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Bisulfonyl anthracenedione dioxime derivative serving as P2X<3> and P2X<2/3> receptor antagonists

A sulfonyl and receptor technology, applied in the field of medicinal chemistry, can solve the problems of long-distance and long-term signal transmission and its mechanism is not very clear.

Inactive Publication Date: 2016-08-10
CHENGDU UNIVERSITY OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The traditional view is that the P2X located at the nerve endings 3 After the receptor is activated, it can cause the influx of extracellular calcium ions to trigger the release of action potentials, while for P2X 3 The way and mechanism of long-distance and long-term signal transmission of receptors are not very clear

Method used

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  • Bisulfonyl anthracenedione dioxime derivative serving as P2X&lt;3&gt; and P2X&lt;2/3&gt; receptor antagonists
  • Bisulfonyl anthracenedione dioxime derivative serving as P2X&lt;3&gt; and P2X&lt;2/3&gt; receptor antagonists
  • Bisulfonyl anthracenedione dioxime derivative serving as P2X&lt;3&gt; and P2X&lt;2/3&gt; receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Step 1: Preparation of 2,7-bis(cyclohexylmercapto)-anthracene-9,10-dione

[0045]

[0046] Under nitrogen protection, 2,7-diiodoanthracene-9,10-dione (11.5g, 25mmol), cyclohexyl mercaptan (3.48g, 30mmol), cesium carbonate (24.4g, 75mmol), palladium acetate ( 113mg, 0.5mmol), (±) BINAP (155mg, 0.25mmol) was added to 120mL DMF, heated to 120°C, after the reaction was detected by TLC, the temperature was lowered. Add 200mL of water to the reaction solution, extract with ethyl acetate (200mL×3), collect the organic phase and dry it with anhydrous sodium sulfate, concentrate under reduced pressure, the crude product is obtained by silica gel column chromatography (PE / EA=80 / 20) to obtain 2 , 9.99 g of 7-bis(cyclohexylmercapto)-anthracene-9,10-dione (yield: 91.6%). LC / MS(M+1) + = 436.2.

[0047] Step 2: Preparation of 2,7-bis(cyclohexylsulfonyl)-anthracene-9,10-dione

[0048]

[0049] 2,7-bis(cyclohexylmercapto)-anthracene-9,10-dione (4 g, 9 mmol) was dissolved in 10...

Embodiment 2

[0054] Step 1: Preparation of 2,6-bis(cyclohexylmercapto)-anthracene-9,10-dione

[0055]

[0056] Under nitrogen protection, 2,6-dichloroanthracene-9,10-dione (6.9g, 25mmol), cyclohexyl mercaptan (3.48g, 30mmol), cesium carbonate (24.4g, 75mmol), palladium acetate ( 113mg, 0.5mmol), (±) BINAP (155mg, 0.25mmol) was added to 120mL DMF, heated to 120°C, after the reaction was detected by TLC, the temperature was lowered. Add 300mL of water to the reaction solution, extract with ethyl acetate (200mL×3), collect the organic phase, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel column chromatography (PE / EA=80 / 20) to obtain 2 , 10.3 g of 6-bis(cyclohexylmercapto)-anthracene-9,10-dione (yield: 94.2%). LC / MS(M+1) + = 436.2.

[0057] The second step: the preparation of 2,6-di(cyclohexylsulfonyl)-anthracene-9,10-dione

[0058]

[0059] 2,6-bis(cyclohexylmercapto)-anthracene-9,10-dione (8 g, 18 mmol) was dissolved in 100 mL of chlorofor...

Embodiment 3

[0064] 2,7-bis(cyclopentylsulfonyl)-anthracene-9,10-dioxime 1 HNMR and LC / MS

[0065]

[0066] 1 H-NMR (400MHz, DMSO-d 6 ): δ9.03(d, J=1.6Hz, 1H), 9.01(d, J=1.6Hz, 1H), 8.75(d, J=8.0Hz, 1H), 8.68(d, J=8.4Hz, 1H ),8.63-8.56(m,2H),3.68-3.60(m,2H),3.19-2.99(m,8H),2.37-2.27(m,8H);LC / MS(M+1) + = 503.1.

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Abstract

The invention discloses a bisulfonyl anthracenedione dioxime derivative serving as P2X<3> and P2X<2 / 3> receptor antagonists. The invention relates to a compound shown as a formula I and / or pharmaceutical salts thereof, a preparation method of the compound and / or pharmaceutical salts thereof, as well as a pharmaceutical composition containing the compound. The compound and the pharmaceutical salts thereof can be treating and / or preventing P2X<3> and P2X<2 / 3> receptor mediated diseases such as frequent micturition, urgent urination, uracratia, spontaneous bladder hypersensitivity, prostatitis, urocystitis, pain illnesses, and the like. The structural formula is as shown in the specification. If the substitution position of sulfonyl connected with R1 on an anthracene ring is defined as a position 2 of anthracene, a substitution position of sulfonyl connected with R2 on an anthracene ring is defined as a position 6 or 7, and 2,6- or 2,7-bis-substituted sulfonyl anthracene 9,10-diketone dioxime derivatives are formed. The R1 and R2 are independently selected from C1-C6 straight chain or branched alkyl, 3-8-membered alicyclic groups, aryl and heterocyclic aryl.

Description

technical field [0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a bissulfonyl anthracene dione bis-oxime derivative and its physiologically acceptable salts described in the claims, their preparation and their use in the treatment and / or prevention of P2X 3 or P2X 2 / 3 Receptor-mediated urinary frequency, urgency, urinary incontinence, spontaneous hypersensitivity bladder, prostatitis, cystitis; pain diseases, the pain diseases are selected from inflammatory pain, toothache, central neuralgia, migraine, Use in diseases related to neuritis and surgical pain. technical background [0002] The present invention relates to compounds for treating diseases related to P2X purinergic receptors, especially P2X for treating and / or preventing urinary system and inflammatory pain diseases 3 or P2X 2 / 3 receptor antagonists. [0003] P2X receptors (P2X receptors, or P2X purinoreceptors, English P2X purinoreceptor) is a family of cat...

Claims

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Application Information

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IPC IPC(8): C07C317/32C07C315/04C07D213/71A61K31/15A61K31/444A61P13/00A61P13/02A61P13/08A61P29/00A61P13/10A61P25/04A61P25/06A61P25/00
CPCC07C317/32C07D213/71
Inventor 周立宏
Owner CHENGDU UNIVERSITY OF TECHNOLOGY