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Cholic acid derivative with antibacterial activity and pharmaceutical composition thereof

A technology of compounds and solvates, applied in the field of medicine

Active Publication Date: 2020-03-13
CHENGDU BIOBEL BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It has been reported that cholic acid compounds or derivatives chemically modified on the basis of their structures have more biological activities. Ursodeoxycholic acid is an endogenous cholic acid compound that has been approved for marketing in the treatment of cholestatic liver cirrhosis; other bile acids Acid derivatives have been reported to have the activity of inhibiting the germination of Clostridium difficile spores, such as the compound CamSA (systematic name: 3-[(3α,7α,12α-trihydroxy -24-oxo-5β-cholan-24-yl)amino]benzenesulfonic acid) and compound 12a reported in J.Med.Chem.2018,61,6759-6778 (systematic name: N-(Phenyl)-3α, 7α,12α-trihydroxy-5β-cholan-24-amide), but so far no bile acid derivatives that have the effect of inhibiting Clostridium difficile have been reported

Method used

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  • Cholic acid derivative with antibacterial activity and pharmaceutical composition thereof
  • Cholic acid derivative with antibacterial activity and pharmaceutical composition thereof
  • Cholic acid derivative with antibacterial activity and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Embodiment 1: the synthesis of compound 1-1:

[0076]

[0077] Add 1 g of nor-CDCA, 15 ml of DMF (N,N-dimethylformamide), 0.86 g of TBTU (benzotriazole tetramethyltetrafluoroboric acid), 1 g of DIPEA (N, N-diisopropylethylamine) and 0.35 g of 2-amino-5-nitrothiazole, stirred at room temperature for 5-6 hours, TLC monitored the progress of the reaction until the nor-CDCA reaction was complete, added 50 ml of water and 50 ml of ethyl acetate , after stirring, stand still, separate the organic phase, extract the water phase with ethyl acetate twice and combine, the organic phase is washed successively with 10 ml of 2% dilute hydrochloric acid, 1% potassium carbonate aqueous solution, and saturated brine, dried, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and washed with petroleum ether / ethyl acetate system to obtain 0.8 g of a light yellow solid.

[0078] 1 HNMR (400MHz, CDCl 3 )δppm:8.33(s,1H),3.90(s,1H),3.61-3.46(m,2H), ...

Embodiment 2

[0080] Embodiment 2: the synthesis of compound 1-2:

[0081]

[0082] The raw materials were changed and synthesized by the same method as in Example 1.

[0083] 1 HNMR (400MHz, CD 3 OD) δppm: 8.40(s, 1H), 4.01-3.95(m, 1H), 3.82(q, J=3.0Hz, 1H), 3.46-3.33(m, 1H), 2.61(ddd, J=14.6, 9.9 ,4.7Hz,1H),2.48(ddd, J=15.1,8.8,6.4Hz,1H),2.38-2.23(m,2H),2.09-1.74(m,8H),1.73-1.30(m,7H), 1.26(t,J=7.1Hz,1H),1.22-0.95(m,2H),1.08(d,J=5.8Hz,3H),0.94(s,3H), 0.74(s,3H);

[0084] ESI-MS m / z:534.01[M-1] - .

Embodiment 3

[0085] Embodiment 3: the synthesis of compound 1-3:

[0086]

[0087] The raw materials were changed and synthesized by the same method as in Example 1.

[0088] 1 HNMR (400MHz, CD 3 OD) δppm: 8.39(s, 1H), 3.82(q, J=2.8Hz, 1H), 3.46-3.34(m, 1H), 2.60(ddd, J=15.0, 9.8, 5.1Hz, 1H), 2.47( ddd,J=15.3,9.3,6.6Hz,1H),2.29(d,J=11.5Hz,1H),2.08-1.94(m,3H),1.92-1.81(m,3H), 1.73-1.37(m, 8H), 1.37-1.09(m, 4H), 1.02(d, J=6.4Hz, 3H), 1.05-1.96(m, 1H), 0.90(s, 3H), 0.72(s, 3H);

[0089] ESI-MS m / z:518.01[M-1] - .

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PUM

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Abstract

The invention provides a compound shown as formula (I), or a stereoisomer, or a salt, or a solvate, or a prodrug, or a metabolite thereof. The compound can effectively inhibit the growth of clostridium difficile thalli, has remarkable antibacterial activity, and has a very promising application prospect in preparing medicines for preventing and / or treating clostridium difficile infectious diseases, recurrence of clostridium difficile infectious diseases or complications of clostridium difficile infectious diseases.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a cholestane derivative with antibacterial activity and a medicinal composition thereof. Background technique [0002] Clostridium difficile (Clostridium difficile) is an obligate anaerobic bacterium of the genus Clostridium, which is very sensitive to oxygen and difficult to isolate and culture, hence the name, and generally parasitizes in the human intestinal tract. Usually Clostridium difficile infection is caused by excessive use of certain antibiotics, which breaks the balance of intestinal flora, makes the growth of Clostridium difficile flora accelerate, and causes inflammation. Clostridium difficile produces exotoxins A and B with different effects at different times. Toxin A is an enterotoxin, which first binds to mucosal cells in the early stage, causing primary damage, leading to inflammation of the intestinal wall, cell infiltration, increased permeabili...

Claims

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Application Information

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IPC IPC(8): C07J43/00A61P31/04A61P1/00A61K31/58
CPCA61P1/00A61P31/04C07J43/003
Inventor 广兵阳泰董韧涵刘进覃传军黄胜谢建赖永新彭向阳许庆占伟彭坚王晓辉
Owner CHENGDU BIOBEL BIOTECHNOLOGY CO LTD
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