CN114656413B - Alfacalcidol heterocyclic ester derivative and preparation method thereof - Google Patents

Alfacalcidol heterocyclic ester derivative and preparation method thereof Download PDF

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CN114656413B
CN114656413B CN202210326832.7A CN202210326832A CN114656413B CN 114656413 B CN114656413 B CN 114656413B CN 202210326832 A CN202210326832 A CN 202210326832A CN 114656413 B CN114656413 B CN 114656413B
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alfacalcidol
heterocyclic
ester derivative
heterocyclic ester
acid
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CN114656413A (en
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施建飞
钱建
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Nantong Huashan Pharmacy Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • C07D213/02—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
    • 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
    • C07D213/60—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 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • C07D213/02—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
    • 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
    • C07D213/60—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 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention belongs to the technical fields of pharmaceutical 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 the corresponding alfacalcidol heterocyclic ester derivative is obtained by reacting alfacalcidol with DMAP, EDCI and corresponding heterocyclic acid in dichloromethane. The alfacalcidol heterocyclic ester derivative obtained by the invention has stronger 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 fields of pharmaceutical chemistry and pharmacology, and particularly relates to an alfacalcidol heterocyclic ester derivative and a preparation method thereof.
Background
Alfacalcidol (alfalcidol) is a fat-soluble sterol in vitamin D compounds, and is a substance involved in the homeostasis of calcium and phosphorus and mineralization of bone. Alfacalcidol was originally developed by the american bone health international company (Bone Care International) and was approved for sale in israel, germany, japan, italy. Can be used for treating calcium metabolism disorder caused by vitamin D metabolic disorder, and can be used for treating osteoporosis, chronic renal insufficiency, parathyroid hypofunction, vitamin D resistant rickets, osteomalacia, etc. In recent years, the analogues calcitriol and dulcitol of alfacalcidol were found to have anti-tumor activity, the mechanism of anti-tumor action being associated with inhibition of Hh signaling pathway, with calcitriol being in clinical study. The anti-tumor activity report of the alfacalcidol derivative is less, so that the novel alfacalcidol derivative is discovered through structural modification, and the development of novel anti-tumor drugs has higher research value. Because the alfacalcidol structure does not contain nitrogen atoms, the nitrogen-containing groups are desirably introduced through chemical modification, so that the water solubility of the drug molecules is improved, and the salt formation is easy, so that the clinical administration is facilitated, and therefore, the invention provides the ester derivative formed by the nitrogen-containing heterocyclic acid and the alfacalcidol.
Disclosure of Invention
The invention aims to: in view of the above, the present invention aims to provide alfacalcidol heterocyclic ester derivatives which have an 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):
wherein R represents H or C 1-7 Hydrocarbyl groups, X represents N or C.
Further, the alfacalcidol heterocyclic ester derivative has a structure as shown in any one of formulas 2a to 2 d:
wherein,
r is hydrogen, and X is N, the alfacalcidol heterocyclic ester derivative is a compound with a structure shown in a formula 2 a;
r is hydrogen, and X is C, the alfacalcidol heterocyclic ester derivative is a compound with a structure shown in a formula 2 b;
r is methyl, and X is N, the alfacalcidol heterocyclic ester derivative is a compound with a structure shown in a formula 2 c;
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:
is prepared by the reaction of alfacalcidol with DMAP, EDCI and corresponding 6-substituted 2-picolinic acid or 6-substituted 2-pyrazinecarboxylic acid in methylene dichloride, wherein the reaction has the following reaction formula:
wherein R represents H or C 1-7 Hydrocarbyl, X represents N or C;
the preparation method specifically comprises the following steps: 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, saturated saline water, and MgSO 4 Drying, 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 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 hours.
Preferably, the organic solvent is at least one of dichloromethane, ethyl acetate and benzene.
The beneficial effects are 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 cytotoxicity is superior to or equivalent to that of positive control etoposide, and the method can be applied to the preparation of medicaments for preventing and treating breast cancer, colon cancer and liver cancer.
Drawings
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 nuclear magnetic resonance of an alfacalcidol heterocyclic ester derivative (2 a) provided in example 1 of the present invention 1 H spectrogram;
FIG. 2 shows nuclear magnetic resonance of an alfacalcidol heterocyclic ester derivative (2 a) provided in example 1 of the present invention 13 C, spectrogram;
FIG. 3 shows nuclear magnetic resonance of an alfacalcidol heterocyclic ester derivative (2 b) provided in example 1 of the present invention 1 H spectrogram;
FIG. 4 shows nuclear magnetic resonance of an alfacalcidol heterocyclic ester derivative (2 b) provided in example 1 of the present invention 13 C spectrogram.
Detailed Description
The following technical solutions in the embodiments of the present invention will be clearly and completely described so that those skilled in the art can better understand the advantages and features of the present invention, thereby making a clearer definition of the protection scope of the present invention. The described embodiments of the present invention are intended to be only a few, but not all embodiments of the present invention, and all other embodiments that may be made by one of ordinary skill in the art without inventive faculty are intended to be within the scope of the present invention.
Example 1
20mg (0.05 mmol) of alfacalcidol is dissolved in 1mL of dichloromethane, 30mg (0.25 mmol) of 2-picolinic acid, 10mg (0.08 mmol) of DMAP and 65mg (0.3 mmol) of EDCI are sequentially added, TLC detection reaction is finished, 20mL of dichloromethane is added for dilution, saturated sodium bicarbonate solution is washed once, and then water washing, saturated saline water washing and MgSO are sequentially carried out 4 Drying, drying under reduced pressure, and column chromatography (petroleum ether: ethyl acetate=2:1) gave alfacalcidol di (pyridine 2-carboxylic acid) ester (2 b) 30mg, 98% yield.
1 H NMR(400MHz,CDCl 3 )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). 13 C NMR(100MHz,CDCl 3 )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
20mg (0.05 mmol) of alfacalcidol is dissolved in 1mL of dichloromethane, 30mg (0.25 mmol) of 2-pyrazinecarboxylic acid, 10mg (0.08 mmol) of DMAP and 65mg (0.3 mmol) of EDCI are sequentially added, TLC detection reaction is finished, 20mL of dichloromethane is added for dilution, saturated sodium bicarbonate solution is washed once, and then water washing, saturated saline water washing and MgSO are sequentially carried out 4 Drying, drying under reduced pressure, and column chromatography (petroleum ether: ethyl acetate=2:1) gave alfacalcidol dipyrazine formate (2 a) 25mg, yield 81%.
1 H NMR(400MHz,CDCl 3 )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). 13 C NMR(100MHz,CDCl 3 )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 experimental results of the inhibition effect of the alfacalcidol heterocyclic ester derivatives provided by the invention on the growth of three tumor cell lines are used for explaining the new application of the alfacalcidol heterocyclic ester derivatives in the field of anti-tumor drug research. 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 the essence of the invention are all within the scope of the invention as claimed.
Drug experiment example 1: test of cytotoxic Activity of Compounds 2 a-2 d and etoposide against human colon cancer cells (HT-29)
Human colon cancer cells HT-29 are cultured in RPMI1640 medium containing 10% foetusBovine serum, 100U/mL penicillin and 100U/mL streptomycin. Cells at 5X 10 per well 3 Is added to a 96-well plate and contains 5% CO at 37 DEG C 2 Is cultured in a humid air incubator for 24 hours.
Compounds 2a to 2d were dissolved in DMSO to prepare 1X 10 -2 Diluting mother liquor with mol/L mother liquor to corresponding concentration with complete culture medium, inoculating logarithmic growth phase cells into 96-well plate, adhering to wall for 24 hr, adding compound solutions with different concentrations, setting 4 parallel holes for each concentration, culturing for 68 hr, adding tetramethyl azoazole (MTT) solution, culturing for 4 hr, discarding culture solution, adding dimethyl sulfoxide 150 μl, oscillating for 10min, measuring 570nm absorbance (A) value with enzyme-labeled instrument, and calculating half inhibition concentration (IC 50 ) As shown in table 1. As can be seen from Table 1, IC of Compound 2a 50 Is 1.2X10 -6 M, while positive control Etoposide versus HT-29 cells IC 50 Is 3.4X10 -6 M。
Pharmaceutical Experimental examples 2-3: test of cytotoxic Activity of Compounds 2 a-2 d and etoposide against human breast cancer cells (MCF-7), human liver cancer cells (HepG 2).
Pharmacological experiments were performed on the growth inhibition effect of human breast cancer cells (MCF-7) and human liver cancer cells (HepG 2) by the method shown in pharmaceutical experimental example 1, and half Inhibition Concentration (IC) was calculated 50 ) As shown in table 1.
Table 1 cytotoxic activity IC of compounds 2 a-2 d and etoposide 50 (μM)
Compounds of formula (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
According to Table 1, the alfacalcidol heterocyclic ester derivatives provided by the invention have important biological activity, and in vitro cytotoxicity tests on three tumor cells, namely human colon cancer cells (HT-29) and human breast cancer cells (MCF-7), human liver cancer cells (HepG 2), show that: the alfacalcidol heterocyclic ester derivative with the structure shown in the formula (1) has an inhibition effect on the growth of tumor cells, and can be possibly developed into a novel medicine for preventing and treating tumors. From the pharmacological examples, the compounds show strong cytotoxicity to all three tumor cells, and the cytotoxicity exceeds or is equivalent to that of positive control etoposide, so that the compounds have potential of developing anti-tumor drugs.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.

Claims (6)

1. An alfacalcidol heterocyclic ester derivative which is characterized in that: the alfacalcidol heterocyclic ester derivative has a structure shown in a formula (I):
wherein R represents H or C 1-7 Hydrocarbyl groups, X both represent N at the same time or X both represent C at the same time.
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 formulae 2a to 2 d:
wherein,
r is hydrogen, and X is N, the alfacalcidol heterocyclic ester derivative is a compound with a structure shown in a formula 2 a;
r is hydrogen, and X is C, the alfacalcidol heterocyclic ester derivative is a compound with a structure shown in a formula 2 b;
r is methyl, and X is N, the alfacalcidol heterocyclic ester derivative is a compound with a structure shown in a formula 2 c;
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 process for the preparation of the alfacalcidol heterocyclic ester derivative according to claim 1, which is characterized in that: the method comprises the following steps: the preparation method comprises the steps of reacting alfacalcidol with DMAP, EDCI and corresponding heterocyclic acid in dichloromethane;
the preparation method specifically comprises the following steps: 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, saturated saline water, and MgSO 4 Drying, 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. the process for producing alfacalcidol heterocyclic ester derivatives according to claim 3, wherein: the DMAP is 4-dimethylaminopyridine, and the EDCI name is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
5. The process for producing alfacalcidol heterocyclic ester derivatives according to claim 3, wherein: the heterocyclic acid is one of 6-substituted 2-picolinic acid or 6-substituted 2-pyrazinecarboxylic acid.
6. The process for producing alfacalcidol heterocyclic ester derivatives according to claim 3, wherein: in the preparation method, the reaction temperature is 25 ℃, and the reaction time is 12 hours.
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Citations (9)

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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
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
CN109503445A (en) * 2018-12-21 2019-03-22 江苏卓和药业有限公司 A kind of Alfacalcidol class compound and preparation method thereof
CN109516938A (en) * 2018-12-21 2019-03-26 江苏卓和药业有限公司 A kind of Alfacalcidol derivative and preparation method thereof
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
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

Patent Citations (9)

* 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
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
CN109503445A (en) * 2018-12-21 2019-03-22 江苏卓和药业有限公司 A kind of Alfacalcidol class compound and preparation method thereof
CN109516938A (en) * 2018-12-21 2019-03-26 江苏卓和药业有限公司 A kind of Alfacalcidol derivative and preparation method thereof
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
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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