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Ocotillol type ginseng sapogenin A ring-aminothiazole ring derivative and preparation method thereof

A technology of aminothiazole and ginseng soap, applied in the direction of drug combination, pharmaceutical formula, steroidal compounds, etc., can solve the problem that ginsenogenin has no anti-tumor activity, and achieve the effect of excellent anti-tumor activity and sensitivity improvement

Active Publication Date: 2020-07-31
YANTAI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, previous studies have found that Ocotillol-type ginsenogenin itself has no anti-tumor activity

Method used

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  • Ocotillol type ginseng sapogenin A ring-aminothiazole ring derivative and preparation method thereof
  • Ocotillol type ginseng sapogenin A ring-aminothiazole ring derivative and preparation method thereof
  • Ocotillol type ginseng sapogenin A ring-aminothiazole ring derivative and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0047] (20S,24R)-epoxy-12β,25-dihydroxy-2,3-[2,3-b]aminothiazole-N-alanyl-dammarane

[0048] Dissolve 20(S)-protopanaxadiol (5.0g, 10.9mmol) in chloroform (30.0mL), add DMAP (0.2g, 1.6mmol) and stir, then slowly add acetic anhydride (4.2mL, 44.3mmol) dropwise , stirred at room temperature for 1h. After rotary evaporation, dilute with ethyl acetate (100.0mL), wash with 10% hydrochloric acid until acidic, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, column chromatography (petroleum ether:ethyl acetate=10:1 ) to obtain 20(S)-3,12-diacetyl protopanaxadiol (5.1 g, 9.3 mmol, 85%) as a white solid.

[0049]Dissolve 20(S)-3,12-diacetyl protopanaxadiol (2.1g, 3.8mmol) in anhydrous dichloromethane (15.0mL), slowly add m-chloroperoxy A solution of benzoic acid (1.9 g, 75%, 10.7 mmol) in dichloromethane (15.0 mL) was raised to room temperature after 0.5 h and stirred for 2 h. Add isopropanol (1.0mL), continue to stir for 1 hour, ad...

Embodiment 2

[0056] (20S,24R)-epoxy-12β,25-dihydroxy-2,3-[2,3-b]aminothiazole-N-phenylalanyl-dammarane

[0057] The synthetic method was referred to Example 1 to obtain compound 2 (65.1 mg, 0.1 mmol, 85%) {(20S, 24R)-epoxy-12β, 25-dihydroxy-2,3-[2,3-b]amino Thiazole-N-benzoyl-dammarane} 1 H-NMR (CDCl 3 ,400MHz)δ(ppm):7.34–7.19(m,5H,Ar-H×5),3.89–3.81(m,1H,-OCH-),3.79(dd,J=9.4,3.9Hz,1H,NH 2 CH-), 3.55(td, J=10.4, 4.3Hz, 1H, -OCH-), 3.34(dd, J=13.9, 3.9Hz, 1H, Bn-H), 2.82–2.77(m, 1H, Bn- H), 2.73(d, J=13.0Hz, 1H, -CH 2 -),2.27(d,J=15.4Hz,1H,-CH 2 -),1.28(s,3H,-CH 3 ),1.26(s,3H,-CH 3 ),1.21(s,3H,-CH 3 ),1.13(s,3H,-CH 3 ),1.09(s,3H,-CH 3 ),1.03(s,3H,-CH 3 ),0.92(s,3H,-CH 3 ),0.89(s,3H,-CH 3 ).

Embodiment 3

[0059] (20S,24R)-epoxy-12β,25-dihydroxy-2,3-[2,3-b]aminothiazole-N-prolyl-dammarane

[0060] The synthetic method was referred to Example 1 to obtain compound 3 (64.0mg, 0.1mmol, 90%) {(20S,24R)-epoxy-12β,25-dihydroxy-2,3-[2,3-b]amino Thiazole-N-prolyl-dammarane} 1 H-NMR (CDCl 3 ,400MHz)δ(ppm):3.95–3.90(m,1H,-NHCHCO-),3.83(dd,J=8.8,6.8Hz,1H,-OCH-),3.54(td,J=10.5,4.5Hz, 1H, -OCH-), 3.06 (dt, J=10.2, 6.8Hz, 1H, -NHCH 2 -),2.97(dt,J=10.2,6.2Hz,1H,-NHCH 2 -),2.71(d,J=15.6Hz,1H,-CH 2 -),2.25(d,J=15.7Hz,1H,-CH 2 -),1.26(s,3H,-CH 3 ),1.25(s,3H,-CH 3 ),1.20(s,3H,-CH 3 ),1.13(s,3H,-CH 3 ),1.08(s,3H,-CH 3 ),1.02(s,3H,-CH 3 ),0.90(s,3H,-CH 3 ),0.87(s,3H,-CH 3 ).

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Abstract

The invention discloses an ocotillol type ginseng sapogenin A ring-aminothiazole ring derivative and a preparation method thereof. The product provided by the invention is prepared according to the following method including: a) by taking 20(S)-protopanaxadiol as a raw material, in the presence of DMAP, protecting 3,12-OH by acetic anhydride, oxidizing by m-CPBA, and removing a protecting group byalkaline hydrolysis to obtain (20S,24R)-epoxy dammar-3beta,12beta,25-triol (OR) and (20S,24S)-epoxy dammarane-3beta,12beta,25-triol (OS); b) respectively oxidizing OR and OS by pyridinium chlorochromate hydrochloride, and then sequentially reacting with pyridinium bromide perbromide and thiourea; c) under the alkaline condition, protecting acid having amino at the terminal end with Boc anhydride;d, in the presence of organic alkali and a condensing agent, reacting the product obtained in the step b with Boc-amino acid; and e) removing Boc under an acidic condition. The invention also discloses a preparation method of the derivatives and a novel application of the derivatives in tumor drug resistance reversion.

Description

technical field [0001] The present invention relates to the fields of organic synthesis and medicinal chemistry, in particular to a class of ocotillol-type ginsenoside A-ring aminothiazole ring derivatives with novel structures, pharmaceutical compositions containing them, preparation methods and their novel effects in reversing tumor drug resistance application. [0002] technical background [0003] Malignant tumors are one of the serious diseases that threaten human health. Chemotherapy is still the main method of clinical anti-tumor at present. Tumor multidrug resistance (MDR) means that once tumor cells develop resistance to a certain chemotherapeutic drug, they also develop cross-resistance to other drugs with different structures and mechanisms of action. The phenomenon of MDR has become the main reason for the failure of chemotherapy. Therefore, finding and developing new compounds with low toxicity and high MDR reversal activity is a hot topic in the research of tu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J71/00A61K31/58A61K31/337A61P35/00
CPCC07J71/0094A61K31/58A61K31/337A61P35/00A61K2300/00Y02P20/55
Inventor 毕毅王洪波曹玉成王恺奕刘书琪刘雪村孟庆国
Owner YANTAI UNIV
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