CN114656413A - Alfacalcidol heterocyclic ester derivative and preparation method thereof - Google Patents

Alfacalcidol heterocyclic ester derivative and preparation method thereof Download PDF

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CN114656413A
CN114656413A CN202210326832.7A CN202210326832A CN114656413A CN 114656413 A CN114656413 A CN 114656413A CN 202210326832 A CN202210326832 A CN 202210326832A CN 114656413 A CN114656413 A CN 114656413A
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alfacalcidol
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施建飞
钱建
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Nantong Huashan Pharmacy Co ltd
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract

The invention belongs to the technical field of medicinal chemistry and pharmacology, and particularly relates to an alfacalcidol heterocyclic ester derivative and a preparation method thereof. The alfacalcidol derivative has a structure shown in a formula (I), and is obtained by reacting alfacalcidol with DMAP, EDCI and corresponding heterocyclic acid in dichloromethane. The alfacalcidol heterocyclic ester derivative obtained by the invention has strong anti-tumor activity and can be used for preparing anti-tumor drugs.

Description

Alfacalcidol heterocyclic ester derivative and preparation method thereof
Technical Field
The invention belongs to the technical field of medicinal chemistry and pharmacology, and particularly relates to an alfacalcidol heterocyclic ester derivative and a preparation method thereof.
Background
Alfacalcidol (alfacalcidol) is a fat-soluble sterol in vitamin D compounds, and is a substance participating in the homeostasis of calcium and phosphorus and the mineralization process of bones. Alfacalcidol was first developed by International Bone health corporation of america (Bone Care International) and was approved for marketing in israel, germany, japan, italy. Can be used for treating calcium metabolism disorder caused by vitamin D metabolic disorder, osteoporosis, chronic renal insufficiency, hypoparathyroidism, vitamin D resistant rickets, osteomalacia, etc. In recent years, the alfacalcidol analogs, calcitriol and doxercalciferol, have been found to have antitumor activity, and the antitumor mechanism of action has been associated with the inhibition of the Hh signaling pathway, with calcitriol being under clinical study. The alfacalcidol derivatives have fewer reports of anti-tumor activity, so that the research value of discovering new alfacalcidol derivatives to develop novel anti-tumor drugs through structural modification is higher. Because the alfacalcidol structure does not contain nitrogen atoms, the introduction of a nitrogen-containing group through chemical modification is hoped to improve the water solubility of a drug molecule, and salt formation is easy to realize, so that the clinical administration is facilitated.
Figure BDA0003571769320000011
Disclosure of Invention
The purpose of the invention is as follows: in view of the above, the present invention aims to provide alfacalcidol heterocyclic ester derivatives, which have activity of inhibiting tumor cell proliferation equivalent to or better than etoposide, and can be used for preparing antitumor drugs.
The technical scheme is as follows: the invention provides an alfacalcidol heterocyclic ester derivative, which has a structure shown in a formula (I):
Figure BDA0003571769320000021
wherein R represents H or C1-7A hydrocarbon group, X represents N or C.
Further, the alfacalcidol heterocyclic ester derivative has a structure shown in any one of formulas 2a to 2 d:
Figure BDA0003571769320000022
wherein,
when R is hydrogen and X is N, the alfacalcidol heterocyclic ester derivative is a compound with a structure shown in a formula 2 a;
when R is hydrogen and X is C, the alfacalcidol heterocyclic ester derivative is a compound with a structure shown in a formula 2 b;
when R is methyl and X is N, the alfacalcidol heterocyclic ester derivative is a compound with a structure shown in a formula 2 c;
when R is ethyl and X is C, the alfacalcidol heterocyclic ester derivative is a compound with a structure shown in a formula 2 d.
The invention also provides a preparation method of the alfacalcidol heterocyclic ester derivative, which comprises the following steps:
obtained by reacting alfacalcidol with DMAP, EDCI and the corresponding 6-substituted 2-picolinic acid or 6-substituted 2-pyrazinecarboxylic acid in dichloromethane, wherein the reaction formula is as follows:
Figure BDA0003571769320000031
wherein R represents H or C1-7A hydrocarbyl group, X represents N or C;
the preparation method specifically comprises the following operations: dissolving alfacalcidol in dichloromethane, sequentially adding heterocyclic acid, DMAP and EDCI, reacting to obtain a first reaction solution, diluting the first reaction solution with an organic solvent, sequentially washing with water, washing with saturated salt water, and MgSO (MgSO) in sequence4Drying, drying under reduced pressure, and performing column chromatography to obtain a white solid, wherein the white solid is an alfacalcidol heterocyclic ester derivative, and the molar ratio of alfacalcidol to heterocyclic acid to DMAP to EDCI is as follows: 1:5:1.6: 6.
preferably, in the above preparation method, the DMAP is 4-dimethylaminopyridine and EDCI is named as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
Preferably, the heterocyclic acid is one of 6-substituted 2-picolinic acid or 6-substituted 2-pyrazinecarboxylic acid.
Preferably, in the preparation method, the reaction temperature is 25 ℃ and the reaction time is 12 h.
Preferably, the organic solvent is at least one of dichloromethane, ethyl acetate and benzene.
Has the advantages that: compared with the prior art, the alfacalcidol heterocyclic ester derivative provided by the invention. In addition, the in vitro tumor cell proliferation inhibition experiment shows that the cytotoxic activity exceeds or is equivalent to that of a positive control etoposide, and the preparation method can be applied to the preparation of medicaments for preventing and treating breast cancer, colon cancer and liver cancer.
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In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 shows the NMR of the heterocyclic ester alfacalcidol derivative (2a) provided in example 1 of the present invention1H, spectrogram;
FIG. 2 shows NMR spectra of heterocyclic ester derivatives of alfacalcidol (2a) provided in example 1 of the present invention13C, spectrum;
FIG. 3 shows NMR spectra of heterocyclic ester derivatives of alfacalcidol (2b) provided in example 1 of the present invention1H, spectrogram;
FIG. 4 shows NMR spectra of heterocyclic ester derivatives of alfacalcidol (2b) provided in example 1 of the present invention13And C, spectrum.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below so that those skilled in the art can better understand the advantages and features of the present invention, and thus the scope of the present invention will be more clearly defined. The embodiments described herein are only a few embodiments of the present invention, rather than all embodiments, and all other embodiments that can be derived by one of ordinary skill in the art without inventive faculty based on the embodiments described herein are intended to fall within the scope of the present invention.
Example 1
Dissolving 20mg (0.05mmol) of alfacalcidol in 1mL of dichloromethane, sequentially adding 30mg (0.25mmol) of 2-picolinic acid, 10mg (0.08mmol) of DMAP and 65mg (0.3mmol) of EDCI, detecting by TLC to end the reaction, diluting with 20mL of dichloromethane, washing with saturated sodium bicarbonate solution once, sequentially washing with water and saturating with waterWashing with salt water, MgSO4Drying, drying under reduced pressure, and column chromatography (petroleum ether: ethyl acetate ═ 2:1) gave alfacalcidol di (pyridine 2-carboxylic acid) ester (2b)30mg, yield 98%.
1H NMR(400MHz,CDCl3)δ8.78(d,J＝2.8Hz,2H),8.07(dd,J＝34.7,7.9Hz,2H),7.89-7.72(m,2H),7.47-7.46(m,2H),6.46(d,J＝11.2Hz,1H),6.02-5.89(m,2H),5.60-5.59(m,1H),5.51(s,1H),5.16(d,J＝1.8Hz,1H),2.92(dd,J＝13.0,4.2Hz,1H),2.80(dd,J＝12.3,4.1Hz,1H),2.65(dd,J＝13.0,8.9Hz,1H),2.54-2.53(m,1H),2.34-2.33(m,1H),1.99-1.89(m,2H),1.65-1.64(mz,2H),1.56-1.45(m,2H),1.34-1.01(m,12H),0.90-0.83(m,10H),0.28(s,3H).13C NMR(100MHz,CDCl3)δ164.4,163.7,150.1,150.0,148.0,148.0,144.0,141.6,137.0,136.9,131.0,126.9,126.8,125.7,125.3,125.2,116.8,116.3,74.5,71.1,56.4,56.2,45.9,41.6,40.4,39.4,36.8,36.0,29.1,28.0,27.5,23.8,23.6,22.8,22.5,22.0,18.8,11.5.
Example 2
Dissolving 20mg (0.05mmol) of alfacalcidol in 1mL of dichloromethane, sequentially adding 30mg (0.25mmol) of 2-pyrazinecarboxylic acid, 10mg (0.08mmol) of DMAP and 65mg (0.3mmol) of EDCI, detecting by TLC to end the reaction, diluting with 20mL of dichloromethane, washing with saturated sodium bicarbonate solution once, sequentially washing with water, washing with saturated salt water, and MgSO 24Drying, drying under reduced pressure, and column chromatography (petroleum ether: ethyl acetate ═ 2:1) gave alfacalcidol dipiyrazine formate (2a)25mg, yield 81%.
1H NMR(400MHz,CDCl3)δ9.28(dd,J＝26.4,1.3Hz,2H),8.80-8.72(m,4H),6.49(d,J＝11.5Hz,1H),5.95-5.89(m,2H),5.66-5.65(m,1H),5.55(s,1H),5.23-5.19(m,1H),2.94(dd,J＝13.0,4.0Hz,1H),2.83-2.77(m,1H),2.66(dd,J＝12.8,9.1Hz,1H),2.56-2.55(m,1H),2.36-2.34(m,J＝13.2,9.2,3.6Hz,1H),1.98-1.89(m,2H),1.66(t,J＝11.1Hz,2H),1.51-1.50(m,2H),1.27-1.26(m,12H),0.96-0.80(m,10H),0.24(s,2H).13C NMR(100MHz,CDCl3)δ163.1,162.7,147.7,147.6,146.3,146.2,144.7,144.6,144.5,143.5,143.4,141.0,130.2,126.1,116.8,116.5,75.0,71.6,56.4,56.2,45.9,41.5,40.3,39.4,36.7,36.0,29.2,28.0,27.5,23.8,23.6,22.8,22.5,22.0,18.8,11.4.
In order to better understand the essence of the invention, the pharmacological experiment results of the inhibitory action of the heterocyclic ester derivatives of alfacalcidol on the growth of three tumor cell lines provided by the invention are used for explaining the new application of the heterocyclic ester derivatives of alfacalcidol in the research field of antitumor drugs. The pharmacological examples give partial activity data for representative compounds. It must be noted that the pharmacological examples of the invention are intended to illustrate the invention and not to limit it. Simple modifications of the invention in accordance with its spirit fall within the scope of the claimed invention.
Drug experimental example 1: test of cytotoxic Activity of Compounds 2a to 2d and Etoposide against human Colon cancer cells (HT-29)
Human colon cancer cells HT-29 were cultured in RPMI1640 medium containing 10% fetal bovine serum, 100U/mL penicillin and 100U/mL streptomycin. Cells were plated at 5X 10 per well3Is added to a 96-well plate containing 5% CO at 37 deg.C2For 24 hours in a humidified air incubator.
Compounds 2a to 2d were dissolved in DMSO to prepare 1X 10-2Diluting the mother liquor to corresponding concentration with complete culture medium, inoculating cells in logarithmic growth phase into a 96-well plate, adding compound solutions with different concentrations after 24h adherence, setting 4 parallel wells for each concentration, adding tetramethyl azozolite (MTT) solution after culturing for 68h, continuing culturing for 4h, discarding the culture solution, adding 150 mu L of dimethyl sulfoxide, oscillating for 10min, measuring the absorbance (A) value at 570nm with an enzyme-linked immunosorbent assay (ELIASA), and calculating the half Inhibition Concentration (IC)50) Specifically, the examples are shown in Table 1. As can be seen from Table 1, IC of Compound 2a50Is 1.2X 10-6M, IC of HT-29 cells with positive control etoposide50Is 3.4X 10-6M。
Drug experimental examples 2 to 3: the compounds 2 a-2 d and etoposide are tested for the cytotoxic activity of human breast cancer cells (MCF-7) and human liver cancer cells (HepG 2).
Pharmacological experiments were conducted on the growth inhibitory effect on human breast cancer cells (MCF-7) and human liver cancer cells (HepG2) by the method shown in drug Experimental example 1, and the median Inhibitory Concentration (IC) was calculated50) Specifically, the examples are shown in Table 1.
TABLE 1 cytotoxic Activity IC of Compounds 2 a-2 d and Etoposide50(μM)
Compound (I) HT-29 MCF-7 HepG2
2a 1.2 3.2 0.4
2b 1.1 5.0 5.1
2c 0.9 1.7 1.5
2d 7.5 4.1 7.9
Etoposide 3.4 5.5 6.3
As can be seen from Table 1, the alfacalcidol heterocyclic ester derivative provided by the invention has important biological activity, and in vitro cytotoxicity tests on three tumor cells, namely human colon cancer cells (HT-29), human breast cancer cells (MCF-7) and human liver cancer cells (HepG2), show that: the alfacalcidol heterocyclic ester derivative with the structure shown in formula (1) has an inhibition effect on the growth of tumor cells, and can be developed into a novel tumor prevention and treatment drug. From the pharmacological examples, we can see that the compounds show stronger cytotoxic activity on the three tumor cells, the cytotoxic activity exceeds or is equivalent to that of the positive control etoposide, and the compounds have the potential of being developed into antitumor drugs.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (7)

1. An alfacalcidol heterocyclic ester derivative, which is characterized in that: the alfacalcidol heterocyclic ester derivative has a structure shown in a formula (I):
Figure FDA0003571769310000011
wherein R represents H or C1-7A hydrocarbon group, X represents N or O.
2. The alfacalcidol heterocyclic ester derivative according to claim 1, wherein the alfacalcidol heterocyclic ester derivative has a structure as shown in any one of formulas 2a to 2 d:
Figure FDA0003571769310000012
wherein,
when R is hydrogen and X is N, the alfacalcidol heterocyclic ester derivative is a compound with a structure shown in a formula 2 a;
when R is hydrogen and X is C, the alfacalcidol heterocyclic ester derivative is a compound with a structure shown in a formula 2 b;
when R is methyl and X is N, the alfacalcidol heterocyclic ester derivative is a compound with a structure shown in a formula 2 c;
when R is ethyl and X is C, the alfacalcidol heterocyclic ester derivative is a compound with a structure shown in a formula 2 d.
3. A preparation method of the alfacalcidol heterocyclic ester derivative is characterized by comprising the following steps: the method comprises the following steps: obtained by reacting alfacalcidol with DMAP, EDCI and the corresponding heterocyclic acid in dichloromethane, wherein the reaction has the formula:
Figure FDA0003571769310000021
wherein R represents H or C1-7A hydrocarbyl group, X represents N or O;
the preparation method specifically comprises the following operations: dissolving alfacalcidol in dichloromethane, sequentially adding heterocyclic acid, DMAP and EDCI, reacting to obtain a first reaction solution, diluting the first reaction solution with an organic solvent, sequentially washing with water, washing with saturated salt water, and MgSO (MgSO) in sequence4Drying, drying under reduced pressure, and performing column chromatography to obtain a white solid, wherein the white solid is an alfacalcidol heterocyclic ester derivative, and the molar ratio of alfacalcidol to heterocyclic acid to DMAP to EDCI is as follows: 1:5:1.6: 6.
4. a process for the preparation of alfacalcidol heterocyclic ester derivatives as claimed in claim 3, characterized in that: the DMAP is 4-dimethylaminopyridine and the EDCI name is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
5. A process for the preparation of alfacalcidol heterocyclic ester derivatives as claimed in claim 3, characterized in that: the heterocyclic acid is 6-substituted 2-picolinic acid or 6-substituted 2-pyrazinecarboxylic acid.
6. A method of preparing alfacalcidol heterocyclic ester derivatives as claimed in claim 3, characterized in that: in the preparation method, the reaction temperature is 25 ℃, and the reaction time is 12 h.
7. A process for the preparation of alfacalcidol heterocyclic ester derivatives as claimed in claim 3, characterized in that: the organic solvent is at least one of dichloromethane, ethyl acetate and benzene.
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CN111440105A (en) * 2020-04-01 2020-07-24 南通华山药业有限公司 Alfacalcidol carbamate derivative and preparation method and application thereof
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0499763A (en) * 1990-08-20 1992-03-31 Hoxan Corp Production of vitamin d2 and d3, or active type vitamin d2 and d3 or derivative thereof and intermediate thereof
JPH07304732A (en) * 1994-05-10 1995-11-21 Daikin Ind Ltd Fluorine-containing vitamin d3 analogue
WO1997011053A1 (en) * 1995-09-21 1997-03-27 Wisconsin Alumni Research Foundation Calcitriol derivatives and their uses
WO2003042171A1 (en) * 2001-11-13 2003-05-22 Schering Aktiengesellschaft Vitamin d derivatives with acyloxy groups at the 24-position of the side chain, a method for producing the same and use thereof in production of medicaments
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CN109336801A (en) * 2018-12-07 2019-02-15 无锡福祈制药有限公司 A kind of doxercalciferol derivative and preparation method thereof
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CN111533712A (en) * 2020-04-28 2020-08-14 南通华山药业有限公司 Alfacalcidol heterocyclic derivative and preparation method and application thereof

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