CN111471080B - ocotillol type ginsengenin A-ring amino thiazole ring derivative and preparation method thereof - Google Patents

Abstract

The invention discloses an ocotillol type ginsengenin A-ring amino thiazole ring derivative and a preparation method thereof. The product of the invention is prepared according to the following method: a. by 20(S) Using protopanoxadiol as raw material, in the presence of DMAP, protecting 3,12-OH with acetic anhydride, and making it pass throughmRemoval of the protecting group by alkaline hydrolysis after oxidation of CPBA (20)S,24R) -epoxy dammar -3β,12β25-triols (OR) and (20)S,24S) -epoxy dammar -3β,12β25-triol (OS); oxidizing OR and OS respectively by pyridinium chlorochromate hydrochloride, and then sequentially reacting with pyridinium tribromide and thiourea; c. under alkaline conditions, Boc anhydride protects an acid with a terminal amino group; d. reacting the product obtained in step b with Boc-amino acid in the presence of an organic base and a condensing agent; e. and removing Boc under acidic conditions. The invention also discloses a preparation method of the derivatives and a new application of the derivatives in tumor drug resistance reversal.

Description

ocotilol type ginsenoside A-ring aminothiazole ring derivative and preparation method

technical field

The invention relates to the fields of organic synthesis and medicinal chemistry, in particular to a class of ocotilol-type ginsenoside A-ring and aminothiazole ring derivatives with novel structures, a pharmaceutical composition containing them, a preparation method and a novel application thereof in the reversal of tumor resistance. application.

technical background

Malignant tumor is one of the serious diseases that threaten human health. At present, the main method of clinical anti-tumor is still chemotherapy. Tumor multidrug resistance (MDR) means that once tumor cells become resistant to a certain chemotherapeutic drug, they also develop cross-resistance to other drugs with different structures and mechanisms of action. The occurrence of MDR phenomenon has now become the main reason for chemotherapy failure. Therefore, finding and developing new compounds with low toxicity and high efficiency for MDR reversal activity is a hot topic in tumor therapy and pharmaceutical research.

Natural products play a very important role in the chemotherapy of cancer. The ocotilol-type ginsenosides are a class of tetracyclic triterpenoid saponins containing furan rings on their side chains, mainly found in Panax plants. Pharmacological studies on ocotilol-type ginsenosides mainly focus on antibacterial, myocardial ischemia protection, drug withdrawal, nootropic and anti-Alzheimer's disease. Moreover, previous studies have found that Ocotilol-type ginsenosides by themselves have no antitumor activity.

SUMMARY OF THE INVENTION

The present invention aims to find a class of ocotilol-type ginsenoside A-ring and aminothiazole ring derivatives with tumor resistance reversal activity, novel structure and convenient preparation, thus providing a class of ocotilol derivatives, and at the same time providing such derivatives Application in the field of tumor resistance reversal.

The technical problem to be solved by the present invention is to find a compound with novel structure and anti-tumor drug resistance reversal activity.

The present invention is achieved through the following technical solutions:

The ocotilol type ginsenoside derivative represented by the general formula (I) and a medically acceptable salt thereof,

in,

R ₁ represents CH ₂ R ₂ NHR ₃ , C(NHR ₃ )R ₂ , C(NHR ₃ )R ₂ X,

R ₂ represents (C1-C9) unsubstituted straight or branched chain alkyl;

R ₃ represents hydrogen, Boc, Fmoc;

X represents hydroxyl, mercapto, sulfur, carboxyl, amino, guanidino, phenyl, p-hydroxybenzyl, imidazole, tetrahydropyrrole, indole.

Preferably,

R ₁ represents CH ₂ R ₂ NHR ₃ , C(NHR ₃ )R ₂ , C(NHR ₃ )R ₂ X,

R ₂ represents (C1-C9) unsubstituted straight or branched chain alkyl;

R ₃ represents hydrogen, Boc;

X represents phenyl, indole.

Preferably,

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

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

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

(20S,24R)-Epoxy-12β,25-dihydroxy-2,3-[2,3-b]aminothiazole-N-leucyl-dammarane;

(20S,24S)-Epoxy-12β,25-dihydroxy-2,3-o[2,3-b]aminothiazole-N-benzamyl-dammarane.

The ocotilol type ginsenoside A-ring and aminothiazole ring derivatives and optical isomers of the above compounds or pharmaceutically acceptable solvates thereof.

The ocotilol-type saponin derivatives of the general formula (I) significantly improve the sensitivity of the tumor-resistant cells KBV resistant to paclitaxel to paclitaxel, so that paclitaxel can produce good anti-tumor activity for it at a very low concentration. It can be seen that the specific implementation Pharmacological tests of the way section.

Use of the ocotilol type saponin derivatives of the general formula (I) of the present invention and their medically acceptable salts for the preparation of tumor resistance reversal agents and/or pharmaceutically acceptable carriers for the treatment of animals, preferably human diseases or conditions .

A tumor resistance reversal agent prepared by an effective amount of the ocotilol type saponin derivative of the general formula (I) and a medically acceptable salt thereof is used in combination with a clinical antitumor drug for the treatment of gastric cancer, lung cancer, cervical cancer, breast cancer or colon cancer diseases or conditions such as cancer.

Preferably, the clinical antitumor drug refers to paclitaxel.

The ocotilol-type sapogenin derivatives of the general formula (I) can be prepared synthetically according to the following reaction scheme and description.

The compound of general formula (I) is synthesized and prepared as follows:

a. Using 20(S)-protopanaxadiol as raw material, in the presence of DMAP, acetic anhydride protects 3,12-OH, and after oxidation by m-CPBA, alkali hydrolysis removes the protective group to obtain (20S,24R)-epoxy Damazol-3β,12β,25-triol (OR) and (20S,24S)-epoxydamazol-3β,12β,25-triol (OS);

b. OR and OS are respectively oxidized by pyridinium chlorochromate hydrochloride and react with pyridinium tribromide and thiourea in turn;

c. Under alkaline conditions, Boc acid anhydride protects the acid with amino group at the end;

d. in the presence of an organic base and a condensing agent, the product obtained in step b is reacted with Boc-amino acid or the product obtained in two steps b and c is reacted;

e. Removal of Boc under acidic conditions.

The present invention develops a new ocotilol-type ginsenoside structure by further chemical modification, that is, the ocotilol-type ginsenoside A-ring and aminothiazole ring derivatives.

The pharmacological activity test of the present invention shows that OR and OS by themselves do not have anti-tumor activity (consistent with the published records in the literature), and OR, OS itself and the anti-tumor drug paclitaxel do not show anti-tumor activity either. Meanwhile, the pharmacological activity test shows that in the tumor cells that have been drug-resistant, neither paclitaxel nor the ocotilol type ginsenoside A-ring and aminothiazole ring derivatives synthesized by the present invention have anti-tumor activity.

However, pharmacological tests showed that: the ocotilol-type sapogenin derivatives of general formula (I) significantly improved the sensitivity of tumor-resistant cells KBV resistant to paclitaxel to paclitaxel. It produces good antitumor activity. After the ocotilol type ginsenoside A-ring aminothiazole ring derivative synthesized by the present invention is combined with paclitaxel, paclitaxel shows significant antitumor activity in drug-resistant tumor cells, and the survival rate of tumor cells KBV Cell after 10 μM combined administration with paclitaxel The tumor cell survival rate of the control drug Verapamil combined with paclitaxel is 27%, and the tumor resistance reversal activity is significantly better than that of Verapamil, which can be effectively used for the preparation of tumor resistance reversal drugs.

beneficial effect

The present invention prepares a new ocotilol-type ginsenoside structure, namely, ocotilol-type ginsenoside A-ring and aminothiazole ring derivatives.

Meanwhile, the present invention provides a method for synthesizing ocotilol-type ginsenoside A-ring and aminothiazole ring derivatives.

In addition, the ocotilol-type ginsenoside A-ring and aminothiazole ring derivatives provided by the present invention do not have anti-tumor activity by themselves, but show obvious tumor resistance reversal activity after being used in combination with paclitaxel, and the anti-tumor activity effect is better than that of conventional ginsenosides. Known drug Verapamil.

Detailed ways

1. The present invention will be described in further detail below through examples, but the present invention is not limited to the following examples.

Example 1

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

20(S)-protopanaxadiol (5.0 g, 10.9 mmol) was dissolved in chloroform (30.0 mL), DMAP (0.2 g, 1.6 mmol) was added and stirred, and then acetic anhydride (4.2 mL, 44.3 mmol) was slowly added dropwise. , and stirred at room temperature for 1 h. After rotary evaporation, it was diluted with ethyl acetate (100.0 mL), washed with 10% hydrochloric acid until acidic, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether:ethyl acetate=10:1 ) to obtain 20(S)-3,12-diacetylprotopanaxadiol (5.1 g, 9.3 mmol, 85%) as a white solid.

20(S)-3,12-diacetylprotopanaxadiol (2.1g, 3.8mmol) was dissolved in anhydrous dichloromethane (15.0mL), and m-chloroperoxygen was slowly added dropwise under ice-salt bath precooling A solution of benzoic acid (1.9 g, 75%, 10.7 mmol) in dichloromethane (15.0 mL) was heated to room temperature after 0.5 h and stirred for 2 h. Add isopropanol (1.0 mL), continue stirring for 1 hour, add saturated sodium bicarbonate solution, stir for 1 hour, and then extract by liquid separation. Dry over sodium, filter, concentrate, and perform column chromatography (petroleum ether:ethyl acetate=8:1) to obtain a white intermediate X1 (1.3 g, 2.4 mmol, 62%).

Intermediate X1 (1.3 g, 2.4 mmol) was dissolved in absolute ethanol (8.0 mL), potassium hydroxide (850.0 mg, 15.2 mmol) was added, and the reaction was stirred at 135° C. for 2 h. After the reaction solution was cooled to room temperature, an appropriate amount of water was added, a large amount of white solid was precipitated, suction filtered, dried, and subjected to column chromatography (petroleum ether:ethyl acetate=2:1-1:1) to obtain the compound OR{(20S, 24R). )-Damarane-3β,12β,25-triol, 660.0 mg, 1.4 mmol, 52%} and OS{(20S,24S)-Damarane-3β,12β,25-triol, 450.0 mg, 1.0 mmol, 39%}.

Dissolve (20S,24R)-epoxidamarane-3β,12β,25-triol (500.0 g, 1.0 mmol) in anhydrous dichloromethane (10.0 mL), add pyridinium chlorochromate hydrochloride ( 340.0 mg, 1.6 mmol), reacted at room temperature for 3 h. Silica gel column chromatography (petroleum ether:ethyl acetate=4:1) to obtain intermediate (20S,24R)-epoxy-12β,25-dihydroxy-dammaran-3-one (370.0 mg, 0.8 mmol, 75%).

The intermediate (20S,24R)-epoxy-12β,25-dihydroxy-dammaran-3-one (360.0 mg, 0.8 mmol) was dissolved in anhydrous dichloromethane (10.0 mL), and tribromide was added. Pyridinium (240.0 mg, 0.8 mmol) was reacted at 35° C. for 4 h. Silica gel column chromatography (petroleum ether:ethyl acetate=10:1) gave Intermediate X2 (340.0 mg, 0.6 mmol, 83%) as a white powder.

Intermediate X2 (200.0 mg, 0.4 mmol) was dissolved in absolute ethanol (10.0 mL), thiourea (41.0 mg, 0.5 mmol) was added, and the reaction was refluxed for 7 h. The solvent was evaporated under reduced pressure, diluted with ethyl acetate, washed with deionized water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. Silica gel column chromatography (petroleum ether:ethyl acetate=2:1) gave Intermediate X3 (140.0 mg, 0.3 mmol, 74%) as a white powder.

Intermediate X3 (60.0 mg, 0.1 mmol) was dissolved in anhydrous dichloromethane (5.0 mL), 4-dimethylaminopyridine (25.0 mg, 0.2 mmol), 1-(3-dimethylaminopropyl) were added -3-ethylcarbodiimide hydrochloride (43.1 mg, 0.2 mmol) and Boc-alanine (55.1 mg, 0.2 mmol) were reacted at room temperature for 4 h. The reaction solution was diluted with dichloromethane, washed with 5% hydrochloric acid, washed with deionized water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The dried intermediate was dissolved in anhydrous dichloromethane, excess trifluoroacetic acid was added, and the reaction was carried out at room temperature for 0.5 h. The reaction solution was diluted with dichloromethane, washed with saturated sodium bicarbonate, deionized water, saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. Silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain compound 1 (60.1 mg, 0.1 mmol, 90%) {(20S,24R)-epoxy-12β,25-dihydroxy-2,3 -Io[2,3-b]aminothiazole-N-alanyl-dammarane} ¹ H-NMR (CDCl ₃ , 400 MHz) δ (ppm): 3.91 (t, J=4.4 Hz, 1H, -OCH -),3.64(q,J=5.4,3.9Hz,1H,-COCHN-),3.55(td,J=11.5,10.4,4.4Hz,1H,-OCH-),2.74(d,J=15.6Hz, 1H), 2.31(d, J＝16.0Hz, 1H), 1.29(s, 6H, -CH ₃ ×2), 1.24(s, 6H, -CH ₃ ×2), 1.15(d, J＝3.5Hz, 6H), 1.08(s, 3H, -CH ₃ ), 0.97(s, 3H, -CH ₃ ), 0.92(s, 3H, -CH ₃ ).

Example 2

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

Refer to Example 1 for the synthesis method to obtain compound 2 (65.1 mg, 0.1 mmol, 85%) {(20S,24R)-epoxy-12β,25-dihydroxy-2,3-do[2,3-b]amino Thiazole-N-benzyl-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 ).

Example 3

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

Refer to Example 1 for the synthesis method to obtain compound 3 (64.0 mg, 0.1 mmol, 90%) {(20S,24R)-epoxy-12β,25-dihydroxy-2,3-do[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, _-NHCH2 -),2.97(dt,J =10.2,6.2Hz,1H, _-NHCH2 -),2.71(d,J=15.6Hz,1H, _-CH2 -),2.25(d,J=15.7Hz,1H, _-CH2 -),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 ).

Example 4

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

For the synthesis method, refer to Example 1 to obtain compound 4 (65.0 mg, 0.1 mmol, 89%) {(20S,24R)-epoxy-12β,25-dihydroxy-2,3-do[2,3-b]amino Thiazole-N-leucyl-dammarane} ¹ H-NMR (CDCl ₃ , 400 MHz) δ (ppm): 3.83 (dd, J=8.7, 6.8 Hz, 1H, -OCH-), 3.58 (dd, J =9.5,3.9Hz,1H,-OCH-),3.52(dd,J= _10.5,4.5Hz ,1H,NH2CH-),2.70(d,J=15.6Hz,1H, _-CH2 -),2.24 (d,J＝15.8Hz,1H, _-CH2 -),1.71(d,J＝10.2Hz,1H,( _CH3 )2CH _- ),1.26(s,3H, _-CH3 ),1.25(s , 3H, -CH ₃ ), 1.23(s, 2H, -CH ₂ -), 1.21(s, 3H, -CH ₃ ), 1.12(s, 3H, -CH ₃ ), 1.07(s, 3H, -CH ₃ ), 1.01(s, 3H, -CH ₃ ), 0.95(d, J=6.3Hz, 3H, -CH ₃ ), 0.92(d, J=6.1Hz, 3H, -CH ₃ ), 0.90(s, 3H,-CH ₃ ),0.86(s,3H,-CH ₃ ).

Example 5

(20S,24S)-Epoxy-12β,25-dihydroxy-2,3-[2,3-b]aminothiazole-N-benziyl-dammarane

Referring to the method of Example 1, (20S,24S)-epoxidamarane-3β,12β,25-triol (450.0 mg, 1.0 mmol) was dissolved in anhydrous dichloromethane (10.0 mL), and chlorine was added. Pyridine chromate hydrochloride (340.0 mg, 1.6 mmol) was reacted at room temperature for 3 h. Silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain intermediate (20S,24S)-epoxy-12β,25-dihydroxy-dammaran-3-one (360.0 mg, 0.8 mmol, 79%). The intermediate (20S,24S)-epoxy-12β,25-dihydroxy-dammaran-3-one (360.0 mg, 0.8 mmol) was dissolved in anhydrous dichloromethane (10.0 mL), and tribromide was added. Pyridium (240.0 mg, 0.8 mmol) was reacted at 35° C. for 4 h. Silica gel column chromatography (petroleum ether:ethyl acetate=10:1) gave Intermediate X4 (340.0 mg, 0.6 mmol, 83%) as a white powder. Intermediate X4 (0.2 g, 0.4 mmol) was dissolved in absolute ethanol (10.0 mL), thiourea (41.0 mg, 0.5 mmol) was added, and the reaction was refluxed for 7 h. The solvent was evaporated under reduced pressure, diluted with ethyl acetate, washed with deionized water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. Silica gel column chromatography (petroleum ether:ethyl acetate=2:1) gave Intermediate X5 (0.1 g, 0.3 mmol, 73%) as a white powder. Intermediate X5 (60.0 mg, 0.1 mmol) was dissolved in anhydrous dichloromethane (5.0 mL), 4-dimethylaminopyridine (25.0 mg, 0.2 mmol), 1-(3-dimethylaminopropyl) were added -3-ethylcarbodiimide hydrochloride (43.1 mg, 0.2 mmol) and Boc-phenylalanine (30.0 mg, 0.2 mmol) were reacted at room temperature for 4 h. The reaction solution was diluted with dichloromethane, washed with 5% hydrochloric acid, washed with deionized water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The dried intermediate was dissolved in anhydrous dichloromethane, excess trifluoroacetic acid was added, and the reaction was carried out at room temperature for 0.5 h. The reaction solution was diluted with dichloromethane, washed with saturated sodium bicarbonate, deionized water, saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. Silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain compound 6 (65.0 mg, 0.1 mmol, 85%) {((20S,24S)-epoxy-12β,25-dihydroxy-2, 3-Io[2,3-b]aminothiazole-N-benzyl-dammarane} ¹ H-NMR (CDCl ₃ , 400MHz)δ(ppm): 7.34-7.18(m,5H,Ar-H ×5),5.76(s,1H,-OH),3.88(dd,J＝10.7,5.3Hz,1H,-OCH-),3.80(dd,J＝9.3,3.9Hz,1H,NH ₂ CH-) ,3.56(td,J＝10.4,4.7Hz,1H,-OCH-),3.33(dd,J＝13.8,3.9Hz,1H,Bn-H),2.83–2.77(m,1H,Bn-H), 2.74(d,J=15.5Hz,1H, _-CH2 -),2.28(d,J=15.5Hz,1H, _-CH2 -),1.26(s,3H, _-CH3 ),1.23(s,3H ,-CH ₃ ),1.21(s,3H,-CH ₃ ),1.12(s,3H,-CH ₃ ),1.09(s,3H,-CH ₃ ),1.05(s,3H,-CH ₃ ), 0.94(s,3H, _-CH3 ),0.92(s,3H, _-CH3 ).

2. The following are the pharmacological test results of some compounds of the present invention.

(1) Experimental method: Example 1-5 Detection of survival rate of antitumor drug paclitaxel in KBV resistant cells

Cell plating: Take the KBV-resistant cells in the logarithmic growth phase with good growth, add the culture medium after trypsinization, and gently pipette to form a single cell suspension. After the cells were counted, the cell concentration was diluted to 3-4×10 ⁴ cells/mL with medium, and seeded in a 96-well cell plate culture plate at a volume of 100 μL/well, and placed in a carbon dioxide incubator for static culture.

Cell administration: 24h after the cells were plated, 10 μM of different compounds were added, and 100 nM of Paclitaxel and the corresponding solvent were added for control culture. 3 parallel holes per group. After dosing, the 96-well plate was placed in an incubator, and cultured for 72 h.

MTT detection: After culturing the cells with corresponding drugs for 72h, the cell viability was detected.

(2) Experimental results:

Table 1 shows the cell viability of Examples 1-5 when administered alone or in combination.

Table 1. Cell viability of Examples 1-5 alone and in combination

Example 1-5 Analysis of the survival rate of antitumor drug paclitaxel in KBV resistant cells:

The results of the evaluation of the survival rate of the KBV drug-resistant cells of the derivatives showed that ocotilol ginsenosides themselves had no tumor resistance reversal activity, that is, OR and OS themselves did not have anti-tumor activity (consistent with the published records in the literature), and OR, OS itself had no anti-tumor activity. It also did not show antitumor activity when used in combination with the antitumor drug paclitaxel. At the same time, the pharmacological activity test shows that the ocotilol type ginsenoside A-ring and aminothiazole ring derivatives synthesized by the present invention also have no antitumor activity.

For tumor cell KBV that has been drug-resistant, the commonly used anti-tumor drug paclitaxel does not have anti-tumor activity against tumor cell KBV, but the ocotilol-type ginsenoside A-ring and aminothiazole ring derivatives synthesized in Examples 1-5 are used in combination with paclitaxel Both have significant antitumor activity. The reason for the analysis is that the ocotilol-type saponin derivatives of the general formula (I) significantly increase the sensitivity of the tumor-resistant cells KBV resistant to paclitaxel to paclitaxel, so that paclitaxel can produce good anti-tumor activity on it at a very low concentration; Moreover, further pharmacological activity tests showed that the survival rate of tumor cells KBV Cell decreased to about 20% after 10 μM of the ocotilol-type ginsenoside A-ring and aminothiazole ring derivatives synthesized in Example 1-5 was combined with paclitaxel, and the anti-tumor activity was reduced to about 20%. It is obviously better than the combination of the control drug Verapamil and paclitaxel (survival rate is about 27%), which shows significant tumor resistance reversal activity, and is better than the known drug Verapamil, especially the best activity is Example 2, which proves that the synthetic drug of the present invention is synthesized. The combination of the ocotilol type ginsenoside A-ring and aminothiazole ring derivatives and paclitaxel can be effectively used for the preparation of a drug for reversing drug resistance of tumors.

The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details of the above-mentioned embodiments. Within the scope of the technical concept of the present invention, various equivalent transformations can be made to the technical solutions of the present invention. These equivalent transformations All belong to the protection scope of the present invention. In addition, it should be noted that each specific technical feature described in the above-mentioned specific implementation manner may be combined in any suitable manner under the circumstance that there is no contradiction. In order to avoid unnecessary repetition, the present invention will not describe various possible combinations. In addition, the various embodiments of the present invention can also be combined arbitrarily, as long as they do not violate the spirit of the present invention, they should also be regarded as the contents disclosed in the present invention.

Claims (3)

1. An ocotillol type ginsengenin A-ring amino thiazole ring derivative is characterized in that,

(20S, 24R) -epoxy-12β25-dihydroxy-2, 3-and [2,3-b ]]aminothiazole-N-alanyl-dammarane;

(20S, 24R) -epoxy-12β25-dihydroxy-2, 3-and [2,3-b ]]aminothiazole-N-benzosyl-dammarane;

(20S, 24R) -epoxy-12β25-dihydroxy-2, 3-and [2,3-b ]]aminothiazole-N-prolyl-dammarane;

(20S, 24R) -epoxy-12β25-dihydroxy-2, 3-and [2,3-b ]]aminothiazole-N-leucyl-dammarane;

(20S, 24S) -epoxy-12β25-dihydroxy-2, 3-and [2,3-b ]]aminothiazole-N-benzoyl-dammarane.

2. Use of an ocotillol-type ginsengenin a-ring-aminothiazole ring derivative according to claim 1, in the preparation of a medicament for reversing drug resistance in tumors, characterized in that the ocotillol-type ginsengenin a-ring-aminothiazole ring derivative is combined with paclitaxel.

3. The method for preparing ocotillol-type ginsengenin A-cycloaminothiazole ring derivative according to claim 1, comprises the following steps,

a. by 20(S) Using protopanoxadiol as raw material, in the presence of DMAP, protecting 3,12-OH with acetic anhydride, and making it pass throughmRemoval of the protecting group by alkaline hydrolysis after oxidation of CPBA (20)S, 24R) -epoxy dammar -3β, 12β25-triols and (20)S, 24S) -epoxy dammar -3β, 12β25-triol;

b.(20S, 24R) -RingOxydama -3β, 12β25-triol, (20)S, 24S) -epoxy dammar -3β, 12βOxidizing 25-triol with pyridinium chlorochromate hydrochloride respectively, and then reacting with pyridinium tribromide and thiourea sequentially;

c. under alkaline conditions, Boc anhydride protects an acid with a terminal amino group;

d. reacting the product obtained in the step b with Boc-amino acid in the presence of organic base and condensing agent, or reacting the products obtained in the two steps b and c;

e. removing Boc under acidic condition to obtain the final product.