[b]pyridin-3-yl)-7-(tetrahydrofuran- 2- base)-1H-benzo[d]imidazol-2-yl)urea preparation (compound 1)

[0153]

[0154] 1) Preparation of 6,7-dihydro-5H-cyclopentyl[b]pyridine 1-oxide

[0155]

[0156] 6,7-dihydro-5H-cyclopentyl[b]pyridine (1.4g, 11.7mmol) was added to dichloromethane (40mL), and 3-chloroperoxybenzoic acid (mass fraction 77% , 5.25g, 23.4mmol), heated to reflux for 2 hours, down to room temperature, added calcium hydroxide (3.47g, 46.8mmol), stirred for 16 hours, suction filtered, the filter cake was washed with dichloromethane, and the organic phases were combined, Concentration in vacuo afforded the title compound (1.38 g, 87.3% yield).

[0157] 2) Preparation of 6,7-dihydro-5H-cyclopentyl[b]pyridin-7-yl acetate

[0158]

[0159] Add 6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (1.38g, 10.2mmol) into acetic anhydride (30mL), heat up to 55°C for 18 hours, concentrate, ...

Embodiment 2

[0177] Example 2 1-ethyl-3-(6-fluoro-5-(8-hydroxyl-5,6,7,8-tetrahydroquinolin-3-yl)-7-(tetrahydrofuran-2-yl)- 1H-Benzo[d] Preparation of imidazol-2-yl)urea (compound 17)

[0178]

[0179] 1) Preparation of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydroquinoline

[0180]

[0181] 5,6,7,8-tetrahydroquinoline (2.0g, 15mmol), bis(1,5-cyclooctadiene)di-μ-methoxydiiridium (I) (297.4mg, 0.45mmol) , 4,4'-di-tert-butyl-2,2'-bipyridine (241mg, 0.9mmol) and biboronic acid pinacol ester (3.81g, 15mmol) were added to tetrahydrofuran (40mL), under nitrogen protection at 75°C After reacting for 11 hours, the crude product (3.89 g) was obtained after concentration, which was directly carried out to the next reaction.

[0182] 2) Preparation of 3-bromo-5,6,7,8-tetrahydroquinoline

[0183]

[0184] 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydroquinoline crude product (3.89 g, 15mmol) was dissolved in methanol (80mL) and copper bromide (11...

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Abstract

The invention belongs to the technical field of medicament, and particularly relates to a compound shown in formula (I) (please see the formula (I) in the description), and acceptable salt, ester or stereoisomer of the compound in pharmacy. R1, R2, a ring A and a ring B are defined in the description. The invention further relates to a preparation method, pharmaceutical preparations and pharmaceutical compositions of the compounds, and application of the compounds in preparation of medicines for treating and preventing bacterial infectious diseases.

Description

1. Technical field [0001] The present invention belongs to the technical field of medicine, and in particular relates to a dual inhibitor compound of gyrase and topoisomerase IV, a pharmaceutically acceptable salt, ester or stereoisomer thereof; the present invention also relates to a preparation method of these compounds, Pharmaceutical preparations, pharmaceutical compositions and uses in the preparation of medicines for treating and / or preventing bacterial infectious diseases. 2. Background technology [0002] With the extensive use of antibiotics, especially non-indication use, inappropriate selection of backup antimicrobials, overtreatment and frequent replacement of antibiotics, the frequency of bacterial resistance to drugs is increasing. In particular, the emergence of some specific bacterial strains, such as: Streptococcus pneumoniae, Mycobacterium tuberculosis and Enterococcus, have made various clinically widely used antibiotics ineffective to varying degrees. The...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14C07D405/04C07D413/14C07D401/14C07D417/14C07D491/048C07D491/052C07D495/04A61K31/435A61K31/4709A61K31/4355A61K31/436A61K31/4365A61P31/04A61P31/06A61P29/00
CPCC07D401/14C07D405/04C07D405/14C07D413/14C07D417/14C07D491/048C07D491/052C07D495/04Y02A50/30
Inventor 吴永谦
Owner BEIJING SIHUAN PHARMA
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